Process for preparation of oxacyclopentane derivatives

Abstract

The present invention relates to the field of organic synthesis, and more specifically to a method for preparing a cyclic ether of formula (I) comprising cyclizing a compound of formula (II) in the presence of a Lewis acid, a protonic acid having a pKa equal to or less than 2, or a mixture thereof.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and more particularly to a method for preparing a cyclic ether of formula (I), comprising cyclizing a compound of formula (II) in the presence of a Lewis acid or a protic acid with a pKa equal to or less than 2. Background Art

[0002] Cyclic ether derivatives represent highly desirable backbones that can be used as such or as key intermediates for the preparation of more complex compounds in diverse fields such as fragrances, cosmetics, pharmaceuticals, or agrochemistry. ((3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan; source: Firmenich SA, Geneva, Switzerland) or ((3aR,5aS,9aS,9bR)-3a,6,6,9a-Tetramethyldodecahydronaphtho[2,1-b]furan; Source: Firmenich SA, Geneva, Switzerland) is a key component of natural ambergris. These fragrance ingredients represent some of the most popular ingredients in the fragrance industry. Several preparation methods have been developed. or An alternative method, specifically a cyclization reaction with 2-[(1SR,4aSR,8aSR)-5,5,8a-trimethyl-2-methylidenedecahydro-1-naphthyl]ethanol or 2-[(1S,4aS,8aS)-5,5,8a-trimethyl-2-methylidenedecahydro-1-naphthyl]ethanol as the final step, is described. In Helv. Chem. Acta, 1985, 2022, the cyclization is performed in nitromethane in the presence of excess p-toluenesulfonic acid. However, yields and selectivities are not reported. The conditions described were applied to close analogs reported in Tetrahedron, 1993, 6251, or Synlett, 2016, 368, affording the desired compounds in moderate yields.

[0003] At the same time, there is a need to promote sustainable methods, such as using catalytic amounts of acids, avoiding hazardous solvents such as nitromethane, and achieving high yields and selectivities to minimize waste.

[0004] WO2009053884 reports the cyclization of a regioisomer or a mixture of regioisomers of a compound of formula (II) in the presence of a substoichiometric amount of a Lewis acid to form a compound of formula (I) in moderate yield and selectivity.

[0005] Therefore, there is still a need to develop a sustainable cyclization method in the presence of catalytic amounts of reagents with improved conversion and selectivity.

[0006] The present invention solves the above problems by using Lewis acids, protic acids with a pKa equal to or less than 2, or mixtures thereof to prepare cyclic ethers of formula (I). To the best of our knowledge, the conditions of the present invention have never been reported in the prior art. Summary of the Invention

[0007] The present invention relates to a novel method for preparing cyclic ethers of formula (I), which can achieve high yield and selectivity by cyclizing a compound of formula (II) in the presence of a Lewis acid or a protic acid with a pKa equal to or less than 2, or a mixture thereof.

[0008] Therefore, the first object of the present invention is to prepare compounds of formula (I):

[0009]

[0010] The bold and hatched lines indicate relative or absolute configurations;

[0011] The method comprises cyclizing a compound of formula (II) in the presence of a Lewis acid, a protic acid having a pKa of 2 or less, or a mixture thereof:

[0012]

[0013] Bold and hatched lines indicate relative or absolute configurations. DETAILED DESCRIPTION

[0014] Surprisingly, it has now been found that the cyclization of compounds of formula (II) in the presence of a catalytic amount of a Lewis acid, a protic acid with a pKa of 2 or less, in particular a protic acid with a pKa of -3 or less, or a mixture thereof, allows the preparation of compounds of formula (I) in high yield and with high selectivity. The process of the invention makes it possible to limit or even prevent the isomerization of double bonds in more stable positions, i.e., endo double bonds, while maintaining or even improving the formation of the desired isomer, i.e., limiting the formation of undesired diastereomers.

[0015] Therefore, a first object of the present invention is a process for preparing cyclic ethers of formula (I):

[0016]

[0017] The bold and hatched lines indicate relative or absolute configurations;

[0018] The method comprises cyclizing a compound of formula (II) in the presence of a Lewis acid, a protic acid having a pKa of 2 or less, or a mixture thereof:

[0019]

[0020] Bold and hatched lines indicate relative or absolute configurations.

[0021] For the sake of clarity, by the term "pKa" or similar terms, it is meant the normal meaning as understood by those skilled in the art, i.e. the negative logarithm to the base -10 of the acid dissociation constant, which indicates the strength of the acid in solution. The pKa in the present invention corresponds to the pKa measured / calculated in water.

[0022] For the sake of clarity, the expression “bold lines and hatched lines indicate relative or absolute configuration” or similar expressions refers to the normal meaning understood by those skilled in the art, that is, in the case of relative configuration, compound (I) is in the form of a stereoisomer mixture containing more than 50% (w / w) of the (3aRS, 5aSR, 9aSR, 9bRS) stereoisomer, and compound (II) is in the form of a stereoisomer mixture containing more than 50% (w / w) of the (1SR, 4aSR, 8aSR) stereoisomer; or in the case of absolute configuration, compound (I) is in the form of a stereoisomer mixture containing more than 50% (w / w) of the (3aR, 5aS, 9aS, 9bR) stereoisomer, and compound (II) is in the form of a stereoisomer mixture containing more than 50% (w / w) of the (1S, 4aS, 8aS) stereoisomer. For the sake of clarity, by the expression “(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).

[0023] According to a particular embodiment, the compound of formula (II) may be a compound comprising a compound of formula (II) and a compound of formula (II) a ) the form of a composition of matter of the compound:

[0024]

[0025] Wherein bold lines and hatched lines indicate relative or absolute configuration. In particular, the compound of formula (II) may be a compound comprising at least 95% of the compound of formula (II) and at most 5% 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 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) does not contain a ) compounds.

[0026] 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 2-((1SR,4aSR,8aSR)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethan-1-ol, or even at least 75% of 2-((1SR,4aSR,8aSR)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethan-1-ol, or even at least 90% of 2-((1SR,4aSR,8aSR)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethan-1-ol. 2-((1SR,4aSR,8aSR)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethan-1-ol, or even at least 95% of 2-((1SR,4aSR,8aSR)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethan-1-ol, or even at least 98% of 2-((1SR,4aSR,8aSR)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethan-1-ol, or even the compound of formula (II) is 2-((1SR,4aSR,8aSR)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethan-1-ol.

[0027] 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 (3aRS, 5aSR, 9aSR, 9bRS) -3a, 6, 6, 9a-tetramethyldodecahydronaphtho[2, 1-b]furan, or even at least 85% of (3aRS, 5aSR, 9aSR, 9bRS) -3a, 6, 6, 9a-tetramethyldodecahydronaphtho[2, 1-b]furan, or even at least 90% of (3aRS, 5aSR, 9aSR, 9bRS) -3a, 6, 6, 9a-tetramethyldodecahydronaphtho[2, 1-b]furan. Tetramethyldodecahydronaphtho[2,1-b]furan, or even at least 95% of (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan, or even at least 98% of (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan, or even the compound of formula (II) is (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan.

[0028] According to any embodiment of the present invention, the compound of formula (I) and the compound of formula (II) are in the form of pure enantiomers. In other words, the compound of formula (I) conforms to the following formula:

[0029]

[0030] The bold and hatched lines indicate the absolute configuration;

[0031] And the compound of formula (II) conforms to the following formula:

[0032]

[0033] The bold and hatched lines indicate the absolute configuration;

[0034] According to any embodiment of the present invention, the Lewis acid is homogeneous with the protic acid having a pKa below 2.

[0035] According to any embodiment of the present invention, the pKa of the protic acid is equal to or less than 0, preferably equal to or less than -2, preferably equal to or less than -3, preferably equal to or less than -4, preferably equal to or less than -4.5, preferably equal to or less than -8.

[0036] According to a particular embodiment, when used in combination with a Lewis acid, the pKa of the protic acid is equal to or less than 2, preferably equal to or less than 0, preferably equal to or less than -2, preferably equal to or less than -3, preferably equal to or less than -4, preferably equal to or less than -4.5, preferably equal to or less than -8.

[0037] According to a particular embodiment, when used without a Lewis acid, the pKa of the protic acid is equal to or less than -3, preferably equal to or less than -4, preferably equal to or less than -4.5, preferably equal to or less than -8.

[0038] According to any embodiment of the present invention, the protonic acid is selected from the group consisting of HBF4, HBF4·OEt2, aqueous tetrafluoroboric acid, hexafluorophosphoric acid, trifluoromethanesulfonic acid, phosphotungstic acid hydrate, phosphomolybdic acid hydrate, fluoroantimonic acid, perchloric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid, and mixtures thereof. In particular, the protonic acid is perchloric acid. The perchloric acid can be formed in situ by adding sulfuric acid to barium perchlorate.

[0039] According to any embodiment of the present invention, the protic acid having a pKa of 2 or less is other than methanesulfonic acid, p-toluenesulfonic acid and trifluoroacetic acid.

[0040] According to any embodiment of the present invention, the Lewis acid conforms to the formula MX n, where M is a metal, X is a weakly coordinating or non-coordinating ligand, and n is 1, 2, or 3 and depends on the oxidation state of the metal and the nature of the anion (divalent ion or monoanion). When the metal is a monovalent metal cation, n is 1; when the metal is a divalent metal cation, n is 2 when X is a monoanion, or n is 1 when X is a divalent ion; and when the metal is a trivalent metal cation, n is 3 when X is a monoanion, or n is 2 when X is a divalent ion and the other X is a monoanion.

[0041] Non-limiting examples of weakly coordinating or non-coordinating ligands include BF4 - 、ClO4 - PF6 - 、HSO4 - 、SO4 2- 、TfO - NTf2 - 、TsO - 、ClSO3 - 、F - 、Cl - or Br - .

[0042] It will be understood that if n is 2 or 3, then the various X groups may be the same or different.

[0043] According to a particular embodiment, n can be 2 and 3. In other words, the Lewis acid conforms to the formula MX2 or MX3, wherein M is a metal selected from the group consisting of B, Bi and Fe, and X is F - or Cl - or trifluoromethanesulfonate, sulfate or hydrogensulfate groups or mixtures thereof. In particular, the metal can be selected from the group consisting of Bi and Fe, and X can be selected from the group consisting of Cl - or triflate, sulfate or bisulfate groups or mixtures thereof.

[0044] 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 can 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.

[0045] The Lewis acid or protic acid used may be in anhydrous or hydrated form, and the Lewis acid may be in a reaction mixture with an ether or a carboxylic acid such as R 1 2O or R2COOH adduct form, where R1 is a C1-C5 alkyl group, such as C2H5 or C4H9, and R 2 C1-C 20 Alkyl, for example methyl, ethyl or hept-3-yl.

[0046] According to a particular embodiment of the present invention, the process of the present invention is carried out in the presence of a Lewis acid and a protic acid having a pKa equal to or less than 2. In particular, the Lewis acid conforms to the formula MX n , wherein M is Fe, X and n have the meanings as defined above. The ratio between the Lewis acid and the protic acid having a pKa of 2 or less is from 0.5:1 to 1:0.5, particularly from 0.8:1 to 1:0.8, and even more particularly, the ratio between the Lewis acid and the protic acid having a pKa of 2 or less is 1:1. Non-limiting examples of suitable Lewis acids include Fe(HSO4)3, FeSO4(HSO4), Fe(Cl)3, FeCl3·6H2O, Fe(OTf)3, or mixtures thereof, and non-limiting examples of suitable protic acids for use in combination with the Lewis acid include HBF4, HBF4·OEt2, aqueous tetrafluoroboric acid, p-toluenesulfonic acid, methanesulfonic acid, hexafluorophosphoric acid, trifluoromethanesulfonic acid, phosphotungstic acid hydrate, phosphomolybdic acid hydrate, fluoroantimonic acid, perchloric acid, or mixtures thereof. In particular, the method of the present invention is carried out 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 protonic acid having a pKa of 2 or less selected from the group consisting of HBF4, aqueous tetrafluoroboric acid, p-toluenesulfonic acid, hexafluorophosphoric acid, trifluoromethanesulfonic acid, fluoroantimonic acid, perchloric acid, and a mixture thereof. In particular, the method of the present invention is carried out in the presence of Fe(Cl)3 as the Lewis acid and a protonic acid having a pKa of 2 or less selected from the group consisting of HBF4, aqueous tetrafluoroboric acid, p-toluenesulfonic acid, hexafluorophosphoric acid, trifluoromethanesulfonic acid, fluoroantimonic acid, perchloric acid, and a mixture thereof. Even more particularly, the method of the present invention is carried out in the presence of Fe(Cl)3 and HBF4.

[0047] According to any embodiment of the present invention, the method is carried out in the presence of an additive. The additive can be selected from water, silicon dioxide, a compound of formula RCOOH or HOOC(R') z COOH or ether of the formula R"OR"; wherein z is 0 or 1; R' is C 1-10 Alkanediyl, R is a hydrogen atom or a C optionally substituted by a hydroxyl group or an oxo group 1-10 alkyl, and R" are independently C 1-4In particular, z can be 0, R can be a hydrogen atom or a C alkyl group optionally substituted by a hydroxyl group or an oxo group. 1-8 alkyl, and R" are independently C 1-3 In particular, z can be 0, R can be a hydrogen atom or a C alkyl group optionally substituted by a hydroxyl group or an oxo group. 1-6 alkyl, and R" are independently C 2-3 Even more particularly, z can be 0, R can be a hydrogen atom or a C alkyl group optionally substituted by a hydroxyl group or an oxo group. 1-4 alkyl, and R" are each independently ethyl or isopropyl. 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, isopropyl ether or mixtures thereof.

[0048] The terms "alkyl" and "alkanediyl" are understood to include both branched and straight-chain alkyl and alkanediyl groups.

[0049] According to any embodiment of the invention, the cyclization of the compound of formula (II) is carried out in the presence of a catalytic amount of an acid.

[0050] Lewis acid and / or protic acid can be added to the reaction medium of the inventive method with a large-scale concentration to form the cyclic ethers of formula (I). As non-limiting examples, the total amount of formula (II) compound can be enumerated as the concentration value of 0.05 to 1.2 equivalents as Lewis acid or protic acid. Especially, the concentration of Lewis acid or protic acid can be 0.1 to 0.5 equivalent. Needless to say, the method also can be carried out when using more Lewis acid and / or protic acid catalyst. However, as known to those skilled in the art, the optimum concentration of Lewis acid or protic acid will depend on the latter's property, temperature and the required time of reaction.

[0051] Additive can be added in the reaction medium of the inventive method with a wide range of concentrations to form the cyclic ether of formula (I). As non-limiting examples, the concentration value of the additive can be enumerated as a concentration value within the range of 0.1 to 1 equivalent relative to the total amount of the compound of formula (II). In particular, the concentration of the additive can be 0.2 to 0.5 equivalent. Needless to say, the method also can be carried out when using more additives. However, as known to those skilled in the art, the optimum concentration of the additive will depend on the latter's property, temperature and the time required for the reaction.

[0052] According to any embodiment of the present invention, the process for preparing the cyclic ether of formula (I) according to the present invention is carried out at a temperature of -15°C to 150°C. In particular, the temperature is in the range of 20°C to 30°C. Of course, a person skilled in the art will also be able to select the preferred temperature based on the melting point and boiling point of the starting and final products and the desired reaction time, conversion rate or selectivity.

[0053] The process of the present invention for preparing the cyclic ether 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, any solvent currently available for this type of reaction can be used for the purposes of the present invention. Non-limiting examples include: C 6-12 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, methyltetrahydrofuran, chlorinated solvents, such as dichloromethane or dichloroethane or mixtures thereof. The choice of solvent depends on the nature of the substrate and / or Lewis acid and / or protic acid catalyst, and a person skilled in the art is fully capable of selecting the most suitable solvent in each case to optimize the reaction.

[0054] Solvent can be added in the reaction medium of the inventive method with a large-scale concentration to form the cyclic ethers of formula (I). As non-limiting example, the total amount of the compound of formula (II) can be enumerated as the concentration value of the solvent in the range of 0.5 to 20 % by weight. Especially, the concentration of the solvent can be 1 to 20 % by weight, or even 1 to 5 % by weight. Needless to say, the method also can be carried out when using more solvent. Yet, as known to those skilled in the art, the optimum concentration of the solvent will depend on the latter's character, temperature and the required time for reaction.

[0055] The process of the present invention for preparing the cyclic ether of formula (I) is carried out under batch or continuous conditions.

[0056] The process of the present invention for preparing the cyclic ether of formula (I) can be carried out under atmospheric pressure or slight vacuum.

[0057] 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-methylidenedecahydronaphthalen-1-yl)ethan-1-ol gives (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan.

[0058] 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% 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. In particular, the compound of formula (I) may be in the 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. 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 present invention may avoid the formation of (3aSR, 5aSR, 9aSR, 9bRS)-3a, 6, 6, 9a-tetramethyldodecahydronaphtho[2, 1-b]furan.

[0059] 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% 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. In particular, the compound of formula (I) may be in the 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. 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 present invention may avoid the formation of (3aS,5aS,9aR,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan.

[0060] Unless otherwise indicated, percentages (%) refer to weight percent of the composition.

[0061] The compound of formula (II) can be prepared by several methods known in the art, such as the method reported in the Australian Journal of Chemistry, 1989, 497. The compound of formula (II) can also be produced in vitro using purified recombinantly produced enzymes, or by fermentation using host cells (e.g., microbial cells) genetically engineered to convert inexpensive carbon sources (e.g., sugars) to the desired compound of formula (II), or in particular, to 2-(5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethyl acetate in the form of any of its stereoisomers or mixtures thereof. 2-(5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethyl acetate can be converted to 2-(5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-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 obvious because it allows easy access to starting materials with high enantiomeric excess.

[0062] According to any of the above embodiments of the process of the present invention, the process is further characterized in that the compound of formula (II), in particular 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethan-1-ol, is prepared by a process comprising the step of contacting farnesyl pyrophosphate with at least one enzyme.

[0063] In some embodiments of the presently claimed methods, an enzyme is used to prepare the compound of formula (II).

[0064] The process for preparing the compounds of formula (II) can be carried out in vitro as well as in vivo, as explained in further detail below.

[0065] When the method is performed in vitro, the enzyme to be used can be extracted from any organism expressing the enzyme using standard enzyme extraction techniques. If the host organism is a unicellular organism or cell, the enzyme can be simply collected from the culture medium, for example by centrifugation, optionally followed by a washing step and resuspension in a suitable buffer solution. If the organism or cell accumulates the enzyme intracellularly, the enzyme can be obtained by disrupting or lysing the cells and further extracting the enzyme from the cell lysate.

[0066] For in vitro methods, the enzyme can be provided in isolated form or as part of a protein extract and suspended in a buffer solution at an optimal pH. If appropriate, salts, DTT, NADPH, NADH, FAD, FMN and other types of enzyme cofactors can be added to optimize enzyme activity. The precursor compound is then added to the reaction mixture and incubated at an optimal temperature, for example 15 to 40°C, preferably 25 to 35°C, more preferably at 30°C. After incubation, the resulting compound of formula (II) can be isolated from the incubation solution by standard isolation procedures, such as solvent extraction and distillation, optionally after removing the enzyme from the solution.

[0067] According to another preferred embodiment, the method for preparing the compound of formula (II) is carried out in vivo. In this case, the method comprises culturing a non-human host organism or cell transformed to express the enzyme in the presence of a starting compound to be converted into the compound of formula (II) or the corresponding ester (e.g., 2-(5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethyl acetate) under conditions favorable for the enzymatic reaction.

[0068] 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 the cell or microorganism. The starting compound will permeate through the membrane of the cell or microorganism and thus can react with the enzyme expressed by the host cell or microorganism.

[0069] Carrying out the method in vivo is particularly advantageous because the method can be carried out without prior isolation of the enzyme. The reaction takes place directly in the organism or cell transformed to express the enzyme.

[0070] To practice the present invention in vivo, the host organism or cell is cultured under conditions that are favorable for the production of the compound of formula (II) or the corresponding ester (e.g., 2-(5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethyl acetate). Such conditions are any conditions that result in the 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, the conditions that are favorable for the production of the compound of formula (II) or the corresponding ester (e.g., 2-(5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethyl acetate) may include the addition of appropriate cofactors to the host's culture medium. In addition, the culture medium may be selected to maximize synthesis.

[0071] Optimal culture conditions are known to those skilled in the art and are not specific to the present invention.

[0072] In a more preferred embodiment, the organism used to carry out the method of the present invention in vivo is a microorganism. Any microorganism can be used, but 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 Escherichia coli and the yeast is Saccharomyces cerevisiae.

[0073] Typical ways of carrying out the process of the invention are reported in the examples hereinafter.

[0074] Example

[0075] The present invention will now be described in further detail by the following examples, in which abbreviations have their usual meanings in the art and temperatures are expressed in degrees Celsius (°C). 1 H) and 100MHz( 13 C) or a Bruker Avance II Ultrashield 400plus operating at 500 MHz ( 1 H) and 125MHz( 13 C) or a Bruker Avance III 500 operating at 600 MHz ( 1 H) and 150MHz( 13 NMR spectra were obtained using a Bruker Avance III 600 cryoprobe operated at 40°C. Spectra were internally referenced to 0.0 ppm tetramethylsilane. 1 H NMR signal shifts are expressed in δ 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 coupling), and were interpreted using Bruker Topspin software. 13 C NMR data are presented as chemical shifts δ ppm and hybridization from DEPT90 and DEPT135 experiments, C, quaternary; CH, methine; CH2, methylene; CH3, methyl.

[0076] Example 1

[0077] Cycling of 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethan-1-ol (B) to prepare (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (A)

[0078] In a typical experiment, 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethan-1-ol (B) (1.g, 4.23mmol) and DCM (30mL) were charged into a 50mL round bottom flask under N2. The solution was stirred at room temperature, and an acid catalyst (1.02mmol) and optional additives were added. The mixture was stirred for a specified period of time. Table 1 reports the desired compound (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-(( The yields of compounds of formula (C) and formula (D) were 1, 2, 3, 4, 5, 6, 7, 8, 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.

[0079] The samples were analyzed by GC innowax.

[0080] Table 1: Preparation of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan by cyclization of 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylidenedecahydronaphth-1-yl)ethan-1-ol

[0081]

[0082]

[0083] 1) Similar conditions were reported in WO2009053884, where the starting material was

[0084] 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-methylidenedecahydronaphthalen-1-yl)ethan-1-ol had low yield and selectivity.

[0085] 2) Use 5.4mmol methanesulfonic acid

[0086] 3) According to the conditions reported in Helv. Chem. Acta, 1985, 2022, 0.85 equivalents of p-toluenesulfonic acid were used at 100°C.

[0087] The process of the present invention allows 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 undesirable 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-naphthyl]ethanol and 2-((4aS,8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphth-1-yl)ethan-1-ol.

[0088] Example 2

[0089] Cycling of 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethan-1-ol (B) to prepare (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan (A)

[0090] Example 1 was repeated using HBF4, but using different solvents as shown in Table 2.

[0091] Table 2: Preparation of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan by cyclization of 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethan-1-ol using different solvents

[0092]

[0093] Example 3

[0094] In the presence of additives, 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalene-1- Cyclization of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b] Furan (A)

[0095] In a typical experiment, 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethan-1-ol (B) (0.8 g, 3.38 mmol) and toluene (37 mL) were charged into a 50 mL round-bottom flask under N2. The solution was stirred at room temperature, and an acid catalyst (0.88 mmol) and optional additives were added. The mixture was stirred for a specified period of time. Table 3 reports the desired compound (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-(( The yields of compounds of formula (C) and formula (D) were 1, 2, 3, 4, 5, 6, 7, 8, 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.

[0096] The samples were analyzed by GC innowax.

[0097] Table 3: Preparation of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan by cyclization of 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethan-1-ol using different solvents

[0098]

[0099] The addition of 2 equivalents of acetic acid allowed similar yields and selectivities to be obtained while reducing the reaction time.

[0100] Example 4

[0101] In the presence of Lewis acid and protonic acid, 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylpyridinium chloride was used to synthesize the Cyclization of decahydronaphthalen-1-yl)ethan-1-ol (B) to prepare (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphthalene 2,1-b]furan (A)

[0102] In a typical experiment, a Lewis acid catalyst (0.38 mmol), diethyl ether (additive) (0.08 mL, 0.76 mmol), PhMe (30 mL), and a protic acid (, 0.38 mmol) were added to a 50 mL round-bottom flask under N2. The mixture was stirred at 22°C. 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-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 stirred for the specified time. Table 4 reports the desired compound (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-((4a GC % yields of compounds of formula (C) and formula (D) corresponding to compounds of formula (C) and formula (D) respectively.

[0103] The samples were analyzed by GC innowax.

[0104] Table 4: Preparation of (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan by cyclization of 2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl)ethan-1-ol using different solvents

[0105]

Claims

1. A method for preparing a compound of formula (I): The bold and hatched lines indicate relative or absolute configurations; The method comprises cyclizing a compound of formula (II) in the presence of a Lewis acid, a protic acid having a pKa of 2 or less, or a mixture thereof: Bold and hatched lines indicate relative or absolute configurations.

2. The process according to 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. The method according to any one of claims 1 to 2, wherein the pKa of the protic acid is equal to or less than -3.

4. The method according to any one of claims 1 to 3, wherein the pKa of the protic acid is equal to or less than -4.

5.

5. The method according to any one of claims 1 to 4, wherein the pKa of the protic acid is equal to or less than -8.

6. The method according to any one of claims 1 to 5, wherein the protonic acid is selected from the group consisting of HBF4, HBF4·OEt2, aqueous tetrafluoroboric acid, hexafluorophosphoric acid, trifluoromethanesulfonic acid, phosphotungstic acid hydrate, phosphomolybdic acid hydrate, fluoroantimonic acid, perchloric acid, hydrogen bromide, hydrogen iodide, hydrochloric acid, and mixtures thereof.

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

8. The method of claim 7, wherein the Lewis acid conforms to the formula MX2 or MX3.

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 the group consisting of Bi and Fe.

10. The method according to any one of claims 7 to 9, wherein X is Cl - 、F - , trifluoromethanesulfonate, sulfate, hydrogensulfate groups or mixtures thereof, in particular Cl - , trifluoromethanesulfonate, sulfate, bisulfate groups or mixtures thereof.

11. The method 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 mixtures thereof.

12. The process according to any one of claims 1 to 11, wherein the process is carried out in the presence of Fe(Cl)3 and HBF4.

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, silicon dioxide and a compound of the formula RCOOH, HOOC(R') z COOH or ether of the formula R"OR"; wherein z is 0 or 1; R' is C 1-10 Alkanediyl, R is a hydrogen atom or a C optionally substituted by a hydroxyl group or an oxo group 1-10 alkyl, and R" are independently C 1-4 alkyl.

14. The method according to any one of claims 1 to 13, wherein the compound of formula (I) conforms to the following formula: The bold and hatched lines indicate the absolute configuration; And the compound of formula (II) conforms to the following formula: The bold and hatched lines indicate the 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.

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