JP2023522866 | Benzyloxyphosphate (phosphonate) compounds |
WO/2023/048572 | TARGETED LIPID NANOPARTICLE FORMULATIONS |
JP2021535119 | Acylated calcitonin mimetic |
ANESINI JASON (US)
VALDES LUCAS (US)
MAGNO ETHAN (US)
GRUCHOT WOJTEK (US)
WO2011119549A1 | 2011-09-29 | |||
WO2014082065A1 | 2014-05-30 | |||
WO2019032961A1 | 2019-02-14 |
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CLAIMS What is claimed is: 1. A compound of Formula (I): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; wherein: R1 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; -ORA1; -C(=O)RA2; -CO2RA2; -CN; -SCN; -SRA1; -SORA1; -SO2RA1; -NO2; -N3; -N(RA2)2; -NRA2C(=O)RA2; -NRA2C(=O)N(RA2)2; -OC(=O)ORA1; -OC(=O)RA2; -OC(=O)N(RA2)2; -NRAC(=O)ORA1; or -C(RA2)3; wherein each occurrence of RA1 is independently hydrogen; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or two RA1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; and wherein each occurrence of RA2 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; -ORA1; -SRA1; or -N(RA1)2, or two RA2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; with the proviso that if R1 is -ORA1, RA1 is not 4- methoxybenzyl or carbohydrate. R2 is hydrogen; or R1 and R2 are joined to form =O; =N(RA2); or =S; R3 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; - ORC1; -C(=O)RC2; -CO2RC1; -CN; -SCN; -SRC1; -SORC1; -SO2RC2; -NO2; -N3; -N(RC2)2; - NHC(=O)RC2; -NRC2C(=O)N(RC2)2; -OC(=O)ORC1; -OC(=O)RC2; -OC(=O)N(RC2)2; -NRC2C(=O)ORC1; or -C(RC2)3; wherein each occurrence of RC1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or two RC1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; and wherein each occurrence of RC2 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; -ORC1; -SRC1; or -N(RC1)2; or two RC2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; R4 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; - ORD1; -C(=O)RD2; -CO2RD2; -CN; -SCN; -SRD1; -SORD1; -SO2RD2; -NO2; -N3; -N(RD2)2; -NRD2C(=O)RD2; -NRD2C(=O)N(RD2)2; -OC(=O)ORD1; -OC(=O)RD2; -OC(=O)N(RD2)2; -NRD2C(=O)ORD1; or -C(RD2)3; wherein each occurrence of RD1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or two RD1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; and wherein each occurrence of RD2 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; -ORD1; -SRD1; or -N(RD1)2; or two RD2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; R5 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; - ORE1; -C(=O)RE2; -CO2RE1; -CN; -SCN; -SRE1; -SORE1; -SO2RE2; -NO2; -N3; -N(RE2)2; -NRE2C(=O)RE2; -NRE2C(=O)N(RE2)2; -OC(=O)ORE1; -OC(=O)RE2; -OC(=O)N(RE2)2; -NRE2C(=O)ORE1; or -C(RE2)3; wherein each occurrence of RE1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or two RE1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; and wherein each occurrence of RE2 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; -ORE1; -SRE1; or -N(RE1)2; or two RE2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; R6 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; - ORF1; -C(=O)RF2; -CO2RF1; -CN; -SCN; -SRF1; -SORF1; -SO2RF2; -NO2; -N3; -N(RF2)2; -NRF2C(=O)RF2; -NRF2C(=O)N(RF2)2; -OC(=O)ORF1; -OC(=O)RF2; -OC(=O)N(RF2)2; -NRF2C(=O)ORF1; or -C(RF2)3; wherein each occurrence of RF1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or two RF1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; and wherein each occurrence of RF2 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; -ORF1; -SRF1; or -N(RF1)2; or two RF2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; R7 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; - ORG1; -C(=O)RG2; -CO2RG1; -CN; -SCN; -SRG1; -SORG1; -SO2RG2; -NO2; -N3; -N(RG)2; -NRG2C(=O)RG2; -NRG2C(=O)N(RG2)2; -OC(=O)ORG1; -OC(=O)RG2; -OC(=O)N(RG2)2; -NRG2C(=O)ORG1; or -C(RG2)3; wherein each occurrence of RG1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or two RG1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; and wherein each occurrence of RG2 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; -ORG1; -SRG1; or -N(RG1)2; or two RG2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; R8 is hydrogen; an oxygen protecting group; a carbohydrate; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted heteroaliphatic; acyl; –ORH9; –OC(=O)RH9; –N(RH9)2; or –NHC(=O)RH9; wherein each occurrence of RH9 is independently hydrogen; substituted or unsubstituted alkyl; an oxygen protecting group when attached to an oxygen atom; or a nitrogen protecting group when attached to a nitrogen atom; or two RH9 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; R9 is hydrogen or -C(RI1)3; wherein each occurrence of RI1 is independently hydrogen; carbohydrate; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; –ORI2; -SRI2; azido; halogen; or -N(RI2)2; with the proviso that not more than one occurrence of RI1 is –ORI2; wherein each occurrence of RI2 is independently hydrogen; carbohydrate; protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted heteroarylalkyl; substituted or unsubstituted phosphono; -L-A-B; or -L-T; or two RI2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; R10 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; - ORB1; -C(=O)RB2; -CO2RB2; -CN; -SCN; -SRB1; -SORB1; -SO2RB2; -NO2; -N3; -N(RB2)2; - NRB2C(=O)RB2; -NRB2C(=O)N(RB2)2; -OC(=O)ORB1; -OC(=O)RB2; -OC(=O)N(RB2)2; - NRB2C(=O)ORB1; or -C(RB2)3; wherein each occurrence of RB1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or two RB1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; and wherein each occurrence of RB2 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; -ORB1; -SRB1; or -N(RB1)2; or two RB2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; or R1 and R10 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety; or R10 and R3 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety; or R1 and R4 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety; or R4 and R7 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety; or R6 and R7 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety; L is a linker; A is a bond or a group of formula: Q is –S– or –O–; RW1 is independently hydrogen, substituted or unsubstituted alkyl; or a nitrogen protecting group; B is a targeting moiety; and T is hydrogen, -N=C=S, RX1 is a leaving group; and RX2 is hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or an oxygen protecting group. 2. The compound of claim 1, wherein the compound is of Formula (I-a): or a pharmaceutically acceptable salt thereof. 3. The compound of any of claims 1-2, wherein the compound is of Formula (I-b): or a pharmaceutically acceptable salt thereof. 4. The compound of any of claims 1-3, wherein the compound is of Formula (I-c): or a pharmaceutically acceptable salt thereof. 5. The compound of any of claims 1-4, wherein R1 is hydrogen. 6. The compound of any of claims 1-4, wherein R1 and R2 together form =O. 7. The compound of any of claims 1-6, wherein R4 is -ORD1. 8. The compound of any of claims 1-7, wherein RD1 is C1-6 alkyl. 9. The compound of any of claims 1-8, wherein R5 is -ORE1. 10. The compound of claim 9, wherein RE1 is hydrogen. 11. The compound of any of claims 1-10, wherein R6 is C1-6 alkyl. 12. The compound of any of claims 1-11, wherein R6 is –CH3. 13. The compound of any of claims 1-12, wherein R7 is hydrogen. 14. The compound of any of claims 1-13, wherein R8 is hydrogen, a carbohydrate, or C1-6 alkyl. 15. The compound of claim 14, wherein the carbohydrate of R8 is: wherein Ra and Rb are independently hydrogen; carbohydrate; an oxygen protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl. 16. The compound of any of claims 1-14, wherein R8 is C1-6 alkyl. 17. The compound of any of claims 1-14 or 16, wherein R8 is –CH3. 18. The compound of any of claims 1-14, wherein R8 is hydrogen. 19. The compound of any of claims 1-18, wherein the compound is of Formula (I-d): or a pharmaceutically acceptable salt thereof, wherein RI2 is hydrogen, carbohydrate, protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted phosphono; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl. 20. The compound of claim 19, wherein RI2 is hydrogen; oxygen protecting group; carbohydrate; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted phosphono; or substituted or unsubstituted heteroarylalkyl. 21. The compound of any of claims 19-20, wherein RI2 is hydrogen, oxygen protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; or substituted or unsubstituted phosphono. 22. The compound of any of claims 19-21, wherein RI2 is hydrogen, protecting group, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkenyl, substituted or unsubstituted C1-6 alkynyl, or substituted or unsubstituted phosphono. 23. The compound of any of claims 19-22, wherein RI2 is hydrogen; benzyl; n-propyl; 2- propenyl; 2-propynyl; or -P(=O)(OH)2. 24. The compound of any of claims 19-20, wherein RI2 is substituted or unsubstituted heteroarylalkyl. 25. The compound of any of claims 19-20, wherein RI2 is a carbohydrate. 26. The compound of any of claims 19-20 or 25, wherein RI2 is: wherein Ra and Rb are independently hydrogen; carbohydrate; an oxygen protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or acyl; and Rc, Rd, and Re are independently hydrogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; or acyl. 27. The compound of claim 26, wherein Ra and Rb are independently hydrogen; carbohydrate; oxygen protecting group; or acyl. 28. The compound of any of claims 26 or 27, wherein Rc, Rd, and Re are independently hydrogen; substituted or unsubstituted alkyl; or acyl. 29. The compound of any of claims 26-28, wherein Rc, Rd, and Re are independently hydrogen; substituted or unsubstituted C1-6 alkyl; or acyl. 30. The compound of any of claims 1-20 or 25-29, wherein RI2 is: wherein Ra is hydrogen; carbohydrate; or oxygen protecting group. 31. The compound of any of claims 1-20 or 25-30, wherein RI2 is: 32. The compound of any of claims 1-20 or 25-29, wherein RI2 is wherein Rb is hydrogen; carbohydrate; or oxygen protecting group. 33. The compound of any of claims 1-20, 25-29, or 32, wherein RI2 is 34. The compound of any of claims 1-20, 25-29, or 32, wherein RI2 is . 35. The compound of any of claims 1-20, 25-29, or 32, wherein RI2 is 36. The compound of any of claims 1-20 or 25-29, wherein RI2 is: wherein Ra is hydrogen; carbohydrate; or oxygen protecting group. 37. The compound of any of claims 1-20, 25-29, or 36, wherein RI2 is: 38. The compound of any of claims 1-20 or 25, wherein RI2 is: wherein Ra, Rb, Rc, and Rd are independently hydrogen; carbohydrate; an oxygen protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl. 39. The compound of any of claims 1-20, 25, or 38, wherein Ra, Rb, Rc, and Rd are independently hydrogen; carbohydrate; or oxygen protecting group. 40. The compound of any of claims 1-20, 25, or 38-39, wherein RI2 is: . 41. The compound of any of claims 1-18, wherein the compound is of Formula (I-e): or a pharmaceutically acceptable salt thereof. 42. The compound of claim 41, wherein RI1 is hydrogen; carbohydrate; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; –ORI2; -SRI2; azido; halogen; or -N(RI2)2. 43. The compound of any of claims 41 or 42, wherein RI1 is azido; -N(RI2)2; -SRI2; or halogen. 44. The compound of claim 43, wherein each occurrence of RI2 is independently hydrogen; protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; or acyl; or two RI2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring. 45. The compound of any of claims 41-44, wherein RI1 is azido; -NH2; -SH; - S(C=O)CH3; chloro; bromo; or iodo. 46. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof. 47. The compound of any of claims 1-18, wherein at least one occurrence of RI1 is -ORI2, -N(RI2)2, or -SRI2. 48. The compound of claim 47, wherein one occurrence of RI2 is -L-A-B. 49. The compound of any of claims 1, 47, or 48, wherein the compound is: or a pharmaceutically acceptable salt thereof. 50. The compound of claim 47, wherein one occurrence of RI2 is -L-T. 51. The compound of any of claims 1, 47, or 50, wherein the compound is: or a pharmaceutically acceptable salt thereof. 52. A compound of Formula (II): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; wherein: R1 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; -ORA1; -C(=O)RA2; -CO2RA2; -CN; -SCN; -SRA1; -SORA1; -SO2RA1; -NO2; -N3; -N(RA2)2; -NRA2C(=O)RA2; -NRA2C(=O)N(RA2)2; -OC(=O)ORA1; -OC(=O)RA2; -OC(=O)N(RA2)2; -NRAC(=O)ORA1; or -C(RA2)3; wherein each occurrence of RA1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or two RA1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; and wherein each occurrence of RA2 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; -ORA1; -SRA1; or -N(RA1)2; or two RA2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; with the proviso that if R1 is -ORA1, RA1 is not 4- methoxybenzyl or carbohydrate. R2 is hydrogen; or R1 and R2 are joined to form =O; =N(RA2); or =S; R3 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; - ORC1; -C(=O)RC2; -CO2RC1; -CN; -SCN; -SRC1; -SORC1; -SO2RC2; -NO2; -N3; -N(RC2)2; - NHC(=O)RC2; -NRC2C(=O)N(RC2)2; -OC(=O)ORC1; -OC(=O)RC2; -OC(=O)N(RC2)2; -NRC2C(=O)ORC1; or -C(RC2)3; wherein each occurrence of RC1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or two RC1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; and wherein each occurrence of RC2 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; -ORC1; -SRC1; or -N(RC1)2; or two RC2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; R4 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; - ORD1; -C(=O)RD2; -CO2RD2; -CN; -SCN; -SRD1; -SORD1; -SO2RD2; -NO2; -N3; -N(RD2)2; -NRD2C(=O)RD2; -NRD2C(=O)N(RD2)2; -OC(=O)ORD1; -OC(=O)RD2; -OC(=O)N(RD2)2; -NRD2C(=O)ORD1; or -C(RD2)3; wherein each occurrence of RD1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or two RD1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; and wherein each occurrence of RD2 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; -ORD1; -SRD1; or -N(RD1)2; or two RD2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; R5 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; - ORE1; -C(=O)RE2; -CO2RE1; -CN; -SCN; -SRE1; -SORE1; -SO2RE2; -NO2; -N3; -N(RE2)2; -NRE2C(=O)RE2; -NRE2C(=O)N(RE2)2; -OC(=O)ORE1; -OC(=O)RE2; -OC(=O)N(RE2)2; -NRE2C(=O)ORE1; or -C(RE2)3; wherein each occurrence of RE1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or two RE1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; and wherein each occurrence of RE2 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; -ORE1; -SRE1; or -N(RE1)2; or two RE2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; R6 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; - ORF1; -C(=O)RF2; -CO2RF1; -CN; -SCN; -SRF1; -SORF1; -SO2RF2; -NO2; -N3; -N(RF2)2; -NRF2C(=O)RF2; -NRF2C(=O)N(RF2)2; -OC(=O)ORF1; -OC(=O)RF2; -OC(=O)N(RF2)2; -NRF2C(=O)ORF1; or -C(RF2)3; wherein each occurrence of RF1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or two RF1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; and wherein each occurrence of RF2 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; -ORF1; -SRF1; or -N(RF1)2; or two RF2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; R7 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; - ORG1; -C(=O)RG2; -CO2RG1; -CN; -SCN; -SRG1; -SORG1; -SO2RG2; -NO2; -N3; -N(RG)2; -NRG2C(=O)RG2; -NRG2C(=O)N(RG2)2; -OC(=O)ORG1; -OC(=O)RG2; -OC(=O)N(RG2)2; -NRG2C(=O)ORG1; or -C(RG2)3; wherein each occurrence of RG1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or two RG1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; and wherein each occurrence of RG2 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; -ORG1; -SRG1; or -N(RG1)2; or two RG2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; R8 is hydrogen; an oxygen protecting group; a carbohydrate; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted heteroaliphatic; acyl; –ORH9; –OC(=O)RH9; –N(RH9)2; or –NHC(=O)RH9; wherein each occurrence of RH9 is independently hydrogen; substituted or unsubstituted alkyl; an oxygen protecting group when attached to an oxygen atom; or a nitrogen protecting group when attached to a nitrogen atom; or two RH9 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; R9 is hydrogen or -C(RI1)3; wherein each occurrence of RI1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; -ORI2; -SRI2; -N(RI2)2; azido; or halogen; with the proviso that not more than one occurrence of RI1 is -ORI2; wherein each occurrence of RI2 is independently hydrogen; carbohydrate; protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted heteroarylalkyl; substituted or unsubstituted phosphono; -L-A-B; or -L-T; or two RI2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; R10 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; - ORB1; -C(=O)RB2; -CO2RB2; -CN; -SCN; -SRB1; -SORB1; -SO2RB2; -NO2; -N3; -N(RB2)2; - NRB2C(=O)RB2; -NRB2C(=O)N(RB2)2; -OC(=O)ORB1; -OC(=O)RB2; -OC(=O)N(RB2)2; - NRB2C(=O)ORB1; or -C(RB2)3; wherein each occurrence of RB1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or two RB1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; and wherein each occurrence of RB2 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; -ORB1; -SRB1; or -N(RB1)2; or two RB2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; R11 is hydrogen; substituted or unsubstituted aliphatic; acyl; -L-A-B; or -L-T; X is a halogen; or R1 and R10 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety; or R10 and R3 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety; or R1 and R4 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety; or R4 and R7 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety; or R6 and R7 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety; L is a linker; A is a bond or a group of formula: Q is –S– or –O–; RW1 is independently hydrogen, substituted or unsubstituted alkyl; or a nitrogen protecting group; B is a targeting moiety; and T is hydrogen, -N=C=S, RX1 is a leaving group; and RX2 is hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or an oxygen protecting group. 53. The compound of claim 52, wherein the compound is of Formula (II-a): or a pharmaceutically acceptable salt thereof. 54. The compound of any of claims 52-53, wherein the compound is of Formula (II-b): or a pharmaceutically acceptable salt thereof. 55. The compound of any of claims 52-54, wherein the compound is of Formula (II-c): or a pharmaceutically acceptable salt thereof. 56. The compound of any of claims 52-55, wherein R1 is hydrogen. 57. The compound of any of claims 52-55, wherein R1 and R2 together form =O. 58. The compound of any of claims 52-57, wherein R4 is -ORD1. 59. The compound of any of claims 52-58, wherein RD1 is C1-6alkyl. 60. The compound of any of claims 52-59, wherein R5 is -ORE1. 61. The compound of claim 60, wherein RE1 is hydrogen. 62. The compound of any of claims 52-61, wherein R6 is C1-6 alkyl. 63. The compound of any of claims 52-62, wherein R6 is –CH3. 64. The compound of any of claims 52-63, wherein R7 is hydrogen. 65. The compound of any of claims 52-64, wherein R8 is hydrogen, a carbohydrate, or C1- 6 alkyl. 66. The compound of claim 65, wherein R8 is a carbohydrate of formula: wherein Ra and Rb are independently hydrogen; carbohydrate; an oxygen protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl. 67. The compound of any of claims 52-65, wherein R8 is C1-6 alkyl. 68. The compound of any of claims 52-65 or 67, wherein R8 is –CH3. 69. The compound of any of claims 52-65, wherein R8 is hydrogen. 70. The compound of any of claims 52-69, wherein X is –Cl, –Br, or –I. 71. The compound of any of claims 52-70, wherein X is –Br. 72. The compound of any of claims 52-71, wherein the compound is of Formula (II-d): or a pharmaceutically acceptable form thereof, wherein RI2 is hydrogen, carbohydrate, protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted phosphono; or substituted or unsubstituted heteroarylalkyl. 73. The compound of claim 72, wherein RI2 is hydrogen; oxygen protecting group; substituted or unsubstituted phosphono; carbohydrate; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; or substituted or unsubstituted heteroarylalkyl. 74. The compound of claim 72 or 73, wherein RI2 is hydrogen, oxygen protecting group, substituted or unsubstituted phosphono, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. 75. The compound of any of claims 72-74, wherein RI2 is hydrogen, protecting group, substituted or unsubstituted phosphono, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 alkenyl, or substituted or unsubstituted C1-6 alkynyl. 76. The compound of any of claims 72-75, wherein RI2 is hydrogen; benzyl; n-propyl; 2- propenyl; 2-propynyl; or -P(=O)(OH)2. 77. The compound of any of claims 72 or 73, wherein RI2 is substituted or unsubstituted heteroarylalkyl. 78. The compound of any of claims 72 or 73, wherein RI2 is a carbohydrate. 79. The compound of any of claims 72, 73, or 78 wherein RI2 is: wherein Ra and Rb are independently hydrogen; carbohydrate; an oxygen protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or acyl; and Rc, Rd, and Re are independently hydrogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; or acyl. 80. The compound of any of claims 72, 73, 78, or 79, wherein Ra and Rb are independently hydrogen; carbohydrate; oxygen protecting group; or acyl. 81. The compound of any of claims 72, 73, or 78-80, wherein Rc, Rd, and Re are independently hydrogen; substituted or unsubstituted alkyl; or acyl. 82. The compound of any of claims 72, 73, or 78-81, wherein Rc, Rd, and Re are independently hydrogen; substituted or unsubstituted C1-6 alkyl; or acyl. 83. The compound of any of claims 72, 73, or 78-82, wherein RI2 is: wherein Ra is hydrogen; carbohydrate; or oxygen protecting group. 84. The compound of any of claims 72, 73, or 78-83, wherein RI2 is: 85. The compound of any of claims 72, 73, or 78-82, wherein RI2 is: wherein Rb is hydrogen; carbohydrate; or oxygen protecting group. 86. The compound of any of claims 72, 73, 78-82, or 85, wherein RI2 is: 87. The compound of any of claims 72, 73, 78-82, or 85, wherein RI2 is: 88. The compound of any of claims 72, 73, 78-82, or 85, wherein RI2 is: 89. The compound of any of claims 72, 73, or 78-82, wherein RI2 is: wherein Ra is hydrogen; carbohydrate; or oxygen protecting group. 90. The compound of any of claims 72, 73, 78-82, or 89, wherein RI2 is: . 91. The compound of any of claims 72, 73, or 78, wherein RI2 is: , wherein Ra, Rb, Rc, and Rd are independently hydrogen; carbohydrate; an oxygen protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl. 92. The compound of any of claims 72, 73, 78, or 91, wherein Ra, Rb, Rc, and Rd are independently hydrogen; carbohydrate; or oxygen protecting group. 93. The compound of any of claims 72, 73, 78, 91, or 92, wherein RI2 is: . 94. The compound of any of claims 52-71, wherein the compound is of Formula (II-e): or a pharmaceutically acceptable salt thereof. 95. The compound of claim 94, wherein RI1 is hydrogen; carbohydrate; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; –ORI2; -SRI2; azido; halogen; or -N(RI2)2. 96. The compound of any of claims 94 or 95, wherein RI1 is azido; -N(RI2)2; -SRI2; or halogen. 97. The compound of claim 96, wherein each occurrence of RI2 is independently hydrogen; protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; or acyl; or two RI2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring. 98. The compound of any of claims 94-97, wherein RI1 is azido; -NH2; -SH; -SAc; chloro; bromo; or iodo. 99. The compound of any of claims 52-98, wherein R11 is of formula: R20 is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene; X1 is ; heterocyclylene; or heteroarylene; R21 is independently substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl; or two R21 groups are joined to form an optionally substituted heterocyclyl ring; R22 is hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted carbocyclyl; or Ar is substituted or unsubstituted aryl. 100. The compound of claim 52, wherein the compound is: or a pharmaceutically acceptable salt thereof. 101. The compound of any of claims 52-71, wherein at least one occurrence of RI1 is - ORI2, -N(RI2)2, or -SRI2. 102. The compound of claim 101, wherein RI2 is -L-A-B, provided that R11 is not -L-A-B or -L-T. 103. The compound of claim 101, wherein RI2 is -L-T, provided that R11 is not -L-A-B or - L-T. 104. The compound of any of claims 1-18, 51-71, 102, or 103, wherein L is of formula: R20 is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene; X1 is heterocyclylene; or heteroarylene; R21 is independently substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl; or two R21 groups are joined to form an optionally substituted heterocyclyl ring; R22 is hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted carbocyclyl; or Ar is substituted or unsubstituted arylene; each occurrence of Z is independently an amino acid; each occurrence of Y is independently an amino acid; E is a bond or an amino acid; m is independently 1, 2, or 3; k is 0 or 1; Ar1 is a bond or substituted or unsubstituted heteroarylene; R40 is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene. 105. The compound of claim 104, or a pharmaceutically acceptable salt thereof, wherein R20 is substituted or unsubstituted alkylene. 106. The compound of any of claims 104 or 105, or a pharmaceutically acceptable salt thereof, wherein R20 is unsubstituted alkylene. 107. The compound of any of claims 104-106, or a pharmaceutically acceptable salt thereof, wherein: X1 is ; and R22 is hydrogen; substituted or unsubstituted alkyl; or substituted or unsubstitued carbocyclyl. 108. The compound of any of claims 104-107, or a pharmaceutically acceptable salt thereof, wherein: X1 is and R22 is substituted alkyl. 109. The compound of any of claims 104-108, or a pharmaceutically acceptable salt thereof, wherein Ar is substituted or unsubstituted phenylene. 110. The compound of any of claims 104-109, or a pharmaceutically acceptable salt thereof, wherein Z is alanine, lysine, arginine, histidine, ornithine, or citrulline. 111. The compound of any of claims 104-110, or a pharmaceutically acceptable salt thereof, wherein Z is alanine or citrulline. 112. The compound of any of claims 104-111, or a pharmaceutically acceptable salt thereof, wherein Z is alanine. 113. The compound of any of claims 104-112, or a pharmaceutically acceptable salt thereof, wherein Y is alanine, valine, leucine, isoleucine, methionine, phenylalanine, or tryptophan. 114. The compound of any of claims 104-113, or a pharmaceutically acceptable salt thereof, wherein Y is valine. 115. The compound of any of claims 104-114, or a pharmaceutically acceptable salt thereof, wherein each occurrence of m is 1. 116. The compound of any of claims 104-115, or a pharmaceutically acceptable salt thereof, wherein -Zm-Ym- is -alanine-valine-. 117. The compound of any of claims 104-116, or a pharmaceutically acceptable salt thereof, wherein Ar1 is a bond. 118. The compound of any of claims 104-116, or a pharmaceutically acceptable salt thereof, wherein Ar1 is substituted or unsubstituted heteroarylene. 119. The compound of any of claims 104-118, or a pharmaceutically acceptable salt thereof, wherein k is 0. 120. The compound of any of claims 104-118, or a pharmaceutically acceptable salt thereof, wherein k is 1. 121. The compound of any of claims 104-120, or a pharmaceutically acceptable salt thereof, wherein E is a bond. 122. The compound of any of claims 104-120, or a pharmaceutically acceptable salt thereof, wherein E is of formula: wherein R70 is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. 123. The compound of any of claims 104-122, or a pharmaceutically acceptable salt thereof, wherein R40 is substituted or unsubstituted alkylene. 124. The compound of any of claims 104-122, or a pharmaceutically acceptable salt thereof, wherein R40 is substituted or unsubstituted heteroalkylene. 125. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein A is a group of formula: 126. The compound of any of claims 104-125, or a pharmaceutically acceptable salt thereof, wherein L is of formula: R20 is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene; X1 is heterocyclylene; or heteroarylene; R21 is independently substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl; or two R21 groups are joined to form an optionally substituted heterocyclyl ring; R22 is hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted carbocyclyl; or Ar is substituted or unsubstituted arylene; each occurrence of Z is independently an amino acid; each occurrence of Y is independently an amino acid; E is a bond or an amino acid; m is independently 1, 2, or 3; R40 is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene; A is a group of formula: Q is –S– or –O–; and RW1 is independently hydrogen, substituted or unsubstituted alkyl; or a nitrogen protecting group. 127. The compound of any of claims 104-126, or a pharmaceutically acceptable salt thereof, wherein -L- is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R22 is hydrogen, or substituted or unsubstituted C1-6 alkyl; R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; R50 is the sidechain of alanine, lysine, arginine, histidine, ornithine, or citrulline; and R60 is the sidechain of alanine, valine, leucine, isoleucine, methionine, phenylalanine, or tryptophan. 128. The compound of any of claims 104-126, or a pharmaceutically acceptable salt thereof, wherein -L- is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R22 is hydrogen, or substituted or unsubstituted C1-6 alkyl; R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; R50 is the sidechain of alanine, lysine, arginine, histidine, ornithine, or citrulline; and R60 is the sidechain of alanine, valine, leucine, isoleucine, methionine, phenylalanine, or tryptophan; and R80 is a substituted sidechain of a lysine, arginine, histidine, ornithine, or citrulline. 129. The compound of any of claims 104-125, or a pharmaceutically acceptable salt thereof, wherein -L- is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R22 is hydrogen, or substituted or unsubstituted C1-6 alkyl; R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; Ar1 is substituted or unsubstituted heteroarylene; and Ra is a substituted heterocycle. 130. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-A- is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R22 is hydrogen, or substituted or unsubstituted C1-6 alkyl; R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; R50 is the sidechain of alanine, lysine, arginine, histidine, ornithine, or citrulline; and R60 is the sidechain of alanine, valine, leucine, isoleucine, methionine, phenylalanine, or tryptophan. 131. The compound of any of claims 104-126, or a pharmaceutically acceptable salt thereof, wherein -L-A- is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R22 is hydrogen, or substituted or unsubstituted C1-6 alkyl; R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; R50 is the sidechain of alanine, lysine, arginine, histidine, ornithine, or citrulline; and R60 is the sidechain of alanine, valine, leucine, isoleucine, methionine, phenylalanine, or tryptophan; and R80 is an optionally substituted sidechain of a lysine, arginine, histidine, ornithine, or citrulline. 132. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-A- is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R22 is hydrogen, or substituted or unsubstituted C1-6 alkyl; R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; Ar1 is substituted or unsubstituted heteroarylene; and Ra is a substituted heterocycle. 133. The compound of any of claims 104-126, or a pharmaceutically acceptable salt thereof, wherein -L-A- is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R22 is hydrogen, or substituted or unsubstituted C1-6 alkyl; and R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene. 134. The compound of any of claims 104-126, or a pharmaceutically acceptable salt thereof, wherein -L-A- is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R22 is hydrogen, or substituted or unsubstituted C1-6 alkyl; R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; and R70 is substituted or unsubstituted heteroalkyl. 135. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-A- is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R22 is hydrogen, or substituted or unsubstituted C1-6 alkyl; and R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; and Ra is a substituted heterocycle. 136. The compound of any of claims 104-126, or a pharmaceutically acceptable salt thereof, wherein -L-A- is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; and R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene. 137. The compound of any of claims 104-126, or a pharmaceutically acceptable salt thereof, wherein -L-A- is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; and R70 is substituted or unsubstituted heteroalkyl. 138. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-A- is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; and Ra is substituted or unsubstituted heterocycle. 139. The compound of any of claims 104-126, or a pharmaceutically acceptable salt thereof, wherein -L-A- is a group of formula: wherein: R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene. 140. The compound of any of claims 104-126, or a pharmaceutically acceptable salt thereof, wherein -L-A- is a group of formula: wherein: R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; and R70 is substituted or unsubstituted heteroalkyl. 141. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-A- is a group of formula: wherein: R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; and Ra is substituted or unsubstituted heterocycle. 142. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-A- is a group of formula: 143. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-A- is a group of formula: 144. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-A- is a group of formula: 145. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-A- is a group of formula: 146. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein T is a group of formula: 147. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein –L-T is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R22 is hydrogen, or substituted or unsubstituted C1-6 alkyl; R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; R50 is the sidechain of alanine, lysine, arginine, histidine, ornithine, or citrulline; and R60 is the sidechain of alanine, valine, leucine, isoleucine, methionine, phenylalanine, or tryptophan. 148. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein –L-T is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R22 is hydrogen, or substituted or unsubstituted C1-6 alkyl; R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; R50 is the sidechain of alanine, lysine, arginine, histidine, ornithine, or citrulline; R60 is the sidechain of alanine, valine, leucine, isoleucine, methionine, phenylalanine, or tryptophan; and and R80 is a substituted sidechain of a lysine, arginine, histidine, ornithine, or citrulline. 149. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein –L-T is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R22 is hydrogen, or substituted or unsubstituted C1-6 alkyl; R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; Ra is a substituted heterocycle; and Ar1 is substituted or unsubstituted heteroarylene. 150. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-T is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R22 is hydrogen, or substituted or unsubstituted C1-6 alkyl; and R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene. 151. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-T is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R22 is hydrogen, or substituted or unsubstituted C1-6 alkyl; R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; and and R70 is substituted or unsubstituted heteroalkyl. 152. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-T is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R22 is hydrogen, or substituted or unsubstituted C1-6 alkyl; R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; and Ra is substituted or unsubstituted heterocycle. 153. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-T is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; and R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene. 154. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-T is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; and R70 is substituted or unsubstituted heteroalkyl. 155. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-T is a group of formula: wherein: R20 is substituted or unsubstituted C1-6 alkylene; R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; and Ra is substituted or unsubstituted heterocycle. 156. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-T is a group of formula: wherein: R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene. 157. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-T is a group of formula: wherein: R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; and R70 is substituted or unsubstituted heteroalkyl. 158. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-T is a group of formula: wherein: R40 is substituted or unsubstituted C1-6 alkylene, or substituted or unsubstituted C1-40 heteroalkylene; and Ra is substituted or unsubstituted heterocycle. 159. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-T is a group of formula: 160. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-T is a group of formula: 161. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-T is a group of formula: 162. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein -L-T is a group of formula: 163. The compound of any of claims 104-124, or a pharmaceutically acceptable salt thereof, wherein L is a bond; and T is hydrogen. 164. The compound of any of claims 52-99 or 146-163, wherein the compound is: or a pharmaceutically acceptable salt thereof. 165. The compound of claim 52, wherein the compound is: or a pharmaceutically acceptable salt thereof. 166. The compound of any preceding claim, wherein the compound is: or a pharmaceutically acceptable salt thereof. 167. The compound of any of claims 1-166, or a pharmaceutically acceptable salt thereof, wherein B is an antibody or an antibody fragment. 168. The compound of any of claims 1-167, or a pharmaceutically acceptable salt thereof, wherein B is an antibody selected from Adecatumumab, Afutuzumab, Alemtuzumab (CAMPATH), Bavituximab, Belantamab, Belimumab, Bevacizumab (AVASTIN), Brentuximab, Cantuzumab, Cetuximab (ERBITUX), Citatuzumab, Cixutumumab, Conatumumab, Dacetuzumab, Elotuzumab, Enfortumab, Etaracizumab, Farletuzumab, Figitumumab, Gemtuzumab, Ibritumomab, Inotuzumab, Ipilimumab (YERVOY), Iratumumab, Labetuzumab, Lexatumumab, Lintuzumab, Loncastuximab, Lucatumumab, Mapatumumab, Matuzumab, Milatuzumab, Moxetumomab, Necitumumab, Nimotuzumab, Ofatumumab (ARZERRA), Olaratumab, Oportuzumab, Panitumumab (VECTIBIX), Pertuzumab (PERJETA), Polatuzumab, Pritumumab, Rituximab (RITUXAN), Robatumumab, Sacituzumab, Sibrotuzumab, Siltuximab, Tacatuzumab, Tigatuzumab, Tositumomab (BEXXAR), Trastuzumab (HERCEPTIN), Tucotuzumab, Veltuzumab, Votumumab, Zalutumumab, and fragments thereof. 169. A method of preparing a compound of any of claims 1-51, the method comprising deprotecting a cycloadduct of Formula (A): or salt thereof, wherein R12 is a cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 170. The method of claim 169 further comprising reacting a silacycle of Formula (B): or a salt thereof, with an α-epoxy-β-oxodiazoketone of formula: or a salt thereof, to provide the cycloadduct of Formula (A): or salt thereof. 171. A method of preparing a compound of any of claims 1-51, the method comprising alkylating a compound of Formula (I): or salt thereof, wherein R8 is hydrogen; to provide a compound of Formula (I), or a salt thereof, wherein R8 is alkyl. 172. A method of preparing a compound of any of claims 1-51, the method comprising providing a compound of Formula (I-f): or salt thereof, wherein R8 is hydrogen; and RI2 is a protecting group; alkylating and deprotecting the compound to provide a compound of Formula (I-f): or a salt thereof, wherein R8 is alkyl, and RI2 is hydrogen. 173. A method of preparing a compound of any of claims 52-100, the method comprising providing a compound of Formula (I): or a pharmaceutically acceptable salt thereof, and ring-opening the compound to provide a compound of Formula (II): or a pharmaceutically acceptable salt thereof. 174. A method of preparing a compound of Formula (C): or salt thereof, the method comprising deprotecting and oxidizing a compound of formula (D): or salt thereof, wherein: PG is a protecting group; and R9 is hydrogen or -C(RI1)3; wherein each occurrence of RI1 is independently hydrogen; carbohydrate; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; –ORI2; -SRI2; azido; halogen; or -N(RI2)2; with the proviso that not more than one occurrence of RI1 is –ORI2; wherein each occurrence of RI2 is independently hydrogen; carbohydrate; protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted heteroarylalkyl; C(=O)RI1; -L-A-B; or -L-T; or two RI2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring. 175. The method of claim 174 further comprising hydrolyzing a compound of Formula (E): or salt thereof; wherein R is cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; to provide a compound of Formula (F): or a salt thereof; and converting the compound of Formula (F) to the compound of Formula (D): or salt thereof. 176. The method of claim 175 further comprising epoxidizing and protecting a compound of Formula (G): or a salt thereof; to provide the compound of Formula (E): or salt thereof. 177. The method of claim 176, further comprising reacting an aldehyde of Formula (H): or salt thereof; with an acrylate, or salt thereof, to provide the compound of Formula (G): or a salt thereof. 178. The method of claim 175, wherein the compound of Formula (E) is the compound of Formula (E-1): the method further comprising stereoselectively epoxidizing and protecting the compound of Formula (G): or a salt thereof; to provide the compound of Formula (E-1), or a salt thereof. 179. The method of claim 175, wherein the compound of Formula (E) is the compound of Formula (E-2): the method further comprising enantioenriching, protecting, and epoxidizing the compound of Formula (G): or a salt thereof; to provide the compound of Formula (E-2), or salt thereof. 180. A compound of Formula: or a salt thereof; wherein: R9 is hydrogen or -C(RI1)3; wherein each occurrence of RI1 is independently hydrogen; carbohydrate; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; –ORI2; -SRI2; azido; halogen; or -N(RI2)2; with the proviso that not more than one occurrence of RI1 is –ORI2; wherein each occurrence of RI2 is independently hydrogen; carbohydrate; protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted heteroarylalkyl; C(=O)RI1; -L-A-B; or -L-T; or two RI2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring. 181. The compound of claim 180, wherein the compound is or a salt thereof. 182. The compound of any one of claims 1-22 or 52-75, wherein R9 is CH2OCH3. 183. The compound of any one of claims 1-18, 41, 42, 52-71, 94, 95, wherein R9 is methyl. 184. The compound of any one of claims 1-18; 52-71, wherein R9 is hydrogen. 185. A pharmaceutical composition comprising a compound of any of claims 1-168 or 182-184, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 186. A method of treating a cardiovascular disease, a proliferative disease, diabetic retinopathy, an inflammatory disease, an autoimmune disease, or an infectious disease in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any of claims 1-168 or 182-184, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 185. 187. The method of claim 186, wherein the proliferative disease is a cancer. 188. The method of any of claims 186 or 187, wherein the cancer is breast cancer, non- small cell lung cancer, ovarian cancer, colorectal cancer, diffuse large B-cell lymphoma, or multiple myeloma. 189. The method of any of claims 186-188, wherein the cancer is Her2+ breast cancer, TROP2+ breast cancer, TROP2+ non-small cell lung cancer, EGFR+ non-small cell lung cancer, or FRα+ ovarian cancer. 190. The method of any of claims 186-188, wherein the cancer is CD19+ diffuse large B- cell lymphoma or BCMA+ Multiple Myeloma. 191. The method of claim 186, wherein the infectious disease is a bacterial, fungal, or parasitic infection. 192. The method of claim 191, wherein the parasitic infection is malaria. 193. A kit comprising the compound of any of claims 1-168 or 182-184, or the pharmaceutical composition of claim 185, and instructions for its use. |
[00399] In certain embodiments, -L-T is a group of Formula (L T -6-c): Group R 10 [00400] As generally defined herein, R 10 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; -OR B1 ; -C(=O)R B2 ; -CO 2 R B2 ; -CN; -SCN; -SR B1 ; - SOR B1 ; -SO 2 R B2 ; -NO 2 ; -N 3 ; -N(R B2 ) 2 ; -NR B2 C(=O)R B2 ; -NR B2 C(=O)N(R B2 ) 2 ; -C(=O)OR B1 ; -OC(=O)R B2 ; -OC(=O)N(R B2 ) 2 ; -NR B2 C(=O)OR B1 ; or -C(R B2 ) 3 ; wherein each occurrence of R B1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or two R B1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring; and wherein each occurrence of R B2 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; -OR B1 ; -SR B1 ; or -N(R B1 ) 2 ; or two R B2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring. [00401] In certain embodiments, R 10 is hydrogen. Group R 11 [00402] As generally defined above for compounds of Formula (I) and (II), R 11 is hydrogen; substituted or unsubstituted alkyl; acyl; -L-A-B; or -L-T. [00403] In certain embodiments, R 11 is L-A-B, wherein L, A, and B are as defined herein. [00404] In certain embodiments, R 11 is -L-T, wherein L and T are as defined herein. [00405] In certain embodiments, R 11 is of formula: R 20 is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene; X 1 is ; ; heterocyclylene; or heteroarylene; R 21 is independently substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl; or two R 21 groups are joined to form an optionally substituted heterocyclyl ring; R 22 is hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted carbocyclyl; or ; Ar is substituted or unsubstituted aryl. Group X [00406] As generally defined above, X is a halogen. In certain embodiments, X is –Cl, -Br, or –I. In certain embodiments, X is –Br or –I. In certain embodiments, X is –Cl. In certain embodiments, X is -Br. In certain embodiments, X is –I. Additional embodiments of Formula (I) and (II) [00407] Various combinations of the above embodiments are further contemplated herein. One of skill in the art would appreciate that the various embodiments described herein may be combined in various ways and are contemplated by the inventors. [00408] In certain embodiments of the compound of Formula (I) and (II), R 1 and R 2 are each hydrogen or together form =O; and R 10 and R 3 are hydrogen; or R 1 and R 10 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety; or R 10 and R 3 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety; or R 1 and R 4 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety; or R 4 and R 7 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety; or R 6 and R 7 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety. [00409] In certain embodiments, the compound of Formula (I) is: or a pharmaceutically acceptable salt thereof. [00410] In certain embodiments, the compound of Formula (I) is or a pharmaceutically acceptable salt thereof. [00411] In certain embodiments, the compound of Formula (I) is or a pharmaceutically acceptable salt thereof. [00412] In certain embodiments, the compound of Formula (I) is or a pharmaceutically acceptable salt thereof. [00413] In certain embodiments, the compound of Formula (I) is or a pharmaceutically acceptable salt thereof. [00414] In certain embodiments, the compound of Formula (I) is not: [00415] In certain embodiments, the compound of Formula (II) is:
or a pharmaceutically acceptable salt thereof. [00416] In certain embodiments, the compound of Formula (II) is:
or a pharmaceutically acceptable salt thereof. [00417] In certain embodiments, the compound of Formula (II) is: or a pharmaceutically acceptable salt thereof. [00418] In certain embodiments, the compound of Formula (II) is: or a pharmaceutically acceptable salt thereof. [00419] In certain embodiments, the compound of Formula (II) is: or a pharmaceutically acceptable salt thereof. [00420] In certain embodiments, the compound of Formula (II) is: or a pharmaceutically acceptable salt thereof. [00421] In certain embodiments, the compound of Formula (II) is: or a pharmaceutically acceptable salt thereof. [00422] In certain embodiments, the compound of Formula (II) is:
or a pharmaceutically acceptable salt thereof. [00423] In certain embodiments, the compound of Formula (II) is: or a pharmaceutically acceptable salt thereof. [00424] In certain embodiments, the compound of Formula (II) is:
or a pharmaceutically acceptable salt thereof. Group B [00425] As generally defined herein, B is a targeting moiety. In certain embodiments, a targeting moiety is an antibody. In certain embodiments, a targeting moiety is an antibody fragment. [00426] It is generally understood that an antibody or antibody fragment is a large molecule with many possible sites of attachment of the trioxacarcin-linker moiety, i.e., a [trioxacarcin– L–A-] moiety. In certain embodiments, the antibody or antibody fragment comprises 1 to 200 independent instances of a trioxacarcin-linker moiety attached thereto, inclusive, e.g., 1 to 150, 1 to 100, 1 to 75, 1 to 50, 1 to 25, 1 to 15, 1 to 10, inclusive, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 independent instances. [00427] An antibody, as described herein, refers to a full-length (i.e., naturally occurring or formed by normal immunoglobulin gene fragment recombinatorial processes) immunoglobulin molecule (e.g., an IgG antibody) or an immunologically active (i.e., specifically binding) portion of an immunoglobulin molecule, like an antibody fragment. An antibody is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter–connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as V H ) and a heavy chain constant region. The heavy chain constant region is comprised of three subdomains, C H1 , C H2 and C H3 . Each light chain is comprised of a light chain variable region (abbreviated herein as V L ) and a light chain constant region. The light chain constant region is comprised of one subdomain, C L . The V H and V L regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each V H and V L is composed of three CDRs and four FRs arranged from amino–terminus to carboxy–terminus in the following order: FRl, CDRl, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. [00428] As used herein, the term “monoclonal antibody” may refer to an antibody obtained from a single clonal population of immunoglobulins that bind to the same epitope of an antigen. Monoclonal antibodies have the same Ig gene rearrangement and thus demonstrate identical binding specificity. Methods for preparing monoclonal antibodies, as described herein, are known in the art. Monoclonal antibodies can be prepared by a variety of methods. For example, monoclonal antibodies may be made by a hybridoma method (see, e.g., Kohler et al., Nature, 1975, 256: 495), or may be made by recombinant DNA methods (see, e.g., U.S. Patent No.4,816,567). The monoclonal antibodies may also be isolated from phage antibody libraries.(See e.g., Clarkson et al., Nature, 1991, 352: 624–628 and Marks et al., J. Mol. Biol., 1991, 222: 581–597). [00429] Human monoclonal antibodies may be made by any of the methods known in the art, including those disclosed in U.S. Patent No.5567610, U.S. Patent No.5565354, U.S. Patent No.5571893, Kozber, J. Immunol., 1984, 133: 3001, Brodeur, et al., Monoclonal Antibody Production Techniques and Applications, p.51–63 (Marcel Dekker, Inc., new York, 1987), and Boerner et al., J. Immunol., 1991, 147: 86–95. Human antibodies may be obtained by recovering antibody–producing lymphocytes from the blood or other tissues of humans producing antibody to an antigen of interest (e.g., CD20 or EGFR). These lymphocytes can be treated to produce cells that grow independently in the laboratory under appropriate culture conditions. The cell cultures can be screened for production of antibodies to the antigen of interest and then cloned. Clonal cultures can be used to produce human monoclonal antibodies to CD20 and/or EGFR, or the genetic elements encoding the variable portions of the heavy and light chain of the antibodies can be cloned and inserted into nucleic acid vectors for production of antibodies of different types. In addition to the conventional methods for preparing human monoclonal antibodies, such antibodies may also be prepared by immunizing transgenic animals that are capable of producing human antibodies (e.g., Jakobovits et al., PNAS USA, 1993, 90: 2551, Jakobovits et al., Nature, 1993, 362: 255–258, Bruggermann et al., Year in Immunol., 1993, 7:33 and U.S. Patent No.5569825). [00430] As used herein, “humanized monoclonal antibody” may refer to monoclonal antibodies having at least human constant regions and an antigen–binding region, such as one, two, or three CDRs, from a non–human species. Humanized antibodies specifically recognize antigens of interest, but will not evoke an immune response in humans against the antibody itself. As an example, murine CDRs may be grafted into the framework region of a human antibody to prepare the humanized antibody (e.g., Riechmann et al., Nature, 1988, 332, 323, and Neuberger et al., Nature, 1985, 314, 268). Alternatively, humanized monoclonal antibodies may be constructed by replacing the non–CDR regions of non–human antibodies with similar regions of human antibodies while retaining the epitopic specificity of the original antibodies. For example, non–human CDRs and optionally some of the framework regions may be covalently joined to human FR and/or Fc/pFc' regions to produce functional antibodies. [00431] As used herein, the term “chimeric antibody” may refer to a monoclonal antibody comprising a variable region from one source (e.g., species) and at least a portion of a constant region derived from a different source. In some embodiments, chimeric antibodies are prepared by recombinant DNA techniques. In some embodiments, the chimeric antibodies comprise a murine variable region and a human constant region. Such chimeric antibodies may, in some embodiments, be the product of expressed immunoglobulin genes comprising DNA segments encoding murine immunoglobulin variable regions and DNA segments encoding human immunoglobulin constant regions. Methods for producing chimeric antibodies involve conventional recombinant DNA and gene transfection techniques (see, e.g., Morrison et al., Proc. Natl. Acad. Sci. USA, 1984, 81: 6851–6855; U.S. Patent No. 5,202,238; and U.S. Patent No.5,204,244). [00432] An antibody fragment is a portion of an antibody such as F(ab').sub.2, F(ab).sub.2, Fab', Fab, Fv, scFv (single chain Fv) and the like. Such fragments may be prepared by standard methods. See, e.g., Coligan et al. Current Protocols in Immunology, John Wiley & Sons, 1991–1997. Regardless of structure, an antibody fragment binds with the same antigen that is recognized by the intact antibody. An antibody fragment may comprise one or more proteolytic fragments (i.e., fragments produced by cleavage with papain), e.g., a Fab fragment, each containing a light chain domain and a heavy chain domain (designated herein as a “Fab heavy chain domain”), and/or Fc fragment containing two Fc domains. Each light chain domain contains a V L and a C L subdomain, each Fab heavy chain domain contains a V H and a C H1 subdomain, and each Fc domain contains a C H2 and C H3 subdomain. [00433] In certain embodiments, antigen–binding antibody fragments is only a small portion of an antibody molecule, the paratope, is involved in the binding of the antibody to its epitope (see, in general, Clark, W.R. (1986) The Experimental Foundations of Modern Immunology Wiley & Sons, Inc., New York; Roitt, I. (1991) Essential Immunology, 7th Ed., Blackwell Scientific Publications, Oxford). The pFc' and Fc regions of the antibody, for example, are effectors of the complement cascade but are not involved in antigen binding. An antibody from which the pFc' region has been enzymatically cleaved, or which has been produced without the pFc' region, designated an F(ab')2 fragment, retains both of the antigen binding sites of an intact antibody. An isolated F(ab’)2 fragment is referred to as a bivalent monoclonal fragment because of its two antigen binding sites. Similarly, an antibody from which the Fc region has been enzymatically cleaved, or which has been produced without the Fc region, designated an Fab fragment, retains one of the antigen binding sites of an intact antibody molecule. Further, Fab fragments consist of a covalently bound antibody light chain and a portion of the antibody heavy chain denoted Fd (heavy chain variable region, referred to herein as Fab heavy chain domain). The Fd fragments are the major determinant of antibody specificity (a single Fd fragment may be associated with up to ten different light chains without altering antibody specificity) and Fd fragments retain epitope–binding ability in isolation. [00434] The terms Fab, Fc, pFc’, F(ab’) 2 and Fv are employed with either standard immunological meanings (Klein, Immunology (John Wiley, New York, NY, 1982); Clark, W.R. (1986) The Experimental Foundations of Modern Immunology (Wiley & Sons, Inc., New York); Roitt, I. (1991) Essential Immunology, 7th Ed., (Blackwell Scientific Publications, Oxford)). Well–known functionally active antibody fragments include but are not limited to F(ab') 2 , Fab, Fv and Fd fragments of antibodies. These fragments, which lack the Fc fragment of intact antibody, clear more rapidly from the circulation, and may have less non–specific tissue binding than an intact antibody (Wahl et al., J. Nucl. Med.24:316–325 (1983)). For example, single–chain antibodies may be constructed in accordance with the methods described in U.S. Patent No.4,946,778. Such single–chain antibodies include the variable regions of the light and heavy chains joined by a flexible linker moiety. Methods for obtaining a single domain antibody (“Fd”) which comprises an isolated variable heavy chain single domain, also have been reported (see, e.g., Ward et al., Nature, 1989, 341:644–646, disclosing a method of screening to identify an antibody heavy chain variable region (V H single domain antibody) with sufficient affinity for its target epitope to bind thereto in isolated form). Methods for making recombinant Fv fragments based on known antibody heavy chain and light chain variable region sequences are known in the art and have been described, (see, e.g., Moore et al., U.S. Patent No.4,462,334). Other references describing the use and generation of antibody fragments include, e.g., Fab fragments (Tijssen, Practice and Theory of Enzyme Immunoassays (Elsevieer, Amsterdam, 1985)), Fv fragments (Hochman et al., Biochemistry, 1973, 12: 1130; Sharon et al., Biochemistry, 1976, 15: 1591; Ehrilch et al., U.S. Patent No.4,355,023) and portions of antibody molecules (Audilore– Hargreaves, U.S. Patent No.4,470,925). Thus, antibody fragments may be constructed from intact antibodies without destroying the specificity of the antibodies for the CD20 or EGFR epitope. [00435] In certain embodiments, the antibody fragment is a camelid antibody; e.g., a functional antibody devoid of light chains of which the single N-terminal domain is fully capable of antigen binding; i.e., a single-domain antibody fragment. [00436] Exemplary antibodies and their cell markers (targets) contemplated for use include, but are not limited to, antibodies listed in Table A, and antibody fragments thereof. [00437] In certain embodiments, the antibody is any antibody directed to any of the targets listed in table A. [00438] Additional antibodies include, but are not limited to, pembrolizumab, nivolumab, pidilizumab, tremelimumab, durvalumab, atezolizumab, avelumab, PF-06801591, utomilumab, PDR001, PBF-509, MGB453, LAG525, AMP-224, INCSHR1210, INCAGN1876, INCAGN1949, samalizumab, PF-05082566, urelumab, lirilumab, lulizumab, BMS-936559, BMS-936561, BMS-986004, BMS-986012, BMS-986016, BMS-986178, IMP321, IPH2101, IPH2201, varilumab, ulocuplumab, monalizumab, MEDI0562, MEDI0680, MEDI1873, MEDI6383, MEDI6469, MEDI9447, AMG228, AMG820, CC- 90002, CDX-1127, CGEN15001T, CGEN15022, CGEN15029, CGEN15049, CGEN15027, CGEN15052, CGEN15092, CX-072, CX-2009, CP-870893, Chi Lob 7/4, RG6058, RG7686, RG7876, RG7888, TRX518, MK-4166, MGA271, IMC-CS4, emactuzumab, obinutuzumab, cabiralizumab, margetuximab, enoblituzumab, mogamulizumab, carlumab, fresolimumab, FAZ053, TSR022, MBG453, REGN2810, REGN3767, MOXR0916, PF-04518600, RO7009789, BMS986156, GWN323, JTX-2011, NKTR-214, GSK3174998, DS-8273a, NIS793, or BGB-A317 [00439] In certain embodiments, the antibody is trastuzumab (HERCEPTIN) or an antibody fragment thereof. [00440] In certain embodiments, the antibody is rituximab (RITUXAN) or an antibody fragment thereof. Methods of Preparation [00441] In certain embodiments, the method of preparing a compound of Formula (I) comprises deprotecting a cycloadduct of Formula (A): or salt thereof, wherein R 12 is a cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [00442] In certain embodiments, the method of preparing a compound of Formula (I) comprises reacting a silacycle of Formula (B): or a salt thereof, with an α-epoxy-β-oxodiazoketone of formula: or a salt thereof. [00443] In certain embodiments, the method of preparing a compound of Formula (I) comprises alkylating a compound of Formula (I): or salt thereof, wherein R 8 is hydrogen; to provide a compound of Formula (I), or a salt thereof, wherein R 8 is alkyl. [00444] In certain embodiments, the method of preparing a compound of Formula (I) comprises providing a compound of Formula (I-f):
or salt thereof, wherein R 8 is hydrogen; and R I2 is a protecting group; alkylating and deprotecting the compound to provide a compound of Formula (I-f) or a salt thereof, wherein R 8 is alkyl, and R I2 is hydrogen. [00445] In certain embodiments, the method of preparing a compound of Formula (II) comprises providing a compound of Formula (I): or a pharmaceutically acceptable salt thereof, and ring-opening the compound to provide a compound of Formula (II): or a pharmaceutically acceptable salt thereof. [00446] In certain embodiments, the method of preparing a compound of Formula (C): or salt thereof, comprises deprotecting and oxidizing a compound of formula (D): or salt thereof, wherein: PG is a protecting group. [00447] In certain embodiments, the method of preparing a compound of Formula (C) comprises hydrolyzing a compound of Formula (E): or salt thereof; wherein R is cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; to provide a compound of Formula (F): or a salt thereof; and converting the compound of Formula (F) to the compound of Formula (D): or salt thereof. [00448] In certain embodiments, the method of preparing a compound of Formula (C) comprises epoxidizing and protecting a compound of Formula (G): or a salt thereof; to provide the compound of Formula (E): or salt thereof. [00449] In certain embodiments, the method of preparing a compound of Formula (C) comprises reacting an aldehyde of Formula (H): or salt thereof; with an acrylate, or salt thereof, to provide the compound of Formula (G): or a salt thereof. [00450] In certain embodiments, the method of preparing a compound of Formula (C) comprises stereoselectively epoxidizing and protecting the compound of Formula (G): or a salt thereof; to provide the compound of Formula (E-1): or a salt thereof. [00451] In certain embodiments, the method of preparing a compound of Formula (C) comprises enantioenriching, protecting, and epoxidizing the compound of Formula (G): or a salt thereof; to provide the compound of Formula (E-2): or salt thereof. [00452] As is generally understood from the above disclosure, the compounds of Formulae (I) and (II), comprising a group T, are coupled to a targeting moiety to form an antibody-drug conjugate of Formulae (I) or (II). See, e.g., Scheme 1. In certain embodiments, the coupling takes place between a nucleophilic sidechain of an amino acid residue (e.g., cysteine, lysine, serine) of the antibody and an electrophilic T group. Exemplary coupling reactions include, but are not limited to, formation of esters, thioesters, amides (e.g., such as peptide coupling) from activated acids or acyl halides; nucleophilic displacement reactions (e.g., such as nucleophilic displacement of a halide); and Michael additions (e.g., maleimide addition). Scheme 1. [00453] In certain embodiments, the method of preparing a compound of Formulae (I) or (II) comprises coupling a targeting moiety with a compound of Formulae (I) or (II), wherein T is ; Q is –S–, or –O–; and R X2 is hydrogen, substituted or unsubstituted alkyl; substituted or unsubstituted heterocyclyl (e.g., succinimide); substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or an oxygen protecting group, to provide a corresponding compound of Formulae (I) or (II). See, for example, Scheme 2. Scheme 2. Preparation of compounds of Formula (I) via amide, thioester, and ester formation [00454] In certain embodiments, the method of preparing a compound of Formulae (I) or (II) comprises coupling a targeting moiety with a compound of Formulae (I) or (II), wherein T is ; Q is –S–, or –O–; and R X1 is a leaving group (e.g., halogen, tosylate, mesylate, or triflate), to provide a compound of Formulae (I) or (II). See, for example, Scheme 3. Scheme 3. Nucleophilic displacement of a halide or other leaving group [00455] In certain embodiments, the method of preparing a compound of Formulae (I) or (II) comprises coupling a targeting moiety with a compound of Formulae (I) or (II), wherein T is -N=C=S (i.e., isothiocyanate) to provide a compound of Formulae (I) or (II). See, for example, Scheme 4. Scheme 4. Nucleophilic addition to isothiocyanate [00456] In certain embodiments, the method of preparing a compound of Formulae (I) or (II) comprises coupling a targeting moiety with a compound of Formulae (I) or (II), wherein T is a maleimide group to provide a compound of Formulae (I) or (II). See, for example, Scheme 5. Scheme 5. Maleimide addition [00457] In certain embodiments, the method of preparing a compound of Formulae (I) or (II) comprises coupling a targeting moiety with a compound of Formulae (I) or (II), wherein T is 4-nitrobenzenethiol (e.g., wherein the sulfur is attached to a sulfur atom of L 1 ) to provide a compound of Formulae (I) or (II). See, for example, Scheme 6. Scheme 6. Nucleophilic displacement of a thiol Pharmaceutical Compositions [00458] The present disclosure provides pharmaceutical compositions comprising an active ingredient and, optionally, a pharmaceutically acceptable carrier. In certain embodiments, the active ingredient is present in an effective amount, e.g., a therapeutically effective amount or a prophylactically effective amount. [00459] An “active ingredient,” as used herein, refers to compounds of Formula (I) or (II), and pharmaceutically acceptable salts thereof. [00460] A pharmaceutical composition of the present disclosure can be administered via one or more routes of administration using one or more of a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. Preferred routes of administration include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal, or other parenteral routes of administration, for example, by epidermal administration (e.g., by injection or infusion). The phrase “parenteral administration” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion. [00461] Alternatively, the pharmaceutical composition can be administered via a non- parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically. [00462] Depending on the route of administration, the pharmaceutical composition or active ingredient may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound. [00463] Pharmaceutically acceptable excipients include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. General considerations in the formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21 st Edition (Lippincott Williams & Wilkins, 2005). [00464] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the active ingredient into association with the excipient and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single– or multi–dose unit. [00465] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a “unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one–half or one–third of such a dosage. [00466] Relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient. [00467] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition. [00468] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof. [00469] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation–exchange resins, calcium carbonate, silicates, sodium carbonate, cross–linked poly(vinyl–pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross– linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof. [00470] Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl–pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof. [00471] Exemplary binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl–pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and/or combinations thereof. [00472] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. [00473] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. [00474] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. [00475] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. [00476] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. [00477] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta– carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. [00478] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certain embodiments, the preservative is an anti–oxidant. In other embodiments, the preservative is a chelating agent. [00479] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D– gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen–free water, isotonic saline, Ringer’s solution, ethyl alcohol, etc., and combinations thereof. [00480] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof. [00481] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof. [00482] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3–butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with solubilizing agents such as Cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof. [00483] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3–butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono– or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. [00484] The injectable formulations can be sterilized, for example, by filtration through a bacterial–retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00485] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. [00486] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates of this invention with suitable non–irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient. [00487] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise buffering agents. [00488] Solid compositions of a similar type can be employed as fillers in soft and hard– filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard–filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. [00489] The active ingredient can be in micro–encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. [00490] The active ingredient can be prepared with carriers that will protect the active ingredient against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978. [00491] Pharmaceutical compositions can be administered with medical devices known in the art. For example, in a preferred embodiment, a pharmaceutical composition of this disclosure can be administered with a needleless hypodermic injection device, such as the devices disclosed in U.S. Pat. Nos.5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; or 4,596,556. Examples of well-known implants and modules useful in the present disclosure include: U.S. Pat. No.4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Pat. No.4,486,194, which discloses a therapeutic device for administering medicants through the skin; U.S. Pat. No.4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Pat. No.4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; U.S. Pat. No.4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments; and U.S. Pat. No.4,475,196, which discloses an osmotic drug delivery system. These patents are incorporated herein by reference. Many other such implants, delivery systems, and modules are known to those skilled in the art. [00492] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21 st ed., Lippincott Williams & Wilkins, 2005. [00493] The exact amount of the active ingredient required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). [00494] In certain embodiments, an effective amount of an active ingredient for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of the active ingredient per unit dosage form. [00495] In certain embodiments, the active ingredient may be administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. [00496] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. [00497] It will be also appreciated that the active ingredient or composition, as described herein, can be administered in combination with one or more additional therapeutically active agents. The active ingredient or compositions can be administered in combination with additional therapeutically active agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder (for example, a compound can be administered in combination with an anti–cancer agent, etc.), and/or it may achieve different effects (e.g., control of adverse side– effects, e.g., emesis controlled by an anti–emetic). [00498] The active ingredient or composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. In will further be appreciated that the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions. The particular combination to employ in a regimen will take into account compatibility of the active ingredient with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved. In general, it is expected that additional therapeutically active agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually. [00499] Exemplary additional therapeutically active agents include, but are not limited to, cancer therapies, antibiotics, anti–viral agents, anesthetics, anti–coagulants, inhibitors of an enzyme, steroidal agents, steroidal or non–steroidal anti–inflammatory agents, antihistamine, immunosuppressant agents, anti–neoplastic agents, antigens, vaccines, antibodies, decongestant, sedatives, opioids, pain–relieving agents, analgesics, anti–pyretics, hormones, prostaglandins, progestational agents, anti–glaucoma agents, ophthalmic agents, anti– cholinergics, anti–depressants, anti–psychotics, hypnotics, tranquilizers, anti– convulsants/anti–epileptics (e.g., Neurontin, Lyrica, valproates (e.g., Depacon), and other neurostabilizing agents), muscle relaxants, anti–spasmodics, muscle contractants, channel blockers, miotic agents, anti–secretory agents, anti–thrombotic agents, anticoagulants, anti– cholinergics, β–adrenergic blocking agents, diuretics, cardiovascular active agents, vasoactive agents, vasodilating agents, anti–hypertensive agents, angiogenic agents, modulators of cell– extracellular matrix interactions (e.g., cell growth inhibitors and anti–adhesion molecules), or inhibitors/intercalators of DNA, RNA, protein–protein interactions, protein–receptor interactions, etc. Therapeutically active agents include small organic molecules such as drug compounds (e.g., compounds approved by the Food and Drugs Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells. [00500] In certain embodiments, the additional therapeutic agent is a cancer therapy. Cancer therapies include, but are not limited to, surgery and surgical treatments, radiation therapy, and administration of additional therapeutic cancer agents (e.g., biotherapeutic and chemotherapeutic cancer agents). [00501] Exemplary biotherapeutic cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and/or immunodulatory agents (e.g., IL–1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM–CSF) and antibodies (e.g. HERCEPTIN (trastuzumab), T–DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)). [00502] Exemplary chemotherapeutic cancer agents include, but are not limited to, anti– estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g. goscrclin and leuprolide), anti–androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD–MA), phthalocyanine, photosensitizer Pc4, and demethoxy–hypocrellin A (2BA–2–DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g. carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g. busulfan and treosulfan), triazenes (e.g. dacarbazine, temozolomide), platinum containing compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalent such as nanoparticle albumin–bound paclitaxel (Abraxane), docosahexaenoic acid bound–paclitaxel (DHA–paclitaxel, Taxoprexin), polyglutamate bound–paclitaxel (PG–paclitaxel, paclitaxel poliglumex, CT–2103, XYOTAX), the tumor–activated prodrug (TAP) ANG1005 (Angiopep–2 bound to three molecules of paclitaxel), paclitaxel–EC–1 (paclitaxel bound to the erbB2–recognizing peptide EC–1), and glucose–conjugated paclitaxel, e.g., 2'–paclitaxel methyl 2–glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide, topotecan, 9–aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C), anti–metabolites, DHFR inhibitors (e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g. hydroxyurea and deferoxamine), uracil analogs (e.g.5–fluorouracil (5–FU), floxuridine, doxifluridine, ratitrexed, tegafur–uracil, capecitabine), cytosine analogs (e.g. cytarabine (ara C), cytosine arabinoside, and fludarabine), purine analogs (e.g. mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g., 1–methyl–4–phenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycin (e.g., actinomycin D, dactinomycin), bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g. verapamil), Ca 2+ ATPase inhibitors (e.g. thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI–606), cediranib (RECENTIN TM , AZD2171), dasatinib (SPRYCEL®, BMS– 354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI–571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP–701), neratinib (HKI–272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD–2076, PCI–32765, AC220, dovitinib lactate (TKI258, CHIR–258), BIBW 2992 (TOVOK TM ), SGX523, PF–04217903, PF–02341066, PF–299804, BMS– 777607, ABT–869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ–26483327, MGCD265, DCC–2036, BMS–690154, CEP–11981, tivozanib (AV–951), OSI–930, MM– 121, XL–184, XL–647, and/or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI–779), everolimus (RAD–001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF–4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI–027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethyl melamine. [00503] In certain embodiments, the additional pharmaceutical agent is an immunotherapy. In certain embodiments, the immunotherapy is useful in the treatment of a cancer. Exemplary immunotherapies include, but are not limited to, T-cell therapies, interferons, cytokines (e.g., tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies. In certain embodiments, the immunotherapy is a T-cell therapy. In certain embodiments, the T-cell therapy is chimeric antigen receptor T cells (CAR-T). In certain embodiments, the immunotherapy is an antibody. In certain embodiments, the antibody is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIM3 antibody, an anti- OX40 antibody, an anti-GITR antibody, an anti-LAG-3 antibody, an anti-CD137 antibody, an anti-CD27 antibody, an anti-CD28 antibody, an anti-CD28H antibody, an anti-CD30 antibody, an anti-CD39 antibody, an anti-CD40 antibody, an anti-CD47 antibody, an anti- CD48 antibody, an anti-CD70 antibody, an anti-CD73 antibody, an anti-CD96 antibody, an anti-CD160 antibody, an anti-CD200 antibody, an anti-CD244 antibody, an anti-ICOS antibody, an anti-TNFRSF25 antibody, an anti-TMIGD2 antibody, an anti-DNAM1 antibody, an anti-BTLA antibody, an anti-LIGHT antibody, an anti-TIGIT antibody, an anti-VISTA antibody, an anti-HVEM antibody, an anti-Siglec antibody, an anti-GAL1 antibody, an anti- GAL3 antibody, an anti-GAL9 antibody, an anti-BTNL2 (butrophylins) antibody, an anti-B7- H3 antibody, an anti-B7-H4 antibody, an anti-B7-H5 antibody, an anti-B7-H6 antibody, an anti-KIR antibody, an anti-LIR antibody, an anti-ILT antibody, an anti-MICA antibody, an anti-MICB antibody, an anti-NKG2D antibody, an anti-NKG2A antibody, an anti-TGFβ antibody, an anti-TGFβR antibody, an anti-CXCR4 antibody, an anti-CXCL12 antibody, an anti-CCL2 antibody, an anti-IL-10 antibody, an anti-IL-13 antibody, an anti-IL-23 antibody, an anti-phosphatidylserine antibody, an anti-neuropilin antibody, an anti-GalCer antibody, an anti-HER2 antibody, an anti-VEGFA antibody, an anti-VEGFR antibody, an anti-EGFR antibody, or an anti-Tie2 antibody. In certain embodiments, the antibody is pembrolizumab, nivolumab, pidilizumab, ipilimumab, tremelimumab, durvalumab, atezolizumab, avelumab, PF-06801591, utomilumab, PDR001, PBF-509, MGB453, LAG525, AMP-224, INCSHR1210, INCAGN1876, INCAGN1949, samalizumab, PF-05082566, urelumab, lirilumab, lulizumab, BMS-936559, BMS-936561, BMS-986004, BMS-986012, BMS- 986016, BMS-986178, IMP321, IPH 2 101, IPH 2 201, varilumab, ulocuplumab, monalizumab, MEDI0562, MEDI0680, MEDI1873, MEDI6383, MEDI6469, MEDI9447, AMG228, AMG820, CC-90002, CDX-1127, CGEN15001T, CGEN15022, CGEN15029, CGEN15049, CGEN15027, CGEN15052, CGEN15092, CX-072, CX-2009, CP-870893, lucatumumab, dacetuzumab, Chi Lob 7/4, RG6058, RG7686, RG7876, RG7888, TRX518, MK-4166, MGA271, IMC-CS4, emactuzumab, trastuzumab, pertuzumab, obinutuzumab, cabiralizumab, margetuximab, enoblituzumab, mogamulizumab, panitumumab, carlumab, bevacizumab, rituximab, or cetuximab. [00504] In certain embodiments, the compounds or pharmaceutical compositions described herein can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, and transplantation (e.g., stem cell transplantation, bone marrow transplantation). [00505] In other embodiments, the additional therapeutically active agent is an anti– inflammatory agent. Exemplary anti–inflammatory agents include, but are not limited to, aspirin; ibuprofen; ketoprofen; naproxen; etodolac (LODINE ® ); COX–2 inhibitors such as celecoxib (CELEBREX ® ), rofecoxib (VIOXX ® ), valdecoxib (BEXTRA ®) , parecoxib, etoricoxib (MK663), deracoxib, 2–(4–ethoxy–phenyl)–3–(4–methanesulfonyl–pheny l)– pyrazolo[1,5–b] pyridazine, 4–(2–oxo–3–phenyl–2,3–dihydrooxazol–4– yl)benzenesulfonamide, darbufelone, flosulide, 4–(4–cyclohexyl–2–methyl–5–oxazolyl)–2– fluorobenzenesulfonamide), meloxicam, nimesulide, 1–Methylsulfonyl–4–(1,1–dimethyl–4– (4–fluorophenyl)cyclopenta–2,4–dien–3–yl)benzene, 4–(1,5–Dihydro–6–fluoro–7–methoxy– 3–(trifluoromethyl)–(2)–benzothiopyrano(4,3–c)pyrazo l–1–yl)benzenesulfonamide, 4,4– dimethyl–2–phenyl–3–(4–methylsulfonyl)phenyl)cyclo – butenone, 4–Amino–N–(4–(2– fluoro–5–trifluoromethyl)–thiazol–2–yl)–benzene sulfonamide, 1–(7–tert–butyl–2,3– dihydro–3,3–dimethyl–5–benzo–furanyl)–4–cyclop ropyl butan–1–one, or their physiologically acceptable salts, esters or solvates; sulindac (CLINORIL ® ); diclofenac (VOLTAREN ® ); piroxicam (FELDENE ® ); diflunisal (DOLOBID ® ), nabumetone (RELAFEN ® ), oxaprozin (DAYPRO ® ), indomethacin (INDOCIN ® ); or steroids such as PEDIAPED ® prednisolone sodium phosphate oral solution, SOLU–MEDROL ® methylprednisolone sodium succinate for injection, PRELONE ® brand prednisolone syrup. [00506] Further examples of anti–inflammatory agents include naproxen, which is commercially available in the form of EC–NAPROSYN ® delayed release tablets, NAPROSYN ® , ANAPROX ® and ANAPROX ® DS tablets and NAPROSYN ® suspension from Roche Labs, CELEBREX ® brand of celecoxib tablets, VIOXX ® brand of rofecoxib, CELESTONE ® brand of betamethasone, CUPRAMINE ® brand penicillamine capsules, DEPEN ® brand titratable penicillamine tablets, DEPO–MEDROL brand of methylprednisolone acetate injectable suspension, ARAVA TM leflunomide tablets, AZULFIDIINE EN–tabs ® brand of sulfasalazine delayed release tablets, FELDENE ® brand piroxicam capsules, CATAFLAM ® diclofenac potassium tablets, VOLTAREN ® diclofenac sodium delayed release tablets, VOLTAREN ® –XR diclofenac sodium extended release tablets, or ENBREL ® etanerecept products. [00507] In certain embodiments, the additional therapeutically active agent is a pain– relieving agent. Exemplary pain relieving agents include, but are not limited to, analgesics such as non–narcotic analgesics [e.g., salicylates such as aspirin, ibuprofen (MOTRIN ® , ADVIL ® ), ketoprofen (ORUDIS ® ), naproxen (NAPROSYN ® ), acetaminophen, indomethacin] or narcotic analgesics [e.g., opioid analgesics such as tramadol, fentenyl, sufentanil, morphine, hydromorphone, codeine, oxycodone, and buprenorphine]; non– steroidal anti–inflammatory agents (NSAIDs) [e.g., aspirin, acetaminophen, COX–2 inhibitors]; steroids or anti–rheumatic agents; migraine preparations such as beta adrenergic blocking agents, ergot derivatives; tricyclic antidepressants (e.g., amitryptyline, desipramine, imipramine); anti–epileptics (e.g., clonaxepam, valproic acid, phenobarbital, phenytoin, tiagaine, gabapentin, carbamazepine, topiramate, sodium valproate); α 2 agonists; selective serotonin reuptake inhibitors (SSRIs), selective norepinepherine uptake inhibitors; benzodiazepines; mexiletine (MEXITIL); flecainide (TAMBOCOR); NMDA receptor antagonists (e.g., ketamine, detromethorphan, methadone); and topical agents (e.g., capsaicin (Zostrix), EMLA cream, lidocaine, prilocaine). Kits [00508] Still further contemplated herein are pharmaceutical packs and/or kits. Pharmaceutical packs and/or kits provided may comprise a provided composition and a container (e.g., a vial, ampoule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a suitable aqueous carrier for dilution or suspension of the provided composition for preparation of administration to a subject. In some embodiments, contents of provided formulation container and solvent container combine to form at least one unit dosage form. [00509] Optionally, a single container may comprise one or more compartments for containing a provided composition, and/or appropriate aqueous carrier for suspension or dilution. In some embodiments, a single container can be appropriate for modification such that the container may receive a physical modification so as to allow combination of compartments and/or components of individual compartments. For example, a foil or plastic bag may comprise two or more compartments separated by a perforated seal which can be broken so as to allow combination of contents of two individual compartments once the signal to break the seal is generated. A pharmaceutical pack or kit may thus comprise such multi–compartment containers including a provided composition and appropriate solvent and/or appropriate aqueous carrier for suspension. [00510] Optionally, instructions for use are additionally provided in such kits of the invention. Such instructions may provide, generally, for example, instructions for dosage and administration. In other embodiments, instructions may further provide additional detail relating to specialized instructions for particular containers and/or systems for administration. Still further, instructions may provide specialized instructions for use in conjunction and/or in combination with additional therapy. Methods of Use and Treatment [00511] Further provided are methods of using compounds as described herein (e.g., compounds of Formulae (I) and (II), and pharmaceutically acceptable salts thereof). [00512] For example, in one aspect, provided is a method of treating a disease, disorder, or condition selected from the group consisting of cardiovascular disease, proliferative disease (e.g., cancer, benign tumors), diabetic retinopathy, inflammatory disease, autoimmune disease, and infectious disease (e.g., bacterial infections, fungal infections, parasitic infections) comprising administering an effective amount of a compound of the present disclosure to a subject in need thereof. [00513] In certain embodiments, the compound of the present disclosure is useful in the treatment of cardiovascular disease. Exemplary cardiovascular diseases include, but are not limited to, coronary heart disease, cardiomyopathy, hypertensive heart disease, heart failure, inflammatory heart disease, valvular heart disease, stroke, cerebrovascular disease, and peripheral arterial disease. [00514] In certain embodiments, the compound of the present disclosure is useful in the treatment of a proliferative disease. Exemplary proliferative diseases include, but are not limited to, cancers and benign neoplasms. In certain embodiments, the proliferative disease is cancer. Exemplary cancers include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangio-endotheliosarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast, HER2+ breast cancer, TROP2+ breast cancer), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarinoma), Ewing sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g., stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B–cell ALL, T–cell ALL), acute myelocytic leukemia (AML) (e.g., B– cell AML, T–cell AML), chronic myelocytic leukemia (CML) (e.g., B–cell CML, T–cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B–cell CLL, T–cell CLL); lymphoma such as Hodgkin lymphoma (HL) (e.g., B–cell HL, T–cell HL) and non–Hodgkin lymphoma (NHL) (e.g., B–cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B– cell lymphoma (DLBCL), CD19+ diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B–cell lymphomas (e.g., mucosa–associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B–cell lymphoma, splenic marginal zone B–cell lymphoma), primary mediastinal B–cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., “Waldenström’s macroglobulinemia”), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B–lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T–cell NHL such as precursor T– lymphoblastic lymphoma/leukemia, peripheral T–cell lymphoma (PTCL) (e.g., cutaneous T– cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome), angioimmunoblastic T– cell lymphoma, extranodal natural killer T–cell lymphoma, enteropathy type T–cell lymphoma, subcutaneous panniculitis–like T–cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above, e.g., mixed leukemia lymphoma (MLL); multiple myeloma (MM), BCMA+ multiple myeloma), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non–small cell lung cancer (NSCLC), TROP2+ non-small cell lung cancer, EGFR+ non-small cell lung canceradenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia Vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP–NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma, FRα+ ovarian cancer), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors), penile cancer (e.g., Paget’s disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget’s disease of the vulva). [00515] Trioxacarcins are known to be useful in the treatment of various cancers, such as ovarian, colorectal, hepatocellular, pancreatic cancer, and andenocarcinomas. See, e.g., Cassidy et al., Cancer Chemother. Pharmacol. (1993) 31:395–400; Tomita et al., J. Antibiot. (1981) 34:1519–1524. It is contemplated that various compounds of Formula (I) and (II) conjugated to an antibody, will have even higher efficacy against these and other cancers as described herein. [00516] In certain embodiments, the compound of the present disclosure is useful in the treatment of diabetic retinopathy. [00517] In certain embodiments, the compound of the present invention is useful in the treatment of an inflammatory disease. Exemplary inflammatory diseases include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, haemolytic autoimmune anaemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter's arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus, type 2 diabetes mellitus), a skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), endometriosis, Guillain– Barre syndrome, infection, ischaemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine headaches, tension headaches), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet’s syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myeasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious aneaemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g., Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, schleroderma, scierodoma, sarcoidosis, spondyloarthopathies, Sjogren's syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scarring, burns, physical injury), vasculitis, vitiligo and Wegener's granulomatosis. In certain embodiments, the inflammatory disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis and prostatistis. [00518] In certain embodiments, the inflammatory condition is an acute inflammatory condition (e.g., for example, inflammation resulting from infection). In certain embodiments, the inflammatory condition is a chronic inflammatory condition (e.g., conditions resulting from asthma, arthritis and inflammatory bowel disease). The compounds may also be useful in treating inflammation associated with trauma and non–inflammatory myalgia. The compounds may also be useful in treating inflammation associated with cancer. [00519] In certain embodiments, the compound of the present disclosure is useful in the treatment of an autoimmune disease. Exemplary autoimmune diseases include, but are not limited to, arthritis (e.g., including rheumatoid arthritis, spondyloarthopathies, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amylosis, acute painful shoulder, psoriatic, and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), enuresis, eosinophilic disease, gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), and disorders ameliorated by a gastroprokinetic agent (e.g., ileus, postoperative ileus and ileus during sepsis; gastroesophageal reflux disease (GORD, or its synonym GERD); eosinophilic esophagitis, gastroparesis such as diabetic gastroparesis; food intolerances and food allergies and other functional bowel disorders, such as non–ulcerative dyspepsia (NUD) and non– cardiac chest pain (NCCP, including costo–chondritis)). [00520] In certain embodiments, the inflammatory disorder and/or the immune disorder is a gastrointestinal disorder. In some embodiments, the gastrointestinal disorder is selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease(IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS). [00521] In certain embodiments, the compound of the present disclosure is useful in the treatment of an infectious disease (e.g., bacterial infection, fungal infection, and/or parasitic infection). In certain embodiments, the compound is useful in treating a parasitic infection (e.g., malaria). In certain embodiments, the compound is useful in treating a bacterial infection. In certain embodiments, the compound is useful in treating a fungal infection. [00522] Trioxacarcins are known to have antibiotic and antiparasitic (e.g., anti-malarial) activity. See, e.g., U.S. Patent 4,459,291; U.S. Patent 4,511,560; Fujimoto et al., J. Antibiot. (1983) 36:1216–1221; Maiese et al. J. Antibiot. (1990) 43:253–258; Tomita et al., J. Antibiot. (1981) 34:1519–1524; and Maskey et al. J. Antibiot. (2004) 57:771–779 (antibacterial and antimalarial activity). It is contemplated that various compounds of Formula (I) and (II) conjugated to an antibody, will have even higher efficacy against an infectious disease, such as a bacterial infection, and other infectious diseases as described herein. EXAMPLES [00523] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner. [00524] General Experimental Procedures. All reactions were performed in flame-dried round-bottom flasks fitted with rubber septa under positive nitrogen pressure, unless otherwise noted. Air- and moisture-sensitive liquids were transferred via syringe or stainless- steel cannula. Organic solutions were concentrated by rotary evaporation (house vacuum, ca. 25-40 Torr) at ambient temperature, unless otherwise noted. Analytical thin-layer chromatography (TLC) was performed using glass plates precoated with silica gel (0.25 mm, 60 Å pore-size, 230-400 mesh, Merck KGA) impregnated with a fluorescent indicator (254 nm). TLC plates were visualized by exposure to ultraviolet light, then were stained with either an aqueous sulfuric acid solution of ceric ammonium molybdate (CAM), an ethanol- aqueous sulfuric acid solution of 2,4-dinitrophenylhydrazine (DNP), or an aqueous sodium hydroxide-potassium carbonate solution of potassium permanganate (KMnO 4 ) then briefly heated using a heat gun. Flash-column chromatography was performed as described by Still et al., employing silica gel (60 Å, 15-40 μM, EMD Millipore Corp.) [00525] Materials. Commercial solvents and reagents were used as received. [00526] Instrumentation. Proton magnetic resonance ( 1 H NMR) spectra were recorded on Bruker 400 (400 MHz) NMR spectrometers at 23 °C. Proton chemical shifts are expressed in parts per million (ppm, δ scale) and are referenced to residual protium in the NMR solvent (CHCl 3 , δ 7.26). Data are represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and/or multiple resonances, br = broad, app = apparent), integration, and coupling constant (J) in Hertz. Carbon nuclear magnetic resonance spectra ( 13 C NMR) were recorded on Bruker 400 (100 MHz) NMR spectrometers at 23 °C. Carbon chemical shifts are expressed in parts per million (ppm, δ scale) and are referenced to the carbon resonances of the NMR solvent (CDCl 3 , δ 77.0). Infrared (IR) spectra were obtained using a Bruker ALPHA FT-IR spectrometer. Data are represented as follows: frequency of absorption (cm -1 ), intensity of absorption (s = strong, m = medium, w = weak, br = broad). High resolution mass spectra were obtained at the Harvard University Mass Spectrometry Facility. High performance liquid chromatography purifications were performed using an Agilent Technologies 1200 series preparative HPLC system. Synthesis of C16-Modified Trioxacarcins [00527] Methyl 4-(benzyloxy)-3-hydroxy-2-methylenebutanoate (1).3-quinuclidinol (0.847 g, 6.66 mmol, 0.2 equiv.) was added to a solution of 2-(benzyloxy)acetaldehyde (5.00 g, 33.3 mmol, 1.0 equiv), methyl acrylate (9.05 mL, 100 mmol, 3.0 equiv.), and anhydrous methanol (1.00 mL, 25.0 mmol, 0.75 equiv) at 23 °C. After stirring at 23 °C overnight (~18 h), the reaction mixture was partitioned between sat. aq. NH 4 Cl solution and CH 2 Cl 2 . The aqueous layer was then extracted with CH 2 Cl 2 . The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash-column chromatography (10% EtOAc in Hexanes grading to 30% EtOAc in Hexanes) to afford 5.81 g (74% yield) of 1 as a colorless oil. Spectroscopic data was identical to previously reported data. [00528] Methyl (R)-2-((S)-2-(benzyloxy)-1-hydroxyethyl)oxirane-2-carboxylat e (3). A flask charged with anhydrous CH 2 Cl 2 (215 mL) and activated 4 Å molecular sieves (700 mg) was cooled to -20 °C before the sequential dropwise addition of Ti(Oi-Pr) 4 (6.65 mL, 22.5 mmol, 1.0 equiv.) and (+)-DIPT (5.65 mL, 27.0 mmol, 1.2 equiv.). The resultant solution was then stirred at -20 °C for 30 minutes and a tBuOOH solution (4.49 mL, 5 M in decane, 22.5 mmol, 1.0 equiv.) was added dropwise and the temperature of the solution was allowed to warm to -10 °C over 30 minutes. Next, 1 (5.31 g, 22.5 mmol, 1.0 equiv.) was added dropwise as a solution in anhydrous CH 2 Cl 2 (10 mL, resultant solution 0.1 M). The reaction was then stirred at -20 °C for 20 h before it was filtered through celite and partitioned between 1 N HCl solution and CH 2 Cl 2 . The aqueous layer was extracted with CH 2 Cl 2 and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash-column chromatography (10% EtOAc in Hexanes grading to 30% EtOAc in Hexanes) to afford 2.75 g (49% yield.96% ee) of 2 as a colorless oil and 3 contaminated with (+)-DIPT.2 contaminated with (+)-DIPT was then taken up in CH 2 Cl 2 (100 mL). To this solution was added distilled water (80 mL) and brine (20 mL). To this biphasic mixture was then added solid NaOH pellets (6.00 g). The resultant biphasic mixture was vigorously stirred for 30 minutes at 23 °C. After 30 minutes, the biphasic mixture was partitioned between sat. aq. sodium chloride and CH 2 Cl 2 . The aqueous layer was extracted with CH 2 Cl 2 . The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 2.47 g (47% recovery, 96% ee) of 3 as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.53 – 7.25 (m, 5H), 4.56 (s, 2H), 4.15 (dd, J = 5.2, 4.0 Hz, 1H), 3.78 – 3.64 (m, 4H), 3.13 (d, J = 5.8 Hz, 1H), 3.07 (d, J = 5.8 Hz, 1H), 2.74 (s, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 169.73, 137.78, 128.43, 127.79, 127.71, 73.55, 70.75, 69.35, 56.28, 52.65, 50.06. FTIR (neat), cm -1 : 3476 (br), 3030 (s), 2866 (s), 1736 (s). HRMS (ESI): Calcd for (C 13 H 16 O 5 +H) + 253.1071, found 253.1073. [00529] Methyl (S)-4-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-2-methyle nebutanoate (4). TBSOTf (3.65 mL, 20.9 mmol, 2.0 equiv.) was added dropwise to an ice-cooled solution 2 (2.47 g, 10.4 mmol, 1.0 equiv.) and DIPEA (2.64 mL, 11.5 mmol, 1.1 equiv.) in anhydrous CH 2 Cl 2 (33.0 mL, 0.32 M). The solution was then stirred at 0 °C for 1 h. After 1 h, the solution was partitioned between sat. aq. NH 4 Cl and CH 2 Cl 2 . The aqueous layer was then extracted with CH 2 Cl 2 . The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash- column chromatography (5% EtOAc in Hexanes grading to 15% EtOAc in Hexanes) to afford 3.66 g (quant. yield) of 4 as a colorless oil. Spectroscopic data was identical to previously reported data. [00530] Methyl (R)-2-((S)-2-(benzyloxy)-1-((tert-butyldimethylsilyl)oxy)eth yl)oxirane-2- carboxylate (5). TBSOTf (3.81 mL, 21.8 mmol, 2.0 equiv.) was added dropwise to an ice- cooled solution 3 (2.47 g, 10.4 mmol, 1.0 equiv.) and DIPEA (2.76 mL, 12.0 mmol, 1.1 equiv.) in anhydrous CH 2 Cl 2 (33.0 mL, 0.32 M). The solution was then stirred at 0 °C for 1 h. After 1 h, the solution was partitioned between sat. aq. NH 4 Cl and CH 2 Cl 2 . The aqueous layer was then extracted with CH 2 Cl 2 . The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash-column chromatography (5% EtOAc in Hexanes grading to 15% EtOAc in Hexanes) to afford 3.78 g (95% yield) of 5 as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 – 7.25 (m, 5H), 4.51 (s, 2H), 4.47 (t, J = 5.0 Hz, 1H), 3.70 (s, 3H), 3.59 (d, J = 5.1 Hz, 2H), 3.04 (q, J = 6.2 Hz, 2H), 0.86 (s, 9H), 0.07 (d, J = 1.6 Hz, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 169.67, 138.08, 128.35, 127.59, 73.41, 71.89, 68.69, 57.59, 52.40, 48.10, 25.71, 18.20, -4.87, -4.98. FTIR (neat), cm -1 : 2952 (s), 2928 (s), 2886 (s), 2856 (s), 1737 (s). HRMS (ESI): Calcd for (C 19 H 30 O 5 Si+H) + 367.1935, found 367.1934. [00531] Methyl (R)-2-((R)-2-(benzyloxy)-1-((tert-butyldimethylsilyl)oxy)eth yl)oxirane-2- carboxylate (6). A solution of KOtBu in THF (1.04 mL, 1 M, 1.09 mmol, 0.1 equiv.) was added dropwise to a solution of 4 (3.66 g, 10.4 mmol) and tBuOOH (4.20 mL, 5 M, 20.9 mmol, 2.0 equiv.) at 0 °C. After 5 h, a second portion of tBuOOH (4.20 mL, 5 M, 20.9 mmol, 2.0 equiv.) was added to the solution and a second portion of KOtBu in THF (1.04 mL, 1 M, 1.09 mmol, 0.1 equiv.) was added dropwise. The solution was warmed to 4 °C and stirred overnight. After a total reaction period of 24 h, solid Na 2 SO 3 (6.58 g, 52.2 mmol, 5 equiv.) was added in one portion. The resulting mixture was warmed to 23 °C and then stirred at 23 °C for 30 minutes. The reaction mixture was filtered through a pad of Celite eluting with ether. The filtrate was then collected and concentrated under reduced pressure. The residue was purified by flash-column chromatography (5% EtOAc in Hexanes grading to 15% EtOAc in Hexanes) to afford 3.40 g (89% yield) of 6 as a colorless oil. Spectroscopic data was identical to previously reported data. [00532] 1-((R)-2-((S)-2-(Benzyloxy)-1-((tert-butyldimethylsilyl)oxy) ethyl)oxiran-2-yl)-2- diazoethan-1-one (7). Aqueous LiOH solution (20.6 mL, 1 M, 20.6 mmol, 2.0 equiv.) was added to an ice-cooled solution of 5 (3.78 g, 10.3 mmol) in THF (30 mL) and methanol (15 mL). The resultant solution was stirred overnight at 0 °C. After stirring overnight (~18 h), the solution was diluted with EtOAc (40 mL) and adjusted to pH 1 by addition of 1 N HCl (30 mL). The resultant biphasic mixture was then partitioned between EtOAc and brine. The aqueous layer was then extracted with EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude intermediate as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.37 – 7.25 (m, 5H), 4.56 (q, J = 12.1 Hz, 2H), 3.91 (t, J = 4.1 Hz, 1H), 3.70 – 3.56 (m, 2H), 3.12 (d, J = 5.9 Hz, 1H), 2.92 (d, J = 5.9 Hz, 1H), 0.91 (s, 9H), 0.12 (d, J = 4.4 Hz, 6H). HRMS (ESI): Calcd for (C 18 H 28 O 5 Si+H) + 353.1779, found 353.1783. **CAUTION!!** Diazomethane is an explosion hazard and is extremely toxic! The following operation was conducted behind a blast shield. The reaction was run under low lighting; the hood lights were turned off, and after addition of diazomethane the reaction flask was covered with aluminum foil to exclude light. Isobutyl chloroformate (2.81 mL, 21.7 mmol, 2.1 equiv.) was added dropwise to a solution of triethylamine (5.76 mL, 41.3 mmol, 4.0 equiv.) in anhydrous THF (54 mL) at -15 °C. After a fine white suspension forms, the suspension was then stirred at -15 °C for 20 minutes. After 20 minutes, crude intermediate was added dropwise as a solution in anhydrous THF (22 mL). After stirring at -15 °C, TLC (20% EtOAc in Hexanes) shows consumption of crude intermediate and a single major intermediate, the putative mixed anhydride. Next, freshly distilled diazomethane in ether (20.6 mmol, 2.0 equiv., procedure to safely distill diazomethane below) was added portion-wise using a graduated plastic pipette. The resultant suspension was bright yellow. The cooling bath was removed and the solution was allowed to warm to 23 °C. After 2 h, TLC (20% EtOAc in Hexanes) shows consumption of the putative mixed anhydride and the appearance of a single, strongly-UV active spot below. To quench any unreacted diazomethane, a stream of nitrogen was passed into the headspace of the flask through a 19-gauge needle through the septum, and the flask was vented through tubing to an Erlenmeyer flask containing ~300 mL of 50% aq. acetic solution. The mixture was vented for 30 minutes, bubbling of the acid solution indicates that the diazomethane is being quenched. The quenched mixture (still pale yellow) was then partitioned between sat. aq. NaHCO 3 solution and CH 2 Cl 2 . The aqueous layer was then extracted with CH 2 Cl 2 . The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash-column chromatography (5% EtOAc in Hexanes grading to 15% EtOAc in Hexanes) to afford 3.06 g (79% yield) of 7 as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 – 7.26 (m, 5H), 5.66 (s, 1H), 4.55 (t, J = 5.5 Hz, 1H), 4.51 (s, 2H), 3.61 (dd, J = 10.0, 5.8 Hz, 1H), 3.46 (dd, J = 10.0, 5.2 Hz, 1H), 3.12 (d, J = 5.4 Hz, 1H), 2.74 (d, J = 5.4 Hz, 1H), 0.85 (s, 9H), 0.06 (d, J = 1.1 Hz, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 192.44, 138.05, 128.37, 127.62, 73.26, 70.96, 68.81, 61.92, 52.62, 49.68, 25.72, 18.17, -4.72, -5.12. FTIR (neat), cm -1 : 2954 (s), 2928 (s), 2856 (s), 2107 (s), 1740 (s), 1637 (s). HRMS (ESI): Calcd for (C 19 H 28 N 2 O 4 Si+H) + 377.1891, found 377.1894. [00533] To begin, the Aldrich Mini Diazald ® apparatus was charged with a stir bar, KOH (3.20 g, 57.0 mmol, 1.9 equiv.), deionized water (5 mL), and 2-(2-Ethoxyethoxy)ethanol (18 mL). The addition funnel was then charged with Diazald ® (6.40 g, 29.9 mmol) in diethyl ether (25 mL) and the receiving flask was cooled to -78 °C in a dry ice/acetone bath. The round bottom flask containing KOH, water, and 2-(2-Ethoxyethoxy)ethanol was then heated to 65 °C in an oil bath. The Diazald ® ethereal solution was added such that the rate of addition and diazomethane distillation was equal. After Diazald ® addition was complete, ether (25 mL) was added until the resulting distillate was colorless. Distillation of diazomethane was assumed to be 70% yielding as per the manufacturer’s label. Next, the receiving flask containing yellow diazomethane solution was removed and a few pellets of KOH were added. If the ethereal diazomethane solution was not used immediately, the flask was sealed with a yellow plastic cap and covered in aluminum foil to exclude light. The ethereal diazomethane solution was stored at -20 °C. The reaction mixture in the distillation apparatus was carefully quenched by dropwise addition of 50% aq. acetic acid solution. The disassembled glassware was left at 23 °C overnight (~18 h), then washed with water and acetone, and air-dried. [00534] 1-((R)-2-((R)-2-(Benzyloxy)-1-((tert-butyldimethylsilyl)oxy) ethyl)oxiran-2-yl)-2- diazoethan-1-one (8).6 was transformed to 8 using an identical procedure to 7. Crude intermediate was obtained as a faint yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.42 – 7.28 (m, 5H), 4.57 (d, J = 1.3 Hz, 2H), 4.21 (dd, J = 6.5, 5.2 Hz, 1H), 3.64 (qd, J = 9.6, 5.9 Hz, 2H), 3.09 (s, 2H), 0.95 – 0.84 (m, 9H), 0.15 – 0.05 (m, 6H). HRMS (ESI): Calcd for (C 1 8H 2 8O 5 Si+H) + 353.1779, found 353.1783.8 was obtained as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.42 – 7.27 (m, 5H), 5.58 (s, 1H), 4.62 – 4.46 (m, 2H), 3.60 (qd, J = 9.6, 6.5 Hz, 2H), 3.16 (d, J = 5.8 Hz, 1H), 2.75 (d, J = 5.9 Hz, 1H), 0.88 (s, 9H), 0.09 (d, J = 4.9 Hz, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 192.35, 138.16, 128.30, 127.48, 73.34, 71.81, 68.82, 63.95, 52.03, 50.32, 25.75, 18.16 -4.80, -5.02. FTIR (neat), cm -1 : 2954 (s), 2928 (s), 2856 (s), 2107 (s), 1753 (s), 1637 (s). HRMS (ESI): Calcd for (C 19 H 28 N 2 O 4 Si+H) + 377.1891, found 377.1895. [00535] 1-((R)-2-((S)-2-(Benzyloxy)-1-hydroxyethyl)oxiran-2-yl)-2-di azoethan-1-one (9). Triethylamine trihydrofluoride (5.55 mL, 34.1 mmol, 6.0 equiv.) was added dropwise to 7 (2.14 g, 5.68 mmol) in anhydrous acetonitrile (11.0 mL, 0.5 M) at 23 °C. The reaction vessel was wrapped in aluminum foil to exclude light and then stirred at 23 °C for 24 h. After 24 h, the solution was diluted with CH 2 Cl 2 and added slowly to a solution of sat. aq. NaHCO 3 (40 mL). The biphasic mixture was then partitioned between brine and CH 2 Cl 2 . The aqueous layer was then extracted with CH 2 Cl 2 . The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash-column chromatography (10% EtOAc in Hexanes grading to 30% EtOAc in Hexanes) to afford 1.49 g (quant. yield) of 9 as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.32 – 7.17 (m, 5H), 5.52 (s, 1H), 4.50 (s, 2H), 3.87 (ddd, J = 7.5, 5.5, 4.3 Hz, 1H), 3.68 (dd, J = 10.1, 4.3 Hz, 1H), 3.60 (dd, J = 10.0, 5.6 Hz, 1H), 3.39 (dd, J = 7.7, 1.7 Hz, 1H), 3.02 (d, J = 5.1 Hz, 1H), 2.79 (d, J = 5.1 Hz, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 193.65, 137.91, 128.41, 127.71, 127.56, 73.51, 71.50, 71.10, 59.94, 52.81, 51.58. FTIR (neat), cm -1 : 3448 (br), 3112 (s), 2862 (s), 2105 (s), 1624 (s). HRMS (ESI): Calcd for (C 13 H 14 N 2 O 4 +H) + 263.1026, found 263.1030. [00536] 1-((R)-2-((R)-2-(Benzyloxy)-1-hydroxyethyl)oxiran-2-yl)-2-di azoethan-1-one (10). 8 was transformed to 10 using an identical procedure to 9.10 was obtained as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.32 – 7.17 (m, 5H), 5.54 (s, 1H), 4.64 – 4.31 (m, 3H), 3.60 (d, J = 4.8 Hz, 2H), 3.15 (d, J = 5.5 Hz, 1H), 2.66 (d, J = 5.5 Hz, 1H), 2.44 – 2.26 (m, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 192.32, 137.71, 128.46, 127.83, 127.71, 73.47, 70.75, 67.14, 61.99, 52.5749.12. FTIR (neat), cm -1 : 3441 (br), 3115 (s), 2862 (s), 2105 (s), 1742 (s), 1624 (s). HRMS (ESI): Calcd for (C 13 H 14 N 2 O 4 +Na) + 285.0846, found 285.0846. [00537] (S)-2-(Benzyloxy)-1-(2-(2-diazoacetyl)oxiran-2-yl)ethan-1-on e (11). Dess-Martin periodinane (3.00 g, 7.07 mmol, 1.1 equiv.) was added to a suspension of 9 (1.68 g, 6.42 mmol) and NaHCO 3 (5.40 g, 64.2 mmol, 10 equiv.) in CH 2 Cl 2 (64 mL, 0.1 M). The suspension was then stirred at 23 °C for 1 h. After 1 h the reaction mixture was diluted with diethyl ether (50 mL). The reaction mixture was then filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure. The residue was purified by flash- column chromatography (20% EtOAc in Hexanes grading to 40% EtOAc in Hexanes) to afford 1.24 g (75% yield) of 11 as a yellow oil.10 was transformed to 11 using an identical procedure to provide 11 as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.32 – 7.17 (m, 5H), 5.64 (s, 1H), 4.58 – 4.45 (m, 2H), 4.34 (s, 2H), 3.16 (d, J = 6.1 Hz, 1H), 2.92 (d, J = 6.1 Hz, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 199.42, 187.43, 136.95, 128.53, 128.11, 128.02, 73.60, 73.35, 61.08, 53.75, 52.32. FTIR (neat), cm -1 : 3114 (br), 2923 (br), 2110 (s), 2105 (s), 1729 (s), 1628 (s). HRMS (ESI): Calcd for (C 13 H 12 N 2 O 4 +H) + 261.0870, found 261.0873. [00538] (E)-9-Hydroxy-10-methoxy-8-(methoxymethoxy)-6-methyl-7-(prop -1-en-1-yl)- 3,4-dihydroanthracen-1(2H)-one (13). Lithium tert-butoxide (1.0 M solution in THF, 193 mL, 193 mmol, 3.0 equiv.) was added to a solution of 12 (10:1 E/Z, 17.5 g, 64.2 mmol) in anhydrous THF (320 mL) at -78 °C. After 5 minutes, a solution of cyclohexenone (6.21 mL, 64.2 mmol, 1.0 equiv) in anhydrous THF (320 mL) was added by cannula. The reaction flask was allowed to warm to -25 °C over 2.5 h, then dimethyl sulfate (55.2 mL, 578 mmol, 9.0 equiv.) was added. The reaction flask was allowed to warm to 23 °C over 2 h. After an additional 2.5 h, the reaction mixture was diluted with 10% aqueous ammonium hydroxide solution (500 mL) and stirred for 10 minutes to quench excess dimethyl sulfate. The layers were separated and the organic layer was concentrated. The solid residue was dissolved in ethyl acetate (1 L) and the resultant solution was washed sequentially with water (500 mL) then sat. aq. sodium chloride solution (500 mL), and the washed solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated to provide 13 (22.8 g, quant. yield) as an orange solid. This material was analytically pure and used in subsequent steps without further purification. 1 H NMR (10:1 E/Z ratio of alkene isomers, major isomer reported, 500 MHz, CDCl 3 ) δ: 15.02 (s, 1H), 7.59 (s, 1H), 6.53 (dq, J = 16.1, 1.8 Hz, 1H), 6.10 (dq, J = 16.1, 6.2 Hz, 1H), 5.09 (s, 2H), 3.80 (s, 3H), 3.60 (s, 3H), 3.04 (t, J = 6.2 Hz, 2H), 2.74 (t, J = 6.4 Hz, 2H), 2.49 (s, 3H), 2.09 (p, J = 6.4 Hz, 2H), 1.97 (dd, J = 6.5, 1.8 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 205.0, 161.6, 153.8, 143.1, 141.3, 133.5, 132.2, 130.8, 127.9, 125.4, 118.5, 117.3, 110.9, 101.3, 61.1, 58.0, 39.1, 23.6, 22.4, 22.3, 19.5. FTIR (neat), cm-1: 2944 (m), 1612 (s), 1561 (m), 1443 (m), 1396 (m), 1375 (s), 1153 (s), 1040 (s), 961 (s), 912 (s), 731 (w). HRMS (ESI): Calcd for (C 21 H 24 O 5 +H)+ 357.1697, found 357.1689. [00539] (E)-2,2-Di-tert-butyl-7-methoxy-5-methyl-4-(prop-1-en-1-yl)- 9,10- dihydroanthra[1,9-de][1,3,2]dioxasilin-11(8H)-one (14).37% w/w Aqueous hydrochloric acid solution (11.7 mL, 142 mmol, 2.22 equiv.) was added to a suspension of 13 (10:1 E/Z, 22.9 g, 643 mmol) in methanol (640 mL, 1 M) at 0 °C. After 30 minutes, the cooling bath was removed and the resulting red suspension was allowed to warm to 23 °C. The reaction mixture was stirred vigorously at 23 °C for 48 h and then was carefully poured onto a mixture of ethyl acetate (1 L), saturated aqueous NaHCO 3 solution (500 mL), and deionized water (500 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated to approximately 1.5 L total volume and washed with sat. aq. sodium chloride solution (500 mL). The washed organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to provide the crude free phenol as a dark orange solid. The crude product was carried through to the following transformation. Di-tert-butyldichlorosilane (24.3 mL, 115 mmol, 1.8 equiv.) was added to a dark red solution of the crude product, N,N-diisopropylamine (55.8 mL, 320 mmol, 5.0 equiv.), and anhydrous HOBt (4.32 g, 32.0 mmol, 0.5 equiv.) in DMF (1.3 L) at 23 °C. The reaction flask was then heated in an oil bath to 55 °C. After 1 h, the heating bath was removed and the reaction flask was allowed to cool to 23 °C. The reaction mixture was then partitioned between sat. aq. NaHCO 3 solution (1 L) and diethyl ether (1.5 L). The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed successively with water and sat. aq. sodium chloride solution. The washed solution was then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash-column chromatography (0% EtOAc in Hexanes grading to 5% EtOAc in Hexanes; containing 1% triethylamine) to provide 14 (20.6 g, 20:1 E/Z, 71% yield over two steps) as a flaky yellow solid. 1 H NMR (20:1 E/Z ratio of alkene isomers, major isomer reported, 400 MHz, CDCl 3 ) δ: 7.36 (d, J = 1.2 Hz, 1H), 6.46 (dd, J = 15.9, 1.5 Hz, 1H), 6.36 (dq, J = 15.7, 6.1 Hz, 1H), 3.82 (s, 3H), 3.03 (t, J = 6.1 Hz, 2H), 2.64 (t, J = 6.5 Hz, 2H), 2.49 (d, J = 1.0 Hz, 3H), 2.07 (p, J = 5.8 Hz, 2H), 1.97 (dd, J = 6.3, 1.4 Hz, 3H), 1.12 (s, 18H). 13 C NMR (100 MHz, CDCl 3 ) δ: 196.8, 150.7, 150.6, 144.4, 139.8, 131.1, 130.9, 130.3, 124.3, 121.6, 116.0, 114.8, 114.6, 61.1, 41.4, 26.4, 24.2, 22.5, 22.4, 21.3, 20.0. FTIR (neat), cm -1 : 2935 (m), 2860 (w), 1681 (s), 1606 (m), 1553 (m), 1472 (m), 1445 (m), 1402 (m), 1389 (s), 1057 (s), 1014 (m), 887 (s), 828 (s), 661 (m). HRMS (ESI): Calcd for (C 27 H 36 O 4 Si+H) + 453.2456, found 453.2457. [00540] 2,2-Di-tert-butyl-7-methoxy-5-methyl-11-oxo-8,9,10,11-tetrah ydroanthra[1,9- de][1,3,2]dioxasiline-4-carbaldehyde (15).2,6-Lutidine (2.56 mL, 22.1 mmol, 2.0 equiv.) was added to a vigorously stirring, ice-cooled solution of 14 (5.00 g, 11.0 mol) in a mixture of THF (150 mL) and water (75 mL). Sodium periodate (9.45 g, 44.2 mmol, 4.0 equiv.) and potassium osmate dihydrate (0.203 g, 0.552 mmol, 0.05 equiv.) were then added sequentially. After 10 minutes, the cooling bath was removed and the reaction flask was allowed to warm to 23 °C. After 1.5 h, the reaction mixture was partitioned between water (600 mL), ethyl acetate (1.2 L), and hexanes (600 mL). The layers were separated and the organic layer was washed with water (600 mL) and then sat. aq. sodium chloride solution (600 mL). The washed solution was then dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by flash-column chromatography (0% EtOAc in Hexanes grading to 10% EtOAc in Hexanes) to provide 15 (4.06 g, 83% yield) as a yellow solid. 1 H NMR (500 MHz, CDCl 3 ) δ: 10.82 (s, 1H), 7.31 (s, 1H), 3.83 (s, 3H), 3.07 (t, J = 6.0 Hz, 2H), 2.72 (s, 2H), 2.66 (t, J = 6.5 Hz, 2H), 2.10 (p, J = 6.5 Hz, 2H), 1.15 (s, 17H). 13 C NMR (100 MHz, CDCl 3 ) δ: 196.2, 191.0, 160.9, 150.9, 144.8, 140.7, 136.2, 134.1, 119.0, 117.1, 116.0, 114.0, 61.2, 41.2, 26.2, 24.5, 22.7, 22.3, 21.4. FTIR (neat), cm -1 : 2936 (m), 2862 (w), 1681 (s), 1606 (s), 1558 (w), 1327 (s), 1245 (m), 876 (m), 827 (m). HRMS (ESI): Calcd for (C 25 H 32 O 5 +H) + 441.2092, found 441.1980.
[00541] 4-((1S,2S,4S,5R)-1-((Benzyloxy)methyl)-3-oxo-6,7- dioxaspiro[bicyclo[2.2.1]heptane-2,2'-oxiran]-5-yl)-2,2-di-t ert-butyl-7-methoxy-5-methyl- 9,10-dihydroanthra[1,9-de][1,3,2]dioxasilin-11(8H)-one (16).11 (0.673 g, 2.59 mmol, 2.0 equiv.) in anhydrous CH 2 Cl 2 (5.75 mL) was added dropwise via syringe pump at a rate of 0.4 equiv. per hour to a suspension of 15 (0.57 g, 1.29 mmol), diacetoxyrhodium dimer (0.029 g, 0.065 mmol, 0.05 equiv.), activated 4 Å mol. sieves in anhydrous CH 2 Cl 2 (5.75 mL, 0.255 M). After 5 h, all of 11 was dispensed and the reaction mixture was allowed to stir at 23 °C for 10 minutes. After 10 minutes, the reaction mixture was filtered through a plug of silica eluting with CH 2 Cl 2 (50 mL) and 50% EtOAc in Hexanes (50 mL) to remove the mol. sieves and diacetoxyrhodium dimer. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (0% EtOAc in Hexanes grading to 20% EtOAc in Hexanes) to afford a mixture of the cycloadduct products (0.587 g, 67% combined yield) and unreacted 15 (0.120 g, 21% recovery). The cycloadduct products were not separated and carried forward together to the next transformation.
[00542] (2S,2'R,3a'R,13a'R)-2'-((Benzyloxy)methyl)-12',13a'-dihydrox y-7'-methoxy-5'- methyl-3a',4',8',9',10',13a'-hexahydro-2'H,11'H-spiro[oxiran e-2,1'-[2,4]epoxyfuro[3,2- b]naphtho[2,3-h]chromen]-11'-one (17). To a solution of the mixture of cycloadducts (16, 0.855 g, 1.27 mmol) in anhydrous acetonitrile (25.4 mL, 0.05 M) at 23 °C was added dropwise triethylamine trihydrofluoride (0.828 mL, 5.08 mmol, 4.0 equiv.). The yellow solution darkened to a light orange color. After 30 minutes, the solution was diluted with CH 2 Cl 2 (25 mL) and added dropwise to a separatory funnel containing sat. aq. NaHCO 3 solution (50 mL). The aqueous layer was then extracted with CH 2 Cl 2 . The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash-column chromatography (40% EtOAc in Hexanes grading to 60% EtOAc in Hexanes) to afford 0.205 g (quant. yield) of 17 as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 14.86 (d, J = 1.7 Hz, 1H), 7.42 – 7.36 (s, 1H), 7.35 – 7.14 (m, 5H), 5.22 – 5.16 (d, 1H), 4.77 (d, J = 4.0 Hz, 1H), 4.55 (q, J = 12.2 Hz, 2H), 4.39 (s, 1H), 3.76 (s, 2H), 3.73 (s, 3H), 3.16 – 2.91 (m, 4H), 2.68 (t, J = 6.1, 2.9 Hz, 2H), 2.54 (d, J = 0.9 Hz, 3H), 2.09 – 2.00 (m, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.48, 162.87, 151.49, 142.43, 141.57, 137.23, 135.22, 130.25, 128.45, 127.89, 115.80, 113.76, 113.26, 111.02, 104.31, 98.53, 74.13, 73.54, 69.92, 69.59, 65.21, 60.90, 50.57, 38.78, 23.57, 22.08, 20.32. FTIR (neat), cm-1: 3350 (br. s) 2930 (s), 1730 (s), 1620 (s), 1569 (w). HRMS (ESI): Calcd for (C 30 H 28 O 9 +H) + 533.1806, found 533.1809. [00543] (2R,2'R,3a'R,13a'R)-2'-((Benzyloxy)methyl)-12'-hydroxy-7',13 a'-dimethoxy-5'- methyl-3a',4',8',9',10',13a'-hexahydro-2'H,11'H-spiro[oxiran e-2,1'-[2,4]epoxyfuro[3,2- b]naphtho[2,3-h]chromen]-11'-one (18). To a mixture of 17 (0.218 g, 0.409 mmol) and CaSO 4 (0.223 g, 1.64 mmol, 4.0 equiv.) in iodomethane (7.63 mL, 123 mmol, 300 equiv.) at 23 °C was added Ag 2 O (0.104 g, 0.450 mmol, 1.1 equiv.) as one portion. The reaction vessel was covered with aluminum foil to exclude light and stirred at 23 °C for 1.5 h. After 1.5 h, the reaction mixture was diluted with CH 2 Cl 2 (10 mL) and filtered through a pad of Celite. The pad of Celite was washed with CH 2 Cl 2 (25 mL) and filtrate was concentrated under reduced pressure to afford 0.223 g (quant. yield) of 18 as a yellow-green oil. The crude material was used in subsequent transformations without the need for purification. 1 H NMR (400 MHz, CDCl 3 ) δ 14.74 (s, 1H), 7.40 (s, 1H), 7.32 – 7.17 (m, 5H), 5.16 (d, J = 4.1 Hz, 1H), 4.75 (d, J = 4.2 Hz, 1H), 4.63 – 4.48 (q, 2H), 3.71 (m, 5H), 3.69 (s, 3H), 2.99 (td, J = 5.8, 2.5 Hz, 2H), 2.83 (d, J = 5.2 Hz, 1H), 2.75 (d, J = 5.3 Hz, 1H), 2.71 – 2.64 (m, 2H), 2.55 (s, 3H), 2.04 (p, J = 6.3 Hz, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.46, 163.01, 151.43, 142.43, 141.67, 137.39, 135.24, 130.28, 128.42, 127.85, 115.65, 113.58, 113.29, 111.05, 105.11, 102.10, 74.15, 71.67, 69.30, 69.20, 64.96, 60.92, 52.85, 48.15, 38.84, 23.59, 22.13, 20.30. FTIR (neat), cm-1: 2951 (s) 2855 (s), 1715 (s), 1618 (s), 1570 (s), 1495 (s). HRMS (ESI): Calcd for (C 31 H 30 O 9 +H) + 547.1963, found 547.1966. [00544] (2R,2'R,3a'R,13a'R)-12'-Hydroxy-2'-(hydroxymethyl)-7',13a'-d imethoxy-5'-methyl- 3a',4',8',9',10',13a'-hexahydro-2'H,11'H-spiro[oxirane-2,1'- [2,4]epoxyfuro[3,2-b]naphtho[2,3- h]chromen]-11'-one (19). To a solution of 18 (0.223 g, 0.408 mmol) in anhydrous THF (8.16 mL, 0.05 M) was added Pd(OH) 2 (0.143 g, 0.204 mmol, 0.5 equiv.). A hydrogen balloon was placed on the flask and the solution was degassed for 5 minutes. After 5 minutes, the outlet was removed and the reaction was allowed to stir at 23 °C for 1 h. After 1 h, the reaction mixture was diluted with EtOAc (20 mL) and filtered through a pad of Celite. The pad of Celite was washed with EtOAc (20 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by flash-column chromatography (40% EtOAc in Hexanes grading to 60% EtOAc in Hexanes) to afford 0.186 g (quant. yield) of 19 as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 14.80 (s, 1H), 7.47 (s, 1H), 5.20 (d, J = 4.1 Hz, 1H), 4.85 (d, J = 4.2 Hz, 1H), 3.95 (d, J = 13.0 Hz, 1H), 3.80 (m, 4H), 3.76 (s, 3H), 3.05 (dd, J = 7.1, 5.1 Hz, 2H), 2.95 (d, J = 4.8 Hz, 1H), 2.79 – 2.67 (m, 3H), 2.58 (s, 3H), 2.16 – 2.06 (m, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.52, 162.95, 151.40, 142.44, 141.38, 135.30, 130.47, 115.76, 113.31, 111.13, 105.11, 102.09, 71.80, 69.29, 69.14, 60.94, 58.18, 52.89, 47.88, 38.84, 29.71, 23.61, 22.12, 20.14. FTIR (neat), cm-1: 3448 (br) 2930 (br s), 2853 (s), 1715 (s), 1618 (s), 1570 (s). HRMS (ESI): Calcd for (C 24 H 24 O 9 +H) + 457.1493, found 457.1510. [00545] (2S,2'R,3a'R,13a'R)-12',13a'-dihydroxy-2'-(hydroxymethyl)-7' -methoxy-5'-methyl- 3a',4',8',9',10',13a'-hexahydro-2'H,11'H-spiro[oxirane-2,1'- [2,4]epoxyfuro[3,2-b]naphtho[2,3- h]chromen]-11'-one (20). To a solution of 17 (5.00 mg, 9.39 μmol) in anhydrous THF (0.671 mL, 0.014 M) was added Pd(OH) 2 (6.59 mg, 9.39 μmol, 1.0 equiv.). A hydrogen balloon was placed on the flask and the solution was degassed for 5 minutes. After 5 minutes, the outlet was removed and the reaction was allowed to stir at 23 °C for 1 h. After 1 h, the reaction mixture was diluted with EtOAc (5 mL) and filtered through a pad of Celite. The pad of Celite was washed with EtOAc (10 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by flash-column chromatography (40% EtOAc in Hexanes grading to 60% EtOAc in Hexanes) to afford 4.15 mg (99% yield) of 20 as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 14.93 (s, 1H), 7.47 (s, 1H), 5.24 (d, J = 4.0 Hz, 1H), 4.85 (d, J = 4.1 Hz, 1H), 4.34 (s, 1H), 3.97 (d, J = 12.8 Hz, 1H), 3.85 (d, J = 12.9 Hz, 1H), 3.79 (s, 3H), 3.13 (d, J = 4.4 Hz, 1H), 3.09 – 3.00 (m, 3H), 2.73 (td, J = 6.1, 1.4 Hz, 2H), 2.59 (s, 3H), 2.16 – 2.04 (m, 2H), 1.89 (br s, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.52, 162.84, 151.46, 142.47, 141.30, 135.31, 130.47, 128.60, 125.39, 115.94, 113.50, 113.30, 111.11, 104.40, 98.52, 73.77, 69.95, 69.40, 60.93, 58.22, 50.20, 38.79, 29.71. FTIR (neat), cm-1: 3433 (br) 2924 (br s), 2853 (s), 1618 (s), 1570 (s), 1523 (s). HRMS (ESI): Calcd for (C 23 H 23 O 9 +H) + 443.1337, found 443.1340. [00546] (1R,2R,3aR,13aR)-1-(bromomethyl)-1,12-dihydroxy-2-(hydroxyme thyl)-7,13a- dimethoxy-5-methyl-1,2,3a,4,8,9,10,13a-octahydro-11H-2,4-epo xyfuro[3,2-b]naphtho[2,3- h]chromen-11-one (21). To a solution of 19 (5.00 mg, 11.0 μmol) in anhydrous acetonitrile (0.440 mL, 0.025 M) was added lithium bromide (0.029 g, 0.329 mmol, 30 equiv.) followed by cerium trichloride heptahydrate (0.012 g, 0.033 mmol, 3.0 equiv.). The reaction mixture was then wrapped in aluminum foil to exclude light and stirred at 23 °C overnight. After stirring overnight (~18 h), the reaction mixture was partitioned between sat. aq. sodium sulfite solution (5 mL) and EtOAc (5 mL). The aqueous layer was then extracted with EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparatory LCMS (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to afford 5.89 mg (quant. yield) of 21 as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 14.87 (s, 1H), 7.48 (s, 1H), 5.11 (d, J = 3.8 Hz, 1H), 4.69 (d, J = 3.8 Hz, 1H), 4.27 (d, J = 13.0 Hz, 1H), 4.19 (d, J = 13.0 Hz, 1H), 3.86 (s, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.45 (d, J = 11.4 Hz, 1H), 3.36 (d, J = 11.3 Hz, 1H), 3.13 – 3.02 (m, 2H), 2.75 (dd, J = 7.2, 5.3 Hz, 2H), 2.57 (s, 3H), 2.19 – 2.03 (m, 2H), 2.01 (s, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.59, 162.87, 152.18, 142.45, 141.02, 135.44, 130.75, 115.91, 112.59, 111.52, 111.25, 109.35, 104.51, 82.94, 70.66, 69.45, 60.97, 59.78, 53.17, 38.84, 32.59, 23.63, 22.09, 20.01. FTIR (neat), cm-1: 3467 (br) 2954 (s), 2928 (s), 2855 (s), 1729 (s), 1620 (s), 1570 (s). HRMS (ESI): Calcd for (C 2 4H 2 5BrO9+H) + 537.0755, found 537.0759. [00547] (2R,2'R,3a'R,13a'R)-12'-Hydroxy-7',13a'-dimethoxy-5'-methyl- 2'-(propoxymethyl)- 3a',4',8',9',10',13a'-hexahydro-2'H,11'H-spiro[oxirane-2,1'- [2,4]epoxyfuro[3,2-b]naphtho[2,3- h]chromen]-11'-one (22). To a solution of 19 (5.00 mg, 11.0 μmol) in anhydrous THF (0.440 mL, 0.025 M) was added KOtBu (0.022 mL, 1M in THF, 0.022 mmol, 2 equiv.). After the addition was complete, the mixture was allowed to stir at 23 °C for 30 minutes. After 30 minutes, iodopropane (0.011 mL, 0.110 mmol, 10 equiv.) was added in one portion. The next day (~18 h), the reaction mixture was partitioned between EtOAc (5 mL) and sat aq. NH 4 Cl solution (5 mL). The aqueous layer was then extracted with EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparatory LCMS (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to afford 1.60 mg (30% yield) of 22 as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 14.80 (s, 1H), 7.45 (s, 1H), 5.20 (d, J = 4.1 Hz, 1H), 4.80 (d, J = 4.2 Hz, 1H), 3.85 – 3.70 (m, 8H), 3.52 (dt, J = 9.7, 6.7 Hz, 1H), 3.43 (dt, J = 9.6, 6.9 Hz, 1H), 3.05 (dd, J = 7.3, 4.4 Hz, 2H), 2.90 (d, J = 5.4 Hz, 1H), 2.83 (d, J = 5.4 Hz, 1H), 2.73 (t, J = 6.4 Hz, 2H), 2.60 (s, 3H), 2.08 (dq, J = 12.4, 6.2 Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.48, 163.04, 151.47, 142.41, 141.73, 130.91, 128.82, 115.61, 113.57, 111.03, 105.01, 102.12, 74.25, 71.62, 69.30, 69.16, 68.17, 65.72, 60.93, 52.85, 48.19, 23.74, 23.01, 20.32, 14.08, 10.98, 10.33. FTIR (neat), cm-1: 2928 (br) 2858 (s), 1726 (s), 1621 (s), 1572 (s), 1446 (s), 1389 (s). [00548] (2R,2'R,3a'R,13a'R)-2'-((Allyloxy)methyl)-12'-hydroxy-7',13a '-dimethoxy-5'- methyl-3a',4',8',9',10',13a'-hexahydro-2'H,11'H-spiro[oxiran e-2,1'-[2,4]epoxyfuro[3,2- b]naphtho[2,3-h]chromen]-11'-one (23). To a suspension of sodium hydride (3.42 mg, 0.085 mmol, 5.0 equiv., 60% weight suspension) in anhydrous THF (0.342 mL) was added a solution of 19 (7.80 mg, 0.017 mmol) in anhydrous THF (0.342 mL, 0.025 M). After the addition was complete, the mixture was allowed to stir at 23 °C for 30 minutes. After 30 minutes, allyl bromide (0.015 mL, 0.171 mmol, 10 equiv.) was added in one portion. The next day (~18 h), the reaction mixture was partitioned between EtOAc (5 mL) and sat aq. NH 4 Cl solution (5 mL). The aqueous layer was then extracted with EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash-column chromatography (10% EtOAc in Hexanes) to afford 5.60 mg of 23 (66% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 14.80 (s, 1H), 7.45 (s, 1H), 5.86 (ddt, J = 17.3, 10.4, 5.8 Hz, 1H), 5.27 (dq, J = 17.3, 1.6 Hz, 1H), 5.23 – 5.15 (m, 2H), 4.81 (d, J = 4.1 Hz, 1H), 4.14 – 3.99 (m, 2H), 3.91 – 3.69 (m, 8H), 3.05 (td, J = 5.8, 2.3 Hz, 2H), 2.90 (d, J = 5.3 Hz, 1H), 2.81 (d, J = 5.2 Hz, 1H), 2.73 (dd, J = 7.0, 5.8 Hz, 2H), 2.60 (s, 3H), 2.09 (p, J = 6.3 Hz, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.46, 163.02, 151.45, 142.43, 141.69, 135.24, 134.01, 130.27, 118.00, 115.63, 113.55, 113.29, 111.05, 105.03, 102.09, 73.14, 71.67, 69.19, 64.79, 60.92, 52.85, 48.16, 38.84, 29.71, 23.60, 22.13, 20.30. FTIR (neat), cm-1: 2927 (br s) 2853 (br s), 2108 (s), 1621 (s), 1572 (s), 1444 (s). HRMS (ESI): Calcd for (C 27 H 28 O 9 +H) + 497.1806, found 497.1811. [00549] (2R,2'R,3a'R,13a'R)-12'-Hydroxy-7',13a'-dimethoxy-5'-methyl- 2'-((prop-2-yn-1- yloxy)methyl)-3a',4',8',9',10',13a'-hexahydro-2'H,11'H-spiro [oxirane-2,1'-[2,4]epoxyfuro[3,2- b]naphtho[2,3-h]chromen]-11'-one (24). To a suspension of sodium hydride (2.19 mg, 0.055 mmol, 5.0 equiv., 60% weight suspension) in anhydrous THF (0.220 mL) was added a solution of 19 (5.00 mg, 11.0 μmol) in anhydrous THF (0.220 mL, 0.025 M). After the addition was complete, the mixture was allowed to stir at 23 °C for 30 minutes. After 30 minutes, propargyl bromide (0.012 mL, 0.171 mmol, 10 equiv., 80% w/w in toluene) was added in one portion. The next day (~18 h), the reaction mixture was partitioned between EtOAc (5 mL) and sat aq. NH 4 Cl solution (5 mL). The aqueous layer was then extracted with EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash-column chromatography (10% EtOAc in Hexanes) to afford 2.50 mg of 24 (46% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 14.80 (s, 1H), 7.46 (s, 1H), 5.22 (d, J = 4.2 Hz, 1H), 4.82 (d, J = 4.2 Hz, 1H), 4.26 (d, J = 2.4 Hz, 2H), 3.95 (d, J = 11.4 Hz, 1H), 3.86 (d, J = 11.4 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.05 (td, J = 5.8, 2.4 Hz, 2H), 2.91 (d, J = 5.1 Hz, 1H), 2.80 (d, J = 5.1 Hz, 1H), 2.73 (t, J = 6.4 Hz, 2H), 2.60 (s, 3H), 2.45 (t, J = 2.4 Hz, 1H), 2.15 – 1.99 (m, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.50, 162.99, 151.42, 142.42, 141.63, 135.26, 130.35, 115.70, 113.41, 113.23, 111.07, 104.90, 102.01, 78.72, 75.44, 71.70, 69.25, 69.24, 64.34, 60.94, 59.31, 52.89, 48.09, 38.85, 23.60, 22.13, 20.33. FTIR (neat), cm-1: 3272 (br s) 2923 (s), 2853 (s), 2107 (s), 1710 (s), 1620 (s). HRMS (ESI): Calcd for (C 27 H 26 O 9 +H) + 495.1650, found 495.1653. [00550] (2R,2'R,3a'R,13a'R)-2'-(Azidomethyl)-12'-hydroxy-7',13a'-dim ethoxy-5'-methyl- 3a',4',8',9',10',13a'-hexahydro-2'H,11'H-spiro[oxirane-2,1'- [2,4]epoxyfuro[3,2-b]naphtho[2,3- h]chromen]-11'-one (25). To a solution of 19 (5.00 mg, 11.0 μmol) in anhydrous CH 2 Cl 2 (0.220 mL, 0.05 M) was added triethylamine (0.015 mL, 0.110 mmol, 10 equiv.). The reaction mixture was cooled to -20 °C and triflic anhydride (10.0 μL, 0.055 mmol, 5.0 equiv.) was added in one portion. The reaction mixture was then stirred at 0 °C for 1 h. After 1 h, the reaction mixture was warmed to 23 °C and partitioned between brine (5 mL) and CH 2 Cl 2 (5 mL). The aqueous layer was then extracted with CH 2 Cl 2 . The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was then dissolved in anhydrous DMF (0.220 mL, 0.05 M) and sodium azide (7.13 mg, 0.110 mmol, 10 equiv.) was added in one portion. The reaction mixture was then let to stir at 23 °C overnight. After stirring at 23 °C overnight (~18 h), the reaction mixture was partitioned between sat. aq. NaHCO 3 (5 mL) and CH 2 Cl 2 (5 mL). The aqueous layer was then extracted with CH 2 Cl 2 . The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse phase preparatory LCMS (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to afford 3.90 mg of 25 (74% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 14.80 (s, 1H), 7.48 (s, 1H), 5.25 (d, J = 4.2 Hz, 1H), 4.86 (d, J = 4.1 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.66 (d, J = 13.9 Hz, 1H), 3.38 (d, J = 14.0 Hz, 1H), 3.05 (dd, J = 7.3, 5.1 Hz, 2H), 2.93 (d, J = 4.7 Hz, 1H), 2.74 (dt, J = 5.6, 4.1 Hz, 3H), 2.60 (d, J = 1.0 Hz, 3H), 2.10 (p, J = 6.3 Hz, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.53, 162.91, 151.31, 142.47, 141.47, 135.34, 130.50, 115.84, 113.28, 113.22, 111.15, 105.32, 101.90, 72.00, 69.44, 69.15, 60.95, 52.91, 47.77, 46.52, 38.84, 23.61, 22.12, 20.12. FTIR (neat), cm-1: 2951 (br s) 2104 (s), 1621 (s), 1572 (s), 1444 (s), 1399 (s). HRMS (ESI): Calcd for (C 24 H 23 N 3 O 8 +H) + 482.1558, found 482.1560. [00551] (2R,2'R,3a'R,13a'R)-2'-(Aminomethyl)-12'-hydroxy-7',13a'-dim ethoxy-5'-methyl- 3a',4',8',9',10',13a'-hexahydro-2'H,11'H-spiro[oxirane-2,1'- [2,4]epoxyfuro[3,2-b]naphtho[2,3- h]chromen]-11'-one (26). To a solution of 25 (1.05 mg, 2.18 μmol) in anhydrous THF (0.220 mL, 0.01 M) was added sequentially PPh 3 (1.72 mg, 6.54 μmol, 3.0 equiv.) and distilled water (0.393 μL, 0.022 mmol, 10 equiv.). The resulting solution was stirred at 23 °C overnight. After stirring overnight (~18 h), the reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase preparatory LCMS (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to afford 0.70 mg of the 26 (71% yield, 2 steps) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 14.80 (s, 1H), 7.47 (s, 1H), 5.17 (d, J = 4.2 Hz, 1H), 4.82 (d, J = 4.1 Hz, 1H), 3.78 (m, 8H), 3.05 (dd, J = 7.2, 5.1 Hz, 2H), 2.91 (d, J = 4.6 Hz, 1H), 2.74 (t, J = 6.4 Hz, 2H), 2.65 (d, J = 4.7 Hz, 1H), 2.61 – 2.56 (s, 3H), 2.10 (p, J = 6.3 Hz, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.53, 162.96, 151.34, 142.43, 141.36, 135.27, 130.42, 115.74, 113.50, 113.31, 111.11, 102.20, 71.59, 69.44, 69.03, 60.95, 52.91, 47.49, 38.85, 23.60, 22.12, 20.15. FTIR (neat), cm-1: 2951 (br s) 2855 (s), 1713 (s), 1570 (s), 1506 (s), 1444 (s). HRMS (ESI): Calcd for (C 24 H 25 NO 8 +H) + 456.1653, found 456.1649. [00552] (2R,2'R,3a'R,13a'R)-2'-(((1-Benzyl-1H-1,2,3-triazol-4-yl)met hoxy)methyl)-12'- hydroxy-7',13a'-dimethoxy-5'-methyl-3a',4',8',9',10',13a'-he xahydro-2'H,11'H-spiro[oxirane- 2,1'-[2,4]epoxyfuro[3,2-b]naphtho[2,3-h]chromen]-11'-one (27). To a solution of benzyl azide (0.051 mL, 0.404 mmol, 200 equiv.) and 24 (1.00 mg, 2.02 μmol) in anhydrous CH 2 Cl 2 (0.200 mL) was added an anhydrous CH 2 Cl 2 solution (0.200 mL, 0.005 M resultant solution) containing CuI (0.015 g, 0.081 mmol, 40 equiv.), DIPEA (0.028 mL, 0.162 mmol, 80 equiv.), and AcOH (9.26 μL, 0.162 mmol, 80 equiv.). The resulting mixture was stirred at 23 °C overnight. After stirring at 23 °C overnight (~18 h), the reaction mixture was partitioned between sat. aq. NaHCO 3 (5 mL) and CH 2 Cl 2 (5 mL). The aqueous layer was then extracted with CH 2 Cl 2 . The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse phase preparatory LCMS (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to afford 1.27 mg of 27 (quant. yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 14.80 (s, 1H), 7.58 – 7.31 (m, 7H), 5.51 (s, 2H), 5.18 (d, J = 4.2 Hz, 1H), 4.82 – 4.63 (m, 3H), 3.90 – 3.77 (m, 5H), 3.73 (s, 3H), 3.05 (td, J = 5.8, 2.6 Hz, 2H), 2.86 (d, J = 5.2 Hz, 1H), 2.74 (dd, J = 11.3, 5.8 Hz, 3H), 2.57 (s, 3H), 2.09 (p, J = 6.3 Hz, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.50, 162.98, 151.41, 144.99, 142.41, 141.61, 135.25, 134.53, 130.33, 129.13, 128.78, 128.13, 122.61, 115.68, 113.43, 111.06, 104.93, 102.03, 71.58, 69.24, 65.69, 65.17, 60.94, 54.19, 52.86, 48.08, 38.85, 31.84, 29.21, 23.60, 22.67, 22.13. FTIR (neat), cm- 1: 2927 (br s) 1749 (s), 1699 (s), 1621 (s), 1399 (s), 1208 (s). [00553] (2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-(((2R,13a'R)-12'-hydrox y-7',13a'- dimethoxy-5'-methyl-11'-oxo-3a',8',9',10',11',13a'-hexahydro -2'H,4'H-spiro[oxirane-2,1'- [2,4]epoxyfuro[3,2-b]naphtho[2,3-h]chromen]-2'-yl)methoxy)te trahydro-2H-pyran-3,4,5-triyl triacetate (28). To a solution of 19 (5.00 mg, 11.0 μmol) and the trichloracetimidate sugar (0.054 g, 0.110 mmol, 10 equiv.) in anhydrous CH 2 Cl 2 (0.220 mL, 0.05 M) at -78 °C was added TfOH (0.10 μL, 1.10 μmol, 0.1 equiv.). The reaction mixture was maintained at -78 °C for 1 h. After 1 h, the reaction mixture was warmed to 23 °C and was then partitioned between sat. aq. NaHCO 3 (5 mL) and CH 2 Cl 2 (5 mL). The aqueous layer was then extracted with CH 2 Cl 2 . The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse phase preparatory LCMS (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to afford 3.30 mg of 28 (38% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 14.79 (s, 1H), 7.47 (s 1H), 5.23 – 5.11 (m, 2H), 5.06 (t, J = 9.7 Hz, 1H), 4.96 (dd, J = 9.5, 8.0 Hz, 1H), 4.80 (d, J = 4.1 Hz, 1H), 4.58 (d, J = 7.9 Hz, 1H), 4.36 – 4.02 (m, 3H), 3.93 (d, J = 11.0 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 3.05 (q, J = 5.5 Hz, 2H), 2.82 (d, J = 5.4 Hz, 1H), 2.73 (q, J = 6.0, 5.5 Hz, 3H), 2.59 (s, 3H), 2.13 – 2.07 (m, 5H), 2.03 (s, 3H), 2.01 (s, 3H), 1.98 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.53, 170.72, 170.28, 169.52, 169.41, 162.95, 151.35, 142.45, 141.57, 135.27, 130.37, 115.76, 113.40, 113.27, 111.08, 104.24, 102.13, 100.87, 72.79, 71.96, 71.47, 71.01, 69.44, 69.22, 68.22, 65.37, 61.86, 60.96, 52.84, 47.95, 38.85, 23.60, 22.13, 20.78, 20.67, 20.62, 20.26. FTIR (neat), cm-1: 2952 (s) 1756 (s), 1621 (s), 1572 (s), 1444 (s), 1387 (s). HRMS (ESI): Calcd for (C 38 H 42 O 18 +H) + 787.2444, found 787.2446. [00554] (2R,13a'R)-12'-Hydroxy-7',13a'-dimethoxy-5'-methyl-2'-((((2R ,3R,4S,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)met hyl)-3a',4',8',9',10',13a'- hexahydro-2'H,11'H-spiro[oxirane-2,1'-[2,4]epoxyfuro[3,2-b]n aphtho[2,3-h]chromen]-11'- one (29). To a 0 °C solution of 28 (3.00 mg, 3.81 μmol) in anhydrous methanol (0.953 mL) and acetonitrile (0.318 mL, resultant 0.003 M solution) was added in one portion LiOH (0.381 mL, 1M, 0.381 mmol, 100 equiv.). The reaction mixture was then vigorously stirred for 2 h at 0 °C. After 2 h, the reaction mixture was partitioned between 2:1 CH 2 Cl 2 :methanol (5 mL) and brine (5 mL). The residual LiOH was then quenched via addition of formic acid (0.022 mL, 0.572 mmol, 150 equiv.). The aqueous layer was then extracted with 2:1 CH 2 Cl 2 :methanol . The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse phase preparatory LCMS (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to afford 1.40 mg of 28 (60% yield) as a yellow solid. 1 H NMR (400 MHz, MeOD) δ 7.50 (s, 1H), 5.26 (dd, J = 4.4, 2.0 Hz, 1H), 5.02 (dd, J = 4.2, 1.3 Hz, 1H), 4.27 (d, J = 7.8 Hz, 1H), 4.17 (d, J = 11.5 Hz, 1H), 3.85 (d, J = 11.4 Hz, 2H), 3.79 (s, 3H), 3.71 (s, 3H), 3.69 – 3.61 (m, 1H), 3.29 – 3.20 (m, 2H), 3.19 – 3.11 (m, 1H), 3.07 (dt, J = 5.1, 3.5 Hz, 3H), 2.82 – 2.70 (m, 3H), 2.58 (d, J = 1.1 Hz, 3H), 2.08 (p, J = 6.4 Hz, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 209.03, 166.03, 154.95, 146.48, 145.68, 138.98, 134.56, 119.10, 117.86, 116.81, 114.67, 108.59, 107.29, 106.09, 80.63, 80.40, 77.49, 75.50, 74.02, 73.09, 72.95, 67.88, 65.17, 63.84, 55.51, 42.31, 27.06, 25.80, 22.62. FTIR (neat), cm-1: 3390 (br s) 2924 (s), 1730 (s), 1642 (s), 1623 (s), 1572 (s). HRMS (ESI): Calcd for (C 30 H 34 O 14 +H) + 619.2021, found 619.2023. [00555] (2S,3S,4R,6S)-4-Hydroxy-6-(((2R,13a'R)-12'-hydroxy-7',13a'-d imethoxy-5'-methyl- 11'-oxo-3a',8',9',10',11',13a'-hexahydro-2'H,4'H-spiro[oxira ne-2,1'-[2,4]epoxyfuro[3,2- b]naphtho[2,3-h]chromen]-2'-yl)methoxy)-2,4-dimethyltetrahyd ro-2H-pyran-3-yl acetate (30). To a suspension of 1-O-Acetyl Trioxacarcinose A (Prepared according to the procedures of Smaltz et. al., Organic Letters.2012; 14 (7): 1812–1815) (22.0 mg, 0.088 mmol, 2.0 equiv.), 19 (20.0 mg, 44.0 μmol), and crushed 4 Å mol. sieves (1 mg per micromole of 1-O-Acetyl Trioxacarcinose A) in anhydrous CH 2 Cl 2 (0.876 mL, 0.05 M) at -40 °C was added BF 3 •OEt 2 (5.55 μL, 44.0 μmol, 1.0 equiv.) in one portion. The solution changed color from green to red and was stirred at -40 °C for 5 minutes, at which point sat. aq. NaHCO 3 (1.0 mL) was rapidly added, restoring the solution’s original green color, and the reaction vessel was warmed to 23 °C. The reaction mixture was then partitioned between brine (5 mL) and CH 2 Cl 2 (5 mL). The aqueous layer was then extracted with CH 2 Cl 2 . The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash-column chromatography (40% EtOAc in Hexanes) to afford 23.0 mg of 30 (82% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 14.80 (s, 1H), 7.46 (s, 1H), 5.16 (d, J = 4.2 Hz, 1H), 4.99 (d, J = 3.5 Hz, 1H), 4.83 (d, J = 4.1 Hz, 1H), 4.72 (s, 1H), 4.46 – 4.37 (m, 1H), 4.32 (s, 1H), 4.01 (d, J = 11.1 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.68 (d, J = 11.1 Hz, 1H), 3.05 (q, J = 5.7 Hz, 2H), 2.89 (d, J = 5.0 Hz, 1H), 2.78 – 2.69 (m, 3H), 2.57 (d, J = 1.0 Hz, 3H), 2.13- 2.05 (m, 5H), 1.91 (dd, J = 14.5, 3.7 Hz, 1H), 1.72 (dt, J = 14.6, 1.4 Hz, 1H), 1.14 (d, J = 6.5 Hz, 3H), 1.08 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.55, 170.41, 162.92, 151.23, 142.46, 141.56, 135.30, 130.40, 115.83, 113.36, 113.21, 111.10, 104.53, 101.98, 98.00, 74.53, 71.93, 69.11, 68.60, 62.23, 61.62, 60.96, 52.92, 48.06, 38.85, 35.82, 30.97, 25.57, 23.60, 22.13, 20.92, 20.16, 16.66. FTIR (neat), cm-1: 3503 (s) 2935 (s), 1734 (s), 1621 (s), 1572 (s), 1446 (s). HRMS (ESI): Calcd for (C 33 H 38 O 13 +H) + 665.2205, found 665.2190. [00556] (2R,13a'R)-2'-((((2S,4R,5S,6S)-4,5-dihydroxy-4,6-dimethyltet rahydro-2H-pyran-2- yl)oxy)methyl)-12'-hydroxy-7',13a'-dimethoxy-5'-methyl-3a',4 ',8',9',10',13a'-hexahydro- 2'H,11'H-spiro[oxirane-2,1'-[2,4]epoxyfuro[3,2-b]naphtho[2,3 -h]chromen]-11'-one (31). To a 0 °C solution of 30 (23.0 mg, 0.036 mmol, 1.0 equiv) in 3:1 MeOH/MeCN (0.70 mL, 0.05 M) was added LiOH (86 mg, 3.6 mmol, 100 equiv). The reaction was stirred vigorously for 2 hours at 0 °C before it was partitioned between 2:1 CH 2 Cl 2 /MeOH (5 mL) and brine (5 mL). The residual LiOH was quenched with the addition of formic acid (0.206 mL, 5.37 mmol, 150 equiv) and the aqueous layer was extracted with 2:1 CH 2 Cl 2 /MeOH. The organic layers were combined, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC-MS to afford 31 (21.0 mg, 23% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 14.80 (s, 1H), 7.45 (s, 1H), 5.16 (d, J = 4.1 Hz, 1H), 4.93 (d, J = 3.6 Hz, 1H), 4.82 (d, J = 4.2 Hz, 1H), 4.38 (q, J = 6.6 Hz, 1H), 4.00 (d, J = 11.1 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.67 (d, J = 11.1 Hz, 1H), 3.16 (s, 1H), 3.05 (q, J = 5.7 Hz, 2H), 2.89 (d, J = 5.0 Hz, 1H), 2.78 – 2.68 (m, 3H), 2.56 (s, 3H), 2.11 (q, J = 6.7 Hz, 2H), 1.91 (dd, J = 14.7, 3.8 Hz, 1H), 1.28 (s, 1H), 1.26 (s, 1H), 1.23 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.54, 162.93, 151.24, 142.45, 141.54, 135.29, 130.40, 115.80, 113.39, 113.22, 111.10, 104.55, 101.99, 98.04, 74.51, 71.94, 69.92, 69.12, 62.93, 61.66, 60.95, 53.45, 52.92, 48.06, 38.85, 35.03, 25.91, 23.60, 22.13, 20.18, 16.72. FTIR (neat), cm-1: 3498 (s), 2933 (s), 1621 (s), 1399 (s), 1234 (s), 1094 (s). HRMS (ESI): Calcd for (C 31 H 36 O 12 +H) + 623.2099, found 623.2085. [00557] (2S,2'S,3a'R,13a'R)-2'-(Bromomethyl)-12'-hydroxy-7',13a'-dim ethoxy-5'-methyl- 3a',4',8',9',10',13a'-hexahydro-2'H,11'H-spiro[oxirane-2,1'- [2,4]epoxyfuro[3,2-b]naphtho[2,3- h]chromen]-11'-one (32). To a solution of 19 (5.00 mg, 11.0 μmol) in anhydrous CH 2 Cl 2 (0.220 mL, 0.05 M) was added triethylamine (0.015 mL, 0.110 mmol, 10 equiv.). The reaction mixture was cooled to -20 °C and triflic anhydride (10.0 μL, 0.055 mmol, 5.0 equiv.) was added in one portion. The reaction mixture was then stirred at 0 °C for 1 h. After 1 h, the reaction mixture was warmed to 23 °C and partitioned between brine (5 mL) and CH 2 Cl 2 (5 mL). The aqueous layer was then extracted with CH 2 Cl 2 . The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was then dissolved in anhydrous DMF (0.220 mL, 0.05 M) and magnesium bromide etherate (28.0 mg, 0.110 mmol, 10 equiv.) was added in one portion. The reaction mixture was then let to stir at 23 °C overnight. After stirring at 23 °C overnight (~18 h), the reaction mixture was partitioned between sat. aq. NaHCO 3 (5 mL) and CH 2 Cl 2 (5 mL). The aqueous layer was then extracted with CH 2 Cl 2 . The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse phase preparatory LCMS (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to afford 1.10 mg of 32 (20% yield, 2 steps) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 14.80 (s, 1H), 7.48 (s, 1H), 5.24 (d, J = 4.2 Hz, 1H), 4.86 (d, J = 4.2 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.69 (d, J = 12.2 Hz, 1H), 3.37 (d, J = 12.2 Hz, 1H), 3.06 (q, J = 6.4 Hz, 3H), 2.94 (d, J = 4.6 Hz, 1H), 2.79 – 2.69 (m, 3H), 2.60 (d, J = 0.9 Hz, 3H), 2.10 (p, J = 6.6 Hz, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.54, 190.95, 162.93, 151.37, 142.44, 141.50, 140.55, 135.32, 130.50, 115.86, 113.25, 111.13, 103.95, 102.30, 71.76, 69.67, 69.28, 60.96, 52.89, 47.92, 41.06, 38.85, 26.08, 24.35. FTIR (neat), cm- 1: 2955 (s) 1681 (s), 1621 (s), 1572 (s), 1444 (s), 1389 (s). HRMS (ESI): Calcd for (C 24 H 23 BrO 8 +H) + 519.0649, found 519.0654. [00558] S-(((2S,2'S,3a'R,13a'R)-12'-hydroxy-7',13a'-dimethoxy-5'-met hyl-11'-oxo- 3a',8',9',10',11',13a'-hexahydro-2'H,4'H-spiro[oxirane-2,1'- [2,4]epoxyfuro[3,2-b]naphtho[2,3- h]chromen]-2'-yl)methyl)ethanethioate (33). To begin, DIAD (8.63 μL, 0.044 mmol, 4 equiv.) was added in one portion to a 0 °C solution of PPh 3 (0.011 g, 0.044 mmol, 4 equiv.) in anhydrous THF (0.220 mL, 0.05 M). The resulting solution was stirred for 10 minutes at 0 °C after which a yellow precipitate formed. To a 23 °C solution of 19 (5.00 mg, 11.0 μmol) and thioacetic acid (4.63 μL, 0.066 mmol, 6 equiv.) in anhydrous THF (0.220 mL, 0.05 M) was then added the PPh 3 /DIAD solution in one portion. The yellow precipitate clarified and the resulting homogenous solution was stirred at 23 °C for 72 h. After stirring at 23 °C for 72 h, the reaction mixture was partitioned between sat. aq. NaHCO 3 (5 mL) and CH 2 Cl 2 (5 mL). The aqueous layer was then extracted with CH 2 Cl 2 . The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse phase preparatory LCMS (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to afford the desired compound alongside the thioacetate opened-epoxide and residual triphenylphosphine oxide. This combination of material was then purified by flash-column chromatography (10% EtOAc in Hexanes eluting to 30% EtOAc in Hexanes) to afford 2.60 mg of 33 (46% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 14.79 (s, 1H), 7.46 (s, 1H), 5.15 (d, J = 4.2 Hz, 1H), 4.79 (d, J = 4.1 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.42 – 3.33 (d, J = 14.8 Hz, 1H), 3.21 (d, J = 14.8 Hz, 1H), 3.05 (dd, J = 7.3, 4.9 Hz, 2H), 2.92 (d, J = 4.6 Hz, 1H), 2.77 – 2.67 (m, 3H), 2.56 (s, 3H), 2.38 (s, 3H), 2.18 – 2.02 (m, J = 6.8 Hz, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.51, 193.85, 162.95, 151.34, 142.42, 141.47, 135.26, 130.41, 115.71, 113.38, 111.10, 105.37, 102.03, 71.71, 69.51, 69.36, 60.94, 52.89, 47.30, 38.85, 30.34, 29.73, 25.11, 23.60, 22.12, 20.20. FTIR (neat), cm-1: 2923 (s) 2852 (s), 1698 (s), 1698 (s), 1623 (s), 1446 (s). [00559] (2S,2'S,3a'R,13a'R)-12'-hydroxy-2'-(mercaptomethyl)-7',13a'- dimethoxy-5'-methyl- 3a',4',8',9',10',13a'-hexahydro-2'H,11'H-spiro[oxirane-2,1'- [2,4]epoxyfuro[3,2-b]naphtho[2,3- h]chromen]-11'-one (34). To a 0 °C solution of 33 (2.60 mg, 5.05 μmol) in anhydrous methanol (1.263 mL) and acetonitrile (0.421 mL, resultant 0.003 M solution) was added in one portion LiOH (0.505 mL, 1M, 0.505 mmol, 100 equiv.). The reaction mixture was then vigorously stirred for 2 h at 0 °C. After 2 h, the reaction mixture was partitioned between CH 2 Cl 2 (5 mL) and brine (5 mL). The residual LiOH was then quenched via addition of formic acid (0.029 mL, 0.758 mmol, 150 equiv.). The aqueous layer was then extracted with CH 2 Cl 2 . The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse phase preparatory LCMS (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to afford 0.90 mg of 34 (38% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 14.80 (s, 1H), 7.47 (s, 1H), 5.21 (d, J = 4.2 Hz, 1H), 4.83 (d, J = 4.2 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.09 – 2.98 (m, 3H), 2.92 (d, J = 4.8 Hz, 1H), 2.79 (d, J = 4.8 Hz, 1H), 2.75 – 2.66 (m, 3H), 2.60 (d, J = 0.9 Hz, 3H), 2.10 (t, J = 6.2 Hz, 2H). [00560] ((2R,2'R,3a'S,4'S,13a'R)-12'-hydroxy-7',13a'-dimethoxy-5'-me thyl-11'-oxo- 3a',8',9',10',11',13a'-hexahydro-2'H,4'H-spiro[oxirane-2,1'- [2,4]epoxyfuro[3,2-b]naphtho[2,3- h]chromen]-2'-yl)methyl dihydrogen phosphate (35). To a flame-dried vial charged with 19 and a stir bar was added anhydrous THF (0.4 mL). The reaction mixture was cooled to -40 ºC and the phosphoryl dichloride was added in one portion. The reaction was allowed to warm to 0 ºC over 4 hours, then partitioned between 2:1 CH 2 Cl 2 :methanol (5 mL) and brine (5 mL). The aqueous layer was extracted with further 2:1 CH 2 Cl 2 :methanol (5 mL) and the combined organic layers were concentrated under reduced pressure. The crude residue was purified by reverse phase preparatory LCMS (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to afford 1.0 mg of 35 (17% yield) as an orange oil. 1 H NMR (400 MHz, CDCl 3 ) δ 14.80 (s, 1H), 7.47 (s, 1H), 5.21 (d, J = 4.1 Hz, 1H), 4.84 (d, J = 4.1 Hz, 1H), 4.37 (dd, J = 11.9, 7.1 Hz, 1H), 4.24 (dd, J = 11.9, 6.6 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.05 (dd, J = 7.3, 5.1 Hz, 2H), 2.91 (d, J = 4.8 Hz, 1H), 2.80 – 2.68 (m, 3H), 2.58 (s, 3H), 2.10 (p, J = 6.2 Hz, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.69, 163.05, 151.45, 142.58, 141.53, 135.44, 130.64, 115.92, 113.37, 111.28, 103.95, 102.08, 72.10, 69.49, 69.31, 62.16, 61.09, 54.72, 53.05, 48.02, 38.98, 23.74, 22.25, 20.25. 31 P NMR (162 MHz, CDCl 3 ) δ 0.95. FTIR (neat), cm-1: 2956 (s) 1621 (s), 1572 (s), 1446 (s), 1389 (s), 1349 (s). HRMS (ESI): Calcd for (C 24 H 25 PO 12 +H) + 537.1156, found 537.1172. [00561] (2S,3R,4S,5S,6S)-2-(2-Azido-4-((((((2R,2'R,3a'R,4'S,13a'R)-1 2'-hydroxy-7',13a'- dimethoxy-5'-methyl-11'-oxo-3a',8',9',10',11',13a'-hexahydro -2'H,4'H-spiro[oxirane-2,1'- [2,4]epoxyfuro[3,2-b]naphtho[2,3-h]chromen]-2'- yl)methoxy)carbonyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)t etrahydro-2H-pyran-3,4,5- triyl triacetate (37). To a solution of 36 (21.2 mg, 33.0 µmol, 1.0 equiv.) and 19 (5.00 mg, 11.0 µmol, 1.0 equiv.) in dimethylformamide (60.9 μL) and tetrahydrofuran (60.9 µL) was added sodium hydride (0.394 mg, 16.0 µmol, 1.5 equiv.) at 23 ̊C. The reaction mixture was stirred for 3 h, until LCMS analysis indicated full consumption of the starting material. The crude residue was purified by reverse phase preparatory LCMS (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to afford 5.20 mg of 37 (49% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 14.79 (s, 1H), 7.46 (s, 1H), 7.09 (d, J = 1.3 Hz, 2H), 7.05 (s, 1H), 5.37 – 5.25 (m, 3H), 5.19 (d, J = 4.1 Hz, 1H), 5.10 – 5.08 (m, 3H), 4.83 (d, J = 4.1 Hz, 1H), 4.53 (d, J = 12.4 Hz, 1H), 4.35 (d, J = 12.4 Hz, 1H), 4.19 – 4.07 (m, 1H), 3.79 (s, 3H), 3.74 (s, 3H), 3.74 (s, 3H), 3.05 (t, J = 5.7 Hz, 2H), 2.91 (d, J = 4.8 Hz, 1H), 2.75 – 2.73 (m, 3H), 2.55 (s, 3H), 2.14 – 2.10 (m, 2H), 2.09 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.66, 170.28, 169.48, 169.35, 166.85, 163.05, 154.55, 151.47, 148.70, 142.56, 141.61, 135.43, 131.84, 130.82, 130.61, 125.96, 121.01, 118.92, 115.91, 111.38, 113.30, 111.26, 103.87, 102.03, 100.05, 72.79, 72.01, 71.86, 70.94, 69.49, 69.32, 69.10, 62.07, 61.08, 53.19, 53.04, 47.92, 38.98, 29.85, 23.73, 22.25, 20.78, 20.67, 20.29, 1.17. FTIR (neat), cm-1: 2955.74 (w), 2120.14 (m), 1757.58 (vs), 1621.62 (m), 1572.05 (w), 1508.32 (w), 1443.17 (w), 1355.36 (m), 1374.32 (m), 1226.48 (vs), 1181.16 (w), 1093.63 (m), 1069.28 (m), 1038.12 (m), 982.89 (m), 953.14 (w), 913.49 (w), 787.44 (w). HRMS (ESI): Calcd for (C 45 H 45 N 3 O 21 +H) + 964.2618, found 964.2607. [00562] (2S,3R,4S,5S,6S)-2-(2-Azido-4-((((((2R,2'R,3a'R,4'S,13a'R)-1 2'-hydroxy-7',13a'- dimethoxy-5'-methyl-11'-oxo-3a',8',9',10',11',13a'-hexahydro -2'H,4'H-spiro[oxirane-2,1'- [2,4]epoxyfuro[3,2-b]naphtho[2,3-h]chromen]-2'- yl)methyl)carbamoyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)t etrahydro-2H-pyran-3,4,5- triyl triacetate (38). To a solution of PNP-carbonate 36 (21.3 mg, 0.033 mmol, 3.0 equiv.) in dimethylformamide (61.0 μL) was added N,N-diisopropylethylamine (19.1 μL, 0.110 mmol, 10 equiv.) at 23̊C. Amine 26 (5.00 mg, 11.0 μmol, 1.0 equiv.) in dimethylformamide (61.0 μL) was added dropwise to the solution and stirred for 30 min. The reaction solution was diluted with dry dimethylformamide to a total volume of 900 µL and purified directly by preparatory HPLC (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to provide drug-linker 38 as a yellow solid (2.10 mg, 20%). 1 H NMR (400 MHz, CDCl 3 ) δ 14.80 (s, 1H), 7.47 (s, 1H), 7.10 (d, J = 2.0 Hz, 2H), 7.06 (s, 1H), 5.36 – 5.23 (m, 3H), 5.15 (d, J = 4.1 Hz, 1H), 5.08 (d, J = 7.1 Hz, 1H), 5.05 (s, 2H), 4.81 (d, J = 4.2 Hz, 1H), 4.18 – 4.09 (m, 1H), 3.79 (s, 3H), 3.74 (s, 6H), 3.56 (d, J = 5.7 Hz, 2H), 3.05 (t, J = 6.1 Hz, 2H), 2.92 (d, J = 4.6 Hz, 1H), 2.74 (t, J = 6.3 Hz, 2H), 2.67 – 2.61 (m, 1H), 2.55 (s, 3H), 2.12 – 2.08 (m, 5H), 2.05 (s, 3H), 2.04 (s, 3H). [00563] (2S,3S,4S,5R,6S)-6-(2-(4-(13-(2,5-Dioxo-2,5-dihydro-1H-pyrro l-1-yl)-2,5,8,11- tetraoxatridecyl)-1H-1,2,3-triazol-1-yl)-4-((((((2R,2'R,3a'R ,4'S,13a'R)-12'-hydroxy-7',13a'- dimethoxy-5'-methyl-11'-oxo-3a',8',9',10',11',13a'-hexahydro -2'H,4'H-spiro[oxirane-2,1'- [2,4]epoxyfuro[3,2-b]naphtho[2,3-h]chromen]-2'- yl)methyl)carbamoyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetr ahydro-2H-pyran-2- carboxylic acid (39). Protected glucuronic ester linker 38 (2.00 mg, 2.08 μmol, 1.0 equiv.) was dissolved in methanol (519 µL) and acetonitrile (173 µL) at 23̊C and the solution was purged with nitrogen for 5 min. The solution was cooled to 0̊C in an ice bath and a 0.4 M aqueous lithium hydroxide solution (519 µL, 0.208 mmol, 100 equiv.) was added dropwise. The yellow reaction mixture was stirred vigorously at 0̊C for 2 h. Upon complete saponification of the glucuronide esters, the reaction was diluted with 2:1 dichloromethane– methanol (1.5 mL) and saturated aqueous sodium chloride solution (1 mL) then quenched by the addition of formic acid (11.8 µL, 0.312 mmol, 150 equiv.) at 0 ̊C. The mixture was stirred for 5 min, then transferred to a separatory funnel. The funnel was shaken vigorously and the layers were separated. The aqueous layer (now pH ~4.5–5 or adjusted to this pH by further addition of formic acid) was extracted with 2:1 dichloromethane–methanol (3 × 1 mL). The combined organic layers were dried by filtration through a plug of sodium sulfate and the filtrate was concentrated to provide glucuronic acid intermediate as a yellow solid. The crude material was taken forward without further purification assuming quantitative conversion. The intermediate (crude from previous reaction, assuming 1.71 mg, 2.08 μmol, 1.00 equiv.) and Mal-PEG4-alkyne (1.26 μL, 6.24 μmol, 3.00 equiv.) were dissolved in 4:1 water/DMSO (692 µL) at 23 ̊C. A pre-mixed solution of 0.1 M aqueous cupric sulfate (5.20 μL, 0.520 μmol, 0.25 equiv.) and 0.05 M THPTA (52.0 μL, 2.60 µmol, 1.25 equiv.) was added, followed by a 2.0 M aqueous sodium ascorbate solution (5.20 μL, 10.4 µmol, 5.00 equiv.). The reaction mixture was stirred vigorously for 7 h, at which point LCMS analysis indicated complete conversion to product. The reaction mixture was diluted with 2:1 dichloromethane– methanol (2 mL) and saturated aqueous sodium chloride solution (1.5 mL). The pH of the aqueous layer was adjusted to ~4.5–5 by addition of formic acid, then the layers were shaken and separated. The aqueous layer was extracted with 2:1 dichloromethane–methanol (3 × 1.5 mL) and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate concentrated. The residue was purified by preparatory HPLC (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to provide drug- linker 39 as a yellow solid. HRMS (ESI): Calcd for (C 53 H 59 N 5 O 23 +H) + 1134.3674, found 1134.3668. [00564] 4-azidobenzyl(((2R,2'R,3a'S,4'R)-12'-hydroxy-7',13a'-dimetho xy-5'-methyl-11'- oxo-3a',8',9',10',11',13a'-hexahydro-2'H,4'H-spiro[oxirane-2 ,1'-[2,4]epoxyfuro[3,2- b]naphtho[2,3-h]chromen]-2'-yl)methyl)carbamate (40). To a solution of 26 (22.5 mg, 0.049 mmol) in anhydrous DMF (1.5 mL, 0.033 M) was added DIPEA (0.086 mL, 0.494 mmol, 10 equiv.) followed by the mixed carbonate (78.0 mg, 0.247 mmol, 5 equiv.). The reaction mixture was stirred at 23 ̊C overnight. The next day (~18 h), the reaction mixture was diluted with DMF to a total volume of 1.8 mL and and purified directly by preparatory HPLC (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to provide carbamate 40 as a yellow solid (12.9 mg, 41% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 14.80 (s, 1H), 7.46 (s, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 8.5 Hz, 2H), 5.14 (d, J = 4.2 Hz, 1H), 5.09 (s, 2H), 4.81 (d, J = 4.2 Hz, 1H), 3.79 (s, 3H), 3.74 (s, 3H), 3.56 (d, J = 5.8 Hz, 2H), 3.09 – 3.01 (m, 2H), 2.92 (d, J = 4.6 Hz, 1H), 2.74 (t, J = 6.4 Hz, 2H), 2.65 (d, J = 4.5 Hz, 1H), 2.55 (s, 3H), 2.09 (p, J = 6.2 Hz, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.54, 162.92, 154.94, 151.32, 142.44, 141.32, 140.47, 135.29, 131.76, 130.15, 129.91, 119.19, 119.11, 115.76, 113.27, 113.23, 111.14, 104.87, 101.94, 71.73, 69.39, 69.17, 68.99, 66.40, 60.95, 52.90, 47.36, 38.84, 37.58, 23.61, 22.11, 20.15. FTIR (neat), cm-1: 2958 (s) 2110 (s), 1725 (s), 1618 (s), 1570 (s), 1508 (s). HRMS (ESI): Calcd for (C 32 H 30 N 4 O 10 +Na) + 653.1854, found 653.1836. [00565] 4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)- 3- methylbutanamido)propanamido)benzyl (((2R,2'R,3a'S,4'R)-12'-hydroxy-7',13a'-dimethoxy- 5'-methyl-11'-oxo-3a',8',9',10',11',13a'-hexahydro-2'H,4'H-s piro[oxirane-2,1'- [2,4]epoxyfuro[3,2-b]naphtho[2,3-h]chromen]-2'-yl)methyl)car bamate (41). To a flame-dried round bottom flask charged with a magnetic stir bar was added carbamate 40 (12.9 mg, 0.020 mmol) as a solution in THF (0.818 mL) and water (0.205 mL, resultant soln.0.02 M). The dipeptide was added in one portion (0.027 g, 0.041 mmol, 2 equiv.) and the reaction mixture was stirred at 23 ̊C overnight. After 24 h, the reaction mixture was diluted with ethyl acetate and partitioned between sat. aq. brine and ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue by preparatory HPLC (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to provide 41 as a yellow solid (9.5 mg, 47% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 14.79 (s, 1H), 8.38 (s, 1H), 7.76 (d, J = 7.6 Hz, 2H), 7.54 (q, J = 6.9, 5.3 Hz, 4H), 7.46 (s, 1H), 7.40 (t, J = 7.5 Hz, 2H), 7.34 – 7.28 (m, 4H), 6.33 (s, 1H), 5.23 (s, 1H), 5.16 – 5.05 (m, 4H), 4.80 (d, J = 4.1 Hz, 1H), 4.70 – 4.60 (m, 1H), 4.48 (d, J = 6.6 Hz, 2H), 4.20 (t, J = 6.8 Hz, 1H), 3.97 (d, J = 6.9 Hz, 1H), 3.79 (s, 3H), 3.74 (s, 3H), 3.56 (t, J = 5.1 Hz, 1H), 3.05 (t, J = 6.1 Hz, 2H), 2.91 (dd, J = 5.2, 3.2 Hz, 1H), 2.73 (t, J = 6.4 Hz, 2H), 2.64 (d, J = 4.6 Hz, 1H), 2.55 (s, 3H), 2.13 – 2.06 (m, 2H), 1.56 (s, 1H), 1.45 (t, J = 6.4 Hz, 3H), 0.91 (s, 6H), 0.12 (d, J = 4.7 Hz, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.52, 171.61, 171.20, 169.66, 162.94, 156.74, 156.36, 151.32, 143.63, 143.57, 142.43, 141.41, 141.36, 135.28, 132.34, 130.45, 129.12, 128.48, 127.83, 127.70, 127.12, 124.91, 120.07, 119.80, 115.75, 113.28 (d, J = 2.3 Hz), 111.12, 104.89, 101.97, 71.70, 70.92, 69.36, 68.98, 67.03, 66.63, 60.95, 60.78, 60.43, 52.89, 49.57, 47.37, 47.20, 38.84, 37.53, 30.75, 29.72, 25.58, 23.60, 22.12, 21.09, 20.16, 19.21, 17.82, 17.14, 14.22. FTIR (neat), cm -1 : 3309 (br. s) 2931 (s), 1702 (s), 1648 (s), 1621 (s), 1545 (s). HRMS (ESI): Calcd for (C 55 H 56 N 4 O 14 +NH 4 ) + 1014.4131, found 1014.4104. [00566] 4-((17S,20S)-1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-17-iso propyl-20-methyl- 15,18-dioxo-3,6,9,12-tetraoxa-16,19-diazahenicosan-21-amido) benzyl (((2R,2’R,3a’S,4’R)- 12’-hydroxy-7’,13a’-dimethoxy-5’-methyl-11’-oxo-3a ’,8’,9’,10’,11’,13a’-hexahydro- 2’H,4’H-spiro[oxirane-2,1’-[2,4]epoxyfuro[3,2-b]naphth o[2,3-h]chromen]-2’- yl)methyl)carbamate (42). Carbamate 41 (9.50 mg, 9.53 μmol) was dissolved in methanol (3.18 mL) at 23̊C.1 M aqueous lithium hydroxide solution (0.953 mL, 0.953 mmol, 100 equiv.) was added dropwise. The yellow reaction mixture was stirred vigorously at 23 ̊C for 2 h. After 2 h, the reaction was diluted with dichloromethane and saturated aqueous sodium chloride solution and then quenched by the addition of formic acid (0.036 mL, 0.953 mmol, 100 equiv.). The mixture was then transferred to a separatory funnel. The funnel was shaken vigorously and the layers were separated. The aqueous layer was extracted with 2:1 dichloromethane–methanol (3 × 1 mL). The combined organic layers were dried by filtration through a plug of sodium sulfate and the filtrate was concentrated to provide the free amine as a yellow solid. The crude material was taken forward without further purification assuming quantitative conversion. HRMS (ESI): Calcd for (C 40 H 46 N 4 O 12 +NH 4 ) + 1014.4131, found 1014.4104. To a scintillation vial containing the crude free amine and a magnetic stir bar was added anhydrous DMF (0.476 mL, 0.02 M). To the solution was added DIPEA (10 μL, 0.057 mmol, 6 equiv.) and Mal-PEG4-NHS ester (7.4 mg, 0.057 mmol, 6 equiv.). The reaction mixture was allowed to stir at 23̊C overnight. After stirring overnight (~18 h), the reaction mixture was diluted to a total volume of 900 μL and purified directly by preparatory HPLC (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to provide drug-linker 42 as a yellow solid (4.7 mg, 45% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 14.79 (s, 1H), 8.57 (s, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.46 (s, 1H), 7.31 (d, J = 8.1 Hz, 2H), 6.98 (d, J = 16.6 Hz, 1H), 6.84 (s, 1H), 6.70 (s, 1H), 5.20 – 4.97 (m, 4H), 4.81 (d, J = 4.2 Hz, 1H), 4.66 (p, J = 7.2 Hz, 1H), 4.20 (t, J = 6.1 Hz, 1H), 3.79 (s, 3H), 3.74 (s, 3H), 3.65 – 3.52 (m, 18H), 3.04 (dt, J = 5.8, 3.5 Hz, 2H), 2.91 (d, J = 4.6 Hz, 1H), 2.73 (t, J = 6.3 Hz, 2H), 2.70 – 2.60 (m, 2H), 2.55 (s, 3H), 2.48 (ddd, J = 15.0, 5.8, 3.5 Hz, 1H), 2.14 – 2.06 (m, 2H), 1.63 (s, 3H), 1.45 (d, J = 7.1 Hz, 3H), 0.99 (dd, J = 12.2, 6.8 Hz, 6H), 0.07 (s, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.51, 188.27, 173.43, 171.52, 170.70, 162.94, 156.40, 151.32, 142.43, 141.46, 135.28, 134.20, 130.42, 129.00, 119.84, 115.74, 114.69, 114.67, 113.32, 113.26, 111.11, 104.90, 101.99, 71.68, 70.61, 70.48, 70.46, 70.41, 70.19, 69.98, 69.35, 68.98, 67.81, 66.75, 61.24, 60.95, 52.89, 49.40, 47.38, 41.05, 38.85, 37.49, 37.21, 37.19, 37.10, 29.50, 26.07, 23.60, 22.12, 21.25, 20.18, 19.43, 17.89, 17.26, 1.04. FTIR (neat), cm -1 : 3306 (br. s) 2930 (s), 1708 (s), 1621 (s), 1535 (s), 1444 (s). HRMS (ESI): Calcd for (C 55 H 67 N 5 O 19 +Na) + 1124.4322, found 1124.4297. [00567] (2R,2'R,3a'R,4'S,13a'R)-12'-hydroxy-7',13a'-dimethoxy-2'-(me thoxymethyl)-5'- methyl-3a',4',8',9',10',13a'-hexahydro-2'H,11'H-spiro[oxiran e-2,1'-[2,4]epoxyfuro[3,2- b]naphtho[2,3-h]chromen]-11'-one (43). In a flame-dried flask, to a 0 °C suspension of sodium hydride (5 eq., 0.110 mmol, 2.6 mg) in anhydrous THF (0.22 mL) was slowly added a solution of 19 (0.022 mmol, 10.0 mg) in anhydrous THF (0.22 mL). After the addition was complete, the mixture was allowed to stir at rt for 2 h before the dropwise addition of methyl iodide (10 eq., 0.220 mmol, 31.0 mg). After stirring overnight, the suspension was partitioned between EtOAc and sat. aq. NH 4 Cl solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via HPLC to afford 43 (8.0 mg, 78% yield) as a yellow-green solid. 1 H NMR (400 MHz, CDCl 3 ) δ 14.80 (s, 1H), 7.45 (s, J = 1.0 Hz, 1H), 5.22 (d, J = 4.2 Hz, 1H), 4.81 (d, J = 4.2 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 1H), 3.75 (s, 3H), 3.72 (s, 1H), 3.43 (s, 3H), 3.05 (ddd, J = 2.9 Hz, 2H), 2.90 (d, J = 5.2 Hz, 1H), 2.79 (d, J = 5.2 Hz, 1H), 2.73 (dd, J = 7.1, 5.8 Hz, 2H), 2.60 (s, J = 0.9 Hz, 3H), 2.13 – 2.06 (m, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.47, 163.02, 151.44, 142.43, 141.68, 135.25, 130.30, 115.66, 113.50, 113.29, 111.06, 104.89, 102.05, 71.69, 69.26, 69.22, 67.49, 60.92, 60.31, 52.86, 48.13, 38.84, 23.60, 22.12, 20.31. HRMS (ESI): Calcd for (C 25 H 26 O 9 +H) + 471.1650, found 471.1651. [00568] O-(((2R,2'R,3a'S,4'S)-12'-hydroxy-7',13a'-dimethoxy-5'-methy l-11'-oxo- 3a',8',9',10',11',13a'-hexahydro-2'H,4'H-spiro[oxirane-2,1'- [2,4]epoxyfuro[3,2-b]naphtho[2,3- h]chromen]-2'-yl)methyl) 1H-imidazole-1-carbothioate (44).19 (35 mg, 1 Eq, 77 µmol) was added to a flame-dried vial equipped with a stir bar. DCM (0.38 mL) was added, followed by Di-1H-imidazol-1-ylmethanethione (16 mg, 1.2 Eq, 92 µmol). The vial was wrapped in aluminum foil and stirred at RT for 16 hours. The reaction was then quenched with sat. aq ammonium chloride (0.5 mL), extracted with DCM (3 x 0.5 mL), washed with brine (0.5 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by FCC (25 to 45% EtOAc in Hexanes) to afford 44 (24 mg, 42 µmol, 55 %) as a bright yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 14.81 (s, 1H), 8.36 (s, 1H), 7.66 (t, J = 1.5 Hz, 1H), 7.49 (s, 1H), 7.05 (s, 1H), 5.23 (d, J = 4.1 Hz, 1H), 4.95 – 4.86 (m, 2H), 4.83 (d, J = 12.7 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.10 – 3.02 (m, 2H), 2.98 (d, J = 4.5 Hz, 1H), 2.78 – 2.69 (m, 3H), 2.58 (d, J = 0.9 Hz, 3H), 2.14 – 2.02 (m, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.6, 183.4, 162.9, 151.3, 142.5, 141.3, 136.9, 135.4, 131.0, 130.6, 118.3, 115.9, 113.3, 113.0, 111.2, 103.8, 101.8, 72.1, 69.6, 69.2, 65.9, 61.0, 53.0, 47.6, 38.8, 23.6, 22.1, 20.1. HRMS (ESI): Calcd for (C 28 H 26 N 2 O 9 S+H) + 567.1432, found 567.1432. [00569] (2R,2'R,3a'S,4'S)-12'-hydroxy-7',13a'-dimethoxy-2',5'-dimeth yl-3a',4',8',9',10',13a'- hexahydro-2'H,11'H-spiro[oxirane-2,1'-[2,4]epoxyfuro[3,2-b]n aphtho[2,3-h]chromen]-11'- one (45).44 (4.00 mg, 1 Eq, 7.06 μmol) was added to a microwave vial. Tributyltin hydride (4.11 mg, 3.82 μL, 2 Eq, 14.1 μmol) and 2,2'-Azobisisobutyronitrile (174 μg, 215 nL, 0.15 Eq, 1.06 μmol) were dissolved in Toluene (200 µL) and added to the vial. It was then heated to 110 °C for 3 hours, after which the reaction was cooled down to RT and the solvent removed under reduced presure. The crude residue was purified by reverse phase preparatory LCMS (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to afford 45 (0.300 mg, 0.681 μmol, 9.65 %) as a yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 14.80 (s, 1H), 7.46 (d, J = 1.0 Hz, 1H), 5.13 (d, J = 4.2 Hz, 1H), 4.76 (d, J = 4.2 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.05 (dd, J = 7.2, 5.1 Hz, 2H), 2.91 (d, J = 4.8 Hz, 1H), 2.73 (t, J = 6.4 Hz, 2H), 2.60 – 2.55 (m, 4H), 2.14 – 2.05 (m, 2H), 1.42 (s, 3H). HRMS (ESI): Calcd for (C 24 H 24 O 8 +H) + 441.1544, found 441.1544. [00570] (2S,3R,4S,5S,6S)-2-(2-azido-4-((((((1R,13aR)-1-(bromomethyl) -1,12-dihydroxy- 7,13a-dimethoxy-5-methyl-11-oxo-1,3a,4,8,9,10,11,13a-octahyd ro-2H-2,4-epoxyfuro[3,2- b]naphtho[2,3-h]chromen-2-yl)methyl)carbamoyl)oxy)methyl)phe noxy)-6- (methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (46). To a solution of 38 (8.1 mg, 8.41 μmol) in anhydrous acetonitrile (0.841 mL, 0.01 M) was added lithium bromide (0.022 g, 0.252 mmol, 30 equiv.) followed by cerium trichloride heptahydrate (9.40 mg, 0.025 mmol, 3.0 equiv.). The reaction mixture was then wrapped in aluminum foil to exclude light and stirred at 23 °C overnight. After stirring overnight (~18 h), the reaction mixture was partitioned between sat. aq. sodium sulfite solution (5 mL) and EtOAc (5 mL). The aqueous layer was then extracted with EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparatory LCMS (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to afford 7.9 mg (90% yield) of 46 as a yellow solid. [00571] (2S,3R,4S,5S,6S)-2-(2-azido-4-((((((1R,13aR)-1-(bromomethyl) -12-hydroxy-7,13a- dimethoxy-5-methyl-1-(((2-(methylsulfonyl)ethyl)(((4-(((2S,3 R,4S,5S,6S)-3,4,5-triacetoxy-6- (methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)benzyl)oxy)car bonyl)amino)methoxy)-11- oxo-1,3a,4,8,9,10,11,13a-octahydro-2H-2,4-epoxyfuro[3,2-b]na phtho[2,3-h]chromen-2- yl)methyl)carbamoyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)t etrahydro-2H-pyran-3,4,5- triyl triacetate (48). To begin, lithium bromide (3.94 mg, 0.045 mmol, 6 equiv.) was added to a flame-dried reaction vessel. Carbamate 46 was dissolved in anhydrous 1,2-dichloroethane (0.378 mL) and then transferred to the reaction vessel. Next, methyl sulfone (0.024 g, 0.151 mmol, 20 equiv.) 47 as a solution in anhydrous 1,2-dichloroethane (0.378 mL) and 1,2,2,6,6- pentamethylpiperidine were added simultaneously to the reaction mixture. The reaction mixture was then heated to 40 o C and maintained at that temperature for 2 h. After 2 h, the reaction was cooled to room temperature and allowed to stir at rt overnight. After stirring overnight (~18 h), the reaction mixture was concentrated and the residue was resuspended in 900 μL of DMF and purified directly by preparatory HPLC (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to provide protected glucuronic ester linker 48 as a yellow solid (1.2 mg, 5% yield). [00572] (2S,3S,4S,5R,6S)-6-(4-((((((1R,13aR)-1-(bromomethyl)-1-((((( 4- (((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-p yran-2- yl)oxy)benzyl)oxy)carbonyl)(2-(methylsulfonyl)ethyl)amino)me thoxy)-12-hydroxy-7,13a- dimethoxy-5-methyl-11-oxo-1,3a,4,8,9,10,11,13a-octahydro-2H- 2,4-epoxyfuro[3,2- b]naphtho[2,3-h]chromen-2-yl)methyl)carbamoyl)oxy)methyl)-2- (4-(13-(2,5-dioxo-2,5- dihydro-1H-pyrrol-1-yl)-2,5,8,11-tetraoxatridecyl)-1H-1,2,3- triazol-1-yl)phenoxy)-3,4,5- trihydroxytetrahydro-2H-pyran-2-carboxylic acid (49). Protected glucuronic ester linker 48 (0.6 mg, 0.365 μmol) was dissolved in methanol (0.912 mL) and acetonitrile (0.304 mL, 0.0003 M) at room temperature and the solution was purged with nitrogen for 5 minutes. After 5 minutes, the reaction mixture was cooled to 0 o C in an ice bath and lithium hydroxide (0.365 mL, 1 M, 1000 equiv.) was added dropwise. The yellow reaction mixture was stirred vigorously at 0 o C for 2 h. After 2 h, formic acid (0.014 mL, 0.383 mmol, 1050 equiv.) was added and the reaction mixture was filtered through celite, washing with additional methanol. The filtrate was then concentrated to afford a thin off-white/yellow film which was taken forward without further purification assuming quantitative conversion. [00573] Next, the crude product was transferred to a flame-dried vial charged with a magnetic stir bar. To the vial was added DMSO (0.203 mL), water (1.00 mL, 0.3 mM), and Mal-PEG4-alkyne (6.81 mg, 21.9 μmol, 60 equiv.) in that order. To the reaction flask was then added aqueous copper (II) sulfate (18.2 μL, 0.1 M, 1.82 μmol, 5 equiv.), THPTA (0.498 mg, 0.365 μmol, 1 equiv.), and aqueous sodium ascorbate (18.2 μL, 2 M, 36.5 μmol, 100 equiv.) in that order. The reaction mixture was then stirred vigorously at rt for 7 h. After 7 h, the reaction mixture was concentrated under reduced pressure and the residue was resuspended in 900 μL of DMF and purified directly by preparatory HPLC (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to provide drug-linker 49 as a yellow solid (0.6 mg, quant. yield). [00574] 4-azidobenzyl(((2R,2'R,3a'S,4'R)-12'-hydroxy-7',13a'-dimetho xy-5'-methyl-11'- oxo-3a',8',9',10',11',13a'-hexahydro-2'H,4'H-spiro[oxirane-2 ,1'-[2,4]epoxyfuro[3,2- b]naphtho[2,3-h]chromen]-2'-yl)methyl)carbamate (50). To a solution of 26 (22.5 mg, 0.049 mmol) in anhydrous DMF (1.5 mL, 0.033 M) was added DIPEA (0.086 mL, 0.494 mmol, 10 equiv.) followed by the mixed carbonate (78.0 mg, 0.247 mmol, 5 equiv.). The reaction mixture was stirred at 23 ̊C overnight. The next day (~18 h), the reaction mixture was diluted with DMF to a total volume of 1.8 mL and and purified directly by preparatory HPLC (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to provide carbamate 50 as a yellow solid (12.9 mg, 41% yield).
[00575] 4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)- 3- methylbutanamido)propanamido)benzyl (((2R,2'R,3a'S,4'R)-12'-hydroxy-7',13a'-dimethoxy- 5'-methyl-11'-oxo-3a',8',9',10',11',13a'-hexahydro-2'H,4'H-s piro[oxirane-2,1'- [2,4]epoxyfuro[3,2-b]naphtho[2,3-h]chromen]-2'-yl)methyl)car bamate (51). To a flame-dried round bottom flask charged with a magnetic stir bar was added carbamate 50 (12.9 mg, 0.020 mmol) as a solution in THF (0.818 mL) and water (0.205 mL, resultant soln.0.02 M). The dipeptide was added in one portion (0.027 g, 0.041 mmol, 2 equiv.) and the reaction mixture was stirred at 23 ̊C overnight. After 24 h, the reaction mixture was diluted with ethyl acetate and partitioned between sat. aq. brine and ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue by preparatory HPLC (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to provide 51 as a yellow solid (9.5 mg, 47% yield). [00576] 4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)- 3- methylbutanamido)propanamido)benzyl (((1R,2R,3aR)-1-(bromomethyl)-1,12-dihydroxy- 7,13a-dimethoxy-5-methyl-11-oxo-1,3a,4,8,9,10,11,13a-octahyd ro-2H-2,4-epoxyfuro[3,2- b]naphtho[2,3-h]chromen-2-yl)methyl)carbamate (52). To a solution of 51 (11.5 mg, 0.012 mmol) in anhydrous acetonitrile (1.326 mL) and DMF (0.663 mL, 0.0058 M) was added lithium bromide (0.030 g, 0.346 mmol, 30 equiv.) followed by cerium trichloride heptahydrate (0.013 g, 0.035 mmol, 3.0 equiv.). The reaction mixture was then wrapped in aluminum foil to exclude light and stirred at 23 °C overnight. After stirring overnight (~18 h), the reaction mixture was partitioned between sat. aq. sodium sulfite solution (5 mL) and EtOAc (5 mL). The aqueous layer was then extracted with EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparatory LCMS (10% acetonitrile in water grading to 90% acetonitrile in water over 30 minutes) to afford 7.00 mg (56% yield) of 52 as a yellow solid. [00577] (2R,2'R,3a'S)-2'-(azidomethyl)-7',13a'-dimethoxy-5'-methyl-1 1'-oxo- 3a',8',9',10',11',13a'-hexahydro-2'H,4'H-spiro[oxirane-2,1'- [2,4]epoxyfuro[3,2-b]naphtho[2,3- h]chromen]-12'-yl tert-butyl carbonate (53). To a solution of azide 25 (26.6 mg, 55.2 μmol) in anhydrous dichloromethane (1.10 mL, 0.05 M) was added Hunig’s base (0.043 mL, 0.249 mmol, 4.5 equiv.), boc-anhydride (0.064 mL, 0.276 mmol, 5 equiv.), and DMAP (3.37 mg, 27.6 μmol, 0.5 equiv.) in that order. After stirring at rt for 3 h, the reaction mixture was diluted with dichloromethane (1 mL) and quenched with sat. aq. ammonium chloride (2 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified via silica gel flash chromatography to afford 53 (26.4 mg, 82% yield) as an off-white solid. [00578] (1R,2R,3aS)-2-(azidomethyl)-1-(bromomethyl)-1-hydroxy-7,13a- dimethoxy-5- methyl-11-oxo-1,3a,4,8,9,10,11,13a-octahydro-2H-2,4-epoxyfur o[3,2-b]naphtho[2,3- h]chromen-12-yltert-butyl carbonate (54). To a solution of boc-protected azide 53 (40.0 mg, 68.8 μmol) dissolved in acetonitrile (2.30 mL, 0.03M) was added lithium bromide (179 mg, 2.06 mmol, 30 equiv.) and cerium(III) chloride heptahydrate (76.9 mg, 206 μmol, 3 equiv.). After stirring overnight (~18 h), the reaction mixture was partitioned between sat. aq. sodium sulfite solution and ethyl acetate. The organic phase was separate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a crude residue. The crude residue was purified via silica gel flash chromatography to afford 54 (39.0 mg, 86% yield) as an off-white solid. Antiproliferative Assays [00579] Cell Culture: All cell-culture work was conducted in a class II biological safety cabinet. H460 cells (P2-P4, American Type Culture Collection) were maintained in RPMI- 1640 medium supplemented with 10% fetal bovine serum (FBS). HL-60 cells (P2-P4, American Type Cuture Collection) were maintained in RPMI-1640 medium supplemented with 10% FBS. MES-SA/Dx-5 cells (P2-P4, European Collection of Authenticated Cell Cultures) were maintained in McCoy’s 5A medium supplemented with 10% FBS. [00580] Cell Proliferation Assay: H460 and MES-SA/Dx-5 cells were grown to approximately 80% confluence, and then were trpysinized, collected, and pelleted by centrifugation (10 min at 183 × g, 24 °C), and HL-60 cells were grown to confluence and directly pelleted by centrifugation (10 min at 183 × g, 24 °C). The supernatant was discarded and the cell pellet was resuspended in 10 mL of fresh medium. A sample was diluted 10-fold in fresh medium, and the concentration of cells was determined using a hemacytometer. The cell suspension was diluted to a concentration of 3000 cells/100 μL. The wells of a pre- sterilized 96-well plate were charged with 100 μL per well of the diluted cellular suspension. The plate was incubated for 24 h at 37 °C (5% CO2). [00581] Stock solutions of each compound in DMSO were diluted with the appropriate media to 100 nM solutions (1% DMSO), which were then serially diluted with the appropriate media, and 100- μL aliquots of the resulting solutions were added to the wells containing adhered cells to achieve final concentrations of 0.39 nM to 50 nM. After incubating at 37 ºC for 72 h (5% CO2), 20 μL of resazurin solution (Promega CellTiter- Blue® Cell Viability Assay) was added to each well. After incubating at 37 °C for 2.0 h (5% CO2), the fluorescence (544 nm excitation/590 nm emission) was recorded using a microplate reader (SpectraMax PLUS384) as a measure of viable cells. [00582] Percent growth inhibition was calculated for each well, based upon the following formula: Percent growth inhibition = 100 × (S – B0) / (Bt – B0) where S is the sample fluorescence, Bt is the average fluorescence of an untreated population of cells at the completion of the assay, and B0 is the average fluorescence of an untreated population of cells at the beginning of the assay. [00583] Each compound was assayed at eight separate concentrations per experiment. The percent inhibition at each concentration was plotted against log(concentration), and a curve fit was generated using the XLfit4 plugin (IDBS Software) running in Excel (Microsoft). GI50 values were computed to reflect the concentrations at which the resulting curves pass through 50% inhibition. GI50 values for each compound are reported as the average of at least six experiments, with standard deviation. [00584] Compounds of the disclosure are potent inhibitors of the growth of MES-SA/Dx-5 cells as shown in Table 1. Table 1. [00585] Compounds of the disclosure are potent inhibitors of the growth of H460 cells as shown in Table 2. Table 2. [00586] These data indicate that small permutations to the chemical moiety present at C16 do not drastically perturb the potency of the resulting compound. Increasing the oxygenation of the propyl chain (22) to the propargyl alkyne (14) results in a corresponding increase in potency which is consistent with a reduction in rotatable bonds. Addition of a triazole-benzyl projection via ‘click’ chemistry (27) ablates potency, likely through a steric clash that prevents the compound from properly intercalating dsDNA. The trioxacarcinose A residue is well tolerated (30) while the non-native glucose residue (28, 29) is poorly tolerated, likely through increased uptake in efflux pathways. Substitution of the C16 alcohol with a halogen (32), azide (25), amine (26), or phosphate (35) all showed good tolerance. The surprising activity of the primary amine suggests that its pKa is high enough to not be protonated under physiologically relevant conditions. Sulfur based substitutions were not well tolerated at C16. 1 H NMR studies pointed to a rapid, non-productive, decomposition pathway that occurred on an hour time scale when the thiol (34) was not protected as the thioacetate (33). Thioesterase activity on the thioacetate likely forms the unstable thiol in situ which likely explains the similar lack of activity in both sulfur-containing compounds. [00587] Compounds of the disclosure are potent inhibitors of the growth of Ramos cells (B lymphocyte cells) as shown in Table 3. Table 3. Stability and Release Assays [00588] Stability Assay: In a 1.5 mL screw-top conical plastic vial, 42 (FIG.1A) or 39 (FIG.1B) was dissolved in 270 uL of DMSO (5 mM).12 uL of this DMSO drug-linker solution was mixed with 576 uL pH 5.0 sodium acetate buffer (50 mM sodium acetate, 100 mM NaCl, 4 mM EDTA).1-naphthalene acetic acid in DMSO (12 uL, 5 mM, 1 equiv.) was added as an internal standard. The vial was then placed in a heating block at 37 C and protected from direct light.25 uL aliquots of the reaction mixture were removed at 0 h, 4 h, 24 h, 48 h, 72 h, and 1 week and analyzed by LC-MS. LC-MS peaks were integrated using Agilent OpenLab ChemStation and the areas of each peak were normalized to 1-napthalene acetic acid at 280 nM. Percent drug-linker remaining is defined as the normalized peak area at a given time point divided by the normalized peak area at 0 hours x 100%. Each assay was also performed at pH 7.4 (phosphate-buffered solution, Corning), and assays at each pH value were performed with and without the addition of 8 mM N-acetylcysteine. [00589] Release Assay: In a 1.5 mL screw-top conical plastic vial, 42 was dissolved in 270 uL of DMSO (5 mM).12 uL of this DMSO drug-linker solution was mixed with a DMSO solution of N-acetylcysteine (10 mM, 12 uL, 2 equiv.). To the solution was then added 510 uL pH 5.0 sodium acetate buffer (50 mM sodium acetate, 100 mM NaCl, 4 mM EDTA, 8 mM N-acetylcysteine).1-Naphthalene acetic acid in DMSO (12 uL, 5 mM, 1 equiv.) was added as an internal standard. The vial was then placed in a heating block at 37 C for 30 minutes. After 30 minutes, 54 uL of cathepsin B solution (379 U/mL, Enzo LIfe Sciences) was added. The vial was returned to the heating block at 37 C and protected from direct light. 25 uL aliquots of the reaction mixture were removed at 0 min, 20 min, 40 min, 60 min, 120 min, and 180 min and analyzed by LC-MS. LC-MS peaks were integrated using Agilent OpenLab ChemStation and the areas of each peak were normalized to 1-napthalene acetic acid at 280 nM. Percent drug-linker remaining is defined as the normalized peak area at a given time point divided by the normalized peak area at 0 hours x 100% (FIG.2A). A similar procedure was used for the release assay of 39, using glucuronidase instead of cathepsin B (FIG.2B). [00590] Both drug-linker systems (i.e., 42 and 39) were stable at physiologically relevant pH and temperature for over 1 week. After 1 week, 75% of the glucuronide- and dipeptide drug-linker system remained. Then, when the appropriate enzyme was added, both drug- linker systems rapidly liberated the C16 primary amine warhead with a half-life of approximately 15 minutes. Preparation of Trioxacarcin-Antiboduy Conjugates [00591] The methods for preparing and characterizing the antibody-drug conjugates are described below. [00592] Partial reduction of interchain disulfides: To a solution of rituximab (500 μg, 25 μL of 20 mg/mL in PBS) was added a solution of tris(2-carboxyethyl)phosphine hydrochloride (1.7 μL, 5 mM in water, 2.5 equiv) and diluted to 15 mg/mL final antibody concentration using PBS pH 7.4 containing ethylenediaminetetraacetic acid (5 mM, 8.3 μL). The reaction was incubated at 37 ˚C for 2 h. The resulting antibodies contained on average 4 free thiols per antibody. [00593] Conjugation of trioxacarcin-linker: To a solution of partially reduced rituximab was added drug-linker (6.9 μL, 5 mM in DMSO, 11.5 equiv). DPBS pH 7.4 containing ethylenediaminetetraacetic acid (5 mM, 8.3 μL) was added to achieve 10 mg/mL final antibody concentration. The reaction was incubated for 2 h at 37 ˚C with agitation at 500 rpm. After conjugation, the antibody solution was diluted to 100 μL with PBS (47.5 μL) and loaded onto a PD SpinTrap G-25 Column (GE Healthcare, Chicago, IL, USA) pre- equilibrated with PBS according to the manufacturer’s protocol. An additional 40 μL of PBS was added to the column once the ADC solution had fully entered the media. The column was centrifuged at 800 Å~ g for 2 min and the filtrate was collected (140 μL total). The filtrate was diluted to 200 μL with PBS (60 μL), generating an ADC concentration of ~2.5 mg/mL. The resulting antibody-drug conjugate was analyzed by HRMS and stored at –80 ˚C. OTHER EMBODIMENTS [00594] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. [00595] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub–range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. [00596] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art. [00597] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.