Preparation process of oxacyclopentane derivatives

Abstract

The present invention relates to the field of organic synthesis, and more particularly to a process for the preparation of cycloethers of formula (I) comprising the cyclization of compounds of formula (II) in the presence of a Lewis acid, a protic acid having a pKa of 2 or less, or a mixture thereof.

Description

[Technical Field]

[0001] The present invention relates to the field of organic synthesis, and more particularly to a process for the preparation of cycloethers of formula (I) comprising the cyclization of compounds of formula (II) carried out in the presence of a Lewis acid or a protic acid having a pKa of 2 or less.

[0002] background Cycloether derivatives represent highly desirable skeletons that can be used as such or as key intermediates to prepare more complex compounds in different fields, such as perfumery, cosmetics, pharmacology, and agricultural chemistry, among others. Relevant cycloether derivatives in the perfumery industry are, for example, Cetalox® ((3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; source: Firmenich SA, Geneva, Switzerland) or Ambrox® ((3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; source: Firmenich SA, Geneva, Switzerland), which are important components of natural ambergris. These perfume ingredients represent some of the most popular ingredients in the perfumery industry. Several process options for preparing Cetalox® or Ambrox® have been developed, particularly via the cyclization of 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 the final step, respectively. Cyclization was performed in the presence of excess paratoluenesulfonic acid in nitromethane, as described in Helv. Chem. Acta, 1985, 2022. However, yields and selectivities were not reported. The same conditions were also implemented with close analogs, such as those reported in Tetrahedron 1993, 6251 or Synlett 2016, 368, leading to the desired compounds in moderate yields.

[0003] On the other hand, today there is a need to promote sustainable processes that obtain high yields and selectivities, for example using catalytic amounts of acid, avoiding harmful solvents such as nitromethane, and minimizing waste.

[0004] The cyclization of a regioisomer or a mixture of regioisomers of compounds of formula (II) in the presence of a sub-stoichiometric amount of Lewis acid was reported in WO2009053884 and resulted in the formation of compounds of formula (I) in moderate yield and selectivity.

[0005] Therefore, there remains a need to develop a sustainable cyclization process in the presence of catalytic amounts of reagents while improving conversion and selectivity.

[0006] The present invention makes it possible to solve the above problems by using Lewis acids, protic acids with a pKa of less than or equal to 2 or mixtures thereof to prepare cycloethers of formula (I).To the best of the inventors' knowledge, this state of the art has not been reported.

[0007] Summary of the Invention The present invention relates to a novel process which allows the preparation of cycloethers of formula (I) by cyclization of compounds of formula (II) in the presence of a Lewis acid or a protic acid with a pKa of less than or equal to 2 or a mixture thereof, making it possible to achieve high yields and selectivities.

[0008] Therefore, a first object of the present invention is to Compounds of formula (I) in the presence of a Lewis acid or a protic acid having a pKa of 2 or less or a mixture thereof. [ka] (Bold and hatched lines indicate relative or absolute positioning.) 2. The preparation of Compound of formula (II) [ka] (Bold and hatched lines indicate relative or absolute positioning.) This includes the cyclization of

[0009] Description of the Invention It has now been surprisingly found that the cyclization of compounds of formula (II) in the presence of a catalytic amount of a Lewis acid, a protic acid having a pKa of 2 or less, in particular a protic acid having a pKa of -3 or less, or a mixture thereof, allows the preparation of compounds of formula (I) in high yield and high selectivity. The process of the present invention makes it possible to limit isomerization of the double bond at the more stable position, i.e., even to prevent isomerization of the double bond at the endo position, while further improving the formation of the desired isomer, i.e., limiting the formation of undesired diastereoisomers.

[0010] A first subject of the present invention is therefore the synthesis of cycloethers of formula (I) in the presence of a Lewis acid or a protic acid with a pKa of less than or equal to 2 or a mixture thereof [ka] (Bold and hatched lines indicate relative or absolute positioning.) A process for preparing Compound of formula (II) [ka] (Bold and hatched lines indicate relative or absolute positioning.) The preparation process includes the cyclization of

[0011] For clarity, terms such as "pKa" have their ordinary meaning as understood by those skilled in the art, i.e., the negative base 10 logarithm of the acid dissociation constant, which represents the strength of an acid in solution. pKa in this invention corresponds to the pKa measured and calculated in water.

[0012] For clarity, the expression "bold and hatched lines indicate relative or absolute configuration" or similar expressions have the usual meaning understood by a person skilled in the art, i.e., in the case of relative configuration, compound (I) is in the form of a mixture of stereoisomers containing more than 50% (w / w) of the (3aRS, 5aSR, 9aSR, 9bRS) stereoisomer, and compound (II) is in the form of a mixture of stereoisomers containing more than 50% (w / w) of the (1SR, 4aSR, 8aSR); or in the case of absolute configuration, compound (I) is in the form of a mixture of stereoisomers containing more than 50% (w / w) of the (3aR, 5aS, 9aS, 9bR) stereoisomer, and compound (II) is in the form of a mixture of stereoisomers containing more than 50% (w / w) of the (1S, 4aS, 8aS) stereoisomer. For clarity, the expressions "(3aRS,5aSR,9aSR,9bRS)" or "1SR,4aSR,8aSR" refer to 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).

[0013] According to a particular embodiment, the compound of formula (II) is a compound of formula (II) and formula (II a The compound may be in the form of a composition of matter comprising the compound of formula (I). [ka] (Bold and hatched lines indicate relative or absolute positioning.) In particular, the compound of formula (II) is a compound of at least 95% of formula (II) and at most 5% of formula (II) a In particular, the compound of formula (II) may be in the form of a composition of matter comprising at least 98% of the compound of formula (II) and at most 2% of the compound of formula (II a In particular, the compound of formula (II) may be in the form of a composition of matter comprising at least 99% of the compound of formula (II) and at most 1% of the compound of formula (II). a In particular, the compound of formula (II) may be in the form of a composition of matter comprising at least 99.5% of the compound of formula (II) and at most 0.5% of the compound of formula (II).a Even more particularly, the compound of formula (II) may be in the form of a composition of matter comprising a compound of formula (II a ) compounds.

[0014] According to certain embodiments, the compound of formula (II) is at least 60% (w / w) 2-((1SR,4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol, further at least 75% 2-((1SR,4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol, further at least 90% 2-((1SR,4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol, Furthermore, it is in the form of a mixture of stereoisomers comprising at least 95% 2-((1SR,4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol, further at least 98% 2-((1SR,4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol, and even more preferably the compound of formula (II) is 2-((1SR,4aSR,8aSR)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol.

[0015] According to certain embodiments, the compound of formula (I) is at least 80% (w / w) (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan, or even at least 85% (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan, or even at least 90% (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan, or Furthermore, the compound of formula (II) is in the form of a mixture of stereoisomers comprising at least 95% (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan, or even at least 98% (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan, and even more preferably, the compound of formula (II) is (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan.

[0016] According to any embodiment of the present invention, the compounds of formula (I) and (II) are in the form of pure enantiomers. In other words, the compounds of formula (I) are represented by the following formula: [ka] (The bold and hatched lines indicate absolute configuration.) It is of The compound of formula (II) has the following formula: [ka] (The bold and hatched lines indicate absolute configuration.) It is of the type.

[0017] According to any embodiment of the present invention, the Lewis acid and the protic acid having a pKa of less than 2 are homogeneous.

[0018] According to any embodiment of the present invention, the protic acid has a pKa of 0 or less, preferably -2 or less, preferably -3 or less, preferably -4 or less, preferably -4.5 or less, preferably -8 or less.

[0019] According to certain embodiments, the protic acid when used in combination with a Lewis acid has a pKa of 2 or less, preferably 0 or less, preferably −2 or less, preferably −3 or less, preferably −4 or less, preferably −4.5 or less, preferably −8 or less.

[0020] According to certain embodiments, the protic acid when used without a Lewis acid has a pKa of −3 or less, preferably −4 or less, preferably −4.5 or less, preferably −8 or less.

[0021] According to any embodiment of the present invention, the protonic acid is selected from the group consisting of HBF, HBF.OEt, aqueous tetrafluoroboric acid, hexafluorophosphoric acid, triflic acid, phosphotungstic acid hydrate, phosphomolybdic acid hydrate, fluoroantimonic acid, perchloric acid, hydrogen bromide, hydrogen iodide, hydrochloric acid, and mixtures thereof. In particular, the protonic acid is perchloric acid. Perchloric acid can be formed in situ by adding sulfuric acid to barium perchlorate.

[0022] According to any embodiment of the present invention, the protic acid having a pKa of 2 or less is not methanesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid.

[0023] According to any embodiment of the present invention, the Lewis acid is of formula MX nwhere M is a metal, X is a weakly or non-coordinating ligand, and n is 1, 2, or 3, depending on the oxidation state of the metal and the nature of the anion (dianion or monoanion). If the metal is a monovalent metal cation, n is 1; if the metal is a divalent metal cation, n is 2 if X is a monoanion, or n is 1 if X is a dianion; if the metal is a trivalent metal cation, n is 3 if X is a monoanion, or n is 2 if one X is a dianion and another X is a monoanion.

[0024] 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 - Examples include:

[0025] It is understood that when n is 2 or 3, each of the X groups can be the same or different.

[0026] According to certain embodiments, n can be 2 and 3. In other words, the Lewis acid is of formula MX2 or MX3, where M is a metal selected from the group consisting of B, Bi and Fe, and X is F - Or Cl - or a triflate, sulfate or hydrogen sulfate group or a mixture thereof. In particular, the metal may be selected from the group of Bi and Fe, and X is Cl. - Alternatively, it may be selected from the group of triflate, sulfate or hydrogen sulfate groups and mixtures thereof.

[0027] Non-limiting examples of suitable Lewis acids include Fe(HSO4)3, FeSO4(HSO4), BF3.OEt2O, Bi(OTf)3, Fe(Cl)3, FeCl3·6H2O, Bi(Cl)3, Fe(OTf)3, and mixtures thereof. In particular, 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 mixtures thereof.

[0028] The Lewis acids or protic acids used may be in the anhydrous or hydrated form, and the Lewis acids may be in the form of ethers or adducts with carboxylic acids, e.g. R 1 2O or R 2 COOH, where R 1 is a C1-C5 alkyl group, e.g., C2H5 or C4H9, and R 2 is C1-C 20 It is an alkyl group, for example a methyl group, an ethyl group or a hept-3-yl group.

[0029] According to a particular embodiment of the invention, the process of the invention is carried out in the presence of a Lewis acid and a protic acid having a pKa of less than or equal to 2. In particular, the Lewis acid is a compound of formula MX nwhere M is Fe and X, and n is as defined above. The ratio of the Lewis acid to the protic acid having a pKa of 2 or less is between 0.5:1 and 1:0.5, particularly between 0.8:1 and 1:0.8, and even more particularly, the ratio of the Lewis acid to the protic acid having a pKa of 2 or less is 1:1. Non-limiting examples of suitable Lewis acids include Fe(HSO), FeSO(HSO), Fe(Cl), FeCl·6H0, Fe(OTf), or mixtures thereof. Non-limiting examples of suitable protic acids used in combination with Lewis acids include HBF, HBF·OEt, aqueous tetrafluoroboric acid, paratoluenesulfonic acid, methanesulfonic acid, hexafluorophosphoric acid, triflic acid, phosphotungstic acid hydrate, phosphomolybdic acid hydrate, fluoroantimonic acid, perchloric acid, or mixtures thereof. In particular, the process of the present invention is carried out in the presence of a Lewis acid selected from the group consisting of Fe(HSO), FeSO(HSO), Fe(Cl), FeCl·6H0, Fe(OTf), or mixtures thereof, and a protic acid having a pKa of 2 or less selected from the group consisting of HBF, aqueous tetrafluoroboric acid, paratoluenesulfonic acid, hexafluorophosphoric acid, triflic acid, fluoroantimonic acid, perchloric acid, and mixtures thereof. In particular, the process of the present invention is carried out in the presence of a Lewis acid that is Fe(Cl) and a protic acid having a pKa of 2 or less selected from the group consisting of HBF, aqueous tetrafluoroboric acid, paratoluenesulfonic acid, hexafluorophosphoric acid, triflic acid, fluoroantimonic acid, perchloric acid, and mixtures thereof. Even more particularly, the process of the present invention is carried out in the presence of Fe(Cl) and HBF.

[0030] According to an optional embodiment of the present invention, the process is carried out in the presence of an additive, said additive being water, silica, a compound of formula RCOOH or HOOC(R') z COOH or a carboxylic acid or an ether of formula R"OR"; where z is 0 or 1; R' is C 1-10is an alkanediyl group, and R is a hydrogen atom or a C optionally substituted with a hydroxy or oxo group. 1-10 alkyl group, and R" are independently C 1-4 In particular, z may be 0 and R is a hydrogen atom or a C alkyl group optionally substituted with a hydroxy or oxo group. 1-8 R" may be independently an alkyl group, and R" may be independently an alkyl group, and C 1-3 In particular, z may be 0 and R is a hydrogen atom or a C alkyl group optionally substituted with a hydroxy or oxo group. 1-6 R" may be independently an alkyl group, and R" may be independently an alkyl group, and C 2-3 More particularly, z may be 0 and R is a hydrogen atom or a C alkyl group optionally substituted with a hydroxy or oxo group. 1-4 R" may be an alkyl group, and R" each independently is an ethyl or isopropyl group. Non-limiting examples of suitable carboxylic acids include formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, lactic acid, pyruvic acid, oxalic acid, acetoacetic acid. Non-limiting examples of suitable ethers include diethyl ether, diisopropyl ether, or mixtures thereof.

[0031] The terms "alkyl" and "alkanediyl" are understood to include both branched and straight chain alkyl and alkanediyl groups.

[0032] According to an optional embodiment of the present invention, the cyclization of the compound of formula (II) is carried out in the presence of a catalytic amount of an acid.

[0033] Lewis acids and / or protic acids can be added to the reaction medium of the process of the present invention to form the cycloether of formula (I) over a wide range of concentrations. Non-limiting examples of Lewis acid or protic acid concentrations include values ​​ranging from 0.05 to 1.2 equivalents relative to the total amount of compound of formula (II). In particular, the Lewis acid or protic acid concentration can be between 0.1 and 0.5 equivalents. It goes without saying that the process also works with higher amounts of Lewis acid and / or protic acid catalyst. However, the optimal concentration of Lewis acid or protic acid depends on the nature of the latter, the temperature, and the desired reaction time, as known to those skilled in the art.

[0034] Additives can be added to the reaction medium of the process of the present invention to form the cycloether of formula (I) in a wide range of concentrations. Non-limiting examples of additive concentration values ​​include those in the range of 0.1 to 1 equivalent relative to the total amount of compound of formula (II). In particular, the additive concentration can be between 0.2 and 0.5 equivalents. It goes without saying that the process also works with larger amounts of additive. However, the optimal concentration of the additive depends on the nature of the latter, the temperature, and the desired reaction time, as known to those skilled in the art.

[0035] According to any one of the embodiments of the present invention, the inventive process for preparing cycloethers of formula (I) is carried out at a temperature comprised between −15° C. and 150° C. In particular, the temperature is in the range of 20° C. to 30° C. Of course, the skilled person will also be able to select the preferred temperature as a function of the melting and boiling points of the starting and final products and the desired reaction time, conversion or selectivity.

[0036] The process of the present invention for preparing cycloethers of formula (I) can be carried out in the presence or absence of a solvent. If a solvent is required or used for practical reasons, any solvent conventional for the purposes of the present invention can be used in such reaction types. Non-limiting examples include C 6-12Examples of suitable solvents include aromatic solvents such as xylene, toluene, 1,3-diisopropylbenzene, cumene pseudocumene, anisole, or chlorobenzene, or mixtures thereof; hydrocarbon solvents such as cyclohexane, heptane, or mixtures thereof; nitrile solvents such as acetonitrile; ester solvents such as ethyl acetate; or ether solvents such as tetrahydrofuran, dimethoxyethane, diethyl ether, or methyltetrahydrofuran; chlorinated solvents such as dichloromethane or dichloroethane, or mixtures thereof. The choice of solvent is a function of the nature of the substrate and / or the Lewis acid and / or protic acid catalyst, and those skilled in the art are fully capable of selecting the most suitable solvent in each case to optimize the reaction.

[0037] The solvent can be added to the reaction medium of the process of the present invention to form the cycloether of formula (I) in a wide range of concentrations. As a non-limiting example, solvent concentration values ​​can be in the range of 0.5 to 20% by weight, relative to the total amount of the compound of formula (II). In particular, the solvent concentration can be between 1 and 20% by weight, or even between 1 and 5% by weight. It goes without saying that the process also works with larger amounts of solvent. However, the optimal concentration of the solvent depends on the nature of the latter, the temperature, and the desired reaction time, as known to those skilled in the art.

[0038] The process of the present invention for preparing cycloethers of formula (I) may be carried out under batch or continuous conditions.

[0039] The process of the present invention for preparing cycloethers of formula (I) may be carried out under atmospheric pressure or a slight vacuum.

[0040] According to any embodiment of the present invention, the process of the present invention 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.

[0041] According to a particular embodiment of the present invention, the compound of formula (I) may be in the form of a composition of matter comprising at least 95% (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan and at most 2% (3aSR,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. In particular, the compound of formula (I) may be in the form of a composition of matter comprising at least 95% (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan and at most 1% (3aSR,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. In particular, the compound of formula (I) may be in the form of a composition of matter comprising at least 95% (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan and at most 0.7% (3aSR,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. In particular, the compound of formula (I) may be in the form of a composition of matter comprising at least 95% (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan and at most 0.6% (3aSR,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. In particular, the compound of formula (I) may be in the form of a composition of matter comprising at least 95% (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan and at most 0.5% (3aSR,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. Even more particularly, the process of the invention makes it possible to avoid the formation of (3aSR,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan.

[0042] According to a particular embodiment of the present invention, the compound of formula (I) may be in the form of a composition of matter comprising at least 95% (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan and at most 2% (3aS,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. In particular, the compound of formula (I) may be in the form of a composition of matter comprising at least 95% (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan and at most 1% (3aS,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. In particular, the compound of formula (I) may be in the form of a composition of matter comprising at least 95% (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan and at most 0.7% (3aS,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. In particular, the compound of formula (I) may be in the form of a composition of matter comprising at least 95% (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan and at most 0.6% (3aS,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. In particular, the compound of formula (I) may be in the form of a composition of matter comprising at least 95% (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan and at most 0.5% (3aS,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan. Even more particularly, the process of the invention makes it possible to avoid the formation of (3aS,5aS,9aR,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan.

[0043] Unless otherwise stated, percentages (%) are meant to indicate percentages by weight of the composition.

[0044] The compound of formula (II) can be prepared by several methods known in the art, for example, the method reported in Australian Journal of Chemistry, 1989, 497. The compound of formula (II) can also be produced in vitro using purified recombinantly prepared enzymes or by fermentation using host cells, e.g., microbial cells, genetically engineered to convert inexpensive carbon sources (such as sugars) to the desired compound of formula (II), or in particular, to any one form or mixture of stereoisomers of ethyl 2-(5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)acetate. Chemical or enzymatic conditions known in the art can be used to convert ethyl 2-(5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)acetate to 2-(5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol. The advantage of using a compound of formula (II) obtained by fermentation is clear as it allows easy access to starting materials in high enantiomeric excess.

[0045] According to any one of the above embodiments of the process of the invention, 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 a step of contacting farnesyl pyrophosphate with at least one enzyme.

[0046] In some embodiments of the presently claimed process, an enzyme is used to prepare the compound of formula (II).

[0047] The process for preparing the compounds of formula (II) can be carried out in vitro and in vivo, as will be explained in more detail below.

[0048] When the process is carried out in vitro, the enzyme used can be obtained by extraction from any organism that expresses it using standard enzyme extraction techniques. If the host organism is a unicellular organism or cell, the enzyme can be simply recovered from the culture medium, for example, by centrifugation, optionally followed by a washing step and resuspension in an appropriate buffer. If the organism or cell accumulates the enzyme intracellularly, the enzyme can be obtained by disrupting or lysing the cell and further extracting the enzyme from the cell lysate.

[0049] For in vitro methods, the enzyme may be provided in isolated form or as part of a protein extract and suspended in a buffer solution at an optimal pH. Where appropriate, salts, DTT, NADPH, NADH, FAD, FMN, and other enzyme cofactors may be added to optimize enzyme activity. The precursor compound is then added to the reaction mixture, which is then incubated at an optimal temperature, e.g., 15-40°C, preferably 25-35°C, and more preferably 30°C. After incubation, the compound of formula (II) produced can be isolated from the incubated solution by standard isolation procedures, such as solvent extraction and distillation, optionally after removing the enzyme from the solution.

[0050] According to another preferred embodiment, the process for preparing a compound of formula (II) is carried out in vivo, comprising culturing a non-human host organism or cell transformed to express an enzyme in the presence of a starting compound that is converted to a compound of formula (II) or to a corresponding ester, such as ethyl 2-(5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)acetate, under conditions favoring the enzymatic reaction.

[0051] In one embodiment, when 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 permeating the membrane of the cell or microorganism and therefore being available to react with the enzyme expressed by said host cell or microorganism.

[0052] Performing the method in vivo is particularly advantageous because the method can be performed without prior isolation of the enzyme: the reaction occurs directly within an organism or cell that has been transformed to express the enzyme.

[0053] To practice the present invention in vivo, a host organism or cell is cultured under conditions that promote the production of the compound of formula (II) or a corresponding ester, such as ethyl 2-(5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)acetate. Such conditions may be any that result in the growth of the host organism or cells. Preferably, such conditions are designed for optimal growth of the host organism or cells. When the host is a unicellular organism, conditions that promote the production of the compound of formula (II) or a corresponding ester, such as ethyl 2-(5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)acetate, may include adding appropriate cofactors to the host culture medium. Furthermore, the culture medium may be selected to maximize synthesis.

[0054] Optimal culture conditions are known to those skilled in the art and are not specific to the present invention.

[0055] In a more preferred embodiment, the organism used to carry out the method of the present invention in vivo is a microorganism. While any microorganism can be used, according to an even more preferred embodiment, the microorganism is a bacterium or a fungus. Preferably, the fungus is a yeast. Most preferably, the bacterium is E. coli and the yeast is Saccharomyces cerevisiae.

[0056] Typical modes for carrying out the process of the invention are reported below in the Examples. [Example]

[0057] The invention will now be described in further detail by the following examples, in which abbreviations have their usual meaning in the art and temperatures are given in degrees Celsius (°C). NMR spectra were obtained at 400 MHz, 1 H), and 100MHz ( 13 Bruker Avance II Ultrashield 400 plus or 500MHz ( 1 H) and 125MHz ( 13 Bruker Avance III 500 or 600MHz ( 1 H) and 150MHz ( 13 C). Spectra were internally referenced to tetramethylsilane at 0.0 ppm. 1 H NMR signal shifts are expressed in δ ppm and coupling constants (J) are expressed in Hz with the following multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and b, broad (indicating unresolved coupling) and were interpreted using Bruker Topspin software. 13 C NMR data are expressed as chemical shifts δ ppm and hybridization from DEPT 90 and DEPT 135 experiments, C, quaternary; CH, methine; CH, methylene; CH, methyl.

[0058] Example 1 Preparation of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (A) by cyclization of 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-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, 4.23 mmol) and DCM (30 mL). The solution was stirred at room temperature, and an acid catalyst (1.02 mmol) and optional additives were added. The mixture was left stirring for a period of time. Table 1 shows the desired (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (compound of formula (A)), its isomer (3aS,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (corresponding to compound E) and the starting material isomer 2-((4aS,8aS)-2,5,5 The yields of 2-((1S,4aS,8aS)-2,5,5,8a-tetramethyl-1,4,4a,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 to compounds of formula (C) and (D), respectively) were reported.

[0059] The samples were analyzed by GC innowax. [Table 1-1] [Table 1-2]

[0060] The process of the present invention makes it possible to obtain (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan corresponding to the compound of formula (I) very selectively with little 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.

[0061] Example 2 Preparation of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (A) by cyclization of 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol (B) Example 1 was repeated using HBF4, but with a different solvent, as summarized in Table 2. [Table 2]

[0062] Example 3 Preparation of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (A) by cyclization of 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol (B) in the presence of an additive In a typical experiment, a 50 mL round-bottom flask under N was charged with 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol (B) (0.8 g, 3.38 mmol) and toluene (37 mL). The solution was stirred at room temperature, and an acid catalyst (0.88 mmol) and optional additives were added. The mixture was left stirring for a period of time. Table 3 shows the desired (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (compound of formula (A)), its isomer (3aS,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (corresponding to compound E) and the starting material isomer 2-((4aS,8aS)-2,5,5 The yields of 2-((1S,4aS,8aS)-2,5,5,8a-tetramethyl-1,4,4a,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 to compounds of formula (C) and (D), respectively) were reported.

[0063] The samples were analyzed by GC innowax. [Table 3]

[0064] The addition of two equivalents of acetic acid makes it possible to obtain similar yields and selectivities while shortening the reaction time.

[0065] Example 4 Preparation of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (A) by cyclization of 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol (B) in the presence of Lewis acid and protic acid In a typical experiment, a 50 mL round-bottom flask under N2 was charged with Lewis acid catalyst (0.38 mmol), diethyl ether (additive) (0.08 mL, 0.76 mmol), PhMe (30 mL), and protic acid (0.38 mmol). The mixture was stirred at 22 °C. 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethan-1-ol (B) (3 g, 12.7 mmol) was dissolved in PhMe (4.7 mL) and added to the flask. The mixture was left stirring for a period of time. Table 4 shows the desired (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (compound of formula (A)), its isomer (3aS,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (corresponding to compound E) and the starting material isomer 2-((4aS,8aS)-2,5,5,8 The GC % yields of a-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 to compounds of formula (C) and (D), respectively) were reported.

[0066] The samples were analyzed by GC innowax. [Table 4]

Claims

1. a compound of formula (I) in the presence of a Lewis acid, a protic acid having a pKa of 2 or less, or a mixture thereof; 【Chemistry 1】 (Bold and hatched lines indicate relative or absolute configuration.) A method for producing Compound of formula (II) 【Chemistry 2】 (Bold and hatched lines indicate relative or absolute configuration.) The method comprises cyclizing

2. 2. The method of claim 1, wherein the cyclization of the compound of formula (II) is carried out in the presence of a catalytic amount of an acid.

3. 3. The method of claim 1, wherein the protonic acid has a pKa of −3 or less.

4. 4. The method of claim 1, wherein the protonic acid has a pKa of −4.5 or less.

5. 5. The method of claim 1, wherein the protic acid has a pKa of −8 or less.

6. The protonic acid is HBF ４ , H.B.F. ４ . OEt ２ 6. The method of claim 1, wherein the acid is selected from the group consisting of aqueous tetrafluoroboric acid, hexafluorophosphoric acid, triflic acid, phosphotungstic acid hydrate, phosphomolybdic acid hydrate, fluoroantimonic acid, perchloric acid, hydrogen bromide, hydrogen iodide, hydrochloric acid, and mixtures thereof.

7. The Lewis acid is of formula MX ｎ 3. The method of any one of claims 1 to 2, wherein M is a metal, X is a weakly coordinating or non-coordinating ligand, and n is 1, 2, or 3 (depending on the oxidation state of the metal and the nature of X).

8. The Lewis acid is of formula MX ２ or MX ３ 8. The method of claim 7, wherein

9. 9. The method according to any one of claims 7 to 8, wherein the metal is selected from the group consisting of B, Bi and Fe, in particular Bi and Fe.

10. X is Cl － , F － , triflate, sulfate, hydrogen sulfate groups or mixtures thereof, in particular Cl － 10. The method of any one of claims 7 to 9, wherein the hydroxyl group is a hydroxyl group, a triflate, a sulfate, a hydrogen sulfate group or a mixture thereof.

11. The Lewis acid is Fe(HSO ４ ) ３ , FeSO ４ (HSO ４ ), Bi(OTf) ３ , Fe(Cl) ３ , Bi(Cl) ３ , Fe(OTf) ３ 11. The method of any one of claims 7 to 10, wherein the compound is selected from the group consisting of: and mixtures thereof.

12. Fe(Cl) ３ and HBF ４ 12. The method of claim 1, carried out in the presence of

13. The process is carried out in the presence of an additive; preferably, the additive is a compound of water, silica and a compound of formula RCOOH, HOOC(R') ｚ COOH or a carboxylic acid of formula R"OR"; where z is 0 or 1; R' is C １－１０ an alkanediyl group, and R is a hydrogen atom or a C １－１０ R" is an alkyl group, and R" is independently C １－４ 13. The method of claim 1, wherein the group is an alkyl group.

14. The compound of formula (I) has the following formula: 【Transformation 3】 (The bold and hatched lines indicate the absolute configuration.) It is of The compound of formula (II) is represented by the following formula: 【Chemistry 4】 (The bold and hatched lines indicate the absolute configuration.) 14. The method according to any one of claims 1 to 13, wherein

15. 15. The method of any one of claims 1 to 14, wherein the compound of formula (II) is prepared by a process comprising contacting farnesyl pyrophosphate with at least one enzyme.

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