OXIDATION OF SANTALENE TO SANTALENE

Abstract

The invention relates to the oxidation process of santalene to santalol. The starting material is, in particular, a mixture comprising alpha-santalene, beta-santalene, epi-beta-santalene, trans-alpha-bergamotene, and beta-bisabolene. The oxidation of the santalenes is carried out via a chloro-santalene intermediate. Substitution of the chlorine substituent with acetate yielded the mixture of corresponding santalyl acetates, which were hydrolyzed to produce the corresponding mixture of santalols.

Description

Oxidation of Santalene to Santanol The invention relates to the oxidation process of santalene to santalol. Sandalwood oil is a highly prized natural fragrance and a key ingredient in perfumes, cosmetics, toiletries, aromatherapy, and pharmaceuticals. It has a mild, sweet, woody, and balsamic scent derived primarily from the sesquiterpene alcohols alpha-santalol and beta-santalol. True sandalwood oil comes from Santalum album, a protected, slow-growing, and overexploited tree whose demand cannot be met. To alleviate pressure on natural sources of sandalwood oil, a number of biochemical production processes have been developed to obtain sandalwood or its precursors, particularly through the application of genetically modified microorganisms. For example, the precursor santalene has now become readily available on an industrial scale due to genetically modified microorganisms that have enhanced expression of the genes encoding santalene synthase (document WO2018 / 160066). Furthermore, this santalene synthase produces a spectrum of santalene sesquiterpenes (comprising mainly beta-santhalene, alpha-santhalene, ep / -beta-santhalene, trans-alpha-bergamotene, and beta-bisabolene) that mirrors the composition of the corresponding santalols in sandalwood oil.Consequently, an efficient and scalable oxidation of santalene to santalol would pave the way for the production of an attractive substitute for real natural sandalwood oil on an industrial scale. US 4,510,319 describes a method for the oxidation of santalene (Willis method) in which santalene is first reacted with calcium hypochlorite in the presence of dry ice (solid CO2) to form the intermediate compound chloro-santalene, an allylic halide. This intermediate is then reacted with potassium acetate to form the corresponding santalyl acetate ester. Final hydrolysis of this ester then yields the desired santalol. However, the problem with this method is that it is difficult to scale up. For example, the method exhibits variation in the selectivity of the chlorination reaction. This variation becomes more pronounced as the reaction scale increases, leading to unacceptable proportions of the different sesquiterpenoids in the product. Furthermore, the addition of solid CO2 to the reaction mixture initiates a highly exothermic reaction, which prevents safe scale-up of this reaction. Another problem associated with the Willis method is that solids are present in the reaction mixture at multiple stages of the oxidation process, such as the calcium hypochlorite used in the first stage and the calcium chloride generated during ester formation. These solids make stirring the mixtures difficult and slow down the reactions. This severely complicates scaling up the reaction. Furthermore, removing solid salts in stoichiometric quantities, such as calcium chloride, is not environmentally desirable. Nussbaumer and colleagues disclosed for a perfume ingredient found in the ααηΐτηη / ζζηζ / Ε / γίΛΐ Iso E Supei® synthetically uses a stereoselective synthesis from alpha-ionone; a diastereective conjugated addition of Me2CuLi to alpha-ionone was followed by a haloform reaction, esterification, and isomerization of the C=C single bond by treatment with NaOCl, and the resulting allyl chloride was ozonized and transformed into trimethyl(vinyl)octahydrocoumarin, which underwent further modifications. However, this process is for a different substance and is also problematic in industrial-scale application and for other target molecules, for example, due to the risk of accumulation of explosive Cl2O and / or toxic Cl2 that can form locally when the acid is added to the lye-containing mixture, and the lack of specificity in case more than one double bond is available for chlorination. Therefore, it is an objective of the invention to provide a novel process for the oxidation of santalene to santalol that reduces the risk of accumulation of explosive intermediates such as Cl₂O or toxic substances such as Cl₂ and also allows for safe scaling up to an industrial scale (e.g., processing batches yielding more than 100 kg of santalol) while providing good selectivity for the desired product. It is also an objective to minimize chemical waste in such processes. A further objective of the invention is to provide a process that produces the different santalol sesquiterpenoids in proportions closer to those of natural sandalwood oil than when using conventional synthetic methods, particularly traditional oxidation methods. It has now been discovered that one or more of these objectives can be achieved by applying a particular oxidizing agent in combination with particular reagents and additives. Accordingly, the present invention relates to a process for the synthesis of a compound of Formula (I) R i ^OH (l) where R = a, b, c, doe; αοηΐτηη / ζζηζ / Ε / γίΛΐ comprising the chlorination of a starting compound of Formula (II) to an intermediary of Formula (III) αοηΐτηη / ζζηζ / Ε / γίΛΐ Cl the conversion of the Formula (III) intermediate into the Formula (I) compound; wherein chlorination comprises combining the starting compound of Formula (II) with an acid and an aqueous solution of NaOCl. Preferably, the chlorination step comprises providing a mixture of the starting compound of Formula (II), optionally in the presence of a solvent, for example, but not limited to toluene, with all or at least part of the acid, followed by the subsequent step of contacting the mixture with all or part of the aqueous NaOCl solution. When only a portion of the required amount of aqueous NaOCl solution is used to initially contact the mixture, the step of contacting the mixture with aqueous NaOCl solution is repeated as necessary until the starting compound of Formula (II) is converted to the intermediate of Formula (III) to the desired extent. In one embodiment, the step of contacting the mixture with aqueous NaOCl solution is carried out in stages or continuously at a low rate. Mixing is preferably used during or after each contact of the mixture with aqueous NaOCl solution.The step of bringing the mixture into contact with aqueous NaOCl solution may optionally include the simultaneous addition of a partial amount of the acid. In one embodiment, the chlorination comprises combining the starting compound of Formula (II) with an acid and an aqueous solution of NaOCl by providing the starting compound of Formula (II), optionally in the presence of a solvent, for example, among others, toluene, followed by the simultaneous addition of aqueous solution of NaOCl and acid, preferably while mixing. In one embodiment, the acid used in the methods of the invention can be a mixture of two or more acids, preferably a mixture of mild acids. In a further embodiment, the starting mixture of the starting compound of Formula (II) comprises one or more types of acid, and during contact of the mixture with the aqueous NaOCl solution, acids of the same or different types are added simultaneously. In one embodiment, the pH value of the mixture comprising the starting compound of Formula (II) is stable or increases during the reaction, and preferably increases at the end of the conversion of the intermediate of Formula (III) into the compound of Formula (I) compared to the beginning of the chlorination step. The starting material for the process of the invention comprises one or more santalene sesquiterpenes of Formula (II) selected from the group alpha-santalene (lia), beta-santalene (llb), epi-beta-santalene (He), trans-alpha-bergamotene (lid), and beta-bisabolene (lie). Possibly, other santalene sesquiterpenes are also present in the starting material. αοηΐτηη / ζζηζ / Ε / γίΛΐ abcde Therefore, the product of the process comprises one or more of the corresponding santalol sesquiterpenoids of Formula (I), namely alpha-santalol (la), beta-santalol (Ib), epi-betasantalol (le), trans-alpha-bergamotol (Id) and lanceol (le), respectively. (i) ^OH where R = a, b, c, doe In this description, the term santalene sesquiterpene refers to a compound of Formula (II), and the term santalol sesquiterpenoid refers to a compound of Formula (I). It is possible that other santalol sesquiterpenoid isomers found in natural sandalwood oil in minor quantities may also be produced by the process of the invention when the corresponding santalene sesquiterpene precursors are used as starting materials in the process. For example, c / s-alpha-bergamotol and trans-beta-bergamotol may be formed in minor quantities from c / s-alpha-bergamotene and trans-beta-bergamotene, respectively. The conversion of santalene (II) sesquiterpene to santalol (I) sesquiterpenoid occurs through an intermediate which is the chlorinated santalene of Formula (III). αοηΐτηη / ζζηζ / Ε / γίΛΐ abcde Furthermore, in this description, the term chloro-santalene means a compound of Formula (III), i.e., a santalene sesquiterpene that has undergone a substitution with chlorine in its tail (i.e., in the terminal isoprene fragment). The conversion of chloro-santalene (III) to the desired santalol sesquiterpenoid product (I) is an allylic rearrangement believed to occur via an Sn2' reaction mechanism. It is preferably carried out by reaction with a carboxylate R'-COO, which produces the santalyl acetate intermediate of Formula (IV), followed by its hydrolysis to yield the intended santalol sesquiterpenoid product (I). where R = a, b, c, doe; abcdey where R' comprises an alkyl group of 1 to 7 carbon atoms. The process of the invention can be carried out on a single one of the santalene (II) sesquiterpenes or on any mixture thereof, because the required reactivity in the glue is expected to be similar for the different santalene sesquiterpenes. Given the objective of producing a close imitation of sandalwood oil (which is a mixture comprising at least the five santalol (la-le) sesquiterpenoids as mentioned above), the starting material generally comprises a mixture of the five santalene (lla-lle) sesquiterpenes as mentioned above, possibly supplemented with, for example, the minor components cisalpha-bergamotene and trans-beta-bergamotene. In particular, when the santalene sesquiterpene starting material was obtained using the microbiological methods described in WO2018 / 160066, the most relevant santalene sesquiterpenes present were alpha-santalene (Ha; -40 wt.), beta-santalene (llb; -20 wt.), epnbeta-santalene (lie; ~2 wt.), trans-alpha-bergamotene (lid; -20 wt.), and beta-bisabolene (He; -3 wt.). Subjecting this mixture to the process of the invention yields the corresponding santalol sesquiterpenoids in similar proportions. Possible deviations are, for example, due to excessive chlorination of certain santalene (II) sesquiterpenes in the mixture (see below), because the excess chlorinated products generally cannot be converted into the corresponding santalol sesquiterpenoid. A perfumer who evaluated the product obtained with a process of the invention on its similarity to natural sandalwood oil indicated that the perceived smell was very good. An initial attempt to circumvent the use and production of solids in the process (as in the Willis procedure) was to replace Ca(ClO)₂ with a solution of NaOCl in water (i.e., lye). Although this initially yielded promising results regarding reaction yield and selectivity, undesirable variations in selectivity were observed when the reaction was repeated, particularly when attempts were made to scale up the reaction. This was attributed to pH variations caused by the addition of solid CO₂. The reaction was then attempted under buffered conditions without dry ice. Therefore, different buffers were tested at pH levels ranging from 4 to 10, but all resulted in minimal conversion of the starting material to santalene sesquiterpene. Initially, more acidic environments were avoided due to the risk of Cl₂O formation, a highly reactive and explosive gas that is particularly undesirable when the reaction is carried out on a large scale. The accumulation of such species in the reaction mixture is dangerous due to the risk of explosion. When the reaction was carried out under more acidic conditions, the yields were also very low (only a small percentage conversion to the desired santalol sequiterpenoids). Surprisingly, however, when a small excess of one acid was used in the reaction (relative to NaOCl), the chloro-santalenes were obtained with a yield and selectivity at least as high as those reported for the Willis procedure. Furthermore, no variations in the reaction selectivity were observed when different large-scale runs were performed (e.g., 10 kg of santalene), as was the case with dry ice. The excess acid is usually no more than five equivalents of acid relative to NaOCl. Typically, the excess is in the range of 1.05 to 3.0 equivalents of acid relative to NaOCl. Preferably, it is in the range of 1.1 to 2.0 equivalents of acid, with the strongest preference being in the range of 1.2 to 1.6 equivalents of acid.It can also be in the range of 1.2 to 2.5 equivalents of acid, in the range of 1.4 to 2.2 equivalents of acid, or in the range of 1.6 to 1.9 equivalents of acid. It can also be in the range of 1.05 to 1.8 equivalents of acid, in the range of 1.1 to 1.6 equivalents of acid, in the range of 1.15 to 1.5 equivalents of acid, or in the range of 1.2 to 1.4 equivalents of acid. In chlorination, NaOCl is usually present as an aqueous solution of 5 to 50% by weight of NaOCl. NaOCl is usually present in excess relative to santalene. For example, the molar excess of NaOCl relative to santalene is typically in the range of 1.0 to 2.0, specifically in the range of 1.1 to 1.9, more specifically in the range of 1.2 to 1.8, and even more specifically in the range of 1.3 to 1.7. It can also be in the range of 1.1 to 1.7, in the range of 1.2 to 1.5, or in the range of 1.25 to 1.45. Specifically, the acid is present in the range of 1.2 to 1.5 molar equivalents relative to NaOCl, while NaOCl is present in the range of 1.25 to 1.75 molar equivalents relative to santalene sesquiterpene. More specifically, the acid is present in the range of 1.25 to 1.45 molar equivalents relative to NaOCl, while NaOCl is present in the range of 1.3 to 1.7 molar equivalents relative to santalene sesquiterpene. In this procedure, the acid is typically first mixed with the santalene sesquiterpene, optionally in the presence of a solvent such as toluene. Chlorination is then carried out by very slowly adding NaOCl as an aqueous solution in water (e.g., a 10–20 wt% solution) to the santalene mixture. It is also possible to add the acid simultaneously with the lye, which is usually done at relative rates that correspond to the total relative amounts added, so that the reaction mixture remains acidic throughout the reaction. Simultaneous dosing has the advantage that the pH of the reaction mixture is less subject to change during the reaction; in particular, the initial pH is not as low as it would be if all the acid were present in the reaction mixture before the addition of the lye. Another advantage of this method is that the conversion and selectivity are almost independent of the dosing protocol, allowing for slow dosing of the NaOCl solution into the reactor. This minimizes the risks associated with having a large batch of such an oxidizing material in the reaction mixture. Furthermore, monitoring the conversion of santalene sesquiterpene during the addition of the NaOCl solution revealed that the chlorination of santalene sesquiterpene with the addition of NaOCl is almost instantaneous. Therefore, there is a low risk of accumulation of the explosive Cl₂O₂. This paves the way for the safe scale-up of the conversion of the chloro-santalene(III) intermediate. In principle, the acid can be any acid compatible with the reaction conditions. It can be an inorganic acid, for example, one selected from the group of sulfuric acid, hydrochloric acid, and boric acid. Preferably, the acid has a pKa greater than 0, and more preferably a mild acid with a pKa equal to or greater than 3.0. In a preferred embodiment, the acid is a carboxylic acid. Generally, it is more effective for the acid used to be soluble in water under the applied reaction conditions and / or to have a pKa value of 5.0 or less. If the acid does not dissolve during the reaction, it is preferable that the acid be a liquid during the reaction. When a carboxylic acid is used, it is preferably selected from the group of formic acid, acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, propionic acid, 2-chloropropionic acid, 3-chloropropionic acid, trifluoroacetic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, and benzoic acid. In one embodiment, the methods of the invention use a mild carboxylic acid with a pKa equal to or greater than 3. Preferably, the acid used is acetic acid or formic acid, or mixtures of these, with acetic acid being the most preferred. Reactions carried out in the presence of acetic acid were found to provide very good conversion and selectivity towards the desired monochlorinated products. Furthermore, the reaction exhibited excellent reproducibility. The chlorination reaction is preferably carried out in a two-phase system, which has an aqueous phase comprising NaOCl and an organic phase comprising the starting material santalene(II) and chloro-santalene(III). The solvent for the organic phase preferably comprises or consists of toluene. Other solvents that can be used are hydrocarbons such as a solvent selected from the heptane, hexane, cyclohexane, methylcyclohexane, decane, and dodecane groups. Halogenated hydrocarbons, for example, dichloromethane, can also be used. However, the chlorination reaction appears to be much cleaner in toluene than, for example, dichloromethane, as there are fewer chlorinated byproducts. Furthermore, particularly good yields were found to be obtained when methylcyclohexane was used as the solvent. Another solvent that can be used is diethyl ether. Additionally, it is also possible to carry out the reaction in pure form, that is, without a solvent. The protocol using aqueous NaOCl under acidic conditions in combination with an organic phase is also particularly convenient for a scale-up protocol since 1) all reagents are liquids; 2) no solids are generated during the process; and 3) mechanical stirring is very effective in the two-phase system that is formed with the addition of the lye (aqueous phase and organic phase). It seemed difficult to convert chloro-santalene (III) directly into the intended santalol sesquiterpenoid product (I), but a two-step process through an intermediate ester proved successful. Furthermore, the conversion is preferably carried out by reacting chloro-santhalene (III) with a carboxylate R'-COO to form the corresponding carboxylate ester of Formula (IV), wherein R' comprises an alkyl group of 1 to 7 carbon atoms; ααηΐτηη / ζζηζ / Ε / γίΛΐ O^R' (IV) hydrolyze the ester of Formula (IV) to the corresponding compound of Formula (I). In this process, which involves a substitution reaction, the carboxylate is usually an alkyl carboxylate, for example, with an alkyl chain of 1 to 8 carbon atoms, which may include branches. In the case of a branched chain, the total number of carbon atoms in the carboxylate is preferably in the range of 3 to 10. Preferably, the carboxylate is a C1-C5 carboxylate such as formate, acetate, propionate, butyrate, and valerate. More preferably, the carboxylate is acetate and / or formate. When formate is used as the carboxylate in the method of the invention, the reaction time is further improved and the ratio of santalol isomers from Z to E is also further increased. In another embodiment, potassium and / or sodium salts of the acids are used, preferably potassium acetate and / or potassium formate. The carboxylate can also be selected from the formate, benzoate, and pivalate groups. The carboxylate is added before or during the reaction, usually as a metal carboxylate, for example, sodium or potassium (R'-COONa or R'-COOK). In one embodiment, a mixture of carboxylates is used instead of a single carboxylate. The hydrolysis of the carboxylate ester of Formula (IV) to santalol (I) can be carried out according to standard ester hydrolysis procedures known in the art. For example, it can be carried out in methanol using potassium hydroxide as a base. The present invention therefore relates to a process for the synthesis of a compound of Formula (I) R ¡ (i) ^OH where R = a, b, c, doe; ααηΐτηη / ζζηζ / Ε / γίΛΐ abcde which includes the stages of: provide a mixture of a starting compound of Formula (II) (||) with an acid or a mixture of acids, optionally in the presence of a solvent, for example, among others, toluene; and - contacting the mixture with an aqueous NaOCl solution to produce the intermediate of Formula (III) Formula (I). Accordingly, a process of the invention may be a process in which chlorination is carried out on a mixture of compounds of Formula (II) to produce a mixture of the corresponding intermediates of Formula (III); and the mixture of intermediates of Formula (III) is converted into a mixture of the corresponding compounds of Formula (I). In one embodiment, the conversion of santaleno to santalol is greater than 65%, preferably at least 70%, with greater preference at least 80%, with even greater preference at least 90%. In particular, the mixture of compounds in Formula (II) comprises the compounds in Formula (Ha), Formula (llb), Formula (lie), Formula (lid) and Formula (He). Surprisingly, it was found that when more than one equivalent of NaOCl was used, excessive chlorination of the santalene(II) starter material occurred, with a strong preference for the over-chlorination of trans-alpha-bergamotene (lid) compared to the other santalenes (Ha), (llb), (lie), and (He). Excessive chlorination is defined as the introduction of more than one chlorine substituent into the santalene(II) sesquiterpene starter material, specifically two or three chlorine substituents. Unexpectedly, the over-chlorination was selective for trans-alpha-bergamotene (lid). This means that when chlorination is carried out on a mixture of compounds of Formula (Ha), (llb), (He), (lid) and (lie), the amount of chloro-santhalene of Formula (llld) is disproportionately low as compared to the other chloro-santhalenes (Illa), (Iba), (lile) and (lile).This also has implications for the final santalol sequiterpenoid product (l), as it will contain a significantly lower proportion of trans-alpha-bergamotol than when excessive chlorination was not applied. Since this isomer is not particularly desirable in the santalol blend, sometimes even undesirable, the excessive chlorination method paves the way for producing sandalwood oil with a reduced proportion of trans-alpha-bergamotol. To achieve this, the excessively chlorinated trans-alpha-bergamotene (lid) must be removed or degraded at some stage of the process to the santalol isoprenoids. It was found that distillation of the crude mixture obtained after hydrolysis of the santalyl acetate of Formula (IV) yielded the final santalol sesquiterpenoids of Formula (I) without any mediol amount of excessively chlorinated products, nor any derivatives (such as diols or triols) or degradation products thereof. In one embodiment, the method of the invention is therefore a method as described herein wherein at least 60%, preferably at least 70%, and more preferably at least 80% of trans-alpha-bergamotene is converted into derivatives and these unwanted bergamotene derivatives are readily removed by distillation. The excess NaOCl required for over-chlorination should be sufficient to over-chlorinate the trans-alpha-bergamotene (lid), but a greater excess is not preferred as this results in undesirable over-chlorination and / or degradation of the desired chloro-santalenes (Illa), (lllb), (lile), and (lile). Therefore, when the aim is to decrease the trans-alpha-bergamotene (lid) content in the product mixture, the molar excess of NaOCl is typically in the range of 2.1 to 3.5 with respect to the amount of trans-alpha-bergamotene (lid), preferably in the range of 2.2 to 3.2. However, the ratio can also depend on the reaction conditions, because not all the NaOCl can be consumed as an oxidizing agent. For example, a significant portion of the NaOCl may be converted to Cl₂. Any amount of this gas that escapes from the reaction mixture must be compensated for with a larger quantity of NaOCl used in the chlorination reaction. A person of average skill knows how to arrive at an appropriate excess of NaOCl under certain reaction conditions through routine experimentation and without much inventive effort. Therefore, in the process of the invention, the chlorination of the mixture may comprise the conversion of the compounds of Formula (Ia), (Ilb), (He) and (He) into the intermediates of Formula (Illa), (IIIb), (Ile) and (Ile); and the introduction of two or three chlorine substituents into the compound of Formula (Id) to produce a dichlorinated and / or trichlorinated analogue of the compound of Formula (IIId); wherein the dichlorinated and / or trichlorinated analogue is eliminated from the intermediates of Formula (Illa), (lllb), (lile) and (lile) before or during the conversion of these intermediates into the corresponding compounds of Formula (IVa), (IVb), (IVe) and (IVe) and / or during the conversion of the compounds of Formula (IVa), (IVb), (IVe) and (IVe) into the corresponding compounds of Formula (la), (Ib), (le) and (le). The invention further relates to a compound of Formula (llld), which is chlorinated trans-alpha-bergamotene, which can be separated from the reaction mixture after chlorination. As explained above, this compound is an intermediate in the production of trans-alpha-bergamotol (Id). The invention also relates to a compound of Formula (III) Cl αοηΐτηη / ζζηζ / Ε / γίΛΐ where R = a, b, c, doe; abcde The invention further includes a composition obtainable by the methods of the invention comprising bergamotol, santalol E, and santalol Z, wherein the amount of bergamotol, preferably trans-alpha-bergamotol, is not greater than 15% (w / w), preferably not greater than 12% (w / w), and more preferably not greater than 10% (w / w) of the composition, and wherein santalol Z is in excess over santalol E. Preferably, santalol Z is in excess over santalol E in increasing order of preference by at least 15% (w / w), 20% (w / w), 25% (w / w), 35% (w / w), 50% (w / w), 75% (w / w), 95% (w / w), 120% (w / w), 150% (w / w), 175% (w / w), 180%. (w / w) or 185% (w / w). In another embodiment, the ratio of santalol Z to E is at least 55:45, preferably 60:40 or higher, more preferably 65:35 or higher. Preferably, the composition is a synthetic composition EXAMPLES 1. Chlorination of santalene (II) sesquiterpenes In a 250 mL three-necked round-bottom flask equipped with a magnetic stirrer, thermometer, and dropper funnel, santalene (10.0 g, obtained by the procedures described in WO2018 / 160066) was mixed with toluene (75 mL) and AcOH (6.0 mL). NaOCl (14% Cl₂ solution) (33.75 and 34.50 mL) was placed in the dropper funnel and added very slowly to the reaction mixture over a period of 2 h. An aliquot of the reaction was withdrawn and analyzed by GC. Subsequently, NaOCl (14% Cl₂ solution) (1 mL portions) was added at 30 min intervals until the initial santalene(II) mixture was completely converted to products. Once the reaction was complete, NaHCO₃ solution was added to the reaction mixture, and the organic phase was extracted. The organic phase was washed twice with a NaCl solution, dried, and the solvent was evaporated under vacuum, yielding a yellow oil (11.98 g). The residue was analyzed by GC.Around 80% of trans-alpha-bergamotene was converted into derivatives and these unwanted bergamotene derivatives are easily removed by distillation. 2. Substitution of the chlorine group of chloro-santalenes (III) A 100 mL round-bottom flask fitted with a magnetic stirrer was charged with KOAc (7.46 g), and KI (800 mg) and the chloro-santhalene mixture (5.0 g) obtained in Example 1 were added. DMA (30 mL) or toluene / TBAB (30 mL / 250 mg) was added as solvent. The reaction was placed in an oil bath and stirred at 110°C for 2 h (DMA) or overnight (toluene / TBAB). The progress of the reaction was monitored by GC. Once the reaction was complete, the reaction mixture was cooled to room temperature, and aqueous NaHCO3 and n-pentane solutions were added. The reaction mixture was transferred to a dropper funnel, and the organic phase was extracted and washed with brine (or several times with LiCl solution in the case of DMA). The organic phase was dried in sodium sulfate, filtered, and the solvent was evacuated under vacuum to produce a light yellow oil. The residue was analyzed by GC and NMR. 3. Hydrolysis of santalyl acetate (IV) esters A 100 mL round-bottom flask fitted with a magnetic stirrer was charged with the mixture of santalyl acetates (5.0 g) obtained in Example 2, KOH (5.0 g), H₂O (6.8 mL), and MeOH (34 mL). The reaction mixture was heated to 60°C for 10 min and stirred at room temperature for a further 30 min. After the reaction was complete, water (approximately 60 mL) and n-pentane / EtAc (4 / 1; 60 / 15 mL) were added to the reaction mixture. The organic phase was extracted and washed with brine. The organic phase was then dried on sodium sulfate and filtered. The solvent was removed under vacuum, yielding a light yellow oil (4.0 g) which was analyzed by GC. The santalol sesquiterpenoids of Formula (I) were isolated as a mixture after distillation of this oil. The conversion of santalene to santalol was greater than 90% and santalol was formed as two conformational isomers (Z and E) in a ratio of 65:35. It was also found that trans-alpha-bergamotene caused frans-alpha-bergamotol to be present at much lower levels than the initial irans-a / pha-bergamotene level and compared to the levels when no excess chlorination was applied. When potassium formate replaced potassium acetate in experiment 2, even better results were achieved. Literature cited: Nussbaumer, C., Fráter, G. and Kraft, P. (1999), (±)-1 -[(1 R*,2R*,8aS*)-1,2,3,5,6,7,8,8a-Octahydro-1,2,8,8-tetramethylnaphthalen-2-yl]ethan-1 -one: Isolation and Stereoselective Synthesis of a Powerful Minor Constituent of the Perfumery Synthetic Iso E Super®. HCA, 82: 1016-1024. doi:10.1002 / (SICI)1522-2675(19990707)82:7<1016::AIDHLCA1016>3.0.CO;2-Y.

Claims

1. Process for the synthesis of a compound of Formula (I) ααηΐτηη / ζζηζ / E / γίΛΐ ^OH where R = a, b, c, d; abcde comprising the chlorination of a starting compound of Formula (II) to an intermediate of Formula (III) Cl and the conversion of the intermediate of Formula (III) to the compound of Formula (I); wherein the chlorination comprises combining the starting compound of Formula (II) with an acid and an aqueous solution of NaOCl 2. The process according to claim 1, wherein the acid is a carboxylic acid.

3. The process according to claim 2, wherein the carboxylic acid is selected from the group of formic acid, acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, propionic acid, 2-chloropropionic acid, 3-chloropropionic acid, trifluoroacetic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, and benzoic acid.

4. The process according to any of the preceding claims, wherein the acid is present in an amount in the range of 1.05 to 3.0 acid equivalents with respect to NaOCl, in particular in the range of 1.1 to 2.0 acid equivalents, more particularly in the range of 1.2 to 1.5 acid equivalents.

5. The process according to any of the preceding claims, wherein NaOCl is present in an amount in the range of 1.1 to 1.9 molar equivalents with respect to the starting compound of Formula (II), in particular in the range of 1.3 to 1.7 molar equivalents.

6. The process according to any of claims 1 to 3, wherein the acid is present in an amount in the range of 1.2 to 1.5 acid equivalents relative to NaOCl, while NaOCl is present in an amount in the range of 1.25 to 1.75 molar equivalents relative to the starting compound of Formula (II).

7. The process according to any of the preceding claims, wherein the chlorination is carried out in the presence of an organic solvent, in particular a solvent selected from the toluene, dichloromethane and methylcyclohexane group.

8. The process according to any of the preceding claims, wherein the conversion of the intermediate of Formula (III) into the compound of Formula (I) is carried out by reacting the intermediate of Formula (III) with a carboxylate R'-COO to form the corresponding carboxylate ester of Formula (IV), wherein R' comprises an alkyl group of 1 to 7 carbon atoms; then hydrolyzing the ester of Formula (IV) to the corresponding compound of Formula (I).

9. The process according to claim 8, wherein the carboxylate is acetate, formate or propionate.

10. The process according to any of the preceding claims, wherein chlorination is carried out on a mixture of compounds of Formula (II) to produce a mixture of the corresponding intermediates of Formula (III); and the mixture of intermediates of Formula (III) is converted into a mixture of the corresponding compounds of Formula (I).

11. The process according to claim 10, wherein the mixture of compounds of Formula (II) comprises the compounds of Formula (Ha), Formula (llb), Formula (lie), Formula (lid) and Formula (He).

12. The process according to claim 11, wherein the chlorination of the mixture comprises converting the starting compounds of Formula (Ila), Formula (Ilb), Formula (lie), and Formula (lie) into the intermediates of Formula (Illa), Formula (lllb), Formula (lile), and Formula (lile); and introducing two or three chlorine substituents into the starting compound of Formula (lid) to produce a dichlorinated and / or trichlorinated analogue of the intermediate of Formula (llld); and wherein the dichlorinated and / or trichlorinated analogue is removed from the mixture before or during the conversion of the intermediates of Formula (Illa), Formula (lllb), Formula (lile), and Formula (lile) into the corresponding santalol sesquiterpenoids of Formula (la), Formula (Ib), Formula (le), and Formula (le).

13. The process according to claim 12, wherein NaOCl is present in the chlorination reaction in an amount in the range of 2.1 to 3.5 molar equivalents with respect to the starting compound of Formula (lid), preferably in the range of 2.2 to 3.2 molar equivalents.

14. The process according to claim 12, wherein the compound of Formula (I) is produced in isomers (Z and E) in a ratio of 55:45, preferably 60:40, more preferably 65:35 or higher.

15. Compound of Formula (III) ααηΐτηη / ζζηζ / Ε / γίΛΐ abcde 16. A composition comprising bergamotol, preferably frans-alpha-bergamotol, santalol Z and santalol E, wherein the bergamotol, preferably trans-alpha-bergamotol, is not greater than 10% (w / w) and santalol Z has an excess of santalol E.