Technical field

The present invention relates to the field of organic synthesis and more specifically it concerns a process for preparing compound of formula (I). The compound of formula (V), the compound of formula (VI) and the compound of formula (VIII) are also part of the invention.

Background of the invention

The octahydro-2(lH)-naphthalenone derivatives represent skeletons highly desirables which could be used as such or as key intermediates useful to prepare more complex compounds in different fields such as, among others, perfumery, cosmetic, pharmaceutic or agrochemistry. Relevant octahydro-2(lH)-naphthalenone derivatives in perfumery industry are, for example, 5,5,8a-trimethyloctahydro-2(lH)-naphthalenone which is a valuable intermediate towards 5,5,8a-trimethyldecahydronaphthalen-2-yl acetate representing some of the most sought-after ingredients in the perfumery industry. Both compounds possess several stereocenters and may be in the form of different stereoisomers wherein the perfuming interest is particularly directed toward stereoisomers having a trans decaline. The preparation of compound of formula (I) with high selectivity toward the trans decaline, starting from commercially available geraniol, has been reported in EP579991 and requests eight chemical steps. Alternatively, WO2020173977 discloses the preparation of compound of formula (I) in a high selectivity via the cyclisation of 6, 10-dimethyhindeca- 1,5,9-triene or 6,10-dimethylundeca-5,9-dien-l-yne in the presence of squalene hopene cyclase. However, the conversion and yield are low, the reaction time is very long and the preparation of both starting materials are not industrially applicable.

Being products of industrial interest, there is always a need for new processes showing an improved yield or productivity while limiting the number of steps without compromising the selectivity. Recently, biotechnological methods to produce ((4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen -l-yl)methanol or ((4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen -l-yl)methyl acetate in high selectivity using host cells/microorganisms expressing relevant enzymes have been reported in W02018220113, WO2019229064 or W02020078871. However, the conversion of those compounds into compound of formula (I) has never been reported.

The present invention is a process for preparing compound of formula (I) with high selectivity towards the trans decaline isomer, starting from compound of formula (II) via a novel route through novel intermediates. In particular, the compounds of formula (V), (VI) and (VIII) which are an object of the present invention, have never been reported in the prior art or suggested in the context of the preparation of compounds of formula (I). To the best of our knowledge, the invention’s process or the invention’s compounds of formula (V), (VI) and (VIII) have never been reported in the prior art.

Summary of the Invention

The invention relates to a novel process allowing the preparation of compound of formula (I) starting from compound of formula (II) opening a new route towards compound of formula (IV).

So, the first object of the present invention is a process the preparation of a compound of formula wherein the bold and hatched lines indicate a relative or absolute configuration; comprising the steps of a) oxidative cleavage of compound of formula in the form of any one of its stereoisomers or a mixture thereof, and wherein X represents a vinyl, a CHO, a COOH, a C(=O)OR ¹ or a CH2OR ² group wherein R ¹ represents a Ci-6 alkyl group and R ² represents a hydrogen atom, a benzyl group, a C(=O)R ^a group, a C(=O)OR ^b group, a C(R ^c )20R ^d group or a Si(R ^d )3 group wherein R ^a is a hydrogen atom or a Ci-6 alkyl group, R ^b is a Ci-6 alkyl group, R ^c , independently from each other, are a hydrogen atom or a C1.2 alkyl group and R ^d is a CM alkyl group; or one R ^c and R ^d , when taken together, form a C4-5 oxacycloalkyl group; into an intermediate of formula in the form of any one of its stereoisomers or a mixture thereof, and wherein X’ represents a CHO, a COOH, a C(=O)OR ¹ or a CH2OR ² group and R ¹ and R ² have the same meaning as defined above; and b) the conversion of the intermediate of formula (III) to the compound of formula (I).

A second object of the present invention is a compound of formula wherein the bold and hatched lines indicate a relative or absolute configuration.

A third object of the present invention is a compound of formula in the form of any one of its stereoisomers or a mixture thereof, wherein the bold and hatched lines indicate a relative or absolute configuration; X represents a CHO, a COOH, a C(=O)OR ¹ or a CH2OR ² group wherein R ¹ represents a Ci-6 alkyl group and R ² represents a hydrogen atom, a benzyl group, a C(=O)R ^a group, a C(=O)OR ^b group, a C(R ^c )20R ^d group or a Si(R ^d )3 group wherein R ^a is a hydrogen atom or a Ci- 6 alkyl group, R ^b is a Ci-6 alkyl group, R ^c , independently from each other, are a hydrogen atom or a C1.2 alkyl group and R ^d is a C1.4 alkyl group or one R ^c and R ^d , when taken together, form a C4-5 oxacycloalkyl group.

A further object of the present invention is a compound of formula wherein the bold and hatched lines indicate a relative or absolute configuration. of the invention

It has now been surprisingly found that compound of formula (I) with a trans configuration may be obtained from compound of formula (II) allowing to reduce the number of steps while maintaining a high selectivity and yield. The invention’s process opens a new route starting from a natural product or derivatives from the natural product allowing obtaining compound of formula (IV) with overall higher yield, compared to the methods known from the prior arts and without formation of the cis decaline. So, the first object of the invention is a process for the preparation of a compound of formula wherein the bold and hatched lines indicate a relative or absolute configuration; comprising the steps of a) oxidative cleavage of compound of formula in the form of any one of its stereoisomers or a mixture thereof, and wherein X represents a vinyl, a CHO, a COOH, a C(=O)OR ¹ or a CH2OR ² group wherein

R ¹ represents a Ci-6 alkyl group and R ² represents a hydrogen atom, a benzyl group, a C(=O)R ^a group, a C(=O)OR ^b group, a C(R ^c )2OR ^d group or a Si(R ^d )3 group wherein R ^a is a hydrogen atom or a Ci-6 alkyl group, R ^b is a Ci-6 alkyl group, R ^c , independently from each other, are a hydrogen atom or a C1.2 alkyl group and R ^d is a CM alkyl group; or one R ^c and R ^d , when taken together, form a C4-5 oxacycloalkyl group; into an intermediate of formula in the form of any one of its stereoisomers or a mixture thereof, and wherein X’ represents a CHO, a COOH, a C(=O)OR ¹ or a CH2OR ² group and R ¹ and R ² have the same meaning as defined above; and b) the conversion of the intermediate of formula (III) to the compound of formula (I).

For the sake of clarity, by the expression “the bold and hatched lines indicate a relative or absolute configuration” or the similar, it is meant the normal meaning understood by a person skilled in the art, i.e. that in the case of an relative configuration compound (I) is in the form of a mixture of stereoisomers comprising more than 50% (w/w) of the (4aSR,8aRS) stereoisomer, i.e. a compound having a decaline group in a relative trans configuration as shown in formula (I), or in the case of an absolute configuration compound (I) is in the form of a mixture of stereoisomers comprising more than 50% (w/w) of the (4aS,8R) stereoisomer.

By the term “oxidative cleavage” or similar, it is meant the normal meaning in the art; i.e. a reaction in which a carbon-carbon double bond is cleaved and oxidized generating two compounds having a carbon-oxygen double bond.

The wavy line of compound of formula (II) and (III) indicates that the carbon stereocenter bearing said bond may be in a R or S relative or absolute configuration. In other words, said bond may be in the same side than the methyl group at the ring junction or said bond may be in the opposite side than the methyl group at the ring junction.

For the sake of clarity, by the expression “any one of its stereoisomers or a mixture thereof’, or the similar, it is meant the normal meaning understood by a person skilled in the art, i.e. that the compounds of formula (II) and (III) can be a pure enantiomer or a mixture of enantiomers provided, of course, that the decaline group have a trans configuration. In other words, the compounds of formula (II) and (III) possess three stereocenter which can have two different stereochemistries (e.g. R or S). The compounds of formula (II) and (III) may even be in the form of a pure enantiomer or in the form of a mixture of enantiomers. The compounds of formula (II) and (III) may even be in the form of a pure diastereoisomer or in the form of a mixture of diastereoisomers. The compounds of formula (II) and (III) can be in a racemic form or scalemic form. Therefore, the compounds of formula (II) and (III) can be one stereoisomer or in the form of a composition of matter comprising, or consisting of, various stereoisomers. The term “alkyl” is understood as comprising branched and linear alkyl groups.

For the sake of clarity, by the expression “one R ^c and R ^d , when taken together, form a C4-5 oxacycloalkyl group . . . ”, it is meant that the carbon atom and oxygen atom to which both groups are bonded are included into the C4-5 oxacycloalkyl group. According to a particular embodiment of the invention, the compound of formula

(II) can be a compound of formula wherein the bold and hatched lines and X have the meaning indicated in formula (I).

According to a particular embodiment of the invention, the compound of formula (II) can be a compound of formula wherein the bold and hatched lines and X have the meaning indicated in formula (I).

According to a particular embodiment of the invention, the compound of formula

(II) can be in a form of a composition comprising compound of formula (IF) and compound of formula (II”).

According to a particular embodiment of the invention, the compound of formula

(III) can be a compound of formula wherein the bold and hatched lines and X’ have the meaning indicated in formula (I).

According to a particular embodiment of the invention, the compound of formula (III) can be a compound of formula wherein the bold and hatched lines and X’ have the meaning indicated in formula (I).

According to a particular embodiment of the invention, the compound of formula (III) can be in a form of a composition comprising compound of formula (III’) and compound of formula (III”).

According to any embodiment of the invention, R ¹ may be a Ci-4 alkyl group. Particularly, R ¹ may be a C1.3 alkyl group. Even more particularly, R ¹ may a methyl group.

According to any embodiment of the invention, R ^a may be a hydrogen atom or a Ci- 4 alkyl group. Particularly, R ^a may be a hydrogen atom a C1.3 alkyl group. Particularly, R ^a may be a hydrogen atom or a methyl or an ethyl group. Even more particularly, R ^a may a hydrogen atom or a methyl group. Even more particularly, R ^a may a hydrogen atom.

According to any embodiment of the invention, R ^b may be a C1.4 alkyl group. Particularly, R ^b may be a C1.3 alkyl group. Even more particularly, R ^b may a methyl or an ethyl group.

According to any embodiment of the invention, one R ^c may be a hydrogen atom or a Ci-2 alkyl group and the other R ^c may be a hydrogen atom; i.e. R ² may be a CHR ^c OR ^d group. Particularly, one R ^c may be a hydrogen atom or a methyl group and the other R ^c may be a hydrogen atom. Even more particularly both R ^c may be a hydrogen atom; i.e. R ² may be a CH2OR ^d group.

According to any embodiment of the invention, R ^d may be a C1.3 alkyl group. Even more particularly, R ^d may a methyl or an ethyl group.

According to any embodiment of the invention, one R ^c and R ^d , when taken together, may form a C5 oxacycloalkyl group.

According to any embodiment of the invention, R ² may be a hydrogen atom or a C(=O)R ^a group. Particularly, R ² may be a hydrogen atom.

According to any embodiment of the invention, X may be a CHO, a COOH, a C(=O)OR ¹ or a CH2OR ² group. Particularly, X may be a CHO, a COOH or a CH2OH group. Even more particularly, X may be a CH2OH group.

According to any embodiment of the invention, X’ may be a CHO, a COOH or a CH2OR ² group. Particularly, X’ may be a COOH or a CH2OR ² group. Particularly, X’ may be a COOH or a CH2OH group. Even more particularly, X’ may be a CH2OH group.

Non limiting examples of compound of formula (II) may include ((4aSR,8aSR)-

5,5,8a-trimethyl-2-methylenedecahydronaphthalen-l-yl)meth anol, ((4aS,8aS)-5,5,8a- trimethyl-2-methylenedecahydronaphthalen-l-yl)methanol, ((4aR,8aR)-5,5,8a-trimethyl- 2-methylenedecahydronaphthalen- 1 -yl)methanol, (4aSR,8aSR)-5,5,8a-trimethyl-2- methylenedecahydronaphthalene- 1 -carbaldehyde, (4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalene- 1 -carbaldehyde, (4aR,8aR)-5,5,8a-trimethyl-2- methylenedecahydronaphthalene- 1 -carbaldehyde, (4aSR,8aSR)-5,5,8a-trimethyl-2- methylenedecahydronaphthalene- 1 -carboxylic acid, (4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalene- 1 -carboxylic acid, (4aR,8aR)-5,5,8a-trimethyl-2- methylenedecahydronaphthalene- 1 -carboxylic acid, methyl or ethyl (4aSR,8aSR)-5,5,8a- trimethyl-2-methylenedecahydronaphthalene-l -carboxylate, methyl or ethyl (4aS,8aS)- 5,5,8a-trimethyl-2-methylenedecahydronaphthalene-l-carboxyla te, methyl or ethyl (4aR,8aR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene-l -carboxylate, ((4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen -l-yl)methyl formate, ((4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-l -yl)methyl formate, ((4aR,8aR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-l -yl)methyl formate, ((4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen -l-yl)methyl acetate, ((4aS,8aS)-5,5,8 a-trimethyl -2-methylenedecahydronaphthalen- 1 -yl)methyl acetate, ((4aR,8aR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-l -yl)methyl acetate, trimethyl(((4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydro naphthalen-l- yl)methoxy)silane, trimethyl(((4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalen-l-yl)methoxy)silane, trimethyl(((4aR,8aR)-5,5,8a- trimethyl-2-methylenedecahydronaphthalen-l-yl)methoxy)silane , (4aSR,8aSR)-5-((l- ethoxyethoxy)methyl)-l,l,4a-trimethyl-6-methylenedecahydrona phthalene, (4aS,8aS)-5- ((l-ethoxyethoxy)methyl)-l,l,4a-trimethyl-6-methylenedecahyd ronaphthalene, (4aR,8aR)-5-((l -ethoxyethoxy )methyl)-l,l, 4a-trimethyl-6- methylenedecahydronaphthalene, (4aSR,8aSR)-5-((benzyloxy)methyl)-l,l,4a-trimethyl-

6-methylenedecahydronaphthalene, (4aS,8aS)-5-((benzyloxy)methyl)-l,l,4a-trimethyl-6- methylenedecahydronaphthalene, (4aR,8aR)-5-((benzyloxy)methyl)-l,l,4a-trimethyl-6- methylenedecahydronaphthalene, (4aSR,8aSR)-l,l,4a-trimethyl-6-methylene-5- vinyldecahydronaphthalene, (4aS,8aS)-l,l,4a-trimethyl-6-methylene-5- vinyldecahydronaphthalene, (4aR,8aR)-l,l,4a-trimethyl-6-methylene-5- vinyl decahydronaphth al ene .

According to any embodiments of the invention the compound of formula (II) may be prepared according to method known by the person skilled in the art. Particularly, compound of formula (II) wherein X is a CH2OR ² group wherein R ² represents a hydrogen atom or a C(=O)Me group may be produced in vitro using purified recombinantly prepared enzymes or by fermentation using host cells, such as microbial cells, genetically engineered to convert unexpensive carbon sources (such as sugar) into the desired compound of formula (II), using a Haloacid dehalogenase-like (HAD-like) hydrolase superfamily as reported in W02018220113 or WO2019229064 and then followed, when X is a CH2OR ² group wherein R ² is a C(=O)Me group, by an acetyl transferase as disclosed in W02020078871. The advantage of using a compound of formula (II) obtained by fermentation is evident since it allows an easy access to the starting material with high selectivity.

According to any one of the above embodiments of the invention’s process, said process is further characterized in that the compound of formula (II) is obtained, in a previous step, by contacting famesyl pyrophosphate with at least one enzyme such as the one reported in W02018220113 or WO2019229064 and then optionally with the one reported in W02020078871. Other steps may be needed depending of the nature of the X group, such as protection or oxidation, optionally followed by esterification. Said steps are well known in the art and the person skilled in the art is able to select the most suitable conditions. Non limiting examples of compound of formula (III) may include (4aSR,8aSR)-l-

(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(lH) -one, (4aS,8aS)-l-

(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(lH) -one, (4aSR,8aSR)-5,5,8a- trimethyl-2-oxodecahydronaphthalene-l -carboxylic acid, (4aS,8aS)-5,5,8a-trimethyl-2- oxodecahydronaphthalene-1 -carboxylic acid, methyl or ethyl (4aSR,8aSR)-5,5,8a- trimethyl -2-oxodecahydronaphthalene-l -carboxylate or methyl or ethyl (4aS,8aS)-5,5,8a- trimethyl -2-oxodecahydronaphthalene-l -carboxylate, ((4aSR,8aSR)-5,5,8a-trimethyl-2- oxodecahydronaphthalen- 1 -yl)methyl formate, ((4aS,8aS)-5,5,8a-trimethyl-2- oxodecahydronaphthalen- 1 -yl)methyl formate, ((4aR, 8aR)-5 , 5 , 8a-trimethyl -2- oxodecahydronaphthalen- 1 -yl)methyl formate, ((4aSR,8aSR)-5,5,8a-trimethyl-2- oxodecahydronaphthalen- 1 -yl)methyl acetate, ((4aS,8aS)-5,5,8a-trimethyl-2- oxodecahydronaphthalen- 1 -yl)methyl acetate, ((4aR,8aR)-5,5,8a-trimethyl-2- oxodecahydronaphthalen- 1 -yl)methyl acetate, (4aSR,8aSR)-5,5,8a-trimethyl-l-

(((trimethylsilyl)oxy)methyl)octahydronaphthalen-2(lH)-on e, (4aS,8aS)-5,5,8a-trimethyl- l-(((trimethylsilyl)oxy)methyl)octahydronaphthalen-2(lH)-one , (4aR,8aR)-5,5,8a- trimethyl-l-(((trimethylsilyl)oxy)methyl)octahydronaphthalen -2(lH)-one, (4aSR,8aSR)- l-((l-ethoxyethoxy)methyl)-5,5,8a-trimethyloctahydronaphthal en-2(lH)-one, (4aS,8aS)- l-((l-ethoxyethoxy)methyl)-5,5,8a-trimethyloctahydronaphthal en-2(lH)-one, (4aR,8aR)- l-((l-ethoxyethoxy)methyl)-5,5,8a-trimethyloctahydronaphthal en-2(lH)-one, (4aSR,8aSR)-l-((benzyloxy)methyl)-5,5,8a-trimethyloctahydron aphthalen-2(lH)-one, (4aS,8aS)-l-((benzyloxy)methyl)-5,5,8a-trimethyloctahydronap hthalen-2(lH)-one, (4aR, 8aR)-l -((benzyl oxy )methyl)-5, 5, 8a-trimethyl octahydronaphthal en-2(lH)-one, (4aSR,8aSR,Z)-l-(hydroxymethylene)-5,5,8a-trimethyloctahydro naphthalen-2(lH)-one, (4aS,8aS,Z)-l-(hydroxymethylene)-5,5,8a-trimethyloctahydrona phthalen-2(lH)-one, (4aR,8aR,Z)-l-(hydroxymethylene)-5,5,8a-trimethyloctahydrona phthalen-2(lH)-one.

According to any embodiments of the invention, the oxidative cleavage may be carried out under normal condition known by the person skilled in the art, i.e. in the presence of an oxidizing agent such as ozone, reaction also known as ozonolysis, OsC /NalCh, KMnC /NalCh, RuCh/NalCh, RuCh/NaOCl, HzCh/NaICU or organic peroxide/NalC . Particularly, the oxidative cleavage may be an ozonolysis; i.e. compound of formula (II) reacts with ozone. Even more particularly, the oxidative cleavage may be an ozonolysis performed under reductive conditions. For the sake of clarity, by the expression “under reductive conditions” it is understood by a person skilled in the art that the intermediate trioxolane or hydroperoxide formed, to obtain compound of formula (III), is treated with at least one reducing agent, which is well known to a person skilled in the art. Such treatment with a reducing agent can be performed during the work-up. As non-limiting examples of said reducing agents one may cite the following: an amine in particular a tertiary amine or a pyridine, a sulfite, such as an alkaline sulfite (e.g. sodium or potassium sulfite, sodium bisulfite) or a C2-6 dialkyl sulfide such as dimethyl sulfide or methylphenylsulfide, Na salt of 3,3 '-Thiodipropionic acid, triphenylphosphine, Zn/AcOH, Zn/AcOH/water, Na2S, thiourea, thiodiglycol, 3,3'- Thiodipropanol, 3,3 '-Thiodipropionitrile, H2 and Pd/C or Raney/Ni, P(OMe)?, P(OEt)3, P(OPh)3 MeO(SO)OMe, MeSSMe, etc. In particular one may cite a sulfite, such as an alkaline sulfite (e.g. sodium or potassium sulfite, sodium bisulfite) optionally in combination with Na salt of 3,3 '-Thiodipropionic acid or a C2-6 dialkyl sulfide such as dimethyl sulfide.

When the oxidative cleavage is carried out with compound of formula (II) wherein X is a CHO group, the oxidative cleavage provided a compound of formula (III) wherein X’ is a COOH group. In other words, the CHO group is oxidized under oxidative cleavage conditions.

When the oxidative cleavage is carried out with compound of formula (II) wherein X is a vinyl group, the oxidative cleavage provided a mixture comprising a compound of formula (III) wherein X’ is a COOH group and a compound of formula (III) wherein X’ is a CHO group. In other words, the vinyl group is partly oxidized under oxidative cleavage conditions. A compound of formula (III) wherein X’ is a CHO may be in a form of a enal of formula (III ^a ) wherein the bold and hatched lines indicate a relative or absolute configuration. The ozonolyis can be carried out in the presence or absence of a solvent. When a solvent is required or used for practical reasons, then any solvent wherein the compound of formula (II) is soluble and which is of current use in ozonolysis reactions can be used for the purposes of the invention. Non-limiting examples include Ce-io saturated hydrocarbon solvents such as hexane or cyclohexane, saturated C4-10 ethers or esters such as AcOEt, tetrahydrofuran, dioxane or MTBE, saturated C2-5 carboxylic acids such as acidic or propionic acid, saturated C1.5 polar solvents such as primary or secondary alcohols such as isopropanol, methanol or ethanol, saturated C2-6 ketones such as butanone or isobutylmethylketone, C1.3 chlorinated alkane such as chloroform or di chloromethane, or mixtures thereof. The exact choice of the solvent is a function of the compound of formula (II) and reaction speed required. The person skilled in the art is well able to select the solvent most convenient in each case to optimize the ozonolysis reaction.

The solvent can be added to the reaction medium in a large range of concentrations. As non-limiting examples, one can cite as solvent amounts ranging from 50% to 500% w/w, relative to the amount of compound of formula (II) used.

The temperature at which the oxidation can be carried out is comprised between -100°C and 40°C, particularly, in the range of between -80°C and 20°C, even more particularly, in the range of between -40°C and 0°C. Of course, a person skilled in the art is able to select the preferred temperature as a function of the melting and boiling point of the starting and final products as well as the desired time of reaction or conversion.

The ozone can be added to the reaction medium in a large range of concentrations. As non-limiting examples, one can cite as ozone concentration values ranging from 0.8 molar equivalents to 3 molar equivalents, relative to the amount of the compound of formula (II). Preferably, the ozone concentration will be comprised between 1.0 molar equivalents to 1.2 molar equivalents. It goes without saying that the optimum concentration of ozone will depend, as the person skilled in the art knows, on the nature of the compound of formula (II), the desired conversion, as well as the desired time of reaction.

The reducing agent can be added to the reaction medium in a large range of concentrations. As non-limiting examples, one can cite as reducing agent concentration values those ranging from 0.5 molar equivalents to 10 molar equivalents, relative to the amount of compound of formula (II). Preferably, the reducing agent concentration will be comprised between 0.8 molar equivalents to 10 molar molar equivalents. Even more preferably, the reducing agent concentration will be comprised between 2.0 molar equivalents to 5 molar equivalents. It goes without saying that the optimum concentration of reducing agent will depend, as the person skilled in the art knows, on the nature of the latter, on the nature of the compound of formula (II), the desired conversion, as well as the desired time of reaction.

The conditions used to convert the intermediate of formula (III) to the compound of formula (I) will depend on the nature of the X’ group.

According to a particular embodiment of the invention, when X’ is a CH2OR ² group, the conversion of the intermediate of formula (III) to the compound of formula (I) comprises a retro aldol reaction. When R ² is not a hydrogen atom, a deprotection is carried out prior to the retro aldol. The deprotection step will depend on the nature of the R ² group. The person skilled in the art will be able to select the best conditions. For example, when R ² is a C(=O)R ^a group wherein R ^a is a hydrogen atom or a Ci-6 alkyl group, the deprotection to form a compound of formula (III) wherein X’ is a CH2OH group may be carried out under normal condition known by the person skilled in the art, e.g. in the presence of water and an acid, preferably an acid having a pH in the range comprised between 1 and 2 such as H2SO4, pTsOH, oxalic acid or phosphoric acid; or in the presence of an enzyme such as lipase.

According to a particular embodiment of the invention, the retro aldol reaction is a thermal retro aldol reaction.

The temperature at which the retro-aldol reaction can be carried out is comprised between 450°C and 550°C, particularly, in the range of between 490°C and 550°C, particularly, in the range of between 490°C and 550°C, particularly, in the range of between 490 and 530°C, even more particularly, in the range of between 490 and 510°C. Of course, a person skilled in the art is able to select the preferred temperature as a function of the melting and boiling point of the starting and final products as well as the desired time of reaction or conversion.

The retro-aldol reaction can be carried out in the presence or absence of a solvent. When a solvent is required or used for practical reasons, then any solvent current in such reaction type can be used for the purposes of the invention. In particular, the retro aldol reaction is carried out in a presence of a solvent having a boiling point equal or greater than 65°C, even greater than 75°C, even greater than 80°C, even greater than 110°C, even greater than 130°C. Non-limiting examples of suitable solvents include alcoholic solvent such as methanol, ethanol, 1 -propanol, isopropanol, 1 -hexanol, 1 -octanol, 1 -butanol, 1- pentanol, 4-methylpentan-2-ol, 2 -m ethyl- 1 -pentanol, 1 -heptanol, 2-octylalcohol, cyclohexanol or mixtures thereof, Ce-12 aromatic solvents such as toluene, xylene, or mixtures thereof, hydrocarbon solvents such as n-heptane, n-decane, n-dodecane, n- nonane, cyclohexane or a mixture thereof, ethereal solvents such diisobutyl ether or di n- butylether or mixtures thereof, solvent comprising a ketone functional group such as 4- methyl-2-pentanone MIBK, 2-octanone, cyclohexanonone, 2-heptanone, 6-methyl-2- heptanone, 6-methyl-5-hepten-2-one, isophorone or a mixture thereof, solvent comprising a aldehyde functional group such as hexanal, octanal or a mixture thereof. The choice of the solvent is function of the nature of the substrate and the person skilled in the art is well able to select the solvent most suitable in each case to optimize the reaction.

The retro aldol reaction may be carried out under batch or continuous conditions.

Unexpectedly, the thermal retro aldol reaction allows limiting side product formation. The conditions reported in the prior art for such conversions, such as non- industrially applicable Jones Oxidation, does not allow obtaining compound of formula (I) in high yield. According to a particular embodiment of the invention’s process, at most 20 % of undesired eliminated product of formula (VII) is formed.

According to a particular embodiment of the invention, when X’ is a COOH or a C(=O)OR ¹ group wherein R ¹ has the same meaning as defined above, the conversion of the intermediate of formula (III) to the compound of formula (I) comprises a decarboxylation reaction. The decarboxylation reaction may be carried out under normal condition known by the person skilled in the art, i.e. in the presence of a base such as an alkali metal hydroxide, e.g. NaOH or KOH or in the presence of an acid such as Bronsted acid or Lewis acid. Particularly, the decarboxylation is performed in the presence of a base when X’ is a C(=O)OR ¹ group wherein R ¹ has the same meaning as defined above. The decarboxylation is well known and has been largely reported in the prior art. So, the person skilled in the art will be able to set up the best conditions in order to convert compound of formula (III), wherein X’ is a COOH or a C(=O)OR ¹ group wherein R ¹ has the same meaning as defined above, into compound of formula (I). As non-limiting example, the decarboxylation reaction may be performed under the conditions reported in WO2012069647. Specific and non-limiting examples of Bronsted acid or Lewis acid may be selected from the group consisting of diluted sulfuric acid, para toluene sulfonic acid, methane sulfonic acid, camphor sulfonic acid, Triflic acid, methane disulfonic acid, methane trisulfonic acid, 2,4 dinitrobenzene sulfonic acid, diluted HC1 and AI2O3.

The acid or base can be added into the reaction medium of the invention’s process in a large range of concentrations. As non-limiting examples, one can cite as acid or base concentration values those ranging from about 1 to about 20 mol%, relative to the amount of the of substrate, preferably from 5 to about 10 mol%, relative to the amount of the of substrate The optimum concentration of the acid or base will depend, as the person skilled in the art knows, on the nature of the latter, on the nature of the substrate, on the reaction temperature as well as on the desired time of reaction.

According to any one of the invention’s embodiments, the decarboxylation reaction may be carried out at a temperature comprised between 20°C and 80°C. In particular, the temperature is in the range between 20°C and 60°C. Of course, a person skilled in the art is also able to select the preferred temperature as a function of the melting and boiling point of the starting and final products as well as the desired time of reaction or conversion.

The decarboxylation reaction can be carried out in the presence or absence of a solvent. When a solvent is required or used for practical reasons, then any solvent current in such reaction type can be used for the purposes of the invention. Non-limiting examples include C6-12 aromatic solvents such as toluene, xylene, 1,3 -diisopropylbenzene, cumene or pseudocumene, or mixtures thereof, alcoholic solvent such as methanol, ethanol, or mixtures thereof, hydrocarbon solvents such as cyclohexane or heptane, ethyl acetate or ethereal solvents such as dioxane, methyl tetrahydrofuran, tetrahydrofuran or mixtures thereof. The choice of the solvent is function of the nature of the substrate and/or base or acid and the person skilled in the art is well able to select the solvent most suitable in each case to optimize the reaction.

According to a particular embodiment of the invention, when X’ is a CHO group, the conversion of the intermediate of formula (III) to the compound of formula (I) comprises a decarbonylation reaction or, alternatively, a oxidation reaction followed by a decarboxylation reaction. The decarbonylation reaction may be carried out under normal condition known by the person skilled in the art, i.e. in the presence of an alkali metal hydroxide, e.g. NaOH or KOH; and a RCOOM wherein R is a Cl -8 alkyl group and M is a alkali metal such as KOAc. The oxidation reaction may be carried out under normal condition known by the person skilled in the art such as under Jones conditions. The decarboxylation reaction may be carried out under conditions reported above.

According to any embodiment of the invention, the compound of formula (I) may be converted into a compound of formula wherein the bold and hatched lines indicate a relative or absolute configuration. The conversion of compound of formula (I) into compound of formula (IV) has been largely reported in the prior arts, such as in Journal of Chemical Research, Synopses (1998), (1), 36-37).

The compound of formula (II) when X is a vinyl group is a novel compound and present a number of advantages as explained above and shown in the Examples. Therefore, another object of the present invention is a compound of formula wherein the bold and hatched lines indicate a relative or absolute configuration.

The compound of formula (III) when X’ is a COOH group is a novel compound and present a number of advantages as explained above and shown in the Examples.

Therefore, another object of the present invention is a compound of formula wherein the bold and hatched lines indicate a relative or absolute configuration.

The ozonolyis of compounds of formula (II) provides ozonide intermediates which are novel compounds and present a number of advantages as explained above and shown in the Examples. So another object of the present invention is compound of formula in the form of any one of its stereoisomers or a mixture thereof, and wherein the bold and hatched lines indicate a relative or absolute configuration; X represents a CHO, a COOH, a C(=O)OR ¹ or a CH2OR ² group wherein R ¹ represents a Ci-6 alkyl group and R ² represents a hydrogen atom, a benzyl group, a C(=O)R ^a group, a C(=O)OR ^b group, a C(R ^c )20R ^d group or a Si(R ^d )3 group wherein R ^a is a hydrogen atom or a Ci-6 alkyl group, R ^b is a Ci-6 alkyl group, R ^c , independently from each other, are a hydrogen atom or a C1.2 alkyl group and R ^d is a Ci-4 alkyl group or one R ^c and R ^d , when taken together, form a C4-5 oxacycloalkyl group.

An embodiment of the invention is wherein the compound of formula (II) used in the presently claimed process is obtained by contacting famesyl pyrophosphate with at least one enzyme.

In some embodiments of the presently claimed process enzymes are used to prepare compounds of formula (II). For example, compound of formula (II) wherein X is a CH2OR ² group wherein R ² represents a hydrogen atom or a C(=O)Me group may be produced using a Haloacid dehalogenase-like (HAD-like) hydrolase superfamily as reported in WO2018220113 or WO2019229064 and then followed, when X is a CH ₂ OR ² group wherein R ² is a C(=O)Me group, by an acetyl transferase as disclosed in W02020078871.

In some embodiments of the presently claimed process enzymes are used to prepare compounds of formula (II).

The process to prepare compounds of formula (II) can be carried out in vitro as well as in vivo, as will be explained in details further on.

When the process is carried out in vitro, the enzyme to use can be obtained by extraction from any organism expressing it, using standard enzyme extraction technologies. If the host organism is an unicellular organism or cell the enzyme may simply be collected from the culture medium, for example by centrifugation, optionally followed by washing steps and re-suspension in suitable buffer solutions. If the organism or cell accumulates the enzyme within its cells, the enzyme may be obtained by disruption or lysis of the cells and further extraction of the enzyme from the cell lysate.

For the in vitro method the enzyme can be provided in isolated form or as part of a protein extract and is suspended in a buffer solution at optimal pH. If adequate, salts, DTT, NADPH, NADH, FAD, FMN and other kinds of enzymatic co-factors, may be added in order to optimize enzyme activity. The precursor compound is then added to the reaction mixture and incubated at optimal temperature, for example between 15 and 40°C, preferably between 25 and 35°C, more preferably at 30°C. After incubation, the compounds of formula (II) produced may be isolated from the incubated solution by standard isolation procedures, such as solvent extraction and distillation, optionally after removal of enzymes from the solution.

According to another preferred embodiment, the process to prepare compounds of formula (II) is carried out in vivo. In this case, the process comprises cultivating a nonhuman host organism or cell transformed to express the enzyme in the presence of a starting compound to be converted into the compounds of formula (II) under conditions conducive to the enzymatic reaction.

In an embodiment, in the case where a host cell is used or when the host organism is a microorganism, the compound to be converted can be added to the culture medium of said cell or microorganism. The starting compound will permeate through the membrane of the cell or microorganism, thus being available for reaction with the enzyme expressed by said host cell or microorganism. Carrying out the method in vivo is particularly advantageous since it is possible to carry out the method without previously isolating the enzyme. The reaction occurs directly within the organism or cell transformed to express the enzyme.

To carry out the invention in vivo, the host organism or cell is cultivated under conditions conducive to the production of the compounds of formula (II). Such conditions are any conditions leading to growth of the host organism or cell. Preferably, such conditions are designed for optimal growth of the host organism or cell. If the host is a unicellular organism, conditions conducive to the production of the compounds of formula (II) may comprise addition of suitable cofactors to the culture medium of the host. In addition, a culture medium may be selected, so as to maximize synthesis.

Optimal culture conditions are known to the person skilled in the art and are not specific to the present invention.

In a more preferred embodiment the organism used to carry out the method of the invention in vivo is a microorganism. Any microorganism can be used but according to an even more preferred embodiment said microorganism is a bacteria or fungus. Preferably said fungus is yeast. Most preferably, said bacteria is E. coli and said yeast is Saccharomyces cerevisiae.

Another object of the present invention is the use of compound of formula wherein the bold and hatched lines indicate a relative or absolute configuration; in the preparation of compound of formula (I) and (IV).

Another object of the present invention is the use of compound of formula in the form of any one of its stereoisomers or a mixture thereof, and wherein the bold and hatched lines indicate a relative or absolute configuration; X represents a CHO, a COOH, a C(=O)OR ¹ or a CH2OR ² group wherein R ¹ represents a Ci-6 alkyl group and R ² represents a hydrogen atom, a benzyl group, a C(=O)R ^a group, a C(=O)OR ^b group, a C(R ^c )20R ^d group or a Si(R ^d )3 group wherein R ^a is a hydrogen atom or a Ci-6 alkyl group, R ^b is a Ci-6 alkyl group, R ^c , independently from each other, are a hydrogen atom or a C1.2 alkyl group and R ^d is a Ci-4 alkyl group or one R ^c and R ^d , when taken together, form a C4-5 oxacycloalkyl group; in the preparation of compound of formula (I) and (IV).

Another object of the present invention is the use of compound of formula wherein the bold and hatched lines indicate a relative or absolute configuration; in the preparation of compound of formula (I) and (IV).

Typical manners to execute the invention’s process are reported herein below in the examples.

The invention will now be described in further detail by way of the following examples, wherein the abbreviations have the usual meaning in the art, the temperatures are indicated in degrees centigrade (°C). The preparation of precatalysts and ligands solutions were carried out under an inert atmosphere (Argon) using standard Schlenk techniques. The solvents were dried by conventional procedures and distilled under an argon atmosphere. NMR spectra were recorded at 20 °C on Bruker AV 300, AV 400, or AV 500 MHz spectrometers. Chemical shifts are reported in ppm relative to solvent signals (chloroform, 5H = 7.26 ppm, 6c = 77.0 ppm). The signal assignment was ensured by recording ^ H- COSY, -NOESY, ^C H-HSQC and -HMBC experiments. Gas chromatography was performed on an Agilent 7890 A Series equipped with a HP5 column (30 m x 0.25 mm ID, 0.25pm film) and tetradecane was used as internal standard.

Example 1

Preparation of ((1 S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-l - yDmethanol from ((1 S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-l - vDmethyl acetate

36.0 g (136.2 mmol) ((lS,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthale n-l- yl)methyl acetate were dissolved under stirring in 480 mL MeOH in a 1 L flask in the presence of 38.3 g (578.7 mmol, 4.3 eq) KOH. After 2 hours a full conversion of starting material was observed. The solvent was partly evaporated under reduced pressure (45°C, 15 mbar), and 1.5 L diethyl ether and 500 mL water were added.

The aqueous phase was separated and the organic phase was washed twice with 500 mL water and once with with 500 mL of a saturated aqueous NaCl solution. The organic phase was dried over Na2SO4 and the solvent was evaporated under reduced pressure (45°C, 500- 3 mbar). 100 mL pentane were added and the solvent was evaporated under reduced pressure (45°C, 500-3 mbar). A white solid (29.7 g ((lS,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalen-l-yl)methanol, 133.7 mmol, 98% yield) was obtained. 'H and ¹³ C NMR spectral data are identical to those reported in M. Gohl, K. Seifert, Eur.

J. Org. Chem. 2014, 6975- 6982.

Example 2

Preparation of (1 S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahvdronaphthalene- l- carbaldehyde from ((1 S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahvdronaphthalen-l - yDmethanol 15.61 g (70.2 mmol) of ((lS,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthale n- l-yl)methanol (0.523 g (7.02 mmol) KC1, 2.84 g (7.02 mmol) Fe(NO ₃ ) ₃ 9H ₂ O and 1.097 g (7.02 mmol) TEMPO were dissolved in 150 mL toluene. Air was bubbled into the solution and the mixture was stirred 25.5 hours. A further quantity of catalyst was added (0.523 g (7.02 mmol) KC1, 2.84 g (7.02 mmol) Fe(NO ₃ ) ₃ 9H ₂ O and 1.097 g (7.02 mmol) TEMPO), air was bubbled into the solution and the mixture was stirred for 21 hours. After the addition of 50 mL water and 75 mL Et ₂ O the mixture was stirred 10 min. The organic phase was separated and washed with 50 mL water and 50 mL of a saturated aqueous NaCl solution. After drying over Na ₂ SO4 and filtration the solvent was evaporated under reduced pressure (18.73 g crude). The product was purified by column chromatography (80 g SiO ₂ , Et ₂ O/Cyclohexane 1/9). 13.7 g (lS,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalene-l-carbaldehyde of an orange oil were obtained (98.8% GC purity, 88% yield). Only 0.3 g (1.8 % yield) of (lS,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalene-1 -carboxylic acid were isolated.

³ H and ¹³ C NMR spectral data are identical to those reported in Hua, D. H.; Huang, X.; Chen, Y.; Battina, S. K.; Tamura, M.; Noh, S. K.; Koo, S. I.; Namatame, I.; Tomada, H.; Perchellet, E. M.; Perchellet, J.-P. J. Org. Chem. 2004, 69, 6065-6078.

Example 3

Preparation of (lS,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen e-l- carboxylic acid from (lS,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen e-l- carbaldehyde

20.0 g (69.7 mmol) (lS,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen e-l- carbaldehyde, 13.08 g (218 mmol) AcOH, 28.5 g (386 mmol) isoamylene were added to 50 mL EtOAc. A mixture of 12.31 g (80% purity, 109 mmol) of NaClO ₂ in 60 mL water was introduced slowly under stirring, maintaining the temperature between 25-38°C. At the end of the addition the mixture was heated 30 min at 40°C (oilbath). After cooling down to room temperature 120 mL of a 10% aqueous Na ₂ S ₂ O ₃ solution was added and stirring was continued for 15 minutes. Then a 5 % aqueous NaOH solution was added until a slightly basic pH was measured. After 10 min of stirring a standard acid/base extraction (two extractions with Et ₂ O) was done. After evaporation of the solvent under reduced pressure one obtains 19.9 g as a crystalline solid. The product was purified by column chromatography (300 g SiCh, AcOEt/Cyclohexane 2/8) and 17.4 g of (lS,4aS,8aS)-5,5,8a- trimethyl-2-methylenedecahydronaphthalene-l -carboxylic acid) was isolated as a white solid (99.1% purity, 80% yield).

'H-NMR and ¹³ C-NMR analysis results in CDCh were in accordance with data from literature (T. Laube, J. Schroder, R. Stehle, K. Seifert, Tetrahedron 2002, 58, 4299- 4309). ¹³ C NMR (150 MHz, CDCh): 814.1, 18.9, 21.8, 23.2, 33.4, 33.5, 36.3, 39.1, 39.2, 42.0, 54.5, 63.0, 108.6, 143.2, 177.9.

(1 S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene- l-carboxylic acid can also prepared from ((lS,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthale n-l- yl)methanol using a Jones Oxidation (72% yield).

Example 4

Preparation of methyl (lS,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen e- 1-carboxylate from (1 S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalene- l- carboxylic acid

2 g (8.46 mmol) of (lS,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen e-l- carboxylic acid were heated to reflux under stirring in the presence of 18 g (200 mmol) of dimethylcarbonate (92°C boiling point of dimethyl carbonate) and 1.288 g (8.46 mmol) DBU. After 9 hours a complete conversion was achieved and the excess of dimethylcarbonate was evaporated under reduced pressure. 50 mL AcOEt were added and the solution was washed twice with a 5% aqueous HC1 solution and once with a saturated aqueous NaCl solution. The organic phase was dried over Na2SO4 and the solvent was evaporated under reduced pressure (2.08 g methyl (lS,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalene-1 -carboxylate, 98.5% purity, 97% yield). No further purification was necessary.

'H-NMR and ¹³ C-NMR analysis results in CDCh were in accordance with data from literature (T. Laube, J. Schroder, R. Stehle, K. Seifert, Tetrahedron 2002, 58, 4299- 4309). ¹³ C NMR (150 MHz, CDCh): 8 14.2, 18.9, 21.7, 23.3, 33.4, 33.5, 36.3, 39.1, 39.3, 42.1,

50.9, 54.6, 63.1, 108.4, 143.8, 172.1.

Methyl (lS,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen e-l-carboxylate can also be prepared from methyl (lS,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalene-1 -carboxylate in the presence of Mel and K2CO3 in acetone (4 h, 40°C, 91% yield).

Example 5

Preparation of (1 S,4aS,8aS)-l-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphth alen- 2(lH)-one from ((1 S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-l - yl)methanol

13.0 g (98.1% purity, 57.4 mmol) ((lS,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalen-l-yl)methanol were dissolved in 600 mL MeOH in an ozonolysis reactor. The mixture was cooled to 0°C and ozone was bubbled inside under stirring until a complete conversion of the starting material was observed by GC (KI test positive). After that oxygen (10 min) and nitrogen (10 min) were bubbled into the mixture. 7.13 g (114.7 mmol, 2 eq) Me2S were added at 0°C under stirring. The cooling was removed after 1.5 h and the mixture was stirred overnight at room temperature. As the KI test was slightly positive, 15.0 g (57.4 mmol, 1 eq) PPI13 was added. After 15 min the KI test was negative and the GC showed 96.7% of the product. The mixture was filtered and the solvent was evaporated under reduced pressure (Rotavap in the fumehood, 45°C, 50-5 mbar). Some pentane and dichloromethane were added and evaporated under reduced pressure (crude 32.9 g). The crude (mixed with small amounts of dichloromethane) was purified by flash chromatography (2x330g SiCh, eluent cyclohexane 7/EtOAc 3). 12.92 g (98.6% purity, 56.8 mmol, 99.0 % yield) of (lS,4aS,8aS)-l-(hydroxymethyl)-5,5,8a- trimethyloctahydronaphthalen-2(lH)-one were obtained as a white solid.

'H-NMR and °C-NMR analysis results in CDCh were in accordance with data from literature (Furuichi, N.; Hata, T.; Soetjipto, H.; Kato, M.; Katsumura, S.

Tetrahedron 2001, 57, 8425-8442).

^X H-NMR (500.15 MHz, CDCh): 0.81 (s, 3H), 0.87 (s, 3H), 0.98 (s, 3H), 1.23-1.34 (m, 2H), 1.44-1.56 (m, 4H), 1.64-1.73 (m, 2H), 2.02-2.08 (m, 1H), 2.29-2.36 (m, 2H), 2.47 (ddd, 1H J = 14.4 Hz, J = 5.0 Hz, J = 1.9 Hz), 3.60 (brd, 1H, J = 9.8 Hz) 3.96 (dd, 1H, J = 11.2 Hz, J = 9.5 Hz).

¹³ C NMR (150 MHz, CDCh): 515.9, 18.8, 21.8, 23.3, 33.6, 33.6, 39.1, 41.1, 41.7, 42.1,

53.5, 57.8, 65.4, 214.8. The reduction of the Ozonide can be also done with the mono Na salt of 3,3'- Thiodipropionic acid (2 eq, 99% yield).

The reduction of the Ozonide can be also done with the thiodiglycol (2 eq, 99% yield). The reduction of the Ozonide can be also done with the thiourea (0.5 eq, 95% yield). The same yield could be also obtained in AcOH.

Depending on the reducing reagent and on the pH before the solvent evaporation up to 6% of (lS,4aS,8aS)-l-((hydroxymethoxy)methyl)-5,5,8a-trimethylocta hydronaphthalen-

2(lH)-one could be identified by NMR-spectroscopy (or GC, after silylation). The content of (lS,4aS,8aS)-l-((hydroxymethoxy)methyl)-5,5,8a-trimethylocta hydronaphthalen-

2(lH)-one in (1 S,4aS,8aS)-l-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphth alen- 2(lH)-one did not influence the selectivity and yield of the thermal retro aldol reaction to (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(lH)-one.

(lS,4aS,8aS)-l-((hydroxymethoxy)methyl)-5,5,8a-trimethylo ctahydronaphthalen-2(lH)- one

¹³ C NMR (150 MHz, CDCh):

<515.5, 18.9, 21.7, 23.9, 33.5, 33.7, 39.3, 41.8, 41.9, 42.3, 54.0, 62.0, 64.0, 90.3, 211.4.

NMR signal for the the silylated (lS,4aS,8aS)-l-((hydroxymethoxy)methyl)-5,5,8a- trimethyloctahydronaphthalen-2( 1 H)-one : (lS,4aS,8aS)-5,5,8a-trimethyl-l- ((((trimethylsilyl)oxy)methoxy)methyl)octahydronaphthalen-2( lH)-one

¹³ C NMR (125 MHz, CDCh): -0.2, 15.4, 18.9, 21.7, 24.0, 33.5, 33.7, 39.3, 41.9, 42.0, 42.4, 54.1, 62.0, 63.9, 90.3, 210.5

Example 6

Preparation of (1 S,4aS,8aS)-l-(hvdroxymethyl)-5,5,8a-trimethyloctahvdronaphth alen- 2(lH)-one from ((1 S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahvdronaphthalen-l - yDmethanol with isolation of intermediate ozonide

1.00 g ((1 S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-l -yl)methanol (4.50 mmol) were dissolved in the Ozonolysis flask in 90 mL EtOAc. The mixture was cooled to 0°C and Oxygen was bubbled into the mixture under stirring for 10 min. Then Ozone was bubbled into the solution for 7 min at 0°C. Finally Oxygen and Nitrogen were bubbled into the mixture for 10 min at 0°C. The intermediate (((lS,4aS,8aS)-5,5,8a- trimethyloctahydro- lH-spiro[naphthalene-2,3 '-[1 ,2,4]trioxolan]- 1 -yl)methanol) was analysed by NMR-spectroscopy.

^X H-NMR (500.15 MHz) characteristic signals: 0.82 (s, 3H), 0.83 (s, 3H), 0.89 (s, 3H), 1.81- 1.87 (m, 1H), 1.91 (dd, 1H, J = 6.9 Hz, J = 2.1 Hz) 3.66 (dd, 1H, J = 11.8 Hz, J = 2.2 Hz), 3.92 (dd, 1H, J = 11.7 Hz, J = 16.6 Hz), 4.95 (s, 1H), 5.28 (s, 1H).

¹³ C NMR (125 MHZ, CDCh): 315.6, 18.6, 19.7, 21.6, 33.2, 33.6, 36.4, 38.6, 39.1, 41.7, 54.6, 58.2, 59.1, 93.0, 111.7.

To this intermediate was added 2.36 g (8.99 mmol 2 eq) PPI13 and the mixture was warmed up slowly to room temperature (2 hours). After stirring overnight and washing with a saturated aqueous NaCl solution, the mixture was dried over Na2SO4 and the solvent was evaporated under reduced pressure (Rotavap in the fume hood). The crude was purified by flash chromatography (100 g SiCh, eluent cyclohexane 7/EtOAc 3). 0.969 g (4.32 mmol, 96 % yield) of (lS,4aS,8aS)-l-(hydroxymethyl)-5,5,8a-trimethyloctahydronaph thalen- 2(lH)-one were obtained as a white solid.

The same yield (>95% yield) could be also obtained in CH2Q2.

Example 7

Preparation of (4aS,8aR)-5,5,8a-trimethvloctahvdronaphthalen-2(lH)-one from (lS,4aS,8aS)-l-(hvdroxvmethvl)-5,5,8a-trimethvloctahvdronaph thalen-2(lH)-one

2 g (97.8% purity, 8.72 mmol) (lS,4aS,8aS)-l-(hydroxymethyl)-5,5,8a- trimethyloctahydronaphthalen-2(lH)-one were dissolved in 26 mL 1-octanol. The mixture was added slowly (26 mL/h) from the top (under a N2 flow) to a heated pyrolysis column (23x2 cm, pyrolysis oven at 500°C), which was filled with 56 g glass beads and was connected to a water cooled condenser and a 100 mL flask under the pyrolysis column. When the addition was finished (1 hour), the oven was cooled down. When 50°C oven temperature were reached, the column was washed twice with 5 mL cyclohexane. The cyclohexane was evaporated under reduced pressure and the 1-octanol was distilled off under reduced pressure (Vigreux column). The crude (GC 89%) was purified by flash chromatography (120 g SiCh, eluent cyclohexane 8/EtOAc 2). 1376 mg (7.08 mmol, 81.2% yield) (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(lH)-one were obtainedas a white solid.

'H-NMR and °C-NMR analysis results in CDCh were in accordance with data from literature (A. Gautier, C. Vial, C. Morel, M. Lander, F. Naf, Helv. Chim.

Acta, 1987, 70, 2039 and I. Jabin, G. Revial, K. Melloul, M. Pfau, Tetrahedron'. Asymmetry 1997, 8, 1101-1109)

¹³ C NMR (90 MHz, CDCh): 518.8, 19.4, 21.4, 23.1, 33.2, 33.2, 38.4, 42.0, 42.0, 42.4, 52.2, 59.6, 211.6.

Example 8

Preparation of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(lH)-one and (lR,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-l-ca rboxylic acid from (lS,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahvdronaphthalen e-l-carbaldehvde

3.92 g (98.8% purity, 17.81 mmol) (lS,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalene-l-carbaldehyde were dissolved in 120 mL EtOAc in an ozonolysis reactor. The mixture was cooled to 0°C and ozone was bubbled inside under stirring until a complete conversion of the starting material was observed by GC (30 min, KI test positive). After that oxygen (10 min) and nitrogen (10 min) were bubbled into the mixture. 10.5 g (40.1 mmol, 2.25 eq) PPI13 were added. The cooling was removed after 1.5 h and the mixture was stirred overnight at room temperature (KI test was negative). The mixture was washed twice with a 2.5% aqueous NaOH solution. The organic phase was washed with a saturated aqueous NaCl solution, was dried over Na2SO4 and the solvent was evaporated under reduced pressure (Rotavap in the fumehood). The crude was purified by flash chromatography (120 g SiCh, eluent cyclohexane 8/EtOAc 2). 368 mg (1.89 mmol, 11% yield) (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(lH)-one were obtained as a white solid.

An 5% aqueous HC1 solution was added slowly to the combined aqueous phases (2.5% aqueous NaOH solution) until pH 4 was reached. The aqueous phase was extracted twice with 100 mL EtOAc. The combined organic phases were washed with a saturated aqueous NaCl solution and were dried over Na2SO4 and the solvent was evaporated under reduced pressure (4.70 g). The crude was purified by flash chromatography (220 g SiO2, eluent cyclohexane 8/EtOAc 2 to cyclohexane 6/EtOAc 4). 2 626 mg (11.02 mmol, 62% yield) (lR,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-l-ca rboxylic acid were obtained as a white solid.

(lR,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-l -carboxylic acid:

'H-NMR (500. 15 MHz, CDCh) characteristic signals: 0.88 (s, 3H), 0.98 (s, 3H), 1.05 (s, 3H), 1.23-1.30 (m, 1H), 1.46-1.61 (m, 5H), 1.72-1.82 (m, 2H), 2.09-2.17 (m, 2H), 2.43 (ddd, 1H, J = 13.5 Hz, J = 13.5 Hz, J = 7.5 Hz), 2.54 (ddd, 1H, J = 13.9 Hz, J = 5.0 Hz, J = 1.8 Hz), 3.27 (s, 1H), 12.56 (COOH).

¹³ C NMR (150 MHz, CDCh): £ 15.1, 18.7, 21.6, 23.8, 33.5, 33.8, 39.3, 41.6, 41.7, 43.6, 53.5, 68.8, 171.7, 208.8.

(lR,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-l -carboxylic acid can be transformed to (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(lH)-one in the presence of diluted sulfuric acid (and heating). A quantitative yield was obtained.

Example 9

Preparation of (4aS,8aR)-5,5,8a-trimethvloctahvdronaphthalen-2(lH)-one and (lR,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-l-ca rboxylic acid from (lS,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen e-l-carboxylic acid 0.617 g (2.613 mmol) (lS,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen e- 1-carboxylic acid were dissolved in 30 mL MeOH in an ozonolysis reactor. The mixture was cooled to 0°C and ozone was bubbled inside under stirring until a complete conversion of the starting material was observed by GC (10 min, KI test positive). After that oxygen (10 min) and nitrogen (10 min) were bubbled into the mixture. 0.399 g (6.414 mmol) Me2S were added at 0°C under stirring. The cooling was removed after 1.5 h and the mixture was stirred overnight at room temperature (KI test was negative). The solvent was evaporated under reduced pressure (in the fume hood). The crude was dissolved in diethyl ether and was washed with a 5% aqueous HC1 solution, with water (3 times), and with saturated aqueous NaCl solution. The aqueous phases were reextracted with diethyl ether and the combined organic phases were washed with a 5% aqueous NaOH solution. A precipitation was observed (not soluble in water, Na salt of (lR,4aS,8aS)-5,5,8a-trimethyl-2- oxodecahydronaphthalene-1 -carboxylic acid). The suspension was extracted twice with diethyl ether. The organic phases were separated and the suspension was treated with a 5% aqueous sulfuric acid solution. A CO2 formation was observed during stirring at room temperature. After 20 min the mixture was heated for 10 min at 50°C. After cooling down to room temperature 0.340 mg (1.75 mmol, 67% yield) of an insoluble white solid ((4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(lH)-one) could be separated from the aqueous phase.

Example 10

Preparation of methyl (lR,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-l- carboxylate from methyl (lS,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalene- 1 -carboxylate

13.66 g (54.6 mmol) methyl (lS,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalene-1 -carboxylate (54.27 mmol) were dissolved in the Ozonolysis flask in 350 mL MeOH. The mixture was cooled to 0°C and under stirring Ozone was bubbled into the solution for three hours. Then Oxygen was bubbled in for 15 min at 0°C. Dimethylsulfide (8.53 g, 137 mmol) was added quickly and the mixture was stirred 1.5 hours under Nitrogen bubbling (into the solution) at 0°C. After that the reaction was stirred 18.5 hours at room temperature. After the KI control (which has to be negative) the solvent was evaporated at reduced pressure (40°C) with a Rotavap in the fume hood. 13.34 g methyl (lR,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-l-ca rboxylate (52.6 mmol, 96% yield) were obtained. The product was not further purified and was used for the next step.

'H-NMR and °C-NMR analysis results in CDCh were in accordance with data from literature (Y. Tanada, K. Mori, Eur. J. Org. Chem. 2003, 848-854).

Example 11

Preparation of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(lH)-one from methyl (lR,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-l-ca rboxylate

13.34 g methyl (lR,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-l-ca rboxylate (52.6 mmol, from the previous step) were added to a mixture of 39.5 g (705 mmol) KOH, 78 mL water and 78 mL EtOH (flask with reflux condenser). After heating at 120°C (oil bath) for 26 hours the mixture was cooled down to room temperature. The reaction was added to ice water and was extracted three times with 500 mL Et2O. The combined organic phases were washed with 500 mL water, with 500 mL of a saturated aqueous NaCl solution and the organic phase was dried over Na2SO4. After evaporation of the solvent at reduced pressure one obtains 11.02 g (GC 94.5% purity) of the crude product. The product was purified by column chromatography (330 g SiCh, EtOAc/Cyclohexane 13/87 -> EtOAc/Cyclohexane 3/7). 8.66 g (44.58 mmol, 85% yield) (4aS,8aR)-5,5,8a- trimethyloctahydronaphthalen-2(lH)-one were obtained as a white solid.

The preparation of (-)-Polywood ((2S,4aS,8aR)-5,5,8a-trimethyldecahydronaphthalen-2-yl acetate) from (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(lH)-one was described in the literature:

Cortes, Manuel; Moreno, Luis; Lopez, Jose Journal of Chemical Research, Synopses (1998), (1), 36-37).

Example 12 formula (II) starting from ((lS,4aS,8aS)-5,5,8a-trimethyl-2- -l-yl)methanol a) Preparation of ((lS,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalen-l-yl )methyl formate

2 eq AC2O, 2 eq formic acid, 1 h, 50°C, toluene, 97% yield

'H-NMR (500.15 MHz, CDCh): 0.77 (s, 3H), 0.82 (s, 3H), 0.89 (s, 3H), 1.14 (dd, 1H, J = 12.6 Hz, J = 2.7 Hz), 1.17-1.29 (m, 2H), 1.29-1.39 (m, 1H), 1.39-1.44 (m, 1H), 1.47-1.62 (m, 2H), 1.69-1.77 (m, 2H), 2.00-2.22 (m, 2H), 2.40-2.44 (m, 1H), 4.26 (dd, 1H, J = 11.1 Hz, J = 9.6 Hz), 4.49 (dd, 1H, J = 11.3 Hz, J = 3.4 Hz), 4.52-4.55 (m, 1H), 4.88-4.90 (m, 1H), 8.04 (s, 1H).

¹³ C NMR (125 MHz, CDCh): 8 15.2, 19.1, 21.8, 23.9, 33.5, 33.6, 37.5, 39.0, 39.1, 41.9, 54.8, 55.0, 61.0, 107.2, 146.6, 161.3. b) Preparation of trimethyl(((lS,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalen-l-yl)methoxy) silane

3 eq TMSC1, 3 eq NEt ₃ , 83% yield

¹ H-NMR (500.15 MHz, CDCh): 0.16 (s, 9H), 0.73 (s, 3H), 0.85 (s, 3H), 0.97 (s, 3H), 1.23- 1.24 (m, 1H), 1.30-1.39 (m, 1H), 1.43-1.49 (m, 1H), 1.50-1.56 (m, 3H), 1.59-1.70 (m, 1H), 1.76-1.81 (m, 1H), 2.02-2.10 (m, 1H), 2.30-2.40 (m, 2H), 2.41-2.47 (m, 1H), 3.63 (dd, 1H, J = 9.6 Hz, J = 3.1 Hz), 3.87 (dd, 1H, J = 9.6 Hz, J = 7.6 Hz), 4.81 (d, 1H, J = 5.3 Hz), 4.86 (d, 1H, J = 5.3 Hz).

¹³ C NMR (150 MHz, CDCh): 8 -0.4, 15.2, 19.3, 21.8, 24.0, 33.5, 33.7, 37.9, 39.0, 39.2, 42.0, 55.2, 58.2, 59.0, 107.2, 147.6. c) Preparation of (4aS,5S,8aS)-5-((l-ethoxyethoxy)methyl)-l,l,4a-trimethyl- 6-methylenedecahydronaphthalene

3 eq Ethylvinylether, 0.11 eq CF3COOH, 30°C, 2.5 h 90% yield

¹ H-NMR (500.15 MHz, CDCh): 0.73 (s, 3H), 0.81 (s, 3H), 0.87 (s, 3H), 1.08-1.15 (m, 1H), 1.16-1.28 (m, 1H), 1.20 (td, 3H, J = 7.1 Hz, J = 1.4 Hz), 1.28-1.38 (m, 2H), 1.30 (dd, 3H, J = 5.3 Hz, J = 3.2 Hz), 1.37-1.45 (m, 1H), 1.45-1.59 (m, 2H), 1.67-1.79 (m, 2H), 1.92-1.99 (m, 1H), 2.02-2.11 (m, 1H), 2.37-2.43 (m, 1H), 3.43-3.52 (m, 1.5H), 3.60-3.69 (m, 2H), 4.26 (dd, 0.5H, J = 9.7 Hz, J = 3.4 Hz), 4.59-4.61 (m, 0.5H), 4.66-4.68 (m, 0.5H), 4.65- 4.72 (m, 1H), 4.85-4.87 (m, 0.5H), 4.87-4.89 (m, 0.5H).

¹³ C NMR (125 MHz, CDCh): 8 15.3, 15.4, 19.3, 19.8, 21.8, 24.0, 33.5, 33.7, 37.8, 38.9, 39.2, 42.0, 55.2, 56.1, 60.5, 62.1, 99.9, 107.3, 147.7.

¹³ C NMR (125 MHz, CDCh): 815.3, 15.3, 19.3, 19.6, 21.8, 24.0, 33.5, 33.7, 37.8, 38.8, 39.2, 42.0, 55.2, 56.1, 60.3, 61.0, 99.4, 107.2, 147.6. d) Preparation of (4aS,5S,8aS)-5-((benzyloxy)methyl)-l,l,4a-trimethyl-6- methylenedecahydronaphthalene

1.05 eq Benzyl chloride, 1.05 eq KO Bu, 43 h, rt, THF, 90% yield

'H-NMR (500.15 MHz, CDCh): 0.71 (s, 3H), 0.80 (s, 3H), 0.87 (s, 3H), 1.12 (dd, 1H, J = 12.5 Hz, J = 2.6 Hz), 1.15-1.23 (m, 2H), 1.27-1.36 (m, 1H), 1.36-1.41 (m, 1H), 1.43-1.57 (m, 1H), 1.65-1.74 (m, 2H), 2.01-2.10 (m, 1H), 2.36-2.44 (m, 2H), 2.41-2.47 (m, 1H), 3.57 (dd, 1H, J = 8.7 Hz, J = 8.7 Hz), 3.65 (dd, 1H, J = 9.5 Hz, J = 3.5 Hz), 4.45-4.54 (m, 2H), 4.59-4.61 (m, 1H), 4.86-4.88 (m, 1H), 7.26-7.40 (m, 5H).

¹³ C NMR (150 MHz, CDCh): 815.3, 19.2, 21.8, 24.0, 33.5, 33.7, 37.8, 38.9, 39.2, 42.0,

55.1, 56.0, 67.0, 73.2, 107.3, 127.5, 127.8, 128.3, 138.6, 147.6. Example 13

Preparation of compounds of formula (III) by oxidative cleavage of compounds of formula (II)

The starting material prepared in Example 12 (38.94 mmol) was dissolved in 100 mL solvent in an ozonolysis reactor. The mixture was cooled to 0°C and ozone was bubbled inside under stirring until a complete conversion of the starting material was observed by GC (50 min, KI test positive). After that oxygen (5 min) and nitrogen (5 min) were bubbled into the mixture. 20.43 g (77.88 mmol, 2 eq) PPI13 were added. The cooling was removed after 1.5 h and the mixture was stirred 3 h at room temperature (KI test was negative). In the case of MeOH as the solvent the solvent was evaporated under reduced pressure (Rotavap in the fumehood) and 100 mL EtOAc were added. The organic phase was washed with a saturated aqueous NaHCCE solution (50 mL) and water (50 mL). The solvent was evaporated under reduced pressure (Rotavap in the fumehood). The crude was purified by flash chromatography (Triphenylphosphine oxide can be eliminated by crystallizations in pentane (50 mL) before the flash chromatography). a) ((IS, 4aS, 8aS)-5, 5, 8a-trimethyl-2-oxodecahydronaphthalen-l-yl)methyl formate (Ozonolysis in MeOH, 78% yield):

^X H-NMR (500.15 MHz, CDCh): 0.78 (s, 3H), 0.86 (s, 3H), 0.98 (s, 3H), 1.24-1.29 (m, 1H), 1.36-1.41 (m, 1H), 1.44-1.50 (m, 1H) 1.52-1.62 (m, 3H), 1.63-1.70 (m, 1H), 1.75-1.80 (m 1H), 2.05-2.12 (m, 1H), 2.34 (td, 1H, J = 13.4 Hz, J = 7.1 Hz), 2.45-2.51 (m, 2H), 4.28 (dd, 1H, J = 10.9 Hz, J = 3.2 Hz), 4.51 (dd, 1H, J = 10.9 Hz, J = 8.4 Hz), 8.00 (s, 1H).

¹³ C NMR (150 MHz, DMSO): 814.9, 18.3, 21.4, 23.1, 33.1, 33.1, 38.2, 41.1, 41.2, 41.2, 52.1, 57.8, 61.0, 162.0, 209.1. b) ((IS, 4aS, 8aS)-5, 5, 8a-trimethyl-2-oxodecahydronaphthalen-l-yl)methyl acetate (Ozonolysis in MeOH, 69% yield)

^X H-NMR (500.15 MHz, CDCh): 0.77 (s, 3H), 0.86 (s, 3H), 0.97 (s, 3H), 1.22-1.29 (m, 1H), 1.35-1.42 (m, 1H), 1.44-1.50 (m, 1H) 1.50-1.60 (m, 3H), 1.61-1.70 (m, 1H), 1.75-1.80 (m 1H), 2.00 (s, 3H), 2.04-2.10 (m, 1H), 2.35 (td, 1H, J = 13.4 Hz, J = 7.1 Hz), 2.41-2.50 (m, 2H), 4.18 (dd, 1H, J = 11.0 Hz, J = 3.2 Hz), 4.40 (dd, 1H, J = 10.9 Hz, J = 8.2 Hz).

¹³ C NMR (100 MHz, CDCh): 815.4, 18.8, 21.1, 21.7, 23.8, 33.5, 33.6, 39.1, 41.8, 42.0, 42.2, 53.9, 58.9, 62.4, 171.1, 209.6. c) (IS, 4aS, 8aS)-5, 5, 8a-trimethyl-l-

((( trimethylsilyl)oxy)methyl)octahydronaphthalen-2(lH)-one (Ozonolysis in EtOAc, 77% yield)

^X H-NMR (500.15 MHz, DMSO): 0.44 (s, 9H), 0.62 (s, 3H), 0.80 (s, 3H), 0.93 (s, 3H), 1.21- 1.26 (m, 1H), 1.27-1.34 (m, 1H), 1.35-1.42 (m, 1H), 1.43-1.61 (m, 4H), 1.70-1.77 (m, 1H), 1.92-1.98 (m, 1H), 2.18-2.23 (m, 1H), 2.29-2.34 (m, 1H), 2.39-2.48 (m, 1H), 3.49 (dd, 1H, J = 10.2 Hz, J = 3.3 Hz), 3.88 (dd, 1H, J = 10.3 Hz, J = 7.0 Hz).

¹³ C NMR (125 MHz, DMSO): 8 -0.5, 14.9, 18.4, 21.4, 23.3, 33.1, 33.1, 38.4, 41.3, 41.4, 41.6, 52.5, 55.7, 65.1, 209.8. d) (IS, 4aS, 8aS)-l-( ( I -ethoxyethoxy)methyl)-5, 5, 8a- trimethyloctahydronaphthalen-2(lH)-one (Ozonolysis in EtOAc, 88% yield)

'H-NMR (500.15 MHz, DMSO): 0.64 (s, 3H), 0.81 (s, 3H), 0.94 (s, 3H), 1.09 (td, 3H, J = 7.1 Hz, J = 2.7 Hz), 1.13 (dd, 3H, J = 8.6 Hz, J = 5.3 Hz), 1.19-1.33 (m, 2H), 1.36-1.42 (m, 1H), 1.43-1.61 (m, 4H), 1.67-1.75 (m, 1H), 1.92-2.00 (m, 1H), 2.19-2.25 (m, 1H), 2.34- 2.40 (m, 1H), 2.40-2.49 (m, 1H), 3.49 (dd, 1H, J = 10.2 Hz, J = 3.3 Hz), 3.88 (dd, 1H, J = 10.3 Hz, J = 7.0 Hz), 3.29 (dd, 0.5H, J = 9.6 Hz, J = 3.3 Hz), 3.35-3.41 (m, 1H), 3.47 (dd, 0.5 H, J = 9.6 Hz, J = 3.4 Hz), 3.47-3.58 (m, 1H), 3.59 (dd, 0.5H, J = 9.7 Hz, J = 7.1 Hz), 3.83 (dd, 0.5H, J = 9.5 Hz, J = 6.9 Hz), 4.54-4.61 (m, 1H).

¹³ C NMR (125 MHz, DMSO): 8 15.0, 15.2, 18.4, 19.8, 21.4, 23.3, 33.1, 33.1, 38.4, 41.3,

41.3, 41.4, 52.5, 59.1, 59.9, 62.7, 99.3, 209.7.

¹³ C NMR (125 MHz, DMSO): 8 15.0, 15.1, 18.4, 19.6, 21.4, 23.3, 33.1, 33.1, 38.4, 41.2,

41.3, 41.4, 52.5, 59.1, 58.3, 62.7, 99.8, 209.6. e) (IS, 4aS, 8aS)-l-( (benzyloxy)methyl)-5, 5, 8a-trimethyloctahydronaphthalen- 2(lH)-one (Ozonolysis in MeOH, 78% yield)

^X H-NMR (500.15 MHz, CDCh): 0.72 (s, 3H), 0.84 (s, 3H), 0.96 (s, 3H), 1.21-1.29 (m, 1H), 1.32-1.40 (m, 1H), 1.40-1.60 (m, 4H), 1.60-1.70 (m, 1H), 1.70-1.76 (m 1H), 2.02-2.19 (m, 1H), 2.36 (tdd, 1H, J = 13.1 Hz, J = 7.0 Hz, J = 0.7 Hz), 2.41-2.47 (m, 2H), 3.47 (dd, 1H, J = 9.4 Hz, J = 3.5 Hz), 3.91 (dd, 1H, J = 9.5 Hz, J = 6.8 Hz), 4.45 (d, 1H, J = 11.9 Hz), 4.53 (d, 1H, J = 11.9 Hz), 7.23-7.35 (m, 5H).

¹³ C NMR (125 MHz, CDC1 ₃ ): 815.4, 18.9, 21.7, 23.9, 33.5, 33.6, 39.2, 41.9, 42.0, 42.4, 54.0, 64.1, 64.4, 73.4, 127.5, 127.7, 128.3, 138.6, 210.7.

Example 14

Preparation of (1 S,4aS,8aS)-l-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphth alen- 2(lH)-one

A standard protocol using H2SO4 or KHCO3 was used in most of the cases.

To 0.394 mmol of the starting material prepared in Example 13 in 400 mg MeOH were added 155 mg of a 5% aqueous solution of H2SO4 (0.2 eq). The mixture was stirred at room temperature until a full deprotection to (lS,4aS,8aS)-l-(hydroxymethyl)-5,5,8a- trimethyloctahydronaphthalen-2(lH)-one was observed (GC analysis using silylation). 753 mg of a 10% aqueous solution of K2CO3 (1.4 eq) were added and the MeOH was evaporated under reduced pressure. 5 g of cyclohexane were added and the mixture was washed twice with 5 g of water. The solvent was evaporated under reduced pressure (GC analysis using silylation). or

To 0.394 mmol of the starting material prepared in Example 13 in 400 mg MeOH were added 8 mg of KHCO3 was added (0.2 eq). The mixture was stirred at room temperature until a full deprotection to (lS,4aS,8aS)-l-(hydroxymethyl)-5,5,8a- trimethyloctahydronaphthalen-2(lH)-one was observed (GC analysis using silylation). The MeOH was evaporated under reduced pressure. 5 g of cyclohexane were added and the mixture was washed twice with 5 g of water. The solvent was evaporated under reduced pressure (GC analysis using silylation). a) ((IS, 4aS, 8aS)-5, 5, 8a-trimethyl-2-oxodecahydronaphthalen-l-yl )methyl formate to (!S,4aS,8aS)-l-(hydroxymethyl)-5,5,8a- trimethyloctahydronaphthalen-2 (1H) -one :

0.2 eq H2SO4 in water/MeOH, 4 h at room temperature, 100% conversion, 97.6% (1 S,4aS,8aS)-l-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphth alen-2(lH)-one by GC analysis (using silylation).

0.2 eq KHCOs in MeOH, 3.5 h at room temperature, 99% conversion, 97.4% (!S,4aS,8aS)- l-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphthalen-2(lH)- oneby GC analysis (using silylation). b) ((IS, 4aS, 8aS)-5, 5, 8a-trimethyl-2-oxodecahydronaphthalen-l-yl)methyl acetate to (!S,4aS,8aS)-l-(hydroxymethyl)-5,5,8a- trimethyloctahydronaphthalen-2(lH)-one and (!R,4aS,8aS)-l- (hydroxymethyl)-5, 5, 8a-trimethyloctahydronaphthalen-2(lH)-one :

0.2 eq H2SO4 in water/MeOH, 3 d at room temperature, 99% conversion, 59.1% (lS,4aS,8aS)-l-(hydroxymethyl)-5,5,8a-trimethyloctahydronaph thalen-2(lH)-one and 15.7% of (lR,4aS,8aS)-l-(hydroxymethyl)-5,5,8a-trimethyloctahydronaph thalen-2(lH)- one by GC analysis (using silylation). c) (IS, 4aS, 8aS)-5, 5, 8a-trimethyl-l-

((( trimethylsilyl)oxy)methyl)octahydronaphthalen-2(lH)-one to

(IS, 4aS, 8aS)-l -(hydroxymethyl) -5, 5, 8a-trimethyloctahydronaphthalen- 2(lH)-one:

0.2 eq H2SO4 in water/MeOH, 2 h at room temperature, 100% conversion, 97.5% (1 S,4aS,8aS)-l-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphth alen-2(lH)-one by GC analysis (using silylation). d) (IS, 4aS, 8aS)-l-( 61 -ethoxyethoxy)methyl)-5, 5, 8a- trimethyloctahydronaphthalen-2(lH)-one to (!S,4aS,8aS)-l- (hydroxymethyl) -5, 5, 8a-trime thyloctahydronaphthalen-2 (1H) -one :

0.2 eq H2SO4 in water/MeOH, 2 h at room temperature, 99% conversion, 94.2% (1 S,4aS,8aS)-l-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphth alen-2(lH)-one by GC analysis (using silylation). e) (IS, 4aS, 8aS)-l-( (benzyloxy)methyl)-5, 5, 8a-trimethyloctahydronaphthalen-

2(lH)-one to (!S,4aS,8aS)-l-(hydroxymethyl)-5,5,8a- trimethyloctahydronaphthalen-2 (1H) -one :

300 mg (lS,4aS,8aS)-l-((benzyloxy)methyl)-5,5,8a-trimethyloctahydro naphthalen-2(lH)- one were reacted in the presence of 100 mg Palladium on characoal 10% in 10 mL EtOH in an autoclave (4 h at 20 psi H2). A full conversion was observed (98% selectivity for 1 S,4aS, 8aS)- 1 -(hydroxymethyl)-5 , 5 , 8 a-trimethyl octahydronaphthal en-2( 1 H)-one) . The mixture was filtered on a pad of celite® and the solvent was evaporated under reduced pressure.

Example 15

Preparation of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(lH)-one from (lS,4aS,8aS)-l-(hydroxymethyl)-5,5,8a-trimethyloctahydronaph thalen-2(lH)-one

An isolated Inox tube with heating system (Pyrolysis Oven, 3 cm x 50 cm) was connected to an cooling condenser on the top of the column and to an evaporator system on the bottom. The column was heated up to 530°C (internal) and the evaporator to 240°C during 1 h. The whole system was set under vacuum (10 mbar). A mixture of 8.68 g (38.57 mmol) of (1 S,4aS,8aS)-l-(hydroxymethyl)-5,5,8a-trimethyloctahydronaphth alen-2(lH)-one and 44 mL of 1 -hexanol were added to the evaporator with a syringe pump (115g/h) and the mixture was evaporated at 240°C and distilled through the Inox tube (530°C internal) and the product mixture (96% selectivity by GC) was collected with the cooling condenser in a flask. The evaporator and the column was purged with 1 -hexanol (50 g) and heptane (90 g). After workup (saturated aqueous NaHCO, solution and water washes), solvent evaporation and distillation (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(lH)-one was obtained with 97% selectivity (7.14 g, 36.75 mmol, 95% isolated yield)

Example 16

Preparation of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(lH)-one from (lS,4aS,8aS)-l-(hvdroxvmethvl)-5,5,8a-trimethvloctahvdronaph thalen-2(lH)-one (solvent testing) general protocol:

400 mg (95% purity, 1.69 mmol) (lS,4aS,8aS)-l-(hydroxymethyl)-5,5,8a- trimethyloctahydronaphthalen-2(lH)-one were dissolved in 6 mL of the solvent. The mixture was added slowly (26 mL/h) from the top (under a N2 flow) to a heated pyrolysis column (23x2 cm, pyrolysis oven at 500°C), which was filled with 56 g glass beads and was connected to a water cooled condenser and a 25 mL flask under the pyrolysis column. GC analysis of a drop of the mixture after 4 min gave the selectivity of the formation of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(lH)-one.

1 -octanol: 89% product selectivity (GC) , full conversion (GC)

4-methyl-2 -pentanone: 81% product selectivity (GC), full conversion (GC) 1 -hexanol: 87% product selectivity (GC), full conversion (GC) 1 -butanol: 83% product selectivity (GC), full conversion (GC)

1 -propanol: 92% product selectivity, full conversion (GC)

Ethanol: 89% product selectivity (GC), full conversion (GC)

Methanol: 83% product selectivity (GC after 14 min)

1-hexenal: 80% product selectivity (GC), full conversion (GC) dibutylether: 84% product selectivity (GC), full conversion (GC) cyclohexanone: 87% product selectivity (GC), full conversion (GC) p-xylene: 87% product selectivity (GC), full conversion (GC)

Example 17

Preparation of (4aS,5S,8aS)-l, l,4a-trimethvl-6-methvlene-5-vinvldecahvdronaphthalene The acetate (2-((l S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-l - yl)ethyl acetate) or the tosylate (2-((lS,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalen-l-yl)ethyl 4-methylbenzenesulfonate) of 2-((lS,4aS,8aS)- 5,5,8a-trimethyl-2-methylenedecahydronaphthalen-l-yl)ethan-l -ol can be prepared from (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldecahydronaphtho[2,l- b]furan-2(lH)-one according the literature (G. Ohl off, W. Giersch Croatica Chem. Acta 1985, 5S, 491-509). Elimination reaction of the acetate (thermal pyrolysis at 500°C) or of the tosylate (DBU) gave (4aS,5S,8aS)-l,l,4a-trimethyl-6-methylene-5-vinyldecahydrona phthalene as a yellow liquid.

^X H-NMR (500.15 MHz, CDCh): 0.80 (s, 3H), 0.83 (s, 3H), 0.88 (s, 3H), 0.95-1.02 (m, 1H), 1.06-1.12 (m, 1H), 1.15-1.22 (m, 1H), 1.31-1.55 (m, 5H), 1.65-1.72 (m, 1H), 2.03-2.14 (m, 1H), 2.26-2.32 (m, 1H), 2.40-2.46 (m, 1H), 4.50-4.51 (m, 1H), 4.73-4.75 (m, 1H), 4.99 (dd, 1H, J = 14.8 Hz, J = 2.3 Hz), 5.09 (dd, 1H, J = 10.2 Hz, J = 2.5 Hz), 5.83 (dt, 1H, J = 20.0 Hz, J = 10.1 Hz).

¹³ C NMR (125 MHz, CDCh): 814.9, 19.1, 21.9, 23.4, 33.5, 33.6, 36.8, 38.5, 40.6, 42.3, 54.7, 62.5, 107.7, 117.0, 136.7, 150.1.

Intermediates for the preparation of (4aS,5S,8aS)-l,l,4a-trimethyl-6-methylene-5- vinyl decahydronaphth al ene : (2-((lS,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphth alen-l-yl)ethyl acetate)

¹³ C NMR (150 MHz, CDCh): 8 14.4, 19.3, 21.1, 21.7, 23.1, 24.3, 33.6, 33.6, 38.1, 39.0, 39.4, 42.1, 53.0, 55.5, 64.4, 106.6, 148.1, 171.2.

(2-((lS,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronap hthalen-l-yl)ethyl 4- methylbenzenesulfonate)

¹³ C NMR (150 MHz, CDCh): 814.3, 19.2, 21.6, 23.5, 24.2, 33.5, 33.6, 37.9, 38.8, 39.3, 42.0, 52.2, 55.3, 70.7, 106.4, 127.9, 129.8, 133.4, 144.5, 147.8.

Example 18

1 g (4.58 mmol) (4aS,5S,8aS)-l,l,4a-trimethyl-6-methylene-5-vinyldecahydrona phthalene were dissolved in 100 mL EtOAc in an ozonolysis reactor. The mixture was cooled to 0°C and ozone was bubbled inside under stirring until a complete conversion of the starting material was observed by GC (KI test positive). After that oxygen (10 min) and nitrogen (10 min) were bubbled into the mixture. 4.26 g (16.03 mmol, 3.5 eq) PPI13 were added. The cooling was removed after 1.5 h and the mixture was stirred overnight at room temperature (KI test was negative). The solvent was evaporated under reduced pressure (Rotavap in the fumehood). GC Analysis gave a 1/1 mixture of (4aS,8aR)-5,5,8a- trimethyloctahydronaphthalen-2(lH)-one and (4aS,8aS,Z)-l-(hydroxymethylene)-5,5,8a- trimethyloctahydronaphthalen-2(lH)-one. NMR analysis gave a mixture of (4aS,8aR)- 5 , 5 , 8a-trimethyloctahydronaphthalen-2( 1 H)-one, (lR,4aS,8aS)-5,5,8a-trimethyl-2- oxodecahydronaphthalene- 1 -carboxylic acid and (4aS,8aS,Z)-l-(hydroxymethylene)- 5,5,8 a-trimethyl octahydronaphthal en-2( 1 H)-one .

This mixture could be fully transformed to (4aS,8aR)-5,5,8a- trimethyloctahydronaphthalen-2(lH)-one by an oxidative (CrO,, acetone, heat) treatment (WO2012125488 Anderson, Eric; et al) or a basic (3 eq NaOAc in EtOH, reflux, 16 h, full conversion, selectivity >95%) treatment (decarbonylation/decarboxylation according to Xiang, H.; Zhao, Q.-L.; Xia, P.-J.; Xiao, J.-A.; Ye, Z.-P.; Xie, X.; Sheng, H.; Chen, X.- Q.; Yang, H. Org. Let. 2018, 20, 1363- 1366).

(4aS,8aS,Z)-l-(hydroxymethylene)-5,5,8a-trimethyloctahydr onaphthalen-2(lH)-one ¹³ C NMR (150 MHz, CDC1 ₃ ): 817.7, 18.9, 21.3, 25.0, 32.9, 33.1, 33.3, 35.3, 38.3, 41.4, 50.3, 122.8, 183.0, 188.9.

(4aS,8aS,Z)-l-(hydroxymethylene)-5,5,8a-trimethyloctahydr onaphthalen-2(lH)-one could be also obtained by the oxidation with air (bubbling into the solution for 2 days at room temperature) of the intermediate of Example 6 ((((lS,4aS,8aS)-5,5,8a- trimethyloctahydro- lH-spiro[naphthalene-2,3 '-[1 ,2,4]trioxolan]- 1 -yl)methanol)) in the presence of 20 mol% Fe(NO3)39H2O, 20 mol% KC1 and 20 mol% TEMPO. After the addition of PPI13, aqueous workup/solvent evaporation (in the fume hood) and column chromatography (4aS,8aS,Z)-l-(hydroxymethylene)-5,5,8a- trimethyloctahydronaphthalen-2(lH)-one could be isolated in 67% yield over 2 steps (ozonolysis and oxidation). Smaller quantities (3% yield) of (4aS,8aR)-5,5,8a- trimethyloctahydronaphthalen-2(lH)-one were also isolated.

Example 19

Benzyl (lR,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-l-ca rboxylate could be prepared from (lS,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen e-l- carboxylic acid in 2 chemical steps (BzBr, K2CO3, Acetone and O3, PPI13, MeOH) or according to Pollini, G. P.; Bianchi, A.; Casolari, A.; Risi, C.; Zanirato, V.; Bertolasi, V. Tetrahedron: Asymmetry 2004, 15, 3223 from methyl (lR,4aS,8aS)-5,5,8a-trimethyl-2- oxodecahydronaphthalene- 1 -carboxylate.

Benzyl (lS,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen e-l-carboxylate ^X H-NMR (500.15 MHz, CDCI3): 0.80 (s, 3H), 0.87 (s, 3H), 1.07 (s, 3H), 1.05-1.10 (m, 1H), 1.14-1.23 (m, 2H), 1.35-1.46 (m, 3H), 1.47-1-63 (m, 2H), 1.65-1.72 (m 1H), 2.00-2.10 (m, 1H), 2.36-2.44 (m, 1H), 2.86 (s, 1H), 4.65-4.67 (m, 1H), 4.80-4.83 (m, 1H), 5.10 (s, 2H), 7.28-7.37 (m, 5H). ¹³ C NMR (150 MHz, CDCh): 8 14.3, 18.9, 21.7, 23.3, 33.4, 33.5, 36.3, 39.1, 39.4, 42.0, 54.6, 63.1, 65.7, 108.4, 128.1, 128.2, 128.5, 136.2, 143.7, 171.5.

Benzyl (lR,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-l-ca rboxylate

¹³ C NMR (125 MHz, CDCh): 814.9, 18.6, 21.7, 23.0, 33.5, 33.5, 39.1, 41.3, 41.8, 42.2, 53.2, 66.2, 70.0, 128.2, 128.2, 128.5, 135.8, 168.1, 205.4.

'H-NMR analysis results in CDCL were in accordance with data from literature (Pollini, G. P.; Bianchi, A.; Casolari, A.; Risi, C.; Zanirato, V.; Bertolasi, V. Tetrahedron: Asymmetry 2004, 75, 3223-3231).

Hydrogenation reaction (according to Pollini et al Tetrahedron: Asymmetry 2004, 75, 3223) of 108 mg Benzyl (lR,4aS,8aS)-5,5,8a-trimethyl-2- oxodecahydronaphthalene-1 -carboxylate (33 mg Pd/characoll0%, H2, 2 mL EtOH, 2 h at 20 psi) led to the formation of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(lH)-one (selectivity 100%, full conversion). No trace of (lR,4aS,8aS)-5,5,8a-trimethyl-2- oxodecahydronaphthalene-1 -carboxylic acid was observed (validated by silylation, methylation with trimethyl silyl diazomethane and NMR of the crude).

Example 20

Comparative Example

50 mg Methyl (lR,4aS,8aS)-5,5,8a-trimethyl-2-oxodecahydronaphthalene-l-ca rboxylate was heated in the presence of 10 mg KI in 0.5 mL DMF at reflux (150°C) for 5 h (according to Ohloff, G.; Naf, E; Decorzant, R.; Thommen, W .; Sundt, E. Helv. Chim. Acta 1973, 56, 1414-1448). The formation of (4aS,8aR)-5,5,8a-trimethyloctahydronaphthalen-2(lH)-one was observed (full conversion of starting material). No trace of (lR,4aS,8aS)-5,5,8a- trimethyl-2-oxodecahydronaphthalene-l -carboxylic acid was detected (validated by silylation, methylation with trimethylsilyldiazomethane and NMR of the crude).