EP4658642A1

EP4658642A1 - Process for preparing a oxacylopentane derivative

Info

Publication number: EP4658642A1
Application number: EP24703005.9A
Authority: EP
Inventors: Jean-Francois Basset; Denis Jacoby; Jean-Jacques Riedhauser; Oliver Knopff; Iris MAGPANTAY
Original assignee: Firmenich SA
Current assignee: Firmenich SA
Priority date: 2023-02-01
Filing date: 2024-02-01
Publication date: 2025-12-10
Also published as: JP2026504648A; WO2024160930A1; MX2025006144A; IL320938A; CN120677147A

Abstract

The present invention relates to the field of organic synthesis and, more specifically, it concerns a process for the preparation of a cycloether of formula (I) comprising the cyclisation of compound of formula (II) performed in the presence of Lewis acid, a protic acid having a pKa equal or below (2) or a mixture thereof.

Description

Firmenich SA 1 PROCESS FOR PREPARING A OXACYLOPENTANE DERIVATIVE Technical field The present invention relates to the field of organic synthesis and, more specifically, it concerns a process for the preparation of a cycloether of formula (I) comprising the cyclisation of compound of formula (II) performed in the presence of Lewis acid or a protic acid having a pKa equal or below 2. The cycloether 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 cycloether derivatives in perfumery industry are, for example, Cetalox^® ((3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1- b]furan; origin: Firmenich SA, Geneva, Switzerland) or Ambrox^® ((3aR,5aS,9aS,9bR)- 3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; origin: Firmenich SA, Geneva, Switzerland) being a key constituent of natural ambergris. Those perfuming ingredients represent some of the most sought-after ingredients in the perfumery industry. Several alternative processes to prepare Cetalox^® or Ambrox^® have been developed and in particular via a cyclisation reaction of respectively 2-[(1SR,4aSR,8aSR)-5,5,8a-trimethyl- 2-methylenedecahydro-1-naphthalenyl]ethanol or 2-[(1S,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydro-1-naphthalenyl]ethanol as a last step. In Helv.Chem.Acta, 1985, 2022, the cyclisation was performed in the presence of an excess of paratoluene sulfonic acid in nitromethane. However no yield and selectivity was reported. Said conditions were carried out on close analogues such as reported in Tetrahedron 1993, 6251 or Synlett 2016, 368 leading to a desired compound in a moderate yield. In the meantime, today there is a need to foster sustainable processes, for examples using catalytic amount of acid, avoiding hazardous solvent such as nitromethane and obtaining high yield and selectivity to minimize wastes. The cyclisation of a regioisomer or a mixture of regioisomers of compound of formula (II) in the presence of sub stochiometric amount of Lewis acid was reported in WO2009053884 leading to the formation of compound of formula (I) in medium yield and selectivity. Firmenich SA 2 So, there is still a need to develop a sustainable cyclisation process in the presence of a catalytic amount of reagents while improving the conversion and the selectivity. The present invention allows to solve the above problem by using Lewis acid, a protic acid having a pKa equal or below 2 or a mixture thereof in order to prepare a cycloether of formula (I). To the best of our knowledge, the invention’s conditions have never been reported in the prior art. Summary of the Invention The invention relates to a novel process allowing the preparation of a cycloether formula (I) by the cyclisation of a compound of formula (II) in a presence of Lewis acid or a protic acid having a pKa equal or below 2 or a mixture thereof allowing to achieve high yield and selectivity. So, a first object of the present invention is the preparation of a compound of formula (I) wherein the bold and hatched lines indicate a relative or absolute configuration; comprising the cyclisation of compound of formula (II) wherein the bold and hatched lines indicate a relative or absolute configuration; in the presence of a Lewis acid or a protic acid having a pKa equal or below 2 or a Firmenich SA 3 mixture thereof. Description of the invention Surprisingly, it has now been discovered that the cyclisation of compound of formula (II) in a presence of a catalytic amount of a Lewis acid, a protic acid having a pKa equal or below 2, particularly a protic acid having a pKa equal or below -3, or a mixture thereof allows preparing a compound of formula (I) with high yield and high selectivity. The invention’s process allows limiting even preventing the isomerization of the double bond in a more stable position; i.e. the isomerization of a double bond in an endo position; while maintaining even improving the formation of desired isomers; i.e. limiting the formation of the undesired diastereoisomer. Therefore, a first object of the present invention is a process for the preparation of a cycloether of formula (I) wherein the bold and hatched lines indicate a relative or absolute configuration; comprising the cyclisation of compound of formula (II) wherein the bold and hatched lines indicate a relative or absolute configuration; in the presence of a Lewis acid or a protic acid having a pKa equal or below 2 or a mixture thereof. Firmenich SA 4 For the sake of clarity, by the term “pKa” or the similar, it is meant the normal meaning understood by a person skilled in the art, i.e it is the negative base -10 logarithm of the acid dissociation constant and it represents the strength of an acid in solution. The pKa in the present invention corresponds to the pKa measured/calculated in water. 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 (3aRS,5aSR,9aSR,9bRS) stereoisomer and compound (II) is in the form of a mixture of stereoisomers comprising more than 50% (w/w) of the (1SR,4aSR,8aSR); 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 (3aR,5aS,9aS,9bR) stereoisomer and compound (II) is in the form of a mixture of stereoisomers comprising more than 50% (w/w) of the (1S,4aS,8aS). For the sake of clarity, by the expressions “(3aRS,5aSR,9aSR,9bRS)” or “(1SR,4aSR,8aSR)”, it is meant an equimolar mixture of (3aR,5aS,9aS,9bR) and (3aS,5aR,9aR,9bS) or an equimolar mixture of (1S,4aS,8aS) and (1R,4aR,8aR). According to a particular embodiment, the compound of formula (II) may be in a form of a composition of matter comprising compound of formula (II) and compound of formula (II^a) wherein the bold and hatched lines indicate a relative or absolute configuration. Particularly, compound of formula (II) may be in a form of a composition of matter comprising at least 95% of compound of formula (II) and at most 5% of compound of formula (II^a). Particularly, compound of formula (II) may be in a form of a composition of matter comprising at least 98% of compound of formula (II) and at most 2% of compound of formula (II^a). Particularly, compound of formula (II) may be in a form of a composition of matter comprising at least 99% of compound of formula (II) and at most 1% of Firmenich SA 5 compound of formula (II^a). Particularly, compound of formula (II) may be in a form of a composition of matter comprising at least 99.5% of compound of formula (II) and at most 0.5% of compound of formula (II^a). Even more particularly, the compound of formula (II) is free of compound of formula (II^a). According to a particular embodiment, the compound of formula (II) is in the form of a mixture of stereoisomers comprising at least 60% (w/w) of the 2-((1SR,4aSR,8aSR)- 5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol, even at least 75% of 2- ((1SR,4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol, even at least 90% of 2-((1SR,4aSR,8aSR)-5,5,8a-trimethyl-2- methylenedecahydronaphthalen-1-yl)ethan-1-ol, even at least 95% of 2- ((1SR,4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol, even at least 98% of 2-((1SR,4aSR,8aSR)-5,5,8a-trimethyl-2- methylenedecahydronaphthalen-1-yl)ethan-1-ol, even more compound of formula (II) is 2- ((1SR,4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol. According to a particular embodiment, the compound of formula (I) is in the form of a mixture of stereoisomers comprising at least 80% (w/w) of the (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan, even at least 85% of (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1- b]furan, even at least 90% of (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a- tetramethyldodecahydronaphtho[2,1-b]furan, even at least 95% of (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan, even at least 98% of (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1- b]furan, even more compound of formula (II) is (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a- tetramethyldodecahydronaphtho[2,1-b]furan. According to any embodiments of the invention, the compound of formula (I) and compound of formula (II) are in a form a pure enantiomer. In other words, the compound of formula (I) is of formula Firmenich SA 6 wherein the bold and hatched lines indicate an absolute configuration; and the compound of formula (II) is of formula wherein the bold and hatched lines indicate an absolute configuration; According to any embodiments of the invention, Lewis acid and the protic acid having a pKa below 2 are homogeneous. According to any embodiments of the invention, the protic acid has a pKa equal or below 0, preferably equal or below -2, preferably equal or below -3, preferably equal or below -4, preferably equal or below -4.5, preferably equal or below -8. According to a particular embodiment, the protic acid when used in combination of a Lewis Acid has a pKa equal or below 2, preferably equal or below 0, preferably equal or below -2, preferably equal or below -3, preferably equal or below -4, preferably equal or below -4.5, preferably equal or below -8. According to a particular embodiment, the protic acid when used without a Lewis Acid has a pKa equal or below -3, preferably equal or below -4, preferably equal or below -4.5, preferably equal or below -8. According to any embodiments of the invention, the protic acid is selected from the group consisting of HBF4, HBF4.OEt2, tetrafluoroboric acid aqueous solution, hexafluorophosphoric acid, triflic acid, phosphotungstic acid hydrate, Phosphomolybdic acid hydrate, fluoroantimonic acid, perchloric acid, hydrogen bromide, hydrogen iodide, Firmenich SA 7 hydrochloric acid and a mixture thereof. Particularly, the protic acid is perchloric acid. The perchloric acid may be formed in situ by adding sulfuric acid on barium perchlorate. According to any embodiments of the invention, the protic acid having a pKa equal or below 2 is not methane sulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid. According to any embodiments of the invention, the Lewis acid is of formula MX_n wherein M is a metal, X is a weakly or non-coordinating ligand and n is 1, 2 or 3 and depend on the oxidation state of the metal and the nature of the anion (dianion or monanion). When the metal is a monovalent metal cation, then n is 1, when the metal is a divalent metal cation, then n is 2 when X is a monoanion or n is 1 when X is a dianion, and when the metal is a trivalent metal cation, then n is 3 when X is a monoanion or n is 2 when X is a dianion and another X is a monoanion. Non-limiting examples of suitable weakly or non-coordinating ligands include BF₄- , ClO₄-, PF₆-, HSO4-, SO₄ ^2-, TfO-, NTf₂ -, TsO-, ClSO₃-, F-, Cl-, or Br-. It is understood that whereas n is 2 or 3, then each of X group may be identical or different. According to a particular embodiment, n may be 2 and 3. In other words, the Lewis acid is of formula MX₂ or MX₃ wherein M is a metal selected from the group consisting of B, Bi and Fe and X is a F-or Cl- or a triflate, sulfate or hydrogenosulfate group or a mixture thereof. Particularly, the metal may be selected from the group of Bi and Fe and X may be selected from the group of Cl- or a triflate, sulfate or hydrogenosulfate group and a mixture thereof. Non-limiting examples of suitable Lewis acid include Fe(HSO₄)₃, FeSO₄(HSO₄), BF₃.OEt₂O, Bi(OTf)₃, Fe(Cl)₃, FeCl₃·6H₂O, Bi(Cl)3, Fe(OTf)₃ and a mixture thereof. Particularly, the metal may be selected from the group consisting of Fe(HSO₄)₃, FeSO₄(HSO₄), Bi(OTf)₃, Fe(Cl)₃, Bi(Cl)₃, Fe(OTf)₃ and a mixture thereof Lewis acid or protic acid used may be in a anhydrous or hydrate form and Lewis acid may be in a form of an adducts with an ether or a carboxylic acid, such as R¹ 2O or R²COOH, wherein R¹ is a C₁-C₅ alkyl group, such as C₂H₅ or C₄H₉, and R² is a C₁-C₂₀ alkyl group, such a methyl, ethyl or hept-3-yl. According to a particular embodiment of the invention, the invention’s process is performed in the presence of a Lewis acid and a protic acid having a pKa equal or below 2. Particularly, the Lewis acid is of formula MX_n wherein M is Fe and X and n as the same meaning as defined above. The ratio between the Lewis acid and the protic acid having a Firmenich SA 8 pKa equal or below 2 is comprised between 0.5:1 and 1:0.5, particularly between 0.8:1 and 1:0.8, even more particularly, the ratio between the Lewis acid and the protic acid having a pKa equal or below 2 is 1:1. Non-limiting examples of suitable Lewis acid include Fe(HSO₄)₃, FeSO₄(HSO₄), Fe(Cl)₃, FeCl₃·6H₂O, Fe(OTf)₃, or a mixture thereof and non- limiting example of suitable protic acid used in combination with the Lewis acid include HBF₄, HBF₄.OEt₂, tetrafluoroboric acid aqueous solution, paratoluenesulfonic acid, methanesulfonic acid, hexafluorophosphoric acid, triflic acid, phosphotungstic acid hydrate, Phosphomolybdic acid hydrate, fluoroantimonic acid. perchloric acid or a mixture thereof. Particularly, the invention’s process is performed in the presence of a Lewis acid selected from the group consisting of Fe(HSO₄)₃, FeSO₄(HSO₄), Fe(Cl)₃, FeCl₃·6H₂O, Fe(OTf)₃ or a mixture thereof and a protic acid having a pKa equal or below 2 selected from the group consisting of HBF₄, tetrafluoroboric acid aqueous solution, paratoluenesulfonic acid, hexafluorophosphoric acid, triflic acid, fluoroantimonic acid, perchloric acid and a mixture thereof. Particularly, the invention’s process is performed in the presence of a Lewis acid being Fe(Cl)₃ and a protic acid having a pKa equal or below 2 selected from the group consisting of HBF₄, tetrafluoroboric acid aqueous solution, paratoluenesulfonic acid, hexafluorophosphoric acid, triflic acid, fluoroantimonic acid, perchloric acid and a mixture thereof. Even more particularly, the invention’s process is performed in the presence of Fe(Cl)₃ and HBF₄. According to any embodiments of the invention, the process is carried out in the presence of an additive. Said additive may be selected from the group consisting of water, silica, carboxylic acid of formula RCOOH or HOOC(R’)_zCOOH or ether of formula R’’OR’’; wherein z is 0 or 1; R’ is a C_1-10 alkanediyl group, R is a hydrogen atom or a C_1- ₁₀ alkyl group optionally substituted by a hydroxy or a oxo group and R’’, independently from each other, is a C_1-4 alkyl group. Particularly, z may be 0, R may be a hydrogen atom or a C_1-8 alkyl group optionally substituted by a hydroxy or an oxo group and R’’, independently from each other, is a C_1-3 alkyl group. Particularly, z may be 0, R may be a hydrogen atom or a C_1-6 alkyl group optionally substituted by a hydroxy or a oxo group and R’’, independently from each other, is a C_2-3 alkyl group. Even more particularly, z may be 0, R may be a hydrogen atom or a C_1-4 alkyl group optionally substituted by a hydroxy or a oxo group and R’’, independently from each other, is an ethyl or an isopropyl group. Non- limiting examples of suitable carboxylic acid include formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, lactic acid, pyruvic acid oxalic acid, acetoacetic acid. Non- Firmenich SA 9 limiting examples of suitable ether include diethyl ether, diisopropyl ether or a mixture thereof. The terms “alkyl” and “alkanediyl” are understood as comprising branched and linear alkyl and alkanediyl groups. According to any embodiments of the invention, the cyclisation of the compound of formula (II) is performed in the presence of a catalytic amount of the acid. The Lewis acid and/or protic acid can be added into the reaction medium of the invention’s process to form the cycloether of formula (I) in a large range of concentrations. As non-limiting examples, one can cite, as Lewis acid or protic acid concentration values those ranging from 0.05 to 1.2 equivalents, relative to the total amount of the compound of formula (II). Particularly, the Lewis acid or protic acid concentration may be comprised between 0.1 to 0.5 equivalents. It goes without saying that the process works also with more Lewis acid and/or protic acid catalyst. However the optimum concentration of Lewis acid or protic acid will depend, as the person skilled in the art knows, on the nature of the latter, on the temperature and on the desired time of reaction. The additive can be added into the reaction medium of the invention’s process to form the cycloether of formula (I) in a large range of concentrations. As non-limiting examples, one can cite, as additive concentration values those ranging from 0.1 to 1 equivalents, relative to the total amount of the compound of formula (II). Particularly, the additive concentration may be comprised between 0.2 to 0.5 equivalents. It goes without saying that the process works also with more additive. However the optimum concentration of the additive will depend, as the person skilled in the art knows, on the nature of the latter, on the temperature and on the desired time of reaction. According to any one of the invention’s embodiments, the invention’s process for the preparation of a cycloether of formula (I) is carried out at a temperature comprised between -15°C and 150°C. In particular, the temperature is in the range between 20°C and 30°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, conversion or selectivity. The invention’s process for the preparation of a cycloether of formula (I) 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 C_6-12 aromatic solvents such as xylene, Firmenich SA 10 toluene, 1,3-diisopropylbenzene, cumene pseudocumene, anisole or chlorobenzene or mixtures thereof, hydrocarbon solvents such as cyclohexane, heptane or mixtures thereof, nitrile solvent such as acetonitrile, esteral solvents such as ethyl acetate or ethereal solvents such as tetrahydrofuran, dimethoxyethane, diethyether, methyl tetrahydrofuran, chlorinated solvents such as dichloromethane or dichloroethane or mixtures thereof. The choice of the solvent is function of the nature of the substrate and/or Lewis acid and/or protic acid catalyst and the person skilled in the art is well able to select the solvent most suitable in each case to optimize the reaction. The solvent can be added into the reaction medium of the invention’s process to form the cycloether of formula (I) in a large range of concentrations. As non-limiting examples, one can cite, as solvent concentration values those ranging from 0.5 to 20 wt.%, relative to the total amount of the compound of formula (II). Particularly, the solvent concentration may be comprised between 1 to 20 wt.%, even between 1 to 5 wt.%. It goes without saying that the process works also with more solvent. However the optimum concentration of the solvent will depend, as the person skilled in the art knows, on the nature of the latter, on the temperature and on the desired time of reaction. The invention’s process for the preparation of a cycloether of formula (I) is carried out under batch or continuous conditions. The invention’s process for the preparation of a cycloether of formula (I) may be performed under atmospheric pressure or under a slight vacuum. According to any embodiment of the invention’s, the invention’s process is stereoselective. In other words, the cyclodehydration of 2-((1S,4aS,8aS)-5,5,8a-trimethyl- 2-methylenedecahydronaphthalen-1-yl)ethan-1-ol provides (3aR,5aS,9aS,9bR)-3a,6,6,9a- tetramethyldodecahydronaphtho[2,1-b]furan. According to a particular embodiment of the invention, the compound of formula (I) may be may be in a form of a composition of matter comprising at least 95% of (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan and at most 2% of (3aSR,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1- b]furan. Particularly, the compound of formula (I) may be may be in a form of a composition of matter comprising at least 95% of (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a- tetramethyldodecahydronaphtho[2,1-b]furan and at most 1% of (3aSR,5aSR,9aSR,9bRS)- 3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. Particularly, the compound of formula (I) may be may be in a form of a composition of matter comprising at least 95% of Firmenich SA 11 (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan and at most 0.7% of (3aSR,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1- b]furan. Particularly, the compound of formula (I) may be may be in a form of a composition of matter comprising at least 95% of (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a- tetramethyldodecahydronaphtho[2,1-b]furan and at most 0.6% of (3aSR,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. Particularly, the compound of formula (I) may be may be in a form of a composition of matter comprising at least 95% of (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a- tetramethyldodecahydronaphtho[2,1-b]furan and at most 0.5% of (3aSR,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. Even more particularly, the invention’s process allows avoiding the formation of (3aSR,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. According to a particular embodiment of the invention, the compound of formula (I) may be may be in a form of a composition of matter comprising at least 95% of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan and at most 2% of (3aS,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. Particularly, the compound of formula (I) may be may be in a form of a composition of matter comprising at least 95% of (3aR,5aS,9aS,9bR)-3a,6,6,9a- tetramethyldodecahydronaphtho[2,1-b]furan and at most 1% of (3aS,5aS,9aS,9bR)- 3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. Particularly, the compound of formula (I) may be may be in a form of a composition of matter comprising at least 95% of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan and at most 0.7% of (3aS,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. Particularly, the compound of formula (I) may be may be in a form of a composition of matter comprising at least 95% of (3aR,5aS,9aS,9bR)-3a,6,6,9a- tetramethyldodecahydronaphtho[2,1-b]furan and at most 0.6% of (3aS,5aS,9aS,9bR)- 3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. Particularly, the compound of formula (I) may be may be in a form of a composition of matter comprising at least 95% of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan and at most 0.5% of (3aS,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. Even more particularly, the invention’s process allows avoiding the formation of (3aS,5aS,9aR,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. Firmenich SA 12 Unless stated otherwise, percentages (%) are meant to designate a percentage by weight of a composition. The compound of formula (II), can be prepared by several methods known in the art, for example such as the one reported in Australian Journal of Chemistry, 1989, 497. The compound of formula (II) may also 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) or, in particular, into 2-(5,5,8a-trimethyl-2- methylenedecahydronaphthalen-1-yl)ethyl acetate in a form of any one of its stereoisomers or a mixture thereof. 2-(5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethyl acetate may be converted into 2-(5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1- yl)ethan-1-ol using chemical or enzymatic conditions known in the art. 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 enantiomeric excess. 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), in particular 2- ((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol, is prepared, by a process comprising the step of contacting farnesyl pyrophosphate with at least one enzyme. 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 Firmenich SA 13 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 non- human 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) or into the corresponding ester such as 2-(5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethyl acetate, 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) or the corresponding ester such as 2-(5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1- yl)ethyl acetate. 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) or the corresponding ester such as 2-(5,5,8a-trimethyl-2- methylenedecahydronaphthalen-1-yl)ethyl acetate 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. Firmenich SA 14 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. 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). NMR spectra were acquired using either a Bruker Avance II Ultrashield 400 plus operating at 400 MHz, (¹H) and 100 MHz (¹³C) or a Bruker Avance III 500 operating at 500 MHz (¹H) and 125 MHz (¹³C) or a Bruker Avance III 600 cryoprobe operating at 600 MHz (¹H) and 150 MHz (¹³C). Spectra were internally referenced relative to tetramethyl silane 0.0 ppm. ¹H NMR signal shifts are expressed in ^ ppm, coupling constants (J) are expressed in Hz with the following multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad (indicating unresolved couplings) and were interpreted using Bruker Topspin software. ¹³C NMR data are expressed in chemical shift ^ ppm and hybridization from DEPT 90 and DEPT 135 experiments, C, quaternary; CH, methine; CH₂, methylene; CH₃, methyl. Example 1 1-yl)ethan-1-ol (B) In a typical experiment a 50 mL round bottom flask under N₂ was charged with 2- ((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol (B) (1.g, 4.23mmol) and DCM (30mL). The solution was stirred at RT and acid catalyst (1.02mmol) and optionally an additive. The mixture was left under stirring for a define period. Table 1 reported the yield of the desired (3aR,5aS,9aS,9bR)-3a,6,6,9a- tetramethyldodecahydronaphtho[2,1-b]furan (Compound of formula (A), its isomers Firmenich SA 15 (3aS,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (corresponding to Compound E) and the starting material isomers 2-((4aS,8aS)-2,5,5,8a-tetramethyl- 3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)ethan-1-ol and 2-((1S,4aS,8aS)-2,5,5,8a- tetramethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)ethan-1-ol (corresponding respectively to Compound of Formula (C) and (D)). The samples were analysed by GC innowax. Table 1: Preparation of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1- b]furan by cyclisation of 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalen-1-yl)ethan-1-ol Firmenich SA 16 Firmenich SA 17 1) Similar conditions reported in WO2009053884 wherein the stating material is a mixture of 2-((1S,4aS,8aS)-2,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a- octahydronaphthalen-1-yl)ethan-1-ol, 2-((4aS,8aS)-2,5,5,8a-tetramethyl- 3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)ethan-1-ol and 2-((1S,4aS,8aS)-5,5,8a- trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol provided lower yield and selectivity 2) 5.4 mmol of methanesulfonic acid used 3) Following conditions reported in Helv.Chem.Acta, 1985, 2022 at 100°C with 0,85 equivalents of paratoluene sulfonic acid The process of the present invention allows obtaining (3aR,5aS,9aS,9bR)-3a,6,6,9a- tetramethyldodecahydronaphtho[2,1-b]furan corresponding to the compound of formula (I) very selectively with low or no formation of undesired compounds such as (3aS,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan, 2- [(1S,4aS,8aS)-2,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a-octahydro-1-naphthalenyl]ethanol and 2-((4aS,8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)ethan- 1-ol. Firmenich SA 18 Example 2 Preparation of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (A) by cyclisation of 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen- 1-yl)ethan-1-ol (B) Example 1 was repeated using HBF4 but using different solvents as summarized in Table 2. Table 2: Preparation of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1- b]furan by cyclisation of 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalen-1-yl)ethan-1-ol using different solvents Example 3 Preparation of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (A) by cyclisation of 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen- 1-yl)ethan-1-ol (B) in a presence of an additive In a typical experiment a 50 mL round bottom flask under N₂ was charged with 2- ((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol (B) (0.8g, 3.38mmol) and toluene (37mL). The solution was stirred at RT and acid catalyst (0.88mmol) and optionally an additive was added. The mixture was left under stirring for a define period. Table 3 reported the yield of the desired (3aR,5aS,9aS,9bR)-3a,6,6,9a- tetramethyldodecahydronaphtho[2,1-b]furan (Compound of formula (A), its isomers Firmenich SA 19 (3aS,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (corresponding to Compound E) and the starting material isomers 2-((4aS,8aS)-2,5,5,8a-tetramethyl- 3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)ethan-1-ol and 2-((1S,4aS,8aS)-2,5,5,8a- tetramethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)ethan-1-ol (corresponding respectively to Compound of Formula (C) and (D)). The samples were analysed by GC innowax. Table 3: Preparation of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1- b]furan by cyclisation of 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalen-1-yl)ethan-1-ol using different solvents und mula ) %) The addition of 2 equivalents of acetic acid allows to obtain similar yield and selectivity while reducing the reaction time. Example 4 Preparation of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (A) by cyclisation of 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen- 1-yl)ethan-1-ol (B) in a presence of a Lewis acid and a protic acid In a typical experiment a 50 mL round bottom flask under N2 was charged with lewis acid catalyst (0.38mmol), diethyl ether (additive) (0.08mL, 0.76mmol), PhMe (30 mL) and Firmenich SA 20 protic acid (, 0.38mmol). The mixture was stirred at 22°C. 2-((1S,4aS,8aS)-5,5,8a- trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol (B) (3g, 12.7mmol) was dissolved in PhMe (4.7mL) and added into the flask. The mixture was left under stirring for a define period. Table 4 reported the GC% yield of the desired (3aR,5aS,9aS,9bR)- 3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (Compound of formula (A), its isomers (3aS,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (corresponding to Compound E) and the starting material isomers 2-((4aS,8aS)-2,5,5,8a- tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)ethan-1-ol and 2-((1S,4aS,8aS)- 2,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)ethan-1-ol (corresponding respectively to Compound of Formula (C) and (D)). The samples were analysed by GC innowax. Table 4: Preparation of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1- b]furan by cyclisation of 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2- methylenedecahydronaphthalen-1-yl)ethan-1-ol using different solvents C m nd C m nd C m nd C m nd C m ound mula ) %) 1 5 6 Firmenich SA 21 FeCl₃ · 6H₂O 0.7 0.4 0.4

Claims

Firmenich SA 22 Claims 1. A process for the preparation of a compound of formula (I) wherein the bold and hatched lines indicate a relative or absolute configuration; comprising the cyclisation of compound of formula (II) wherein the bold and hatched lines indicate a relative or absolute configuration; in the presence of a Lewis acid, a protic acid having a pKa equal or below 2 or a mixture thereof. 2. The process according to claim 1, wherein the cyclisation of the compound of formula (II) is performed in the presence of a catalytic amount of the acid. 3. The process according to any one of claims 1 to 2, wherein the protic acid has a pKa equal or below -3. 4. The process according to any one of claims 1 to 3, wherein the protic acid has a pKa equal or below -4.5. 5. The process according to any one of claims 1 to 4, wherein the protic acid Firmenich SA 23 has a pKa equal or below -8. 6. The process according to any one of claims 1 to 5, wherein the protic acid is selected from the group consisting of HBF₄, HBF₄.OEt₂, tetrafluoroboric acid aqueous solution, hexafluorophosphoric acid, triflic acid, phosphotungstic acid hydrate, phosphomolybdic acid hydrate, fluoroantimonic acid, perchloric acid, hydrogen bromide, hydrogen iodide, hydrochloric acid and a mixture thereof. 7. The process according to any one of claims 1 to 2, wherein the Lewis acid is of formula MX_n wherein M is a metal, X is a weakly or non-coordinating ligand and n is 1, 2 or 3 and depend on the oxidation state of the metal and on the nature of X. 8. The process according to claim 7, wherein the Lewis acid is of formula MX₂ or MX₃. 9. The process according to any one of claims 7 to 8, wherein the metal selected from the group consisting of B, Bi and Fe, particularly, Bi and Fe. 10. The process according to any one of claims 7 to 9, wherein X is a Cl-, a F-, a triflate, a sulfate, a hydrogenosulfate group or a mixture thereof, particularly, a Cl-, a triflate, a sulfate, a hydrogenosulfate group or a mixture thereof. 11. The process according to any one of claims 7 to 10, wherein the Lewis acid is selected from the group consisting of Fe(HSO4)3, FeSO4(HSO4), Bi(OTf)3, Fe(Cl)3, Bi(Cl)₃, Fe(OTf)₃ and a mixture thereof. 12. The process according to any one of claims 1 to 11, wherein the process is perform in presence of Fe(Cl)₃ and HBF_4. 13. The process according to any one of claims 1 to 12, wherein the process is carried out in the presence of an additive; preferably the additive is selected from the group consisting of water, silica and carboxylic acid of formula RCOOH, HOOC(R’)_zCOOH or ether of formula R’’OR’’; wherein z is 0 or 1; R’ is a C_1-10 alkanediyl group, R is a hydrogen atom or a C_1-10 alkyl group optionally substituted by a hydroxy or a oxo group and R’’, Firmenich SA 24 independently from each other, is a C_1-4 alkyl group. 14. The process according to any one of claims 1 to 13, wherein the compound of formula (I) is of formula wherein the bold and hatched lines indicate an absolute configuration; and the compound of formula (II) is of formula wherein the bold and hatched lines indicate an absolute configuration. 15. The process according to any one of claims 1 to 14, wherein the compound of formula (II) is prepared by a process comprising the step of contacting farnesyl pyrophosphate with at least one enzyme.