Synthesis method of cedrene cis-diol

Abstract

The present patent application concerns a synthesis method of cedrene cis-diol of formula I comprising the following steps: a) providing α-cedrene of formula II and carrying out the regioselective and stereospecific reaction of α-cedrene of formula II to give cedrene epoxide of formula III, b) carrying out the stereospecific isomerization reaction of cedrene epoxide of formula III to give cedranone of formula IV, c) carrying out the regioselective and stereospecific hydroxylation reaction of cedranone of formula IV to give hydroxycedranone of formula V, d) carrying out the stereoselective reduction reaction of hydroxy cedranone of formula V to give cedrene cis-diol of formula I, characterized in that: in stage a) of the stereospecific epoxidation reaction, the reaction is carried out using a lipase enzyme and hydrogen peroxide, and the reaction temperature is comprised between 20 °C and 35 °C, and the cedrene epoxide of formula III is used as is, i.e. without the need for purification, in the next stereospecific isomerization step b); in stage b) of stereospecific isomerization reaction, the reaction is carried out using a Brönsted acid, and the reaction temperature is comprised between 20 °C and 85 °C, and cedranone of formula IV is purified by distillation; in stage c) of regioselective and stereospecific hydroxylation reaction, the reaction is carried out in the presence of a strong base, and the reaction temperature is comprised between 20 °C and 30 °C, and the hydroxycedranone of formula V is purified by crystallization; in stage d) of stereoselective reduction reaction, the reaction involves the following two sub-steps: dl) adding a Lewis acid, followed by d2) adding a reducing agent, and the reaction temperature is comprised between -5 and 0 °C, and the cedrene cis-diol of formula I is purified by crystallization; in each of the aforementioned steps a)-d) the compounds of formula III, IV, V and I are obtained respectively in a diastereomeric mixture with a diastereoisomeric ratio > 99:1.

Description

[0001] TITLE: "Synthesis method of cedrene cis-diol"

[0002] DESCRIPTION

[0003] FIELD OF THE INVENTION

[0004] The present invention fits in the technical field of the synthesis of cedrene cA-diol from which it is possible to obtain the commercial product Ambrocenide®, by carrying out more environmentally friendly, less aggressive, safer reactions, with less expenditure of organic solvent.

[0005] STATE OF THE ART

[0006] Ambrocenide® is a synthetic fragrance derived from cedrene, developed by Symrise in 1997, and widely used in perfumery for its amber and woody smell. It is produced annually on a scale of tens of tons from natural cedrene extracted from cedar wood and other conifers. Chemically, this is the cA-diol acetonide of compound (-)-a- cedrene.

[0007] The industrial synthesis method of the cA-diol of cedrene consists of

[0008] 1) epoxidation of cedrene to give cedrene epoxide with peracetic acid;

[0009] 2) acid hydrolysis of cedrene epoxide to give a mixture of diols contaminated by the cedranone, the latter being the isomerization product of cedrene epoxide;

[0010] 3) separation of diols by physical methods, such as chromatography or fractional crystallization.

[0011] Problems of the background art

[0012] There are several drawbacks to be overcome in the state of the art.

[0013] For example, it is necessary to introduce a selective method for preparing the cA-diol of cedrene, avoiding or limiting as much as possible the chromatographic separation procedures and reducing the waste products, which is the / ra / z.s-diol.

[0014] In addition to this, there is a need to obtain intermediates with a high diastereoisomeric ratio - therefore, without the need to separate the various diastereoisomers in a mixture -, using reactions characterized by milder conditions, therefore less aggressive, safer and potentially more environmentally friendly, with less expenditure of reagents / reagents and solvents, less expensive than those used at the state of the art, especially in view of a relative application in the industrial field.

[0015] In the literature, for most of the synthetic steps to obtain Ambrocenide®, purification is provided for by known methods, which, however, are time- and resourceconsuming, such as silica gel column chromatography.

[0016] Furthermore, the current method for producing the cedrene diol is not selective and leads to mixtures of stereoisomers (cis and irons') that need to be separated.

[0017] In particular, US 5,892,062 discloses in Example 1 the possibility of preparing (-) -a- cedrene epoxide by using peracetic acid. Examples 2 and 3 describe the preparation of 2a-3a-epoxy cedrene and 2P-3P-epoxycedrene respectively starting from compound (- ) -a-cedrene using AD-mix, the latter being a mixture of commercially available reagents that acts as an asymmetric catalyst for various chemical reactions, including Sharpless asymmetric dihydroxylation of alkenes. Example 4 instead discloses the preparation of the mixture of cedrandiols, as illustrated in Diagram 1 of the same patent document, by using sulfuric acid. Therefore, in this synthetic scheme, there is a need to separate the diols that are in mixture from each other.

[0018] Similarly, EP2947078 also discloses the possibility of forming the cedrene epoxide starting from peracetic acid; moreover, the various diastereomeric diols are obtained in a mixture and are, therefore, to be separated.

[0019] In other cases, the mixture of cedrene diols can also be exploited with biotechnology techniques through an oxidation and reduction sequence with an enzyme belonging to the class of hydroxysteroid ketoreductases. Enzymatic oxidation of the diol mixture leads to alpha-hydroxycedranone, which is then enzymatically reduced by the same enzyme in the presence of a hydride donor to give only the cA-diol.

[0020] An example of using the aforementioned biotechnological methods to obtain the correct diastereoselectivity is included in W0202104614A1, which describes the transition from cedrene epoxide to the compound (8 / ?,9 / ?)- / ra / / .s-cedrene diol by means of an epoxide hydrolase enzyme, then converting the compound (%R.9R)-lrans- cedrene diol into cedrene hydroxytone which, in turn, is converted into the desired (8A,95)-czs-cedrene diol, by using an alcohol dehydrogenase enzyme in the presence of a cofactor (pne-pot reaction).

[0021] However, the aforementioned biotechnological-based reactions are extremely sophisticated and expensive, for example because they require the presence of certain enzymes, which are not commercially available, and are therefore difficult to apply industrially.

[0022] Other synthetic methods, such as the one described in "Stereoselective Synthesis of a cis-Cedrane-8,9-diol as a Key Intermediate for an Amber Odorant" (Org. Process Res. Dev. 2021, 25, 89-97) by Stefanow V. et al, provide for: epoxidation of cedrene; basic isomerization of cedrene to give the allyl alcohol cedranol; protection of the alcohol as acetate; epoxidation of the exocyclic olefin; opening of the epoxide with aluminium hydride and consequent deprotection of the acetate group. This method avoids mixtures of isomers at the expense however of the number of synthetic steps and the use of protective groups, as well as requiring at least one purification by chromatographic column.

[0023] Epoxidation reaction

[0024] Chemo-enzymatic epoxidation of olefins using lipase and hydrogen peroxide is known in the art.

[0025] Fredrik Bjorkling et al in "Lipase-mediated Formation of Per oxycarboxylic Acids used in Catalytic Epoxidation of Alkenes" (J. CHEM. Soc., Chem. COMMUN., 1990, pp 1301-1303) describes the chemo-enzymatic epoxidation reaction on olefin substrates that are not complex and, in any case, different from a-cedrene. It should also be noted that Fredrik Bjorkling et al. explains that, among the different solvents tested for peracid generation catalyzed by lipase, toluene or hexane are those that allow obtaining the highest yields of peroxycarboxylic acid, while lower yields are obtained with the use of dioxane or acetonitrile. These results are in agreement with the observation that lipases generally perform better for synthesis in water-immiscible organic solvents rather than in water-miscible organic solvents.

[0026] Arianna Brandolese et al. in "Synthesis of Biorenewable Terpene Monomers Using Enzymatic Epoxidation under Heterogeneous Batch and Continuous Flow Conditions" (ACS Sustainable Chem. Eng. 2023, 11, 4885-4893) describes the chemo-enzymatic epoxidation reaction on non-complex olefin substrates and, in any case, different from a-cedrene. In addition, purification by chromatographic column is envisaged for the reactions carried out on all three substrates mentioned in the scientific article (3-Carene oxide (CO), Limonene oxide (LO), Limonene dioxide (LDO)).

[0027] As mentioned, Fredrik Bjorkling et al and Arianna Brandolese et al, while disclosing the possibility of using the lipase enzyme for chemo-enzymatic epoxidation, start from substrates other than a-cedrene; the Applicant considers that it is not so obvious to expect good results in terms of diastereomeric ratio and percentage yield of the reaction starting from the a-cedrene substrate, which is more complex and characterized by more centres of chirality than those studied in the cited literature. In addition, in the literature, chromatographic purification is necessary.

[0028] Isomerization reaction

[0029] The stereospecific isomerization reaction of cedrene epoxide to cedranone with Lewis acids is known in the art, for example this is described in "Hydroboration of Terpenes. VI. Hydroboration of a- and f-Cedrones. Configurational Assignments for the Related Cedrane Derivatives" by Shrinivas P. Acharya and Herbert C. Brown (J. Org. Chem. 1970, 35, 196-206). In this article, epoxy cedrene is treated with BF3, a Lewis acid, to obtain cedranone. This reaction is carried out in benzene and at 0 °C and under nitrogen atmosphere.

[0030] Hydroxylation reaction

[0031] The regioselective and stereospecific hydroxylation reaction of cedranone to give a- hydroxycedranone is described in CN112592252. The Chinese patent protects compound 8 of Example 7, therefore it is oriented towards another type of product, different from Ambrocenide. In any case, a-hydroxy cedranone (compound 15 of Example 14) provides for the use of potassium ter-butoxide; the reaction crude is purified by chromatographic column. Further, note that the stereospecificity and regioselectivity of the reaction for compound formation is not reported in Example 14. Substrate reduction reaction a-hydroxy ketone

[0032] The reduction of ketones with a heteroatom linked to the carbon atom in the a position with lithium aluminium hydride is described in the literature on substrates other than hydroxycedranone, in which the product is purified by column chromatography on silica gel (" The Synthesis and Stereochemistry of the Four Isomeric Pinane-2, 3-diols". Robert G. Carlson et al, J. Org. Chem., Vol. 36, No. 16, pp 2319-2324, 1971).

[0033] The reduction reaction of the substrate a-hydroxymethyl cyclohexanone envisages in the literature the use of reducing agents such as Li AIH4 ("Directive Effect of the 2- and 3-Axial Hydroxy Groups That Appeared in the Complex Metal Hydride Reduction of Cyclohexanones" by Yasuhisa Senda et al, Bull. Chem. Soc. Jpn., 73, No. 1 (2000), pp 237-242); in these cases, it is noted that the hydride transfer occurs on the same side of the hydroxy group, leading to the formation of the trans product.

[0034] In "The Total Synthesis of C )-Vindoline" (J. Am. Chem. Soc. 1975, 97, 23, 6880- 6881), Masayoshi Ando et al explain that reduction of the a-hydroxy ketone portion of the complex indoline substrate, employing various hydrides, gave mixtures of epimeric alcohols, but prior addition of aluminium chloride (-25 °C, THF), followed by reduction with sodium bis(2-methoxy-ethoxy) aluminium hydride (REDAL) (-20 °C) gave a single epimer with a yield of 56%. The authors hypothesize that the formation of an aluminium complex, thanks to the coordinating capabilities of the OH group present in position a with respect to the ketone, directs the attack of the hydride on the carbonyl in such a way as to lead to the formation of the cz.s-diol product.

[0035] A rare case of cz.s-selective reduction for a similar cedrenic-based substrate is described for hydroxycedranone oxime which, in the presence of Li AIH4, is reduced to cz.s-amino alcohol. This teaching is given by Yilin Song et al in "Synthesis of Hydroxycedranone and Aminohydroxycedrane" (Synthetic Communications, 29(23), 4171-4178 (1999)). The formation of an aluminium complex is hypothesized which, thanks to the coordinating abilities of the OH group of both the alcohol and the oxime, directs the attack of the hydride on the carbonyl to give czs-aminoalcohol.

[0036] SUMMARY OF THE INVENTION

[0037] The object of the invention is a synthesis method of cedrene cz.s-diol of formula / formula I comprising the following steps: a) providing a-cedrene of formula II and carrying out the regioselective and stereospecific reaction of a-cedrene of formula / / to give cedrene epoxide of formula III formula II formula III b) carrying out the stereospecific isomerization reaction of cedrene epoxide of formula

[0038] III to give cedranone of formula IV formula III formula IV c) carrying out the regioselective and stereospecific hydroxylation reaction of cedranone of formula IV to give hydroxy cedranone of formula V formula IV formula V d) carrying out the stereoselective reduction reaction of hydroxy cedranone of formula V to give cedrene c / .s-diol of formula I formula V formula I characterized in that

[0039] (i) in stage a) of the regioselective and stereospecific reaction, the reaction is carried out using a lipase enzyme and hydrogen peroxide, and the reaction temperature is comprised between 20 °C and 35 °C, and the cedrene epoxide of formula III is used as is, i.e. without the need for purification, in the next step b) of stereospecific isomerization;

[0040] (ii) in stage b) of stereospecific isomerization reaction, the reaction is carried out using a Brbnsted acid, and the reaction temperature is comprised between 20 °C and 85 °C, and the cedranone of formula / Lis purified by distillation,

[0041] (Hi) in stage c) of regioselective and stereospecific hydroxylation reaction, the reaction is carried out in the presence of a strong base, and the reaction temperature is comprised between 20 °C and 30 °C, and the hydroxycedranone of formula Lis purified by crystallization,

[0042] (tv) wherein in stage d) of stereoselective reduction reaction, the reaction involves the following two sub-steps: dl) adding a Lewis acid, followed by d2) adding a reducing agent, and the reaction temperature is comprised between -5 and 0 °C, and the cedrene cv.s-diol of formula / is purified by crystallization,

[0043] (v) in each of the aforementioned steps a)-d), the compounds of formula Ilf IV, V and I are obtained respectively in diastereomeric mixture with a diastereomeric ratio > 99: 1. Advantages of the invention

[0044] The invention, which consists of a synthesis method of cedrene c / .s-diol of formula I to then give Ambrocenide, applicable industrially, is advantageous because:

[0045] - avoids the physical separation of the diol isomers thanks to a selective synthesis method, and this is also advantageous for any scale-up at an industrial level;

[0046] - avoids the use of expensive and extremely sophisticated biotechnological methods, therefore with little industrial application, such as those described at the state of the art for the recovery and enhancement of the mixture of isomeric diols;

[0047] - does not involve the use of toxic and expensive metals, such as osmium, which must be avoided on a large scale for safety and cost reasons;

[0048] - the method requires only distillation and crystallization processes to obtain analytically pure material, without the use of silica gel chromatography;

[0049] - few synthetic steps are required, without the need to insert protective groups;

[0050] - the reactions are safer and non-aggressive, as they are characterised by milder reaction conditions;

[0051] - all reagents are commercially available in bulk, including the enzyme lipase.

[0052] DESCRIPTION OF THE DRAWINGS

[0053] Figure I: Synthesis method according to an embodiment of the invention.

[0054] DETAILED DESCRIPTION OF THE INVENTION

[0055] In the following, the invention and preferred embodiments thereof are described in more detail.

[0056] A diastereoisomeric ratio is intended to mean the ratio existing between two diastereoisomers.

[0057] Note that, in each step a) of regioselective and stereospecific reaction, b) of stereospecific isomerization reaction, c) of regioselective and stereospecific hydroxylation reaction, d) of stereoselective reduction reaction, the compounds of formula III, IV, V and I are obtained respectively in a diastereomeric mixture with a diastereoisomeric ratio > 99: 1. This means that each of the aforementioned steps is characterized by the formation of a particular diastereoisomer in a significantly greater quantity than the other possible diastereoisomers (see Scheme 7).

[0058] Reaction yield, expressed in percentage terms, means the molar percentage ratio of the product obtained to the total moles of the reagent.

[0059] By method of purification of a reaction crude is meant a purification technique that allows to isolate the desired product from a reaction crude; the desired product will be isolated with a certain degree of purity. Examples of purification techniques or methods are: silica gel column chromatography, distillation, crystallization.

[0060] For convenience of exposition, the synthetic scheme or method object of the present invention is summarized below:

[0061] Scheme 1

[0062] Note that the overall duration of stereospecific epoxidation, stereospecific isomerization, regioselective and stereospecific hydroxylation, stereoselective reduction chemical reactions, is preferably < 48 hours, preferably > 24 and < 48 hours, preferably > 24 and < 48 hours, preferably > 24 and < 40 hours, preferably > 24 and < 30 hours.

[0063] Advantageously, the timing of the various synthetic steps is reduced and, overall, the timing for the entire claimed synthetic method is reduced.

[0064] Note that the temperature of the chemical reactions of stereospecific epoxidation, stereospecific isomerization, regioselective and stereospecific hydroxylation, stereoselective reduction, is preferably comprised between a minimum of 0 °C and a maximum of 80 °C.

[0065] Preferably, with the exception of the stereospecific isomerization reaction, the temperature of the chemical reactions of stereospecific epoxidation, regioselective and stereospecific hydroxylation, stereoselective reduction, is preferably comprised between a minimum of 0 °C and a maximum of 30 °C.

[0066] Note that preferably the yield of stereospecific epoxidation, stereospecific isomerization, regioselective and stereospecific hydroxylation, stereoselective reduction chemical reactions is comprised between 50% and 99%, preferably between 56% and 99%, preferably between 60% and 99%, preferably between 64% and 99%, preferably between 64% and 96%.

[0067] Preferably, the crystallization solvent is selected from the group consisting of hexane, heptane, methanol, ethanol, water, diisopropyl ether, toluene, and mixtures thereof.

[0068] Stereospecific epoxidation reaction (step a)

[0069] Step a) involves providing the substrate for the a-cedrene of formula II and carrying out the regioselective and stereospecific reaction of a-cedrene of formula II to give cedrene epoxide of formula III formula II formula III

[0070] This regioselective and stereospecific reaction is carried out using a lipase enzyme and hydrogen peroxide, at a temperature comprised between 20 °C and 35 °C, has the advantage that the cedrene epoxide of formula III is used as it is in the next step b), without further purification.

[0071] Preferably, the lipase enzyme is commercially available, such as Novozym 435.

[0072] Preferably, the lipase enzyme is used in a quantity comprised between 0.5% and 2.5% by weight, preferably between 0.5% and 2% by weight, preferably between 1% and 2% by weight, preferably equal to 1% or 2% by weight, on the total weight (% w / w) of the substrate.

[0073] Note that, in the absence of the enzyme, the reaction does not proceed.

[0074] Preferably, the hydrogen peroxide is at 30% v / v. Preferably, the equivalents of hydrogen peroxide are comprised between 1 and 2, preferably equal to 1.5.

[0075] Preferably, the concentration of a-cedrene is comprised between 0.3 and 1 M, preferably between 0.3 M and 0.7 M, preferably between 0.4 and 0.6 M, preferably equal to 0.5 M.

[0076] Preferably, the solvent of the regioselective and stereospecific reaction is ethyl acetate or is a mixture of ethyl acetate and acetonitrile, still preferably the solvent is a mixture of ethyl acetate and acetonitrile.

[0077] Preferably, ethyl acetate and acetonitrile are in the volume ratio comprised between 1 :0.5 and 1 :2, more preferably of 1 : 1.

[0078] Acetonitrile favours the dissolution of 30% H2O2 solution in the reaction medium. Note that the reaction carried out in the presence of only acetonitrile does not proceed. In fact, ethyl acetate is essential to give peracetic acid by perhydrolysis with hydrogen peroxide mediated by the enzyme. In acetonitrile and in the absence of enzyme, the epoxidation does not proceed via Payne epoxidation (addition of hydrogen peroxide to nitriles in a basic environment, with the formation of an intermediate acid peroxy capable of epoxidizing olefins).

[0079] The temperature of the regioselective and stereospecific reaction is comprised between 20 °C and 35 °C, preferably comprised between 25 °C and 35 °C, preferably equal to 30 °C.

[0080] Note that the reaction does not proceed at a temperature < 20 °C, preferably < 15 °C.

[0081] Preferably, the regioselective and stereospecific reaction has a duration comprised between 12 and 30 hours, preferably between 12 and 24 hours, preferably between 16 and 24 hours, preferably of 24 hours.

[0082] Preferably, the regioselective and stereospecific reaction has a yield > 95%, preferably between 95% and 96%, preferably of 96%.

[0083] Preferably, the diastereomeric ratio is > 99: 1.

[0084] Preferably, the conditions of the regioselective and stereospecific reaction are as follows: .

[0085] 4 h

[0086] ( -)«a-cedrene cedrene epoxide 96% yield >99:1 dr formula II formula III

[0087] The regioselective and stereospecific reaction of cedrene is easier and less dangerous than that described in the literature; in fact, an enzyme is used for the generation in situ of peracetic acid via perhydrolysis of ethyl acetate with hydrogen peroxide catalysed by an enzyme, in particular with lipase. In addition, the use of a commercially available immobilized lipase, such as Novozym 435, allows the use in packed columns for heterogeneous reaction in continuous flow and allows its reuse.

[0088] Stereospecific isomerization reaction (step b)

[0089] Step b) involves carrying out the stereospecific isomerization reaction of cedrene epoxide of formula III to give cedranone of formula IV formula III formula IV wherein the stereospecific isomerization reaction is carried out using a Brbnsted acid, wherein the reaction temperature is comprised between 20 °C and 85 °C, wherein the cedranone of formula IV is purified by distillation.

[0090] It should be noted that, with respect to the state of the art, the isomerization reaction for the method of the invention involves the use of a Brbnsted acid instead of a Lewis acid. In addition, it provides for more economical and practical conditions, for example without the need to employ low reaction temperatures. Preferably, the Brbnsted acid used in the stereospecific isomerization reaction is selected from the group consisting of sulfuric acid, phosphoric acid, perchloric acid, acetic acid, paratoluenesulfonic acid, preferably it is concentrated sulfuric acid.

[0091] Preferably, the equivalents of the Brbnsted acid are comprised between 0.05 and 0.15, preferably equal to 0.1.

[0092] Preferably, the concentration of the Brbnsted acid is comprised between 12 and 20 M, preferably between 16 and 20 M, preferably between 16 and 18 M, preferably equal to 18 M.

[0093] Preferably, the Brbnsted acid is a strong inorganic acid, preferably it is a strong inorganic and concentrated acid.

[0094] It should also be noted that, in the presence of a strong inorganic diluted acid, preferably at a concentration comprised between 3 and 7 M, preferably between 5 and 7 M, preferably equal to 5 M, the diol by-product (therefore a mixture of diastereoisomers) is obtained by hydrolytic opening of the epoxide. Conversely, using strong inorganic acid concentrate reduces the formation of diol, but the formation of allyl alcohol is observed by isomerization of the epoxide.

[0095] Preferably, the solvent of the stereospecific isomerization reaction is selected from the group consisting of: ethyl acetate, dioxane, diisopropyl ether, toluene, preferably it is ethyl acetate.

[0096] The temperature of the stereospecific isomerization reaction is comprised between 25 °C and 85 °C, preferably between 30 °C and 85 °C, preferably between 40 °C and 85°, preferably between 45° and 85°, preferably between 50 °C and 85 °C, preferably between 60 °C and 90 °C, preferably comprised between 70 °C and 80 °C, preferably of 60 °C or of 80 °C.

[0097] Note that, by increasing the temperature, it is possible to increase the yield of cedranone, although allyl alcohol is also obtained, which is then converted into an unidentified mixture of dienes by elimination.

[0098] At the temperature of 80 °C, the reaction leads to the formation of cedranone with a purity of 92%. The remaining 8% is an elimination product, mainly identified in the diene, which is removed in the next step (hydroxylation of cedranone) by crystallization from hexane of hydroxy cedranone.

[0099] Preferably, the stereospecific isomerization reaction has a duration comprised between 5 and 10 minutes, preferably of 10 minutes. Preferably, the stereospecific isomerization reaction has a yield > 56%, preferably between 56% and 65%, preferably of 60%.

[0100] Preferably, the diastereomeric ratio is > 99: 1.

[0101] Preferably, the conditions of the stereospecific isomerization reaction are as follows:

[0102] Regioselective and stereospecific hydroxylation reaction (step c)

[0103] Step c) involves carrying out the stereospecific hydroxylation reaction of cedranone of formula IV to give hydroxy cedranone of formula V formula IV formula V wherein the regioselective and stereospecific hydroxylation reaction is carried out in the presence of a strong base, preferably is an inorganic or organic base, preferably is an organic base, preferably it is a strong and sterically hindered organic base, wherein the reaction temperature is comprised between 20 °C and 30 °C, wherein the hydroxy cedranone of formula V is purified by crystallization, preferably by using an organic solvent immiscible with water, such as cold hexane. Preferably, the strong base used in the regioselective and stereospecific hydroxylation reaction is selected from the group consisting of: potassium te / 7-butoxide (or potassium tert- butyloxide), sodium methylate, sodium hydride preferably is potassium tert- butyloxide.

[0104] Preferably, the equivalents of the base used in the stereospecific hydroxylation reaction are comprised between 0.5 and 1.5, preferably between 1 and 1.5, preferably equal to 1.2.

[0105] Preferably, the stereospecific hydroxylation reaction is carried out in air.

[0106] Preferably, the solvent of the stereospecific hydroxylation reaction is a mixture of DMSO (dimethyl sulfoxide) and methanol.

[0107] Preferably, the volume ratio of DMSO to methanol is comprised between 15: 1 and 5: 1, preferably equal to 10: 1.

[0108] The regioselective and stereospecific hydroxylation reaction is carried out at a temperature comprised between 20 °C and 30 °C, comprised preferably 20 °C and 25 °C, preferably of 25 °C.

[0109] Preferably, the regioselective and stereospecific hydroxylation reaction has a duration comprised between 2 and 6 hours, preferably between 2 and 4 hours, preferably of 4 hours.

[0110] Preferably, the regioselective and stereospecific hydroxylation reaction has a yield > 50%, preferably between 50% and 56%, preferably of 56%.

[0111] Preferably, the diastereomeric ratio is > 99: 1.

[0112] Preferably, the conditions of the regioselective and stereospecific hydroxylation reaction are as follows: formula IV formula V Stereoselective reduction reaction (step d)

[0113] Step d) involves carrying out the stereoselective reduction reaction of hydroxy cedranone of formula V to give cedrene c / .s-diol of formula I formula V formula I wherein the stereoselective reduction reaction involves the following two steps: dl) sub-step of adding a Lewis acid, followed by d2) sub-step of adding a reducing agent, wherein the reaction temperature is comprised between -5 and 0 °C, wherein the cedrene cv.s-diol of formula I is purified by crystallization, preferably by using an organic solvent immiscible with water, such as hexane or cold hexane.

[0114] Preferably, the sub-step of adding a Lewis acid dl) has a duration comprised between 10 and 20 minutes, preferably between 10 and 15 minutes, preferably of 15 minutes.

[0115] Preferably, the Lewis acid used in the stereoselective reduction reaction is a Lewis acid based on aluminium, i.e. a Lewis acid in which at least one aluminium atom is present; they are known to a person skilled in the art.

[0116] Preferably, the Lewis acid used in the stereoselective reduction reaction is selected from the group consisting of: aluminium chloride, zinc dichloride, iron trichloride, aluminium isopropoxide, preferably it is aluminium chloride.

[0117] Preferably, the equivalents of Lewis acid used are between 1 and 2.5, preferably between 1.5 and 2, preferably of 2.

[0118] Preferably, the sub-step of adding the reducing agent d2) has a duration comprised between 30 minutes and 1 hour, preferably comprised between 45 minutes and 1 hour, preferably of 1 hour or of 2 hours. Preferably, the reducing agent used in the stereoselective reduction reaction is selected from the group consisting of: DIBAL (diisobutyl aluminium hydride), REDAL (sodium bi s(2 -methoxy ethoxy aluminium hydride), LiAlIL, NaBPL, preferably it is DIBAL.

[0119] Note that standard reductants such as sodium boron hydride or lithium aluminium hydride, in the absence of Lewis acid, lead to the formation of the trans diol as a single diastereoisomer.

[0120] It should also be noted that the mere presence of reducing agents such as DIBAL and REDAL, in the absence of Lewis acid, leads to the formation of the cv.s-diol as the minority isomer.

[0121] Preferably, the equivalents of reducing agent used are comprised between 1 and 2.5, preferably between 1.5 and 2, preferably of 2.

[0122] Preferably, the Lewis acid and the reducing agent used in the stereoselective reduction reaction are in an equivalent ratio comprised between 1 :0.5 and 1 :2, preferably between 1 : 1 and 1 :2, preferably of 1 : 1.

[0123] The stereoselective reduction reaction is carried out at a temperature comprised between -5 °C and 0 °C, preferably comprised between -2 °C and 0 °C, preferably of 0 °C.

[0124] The Applicant has not tested temperatures lower than those indicated above to avoid cryogenic conditions.

[0125] Preferably, the solvent of the stereoselective reduction reaction is selected from the group consisting of: toluene, THF, diethyl ether, hexane, dichloromethane; preferably, the solvent is toluene.

[0126] When the solvent is toluene, the reducing agent is not LiAlIL; the latter is not soluble in toluene.

[0127] Preferably, the stereoselective reduction reaction has an overall duration comprised between 10 minutes and 2 hours, preferably between 15 minutes and 1 hour and 30 minutes, preferably between 15 minutes and 1 hour and 15 minutes. Preferably, the stereoselective reduction reaction has a yield > 56%, preferably between 56% and 60%, preferably of 60%.

[0128] Preferably, the diastereomeric ratio is > 99: 1.

[0129] Preferably, the conditions of the stereoselective reduction reaction are as follows: formula V formula I Note that stereoselective reduction of alpha-hydroxycedranone with aluminium hydrides is more convenient than the enzymatic method because it uses low-cost available reagents and is more easily scalable.

[0130] As already mentioned in the State of the art, Yilin Song et al show a rare example of cis selectivity with the use of Li Al LU, in which however the substrate of the reaction is different from that of the method of the invention, it is also characterized by an oxime from which a czs-aminoalcohol is obtained as the final product.

[0131] Acetalization reaction (step e)

[0132] The acetalization reaction (or step (e)) involves the synthesis of Ambrocenide® (chemical name: (4a7?,5A,7a5,9A) -octahydro-2, 2, 5,8,8, 9a-hexamethyl-4H-4a, 9- methanoazulene(5,6-d)-l,3-dioxole) starting from cedrene cz.s-diol of formula I.

[0133] This acetalization reaction (or step (e)) follows step d) of carrying out the stereoselective reduction reaction of the hydroxycedranone of formula V to give cedrene cz.s-diol of formula I. formula I Ambrocenide® Preferably, the acetalization reaction involves the use of 1,2-dimethoxypropane and anhydrous paratoluenesulfonic acid (or PTSA).

[0134] Preferably, the equivalents of 1,2-dimethoxypropane are comprised between 10 and 20, preferably between 15 and 20, preferably they are 20.

[0135] Preferably, the equivalents of anhydrous paratoluenesulfonic acid are comprised between 0.01 and 0.1, preferably between 0.03 and 0.05, preferably they are 0.05.

[0136] Preferably, the solvent of the acetalization reaction is selected from the group consisting of: dichloromethane, acetone, 1,2-dimethoxypropane, toluene, preferably it is dichloromethane.

[0137] Preferably, the solvent of the acetalization reaction is anhydrous; this is to avoid decomposition of the Ambrocenide in the reaction mixture. In fact, in the presence of water and acids, Ambrocenide decomposes to a mixture of cedranone isomers.

[0138] Preferably, the acetalization reaction is carried out under an atmosphere of an inert gas, for example nitrogen.

[0139] Preferably, the acetalization reaction is carried out at a temperature comprised between 20 °C and 25 °C, preferably between 23 °C and 25 °C, preferably of 25 °C.

[0140] Preferably, the acetalization reaction has a duration comprised between 12 minutes and 16 hours, preferably between 14 and 16 hours, preferably of 16 hours.

[0141] Preferably, the acetalization reaction has a yield > 60%, preferably between 60% and 65%, preferably of 64%.

[0142] Preferably, the Ambrocenide® product is purified by crystallization, preferably using a water-miscible organic solvent, preferably ethanol.

[0143] Preferably, the diastereomeric ratio is > 99: 1.

[0144] Preferably, the conditions of the acetalization reaction are as follows: EXAMPLES

[0145] Example 1: Characterization of synthetic intermediates and products.

[0146] Cedrene epoxide of formula III

[0147] To a solution of (-)-a-cedrene (5.00 g, 25.00 mmol, 1.00 equiv) in a mixture 1 : 1 of ethyl acetate and acetonitrile (50 mL), 435 (0.05 g, 1% w / w) is added Novozym. A 30% v / v hydrogen peroxide solution (3.22 mL, 37.50 mmol, 1.50 equiv) are added to this mixture. The reaction is maintained under stirring at 150 rpm at the temperature of 30 °C. After 24 hours, the reaction is quenched with a saturated aqueous solution of sodium bisulfite (20 mL). The two phases are separated, and the aqueous phase is extracted with ethyl acetate (25 mL x 2). The organic phases are washed with a saturated aqueous solution of sodium chloride, anhydrified with sodium sulfate and the solvent is evaporated under reduced pressure. Cedrene epoxide is obtained as a pure colourless oil that can be used directly in the next reaction (5.29 g, 96% yield, > 99: 1 dr).

[0148] TLC: Rf= 0.7 (10% ethyl acetate in hexane).

[0149] 'H NMR (400 MHz, CDCI3) δ 2.99 (d, J = 4.5 Hz, 1H), 1.92 (d, J = 14.5 Hz, 1H), 1.85 (d, .7= 4.5 Hz, 1H), 1.83 - 1.78 (m, 1H), 1.78 (d, J= 13.8 Hz, 1H), 1.70 - 1.53 (m, 4H), 1.45 - 1.35 (m, 1H), 1.41 (s, 3H), 1.33 - 1.22 (m, 2H), 1.18 (s, 3H), 0.99 (s, 3H), 0.79 (d, 7 = 7.2 Hz, 3H).

[0150] 13C NMR (101 MHz, CDCI3) δ 61.17, 61.14, 58.45, 53.86, 52.16, 43.19, 41.66, 36.92, 36.06, 35.97, 30.22, 27.62, 25.14, 23.84, 15.67.

[0151] GC-MS: tr= 20.64 min. m / z (%): 220 (M+, 47), 205 (100), 191 (21), 177 (20), 163 (14).

[0152] [«]D25= -58.5 (c 0.78, CHCh). Cedranone of formula IV

[0153] Concentrated sulfuric acid (0.076 mL, 17.80 M, 1.35 mmol, 0.10 equiv) is added to a solution of a-cedrene epoxide (2.80 g, 13.50 mmol, 1.00 equiv) in ethyl acetate (28 mL) heated to reflux (80 °C). After 10 minutes, the reaction is cooled and quenched with the addition of a saturated aqueous solution of sodium bicarbonate (5 mL). The two phases are separated and the aqueous phase is extracted with ethyl acetate (10 mL). The organic phases are washed with a saturated sodium chloride solution, anhydrified with sodium sulfate and the solvent is evaporated under reduced pressure. The reaction crude (brown oil) is distilled to give cedranone as a yellow oil (1.40 g, 60% yield, 90% purity, > 99: 1 dr).

[0154] TLC: Rf= 0.5 (10% ethyl acetate in hexane).

[0155] 'H NMR (400 MHz, CDCI3) δ 2.67 (q, J= 7.5 Hz, 1H), 2.37 (d, J= 16.0 Hz, 2H), 2.21 (d, J= 16.0 Hz, 1H), 1.93 - 1.85 (m, 2H), 1.85 (d, J= 12.0 Hz, 1H), 1.72 (d, J = 10.4 Hz, 1H), 1.71 - 1.65 (m, 1H), 1.66 - 1.54 (m, 3H), 1.50 - 1.38 (m, 1H), 1.36 - 1.27 (m, 1H), 1.14 (d, J= 7.5 Hz, 3H), 0.99 (s, 3H), 0.97 (s, 3H), 0.85 (d, J= 7.0 Hz, 3H).

[0156] 13C NMR (101 MHz, CDCI3) δ 216.61, 58.57, 55.75, 55.24, 49.80, 46.94, 42.80, 41.66, 37.65, 36.83, 27.01, 26.93, 25.79, 18.21, 15.39.

[0157] GC-MS: tr = 21.29 min. m / z (%): 220 (M+, 45), 205 (100), 191 (21), 177 (20), 163 (14).

[0158] [«]D25= -84.0 (c 1.0, CHCI3).

[0159] Idroxy cedranone of formula V Potassium ter-butoxide (0.87 g, 7.76 mmol, 1.20 equiv) is added to a solution of cedranone (1.40 g, 6.47 mmol, 1.00 equiv) in 10: 1 mixture of dimethyl sulfoxide and methanol (13 mL). The reaction is left under stirring 4 hours open to air at room temperature and is then quenched by dilution with water (100 mL). The solution is extracted with ethyl acetate (25 mLx3). The organic phases are washed with a saturated aqueous solution of sodium chloride, anhydrified with sodium sulfate and the solvent is evaporated under reduced pressure. The reaction crude (yellow solid) is triturated with cold hexane to give pure hydroxycedranone as a white crystalline solid (0.63 g, 56% yield, > 99: 1 dr).

[0160] TLC: Rf = 0.4 (10% ethyl acetate in hexane).

[0161] 'H NMR (400 MHz, CDCI3) δ 2.77 (d, J= 14.3 Hz, 1H), 2.44 (d, J= 9.9 Hz, 1H), 2.22 (dd, J = 14.4, 2.9 Hz, 1H), 1.93 (d, J = 4.9 Hz, 2H), 1.91 - 1.84 (m , 1H), 1.69 (ddd, = 12.3, 4.3, 3.0 Hz, 1H), 1.66 - 1.58 (m, 2H), 1.58 - 1.51 (m, 1H), 1.45 (s, 3H), l.44 - 1.36 (m, 1H), 1.36 - 1.27 (m, 1H), 1.01 (s, 3H), 1.00 (s, 3H), 0.87 (d, = 7.0 Hz, 3H).

[0162] 13C NMR (101 MHz, CDCI3) δ 211.42, 77.32, 61.66, 58.82, 55.59, 48.80, 41.52, 41.12, 39.12, 37.18, 29.13, 28.94, 25.82, 24.24, 15.75.

[0163] GC-MS: tr = 22.02 min. m / z (%): 236 (M+, 2), 208 (3), 193 (22), 165 (15), 150 (24), 137 (100). m.p. = 84-87 °C.

[0164] [«]D25= -73.8 (c 0.5, CHCh).

[0165] Cedrene cis-diol of formula I

[0166] The anhydrous aluminium trichloride (2.28 g, 17.00 mmol, 2.00 equiv) is suspended in anhydrous toluene (125 mL) under nitrogen atmosphere and the mixture is cooled to 0 °C. The hydroxycedranone (2.00 g, 8.48 mmol, 1.00 equiv) is added as a solid in one portion and the solution is kept under stirring for 15 minutes at the same temperature. Next, a solution of diisobutyl aluminium hydride (17.00 mL, 1 M in toluene, 17.00 mmol, 2 equiv) is added dropwise. The reaction is left under stirring for two hours at 0 °C. After two hours, the reaction is quenched with the addition of a saturated aqueous solution of sodium potassium tartrate (50 mL). The solution is extracted with ethyl acetate (50 mLx3). The organic phases are washed with a saturated aqueous solution of sodium chloride, anhydrified with sodium sulfate and the solvent is evaporated under reduced pressure. The reaction crude (white solid) is triturated with cold hexane to give the pure cedrene cz.s-diol as a white crystalline solid (1.20 g, 60% yield, > 99: 1 dr).

[0167] TLC: Rf = 0.3 (20% ethyl acetate in hexane).

[0168] 'H NMR (400 MHz, CDCI3) δ 3.74 - 3.63 (m, 1H), 2.05 (s, 1H), 1.92 (d, J = 12.0 Hz, 1H), 1.89 - 1.85 (m, 1H), 1.85 - 1.78 (m, 1H), 1.76 - 1.64 (m, 3H), 1.59 - 1.50 (m, 1H), 1.50 - 1.43 (m, 1H), 1.44 - 1.39 (m, 1H), 1.38 (s, 3H), 1.36 - 1.32 (m, 1H), 1.32 - 1.23 (m, 2H), 1.13 (s, 3H), 1.01 (s, 3H), 0.85 (d, J= 7.1 Hz, 3 H).

[0169] 13C NMR (101 MHz, CDCI3) δ 74.41, 72.33, 60.85, 57.22, 53.49, 41.73, 41.46, 40.68, 39.09, 36.79, 29.26, 28.79, 26.87, 25.67, 15.70.

[0170] GC-MS: tr= 22.70 min. m / z (%): 238 (M+, 27), 223 (70), 205 (93), 193 (40), 177 (48), 123 (100). m.p. = 166-168 °C.

[0171] [a]D20= -25.7 (c 1.8, MeOH).

[0172] Ambrocenide®

[0173] Chemical name Ambrocenide®: (4a7?,5A,7a5,9A)-octahydro-2,2,5,8,8,9a-hexamethyl- 4H-4a,9-methanoazulene(5,6-d)-l,3-dioxole).

[0174] 1,2-dimethoxypropane (12.00 mL, 99.20 mmol, 20.00 equiv) and anhydrous paratoluenesulfonic acid (0.043 g, 0.25 mmol, 0.05 equiv) are added to a solution of cedrene cz.s-diol (1.18 g, 4.96 mmol, 1.00 equiv) in anhydrous di chloromethane (70 mL) and under nitrogen atmosphere. The reaction is left under stirring and under nitrogen atmosphere at room temperature for 16 hours. The reaction is quenched with the addition of a saturated aqueous solution of sodium bicarbonate (50 mL). The two phases are separated and the aqueous phase is extracted with dichloromethane (25x2 mL). The organic phases are washed with a saturated aqueous solution of sodium chloride, anhydrified with sodium sulfate and the solvent is evaporated under reduced pressure. The crude reaction (white solid) is recrystallized from ethanol to give pure Ambrocenide® as a crystalline white solid (0.89 g, 64% yield, > 99: 1 dr).

[0175] TLC: Rf = 0.6 (10% ethyl acetate in hexane).

[0176] 'H NMR (400 MHz, CDCI3) δ 4.07 (dd, J= 9.0, 6.8 Hz, 1H), 2.01 (d, J= 12.1 Hz, 1H), 1.97 - 1.89 (m, 2H), 1.84 (dt, J= 12.0, 6.2 Hz, 1H), 1.75 (h, J = 6.9 Hz, 1H), 1.69 - 1.60 (m, 2H), 1.60 - 1.56 (m, 1H), 1.55 (s, 1H), 1.54 (s, 3H), 1.50 (s, 3H), 1.49 (s, 3H), 1.43 (dt, J = 12.7, 6.5 Hz, 1H), 1.35 - 1.24 (m, 1H), 1.16 (s, 3H), 1.04 (s, 3H), 0.82 (d, J= 1A Hz, 3H).

[0177] 13C NMR (101 MHz, CDCI3) δ 109.06, 85.17, 78.97, 58.74, 57.55, 52.54, 42.60, 42.07, 41.16, 38.65, 36.03, 31.27, 30.40, 29.82, 28.88, 27.71, 25.56, 15.56.

[0178] GC-MS: tr = 23.46 min. m / z (%): 263 ([M-CH3]+, 12), 220 (31), 205 (66), 191 (10), 177 (14), 123 (34), 55 (100). m.p. = 52-54 °C

[0179] [«]D25= -64.6 (c 1.0, CH2C12).

[0180] Example 2: Optimization of stereospecific epoxidation, stereospecific isomerization and stereoselective reduction reactions.

[0181] Glossary

[0182] Cone. = Concentration.

[0183] Conv. = Conversion.

[0184] AcOEt = ethyl acetate.

[0185] CH3CN = acetonitrile.

[0186] AcOH = acetic acid. LA = Lewis acid.

[0187] REDAL = Sodium bi s(2-methoxy ethoxy) aluminium hydride.

[0188] Example 2.1: Optimization of the regioselective and stereospecific reaction (from cedrene to cedrene epoxide). cedrene epoxide 98% yield >99:1 dr

[0189] Table 1

[0190] The reaction does not proceed in the absence of enzyme (Entry 1).

[0191] The optimum temperature is 30 °C. The time to achieve total conversion is 24 h with 1% or 2% enzyme. The ideal concentration of cedrene is 0.5 M, both in pure ethyl acetate and in a mixture with acetonitrile 1 : 1.

[0192] Mixing with acetonitrile makes the reaction more homogeneous, because hydrogen peroxide is more soluble in acetonitrile than in ethyl acetate. This allows possible applications of flow reactors. The reaction in pure acetonitrile does not proceed; in fact, ethyl acetate is fundamental to give peracetic acid via perhydrolysis with hydrogen peroxide mediated by the enzyme. A further control experiment in acetonitrile in the absence of enzyme demonstrates that the epoxidation does not proceed via Payne epoxidation (addition of hydrogen peroxide to nitriles and formation of an intermediate acid peroxy capable of epoxidizing olefins).

[0193] Example 2.2: Optimization of the stereospecific isomerization reaction (from cedrene epoxide to cedranone) cedrene epoxide cedrene diol cedranone diene Table 2

[0194] The reaction does not proceed with acetic acid, but sulfuric acid is necessary (Entry 1).

[0195] With sulphuric acid a temperature of at least 25 °C is required (Entry 2).

[0196] The diol by-product (a mixture of diastereoisomers) is formed by hydrolytic opening of the epoxide when the sulfuric acid is diluted (5 M). In contrast, using concentrated sulfuric acid (18 M) reduces diol formation, but allyl alcohol formation is observed by epoxide isomerization.

[0197] By increasing the temperature, the allyl alcohol is converted to an unidentified mixture of dienes by elimination. At the temperature of 80 °C, the reaction leads to the formation of cedranone with a purity of 92%. The remaining 8% is an elimination product, mainly identified in the diene, which is removed in the next step (hydroxylation of cedranone) by crystallization from hexane of hydroxy cedranone.

[0198] Example 2.3: Optimization of the stereoselective reduction reaction (from hydroxycedranone to cis-diol) hydroxy cedrene cedrene efe-diol© tranS’diaio cedranone

[0199] Table 3

[0200] Standard reductants such as sodium boron hydride or lithium aluminium hydride lead to the formation of the trans diol as a single diastereomer (Entries 1-2). Other reductants, such as REDAL and DIBAL, lead to partial formation of cv.s-diol as minority isomer (Entries 3,4).

[0201] The addition of a Lewis acid has no marked effect on diastereoselection in THF (Entries 5,6), but only in toluene (Entry 7-8); for the latter condition, the formation of c / .s-diol as the majority isomer is observed.

[0202] The combination DIBAL-AlCh in toluene is the best combination for the diastereoselectivity of the reaction (Entry 8).

[0203] An excess of at least 2 equivalents of A1CL per equivalent of hydroxycedranone is required to obtain maximum stereoselectivity (Entries 9-10). 2.3.1. Stereoselective reduction reaction conditions'.

[0204] Lewis acid is added to a solution of hydroxycedranone in the indicated solvent at 0 °C, and the mixture is kept under stirring for 15 min. Subsequently the indicated metal hydride is added in solution and the mixture is kept under stirring for 1 h at 0 °C.

Claims

CLAIMS1. A synthesis method of cedrene c / .s-diol of formula (7)formula (I) comprising the following steps: a) providing a-cedrene of formula (II) and carrying out the stereospecific epoxidation reaction of a-cedrene of formula (IT) to give cedrene epoxide of formula (!!!)formula (II) formula (III) b) carrying out the stereospecific isomerization reaction of cedrene epoxide of formula (!!!) to give cedranone of formula (IV)formula (III) formula (IV) c) carrying out the regioselective and stereospecific hydroxylation reaction of cedranone of formula (IV) to give hydroxy cedranone of formula (V)formula (IV) formula (V) d) carrying out the stereoselective reduction reaction of hydroxy cedranone of formula (F) to give cedrene cv.s-diol of formula (7)formula (V) formula (I) characterized in that(i) in stage a) of the stereospecific epoxidation reaction, the reaction is carried out using a lipase enzyme and hydrogen peroxide, and the reaction temperature is comprised between 20°C and 35°C, and the cedrene epoxide of formula (III) is used as is, i.e. without the need for purification, in the subsequent step b) of stereospecific isomerization;(ii) in stage b) of stereospecific isomerization reaction, the reaction is carried out using a Brbnsted acid, and the reaction temperature is comprised between 20°C and 85°C, and the cedranone of formula (IV) is purified by distillation,(Hi) in stage c) of regioselective and stereospecific hydroxylation reaction, the reaction is carried out in the presence of a strong base, and the reaction temperature is comprised between 20°C and 30°C, and the hydroxycedranone of formula (V) is purified by crystallization,(tv) wherein in stage d) of stereoselective reduction reaction, the reaction involves the following two sub-steps: dl) adding a Lewis acid, followed by d2) adding a reducing agent, and the reaction temperature is comprised between -5 and 0°C, and the cedrene cv.s-diol of formula (I) is purified by crystallization,(v) in each of the aforementioned steps a)-d), the compounds of formula (III), (IV), (V) and (I) are obtained, respectively, in a diastereomeric mixture with a diastereomeric ratio > 99:1.

2. The synthesis method according to claim 1, wherein the lipase enzyme is used in an amount comprised between 0.5% and 2.5% by weight based on the total weight of the substrate.

3. The synthesis method according to claim 1 or 2, wherein the solvent of the stereospecific epoxidation reaction is ethyl acetate or a mixture of ethyl acetate and acetonitrile, preferably in a volume ratio between the two of 1 : 1.

4. The synthesis method according to any one of claims from 1 to 3, wherein the duration of the stereospecific epoxidation reaction is comprised between 12 and 30 hours.

5. The synthesis method according to any one of claims from 1 to 4, wherein the Brbnsted acid used in the stereospecific isomerization reaction is selected from the group consisting of: sulfuric acid, phosphoric acid, perchloric acid, acetic acid, paratoluenesulfonic acid.

6. The synthesis method according to any one of claims from 1 to 5, wherein the strong base used in the stereospecific hydroxylation reaction is a strong organic base, preferably selected from the group consisting of: potassium te / 7-butoxide, sodium methylate, sodium hydride.

7. The synthesis method according to any one of claims from 1 to 6, wherein the strong base used in the regioselective and stereospecific hydroxylation reaction is in an amount comprised between 0.5 and 1.5 equivalents.

8. The synthesis method according to any one of claims from 1 to 7, wherein the duration of the stereospecific hydroxylation reaction is comprised between 2 and 6 hours.

9. The synthesis method according to any one of claims from 1 to 8, wherein the Lewis acid used in the stereoselective reduction reaction is an aluminium-based Lewis acid, preferably selected from the group consisting of: aluminium chloride, zinc chloride, iron trichloride, aluminium isopropoxide.

10. The synthesis method according to any one of claims from 1 to 9, wherein the reducing agent used in the stereoselective reduction reaction is selected from the group consisting of: DIBAL, REDAL, LiAlIL, NaBIL.

11. The synthesis method according to any one of claims from 1 to 10, wherein the Lewis acid and the reducing agent used in the stereoselective reduction reaction are in an equivalents ratio comprised between 1 :0.5 and 1 :2.

12. The synthesis method according to any one of claims from 1 to 11, wherein the overall duration of the stereoselective reduction reaction is comprised between 10 minutes and 2 hours.

13. The synthesis method according to any one of claims from 1 to 12, wherein the yield of the reactions of steps a)-d) is comprised between 50% and 99%.

14. The synthesis method according to any one of claims from 1 to 13, wherein the crystallization solvent is selected from the group consisting of: hexane, heptane, methanol, ethanol, water, diisopropyl ether, toluene and mixtures thereof.

Images