Dihydroxylation of alkenes using osmate(VI)

Abstract

The efficient synthesis of cis-diol compounds by cis-dihydroxylation of olefins using osmate(VI) as a catalyst is disclosed, which has important applications especially in the efficient large-scale preparation of α,α-cedrane diol from α-cedrene.

Description

[0001] Cross - reference to related applications

[0002] This application claims the priority of U.S. Application Serial No. 62 / 930,280, filed on November 4, 2019, the content of which is incorporated herein by reference in its entirety. Technical field

[0003] The present invention relates to a method for preparing diol compounds by the dihydroxylation of olefins, which provides an efficient synthesis of α,α - cedrane - diol by the cis - dihydroxylation of α - cedrene. Background art

[0004] α,α - Cedrane - diol is an intermediate for the synthesis of (4aR,5R,7aS,9R) - octahydro - 2,2,5,8,8,9a - hexamethyl - 4H - 4a,9 - methanoazuleno[5,6 - d] - 1,3 - dioxolene (an extremely strong woody - amber fragrance). Two methods for preparing α,α - cedrane - diol have been reported. One method is based on the acid - catalyzed hydrolysis of α - cedrene epoxide, and the other method is the direct osmium tetroxide - catalyzed dihydroxylation of α - cedrene. The hydrolysis of α - cedrene epoxide usually provides a mixture of products, and the separation of α,α - cedrane - diol involves cumbersome operations and usually results in low yields.

[0005] For example, it has been reported that the hydrolysis of (-) - α - cedrene epoxide in the presence of 4% aqueous H2SO4 at 20 °C produces the epimeric cedrenone and diol (presumably α,β - cedrane - diol) (Recherches [Research], Vol. 16, pp. 104 - 6 (1967)). An improved method for the hydrolysis of (-) - α - cedrene epoxide carried out in the presence of 10% aqueous H2SO4 and aliquote R336 produces a mixture of diastereomers with a yield of only 37.6% (U.S. Patent No. 5892062). U.S. Patent No. 5892062 discloses two methods for preparing α - cedrene epoxide, one method is by epoxidation with 40% peracetic acid in the presence of sodium acetate in diethyl ether, and the other method is by the standard osmium - catalyzed asymmetric dihydroxylation using AD - mix (J. Org. Chem. [Journal of Organic Chemistry], 57(10), pp. 2768 - 2771 (1992)). However, the attempts made by the present inventors according to the reported methods have not been very successful. The hydrolysis of α - cedrene epoxide under the reaction conditions disclosed in Example 4 of U.S. Patent No. 5892062 followed by GC - MS analysis showed that the desired α,α - cedrane - diol was accompanied by four by - products:

[0006]

[0007] This composition is also described in WO 2017186973. Repeated recrystallization of the mixture from aqueous ethanol produced α,α-cedrane diol in a yield of only 5%-6%; thus, this method is not suitable for the economic manufacture of the desired diol.

[0008] The preparation of α,α-cedrane diol by stoichiometric osmium tetroxide dihydroxylation of α-cedrene was reported to proceed only from the least shielded side (J. Org. Chem. [Journal of Organic Chemistry] USSR. 8[6], 1190 (1972)). α-Cedrene reacted with one equivalent of OsO4 in pyridine (Py) at 20 °C for 4 days to give α,α-cedrane diol with a melting point of 159 °C - 160 °C and an isolated yield of 31%. Criegee (Justus Liebigs Ann. Chem. [Liebigs Annalen der Chemie], 550[1], 99 (1942)) reported that pyridine significantly catalyzed the reaction of olefins with osmium tetroxide, including the bulky olefins di-biphenylethylene, tetraphenylethylene, and phenanthrene, and the OsO3·2Py complex was isolated by treating OsO4 with pyridine in cyclohexane-ethanol.

[0009] The Upjohn Company (U.S. Patent No. 2769824) first reported the highly regioselective osmium tetroxide-catalyzed dihydroxylation of pregnadien using N-methylmorpholine N-oxide (NMO) or other aliphatic tertiary amine oxides as reoxidants. The reaction in tert-butanol and water in the presence of 1-5 mol% OsO4 required several days at room temperature to achieve partial conversion. Although the addition of water and pyridine was found to have some beneficial effects on the catalytic efficiency, the pyridine effect could not be attributed to the in-situ formation of pyridine N-oxide, as the latter is a non-reactive reoxidant.

[0010] By adjusting the solvent composition, Upjohn reported (Tet. Let [Tetrahedron Letters], 17

[23] 1973 (1976)) that the reaction time could be significantly shortened:

[0011]

[0012] This process is called the Upjohn dihydroxylation. Under similar conditions, other simple olefins are also converted to the corresponding cis-diol compounds in reasonable to good yields.

[0013] In the OsO4-catalyzed dihydroxylation of sterically hindered nopinol derivatives, it was found that the addition of pyridine was beneficial only when the re-oxidant was trimethylamine N-oxide (Tet. Let. 21[5] 449 (1980)). Under these conditions, the sterically hindered α-pinene was dihydroxylated only on the β-side to afford cis-α-pinane diol in 96.5% yield after refluxing in an aqueous tert-butanol solution in the presence of an equivalent amount of pyridine for 4 days. In contrast, when NMO was used as the re-oxidant, pyridine not only did not improve but rather significantly decreased the relatively mediocre yield of pinane diol (J. Ind. Chem. Soc. 59[2] 119 (1982))

[0014]

[0015] (+)-Pinane diol is a key intermediate in the chiral synthesis of bortezomib (US 7714159 of Millennium Pharmaceuticals), an anticancer drug approved by the FDA for the treatment of multiple myeloma.

[0016] The OsO4-catalyzed cis-dihydroxylation of α-cadinene using trimethylamine N-oxide as the re-oxidant was first reported in Syn. Commun., 28

[20] , 3757 (1998):

[0017]

[0018] The reaction required 3 days to complete in a boiling tert-butanol-water mixture in the presence of an excess of pyridine, although a good yield was obtained, giving a product with m.p. 162 °C - 163 °C and [α] D 30 -27.6° (c 1.8, CH3OH).

[0019] This procedure is not suitable for the economical manufacture of α,α-cadinane diol because the reaction time is long, osmium tetroxide is highly toxic, and the reaction requires a large amount of pyridine, a toxic compound that must be recycled. In addition, since the reaction mixture must be diluted with 10 volumes of water during product isolation, a large amount of toxic waste stream is generated, resulting in low production volume.

[0020] Similar reaction conditions using a commercial 50% aqueous solution of NMO as the re-oxidant were reported in ChemCatChem, 7[6] 907 (2015):

[0021]

[0022] This reaction also takes 3 days to complete and involves the use of toxic osmium tetroxide in boiling aqueous tert-butanol containing an excess of pyridine.

[0023] Therefore, there is still a need to develop a more efficient and safer industrial method for manufacturing this important fragrance product. Summary of the Invention

[0024] The present invention meets the above need by providing an economical and scalable method for preparing α,α-cedrane diol, and the present invention is generally applicable to the dihydroxylation of olefins in the preparation of other fine chemicals containing a diol functional group.

[0025] In one aspect, the present invention provides a method for preparing a diol compound from an olefin, the method comprising oxidizing the olefin with an oxidizing agent at a high temperature in one or more solvents in the presence of a catalytic amount of osmate(VI).

[0026] In some embodiments, and sometimes preferably, the osmate(VI) is potassium osmate or sodium osmate dihydrate, having the formula M2OsO4·2H2O, where M is K or Na, which may exist in the form of M2OsO2(OH)4.

[0027] In some embodiments, the one or more solvents are selected from the group consisting of C1-C6 aliphatic alcohols, mixtures thereof, and mixtures thereof with water. In some preferred embodiments, the aliphatic alcohol is selected from n-butanol, sec-butanol, isobutanol, tert-butanol, pentanol, and mixtures thereof.

[0028] In some embodiments, the oxidizing agent is a tertiary amine N-oxide, including but not limited to trimethylamine N-oxide, tributylamine N-oxide, N-methylmorpholine N-oxide, and the like.

[0029] In a specific aspect, the present invention provides a method for preparing α,α-cedrane diol, the method comprising cis-dihydroxylating α-cedrene with N-methylmorpholine N-oxide at the reflux temperature in a solvent comprising butanol, preferably isobutanol, in the presence of a catalytic amount of potassium osmate dihydrate (K2OsO4·2H2O). The product α,α-cedrane diol can be crystallized from the reaction mixture by cooling and separated by filtration.

[0030] The cis-dihydroxylation of α-cedrene in boiling isobutanol in the presence of a catalytically effective amount of potassium osmate dihydrate and an aqueous solution of N-methylmorpholine-N-oxide as a re-oxidizing agent provides α,α-cedrane diol in high yield and high stereoselectivity in only 24 hours.

[0031] The discovery that the use of isobutanol as a solvent can significantly reduce the reaction time is unexpected and cannot be inferred from the prior art. This appears to be the first use of an aliphatic primary alcohol as a solvent for dihydroxylation. Compared with the use of highly volatile and / or toxic reagents such as OsO4 and pyridine in the above-mentioned literature methods, the use of non-toxic and non-volatile potassium osmate dihydrate allows for the safe large-scale manufacture of α,α-cubebane diol.

[0032] Other aspects and advantages of the invention will become more apparent to those of ordinary skill in the art in light of the following detailed description, examples, and claims. Detailed Description

[0033] The present invention is based on the unexpected discovery that osmate(VI), such as potassium osmate(VI) dihydrate (K2OsO4·2H2O), can be used as a safe alternative to OsO4 in the dihydroxylation of olefins, and is particularly useful for the preparation of α,α-cubebane diol (synthetic (4aR,5R,7aS,9R)-octahydro-2,2,5,8,8,9a-hexamethyl-4H-4a,9-methanoazuleno[5,6-d]-1,3-dioxolane precursor).

[0034] In one aspect, the present invention provides a method for preparing a diol compound from an olefin, the method comprising oxidizing the olefin with an oxidizing agent in one or more solvents at a high temperature in the presence of a catalytic amount of osmate(VI).

[0035] In one embodiment, the osmate(VI) has the general formula M j OsO4, where M is a metal ion or an ammonium ion, and j is 1 or 2, and it may exist in the form of a hydrate M j OsO4·xH2O, where x is selected from 1 to 6, preferably 2 (when j is 1 or 2), for example M j OsO4·2H2O or M j OsO2(OH)4.

[0036] In another embodiment, in the osmate of the formula M j OsO4, M j OsO4·2H2O, or M j OsO2(OH)4, M is potassium (K) or sodium (Na), and j is 2.

[0037] In another embodiment, sometimes preferably, the osmate(VI) is K2OsO4·2H2O or K2OsO2(OH)4.

[0038] In one embodiment, the oxidizing agent is a tertiary amine N-oxide.

[0039] In one embodiment, the tertiary amine N-oxide has the general formula R 1 R 2 R 3 N + -O - , where R 1 , R 2 and R 3 are each independently C1-C 10 alkyl, C3-C8 cycloalkyl, or 3- to 10-membered heterocyclic group; or where R 1 is C1-C 10 alkyl, and R 2 and R 3 together with the N atom to which they are attached form a 5- to 7-membered heterocyclic group optionally containing 1 or 2 additional heteroatoms selected from O and N.

[0040] In another embodiment, sometimes preferably, the oxidant is N-methylmorpholine N-oxide (NMO), and sometimes more preferably an aqueous solution of NMO.

[0041] In another embodiment, the solvent includes aliphatic alcohols, and sometimes preferably a mixture of aliphatic alcohols and water.

[0042] In another embodiment, the aliphatic alcohols are selected from C1-C8 alcohols, their isomers, and mixtures thereof, sometimes preferably C4-C5 alcohols, and sometimes more preferably isobutanol.

[0043] In another embodiment, the high temperature is in the range from 35 °C to the reflux temperature of one or more solvents.

[0044] In another embodiment, the solvent is a mixture of water and one or more C1-C 10 aliphatic alcohols, and the high temperature is the azeotrope temperature of the mixture.

[0045] In another embodiment, the alcohols are selected from the group consisting of: methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, pentanol, isopentanol, and mixtures thereof.

[0046] In another embodiment, sometimes preferably, the solvent is isobutanol.

[0047] In another embodiment, based on the olefin, the catalytic amount of osmate(VI) is in the range of about 0.05 mol% to about 5 mol%.

[0048] In another embodiment, based on the olefin, the catalytic amount of osmate(VI) is in the range of about 0.1 mol% to about 2 mol%.

[0049] In another embodiment, based on the olefin, the catalytic amount of osmate(VI) is in the range of from about 0.2 to about 1 mol%.

[0050] In another embodiment, sometimes preferably, based on the olefin, the catalytic amount of osmate(VI) is in the range of from about 0.3 to about 0.5 mol%.

[0051] In another embodiment, the high temperature is in the range of from about 35 °C to about 150 °C.

[0052] In another embodiment, the high temperature is in the range of from about 50 °C to about 125 °C.

[0053] In another embodiment, the high temperature is in the range of from about 75 °C to about 115 °C.

[0054] In another embodiment, the high temperature is the boiling point of a water-alcohol azeotrope.

[0055] In another embodiment, sometimes preferably, the solvent is a mixture of water and isobutanol, and the high temperature is 93 °C - 95 °C.

[0056] In another embodiment, the olefin is selected from the group consisting of cedrene, valencene, isopulegol, thujyl alcohol, sclareol, α- and β-pinene, camphene, myrcene, ocimene, D-limonene, dipentene, 1-methylcyclohexene, vinylcyclohexane, allyl guaiacol ether, phenyl allyl sulfide, vinyltrimethylsilane, 3-(tert-butyldimethylsilyloxy)-2-methylindene, 3-ethylidene-1,5-dihydro-2,4-benzodioxepine, stilbene, squalene, (2E,4E)-hex-2,4-diene, 6-methylhepta-1,5-diene, 2,6-dimethylhepta-1,5-diene, 1,5,9-cyclododecatriene, terpinolene, α-terpineol, β-terpineol, δ-terpineol, allyl alcohol, allyl acetate, allyl chloride, β-citronellol, hydroxycitronellol, linalool, dehydrolinalool, geraniol, eugenol, β-phellandrene, α-thujene, Δ 3 -carene, nerolidol, trans-β-farnesene, dihydrofarnesol, farnesol, homofarnesol β-caryophyllene, α-bisabolol, 2,4-decadien-1-al, 1-acetylcyclohexene, isofloriffone (1-[(1R,2S)-2,6,6-trimethylcyclohex-3-en-1-yl]ethanone), 6-methylhept-5-en-2-one, ethyl acrylate, ethyl sorbate, (Z)-hex-3-en-1-ol (leaf alcohol).

[0057] In another embodiment, sometimes preferably, the olefin is cedrene, and the diol compound is α,α-cedrane diol.

[0058] In another embodiment, and sometimes preferably, the alkene is cedrene and the weight ratio of isobutanol:cedrene is in the range of about 0.5 to about 4, preferably about 2.

[0059] In another embodiment, the method further comprises the work-up of the reaction and the separation of the diol compound.

[0060] In another embodiment, the separation comprises crystallization, fractional distillation or chromatography.

[0061] In a specific aspect, the present invention provides a method for preparing α,α-cedrane diol, the method comprising oxidizing cedrene with an oxidizing agent in one or more solvents at an elevated temperature in the presence of a catalytic amount of osmate(VI).

[0062] In an embodiment of this specific aspect, the osmate(VI) is potassium osmate dihydrate K2OsO4·2H2O.

[0063] In an embodiment of this specific aspect, the oxidizing agent is N-methylmorpholine N-oxide.

[0064] In an embodiment of this specific aspect, the solvent comprises water and a C1-C6 aliphatic alcohol, and the elevated temperature is in the range of about 75 °C to 115 °C.

[0065] In an embodiment of this specific aspect, the solvent is isobutanol and the elevated temperature is 93 °C - 95 °C.

[0066] In an embodiment of this specific aspect, the method further comprises separating α,α-cedrane diol by crystallizing from the reaction mixture by cooling the reaction mixture and filtering to collect the crystalline product.

[0067] For illustration, when used under Upjohn dihydroxylation conditions, with respect to α-cedrene, using 0.3 - 0.4 mol% K2OsO4·2H2O and a commercial 50% aqueous solution of NMO in a mixture of tert-butanol and acetone, a slow reaction was observed at room temperature, producing only 10% of the desired diol, but with high selectivity. Raising the temperature to 50 °C, the conversion increased to 23% after 48 hours.

[0068] Using DMF or N,N-dimethylacetamide as the solvent and heating to 85 °C - 90 °C greatly improved the conversion, providing 85% of the desired diol (along with the corresponding unwanted keto-alcohol) after 20 hours.

[0069] When using different aliphatic alcohols as the reaction solvent, different results were observed. For example, using boiling ethanol or isopropanol gave a clean reaction, but only partial conversion was observed after 24 hours.

[0070] When tert-butanol was used as the sole solvent, the reaction gave a 68% conversion after boiling at 85 °C for 74 h, and about 18% of by-products were observed.

[0071] Surprisingly, when isobutanol was used as the solvent, heating to 93 °C - 95 °C for 24 h gave a highly selective reaction with a conversion of 96% - 97%. In fact, only α,α-cedrane diol was formed, as shown by the gas chromatography results, and no trace of β,β-cedrane diol was detected. That is, the osmium catalyst approached α,α-cedrene only from the less hindered bottom side (α-attack):

[0072]

[0073] Similar results were obtained when boiling pentanol (mixed isomers) was used. With this solvent mixture, the reaction was completed after 24 h. The boiling point of the reaction mixture was determined by the specific water-alcohol azeotrope. This appears to be the first report on the beneficial use of aliphatic primary alcohols as reaction solvents for osmium-catalyzed olefin dihydroxylation.

[0074] The addition of pyridine (Py) did not accelerate the reaction, and when a large excess of pyridine was used, the reaction became slower, presumably due to the conversion of the catalyst to the less reactive OsO3·2Py.

[0075] By cooling the reaction mixture to 10 °C for 1 h, the desired crystalline α,α-cedrane diol was obtained in 81% yield. When the temperature was lowered to 2 °C for 3 h, the crystalline product was filtered and stirred with hexane at room temperature for 30 min. α,α-Cedrane diol was obtained in quantitative yield with a melting point of 166.7 °C.

[0076] Suitable solvents are butanol, isobutanol, sec-butanol, isobutanol, and pentanol (a mixture of isomers). The preferred solvent is isobutanol.

[0077] The ratio of isobutanol:cedrene can vary from 0.5 to 4, and the preferred ratio is 2.

[0078] The loading of K2OsO4·2H2O can vary from 0.1 mol% to 2 mol%, a more preferred range is 0.2 mol% to 0.6 mol%, and a further preferred range is 0.38 mol%.

[0079] The temperature range varies from 75 °C to 115 °C, and the preferred range is the boiling point of the water-alcohol azeotrope, i.e., 93 °C - 95 °C.

[0080] The new reaction conditions were applied to the other two substrates. When valencene with 85% purity was dihydroxylated in boiling isobutanol according to the new reaction conditions, valencene-11,12-diol was obtained in quantitative yield after 24 hours.

[0081]

[0082] It has been reported (WO 2006128126 A1) that the dihydroxylation of valencene was carried out in an aqueous acetone solution at room temperature in the presence of 1 mol% OsO4 and NMO as a re-oxidant. The conversion was completed in an unspecified yield.

[0083]

[0084] When the new dihydroxylation was applied to isopulegol, p-menthane-3,8,9-triol was obtained in quantitative yield as a single isomer after refluxing for only 12 hours. According to Helv. Chim. Acta [Helvetica Chimica Acta], 87

[10] , 2602 (2004), the application of Sharpless AD-mixture dihydroxylation to isopulegol was unsatisfactory, producing a mixture of C8 epimers.

[0085] The new dihydroxylation conditions were applied to (+)-α-pinene using a refluxing mixture of isobutanol / isopentanol. The reaction was completed within 14 hours, providing (+)-pinanediol quantitatively as a single isomer.

[0086]

[0087] Any terms in this application, unless specifically defined, shall have the ordinary meaning understood by those of ordinary skill in the art.

[0088] As used herein, the singular forms "a / an" and "the" include plural referents unless the context clearly dictates otherwise.

[0089] As used herein, the term "about" generally includes up to plus or minus 10% of the indicated number. For example, "about 10%" may indicate a range from 9% to 11%, and "about 20" may mean from 18 to 22. Sometimes preferably, the term "about" includes up to plus or minus 5% of the indicated value.

[0090] Unless otherwise indicated, all parts, percentages, and ratios mentioned herein and in the claims are by weight.

[0091] As disclosed herein, multiple numerical ranges are provided. It should be understood that each intervening value between the upper and lower limits of that range (to the tenth of the lower limit unless the context clearly dictates otherwise) is also specifically disclosed.

[0092] The phrase "reactor" refers to the apparatus where the reaction actually takes place.

[0093] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including C1-C 12 Straight and branched chain groups. Preferably, the alkyl group is an alkyl group having 1 to 8, sometimes more preferably 1 to 6, carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like.

[0094] "Cycloalkyl" refers to a saturated and / or partially unsaturated monocyclic hydrocarbon radical having 3 to 8 carbon atoms, sometimes preferably 3 to 6 carbon atoms. Representative examples of monocyclic cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.

[0095] "Heterocyclyl" refers to a 3- to 10-membered, sometimes preferably 5- to 6-membered, saturated and / or partially unsaturated, monocyclic or polycyclic hydrocarbon group having one or more heteroatoms selected from the group consisting of N and O. Representative examples of monocyclic heterocyclyls include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like.

[0096] The following non-limiting examples are provided to illustrate certain aspects of the invention.

[0097] Examples

[0098] Example 1.

[0099] To a 1 L reactor equipped with a mechanical stirrer and a reflux condenser was added technical grade (-)-α-cedrene (110 g, 91% purity, 0.49 mol, [α] D 20= -84.2° (pure), isobutanol (200 g), potassium osmate dihydrate (0.7 g, 1.9 mmol, 0.39 mol%), and N-methylmorpholine N-oxide 50 wt% in water (235 g, 1 mol). The reaction mixture was heated to 93 °C - 95 °C and maintained at gentle reflux at this temperature for 24 h. GC analysis showed that only 3% - 4% of the unreacted α-cadinene remained and only a single diastereoisomer of cis-cadinane diol was obtained.

[0100] The reaction mixture was cooled to 2 °C for 3 h to obtain a crystalline product, which was filtered and washed with water. The crystals were transferred to a reactor, to which 3 portions of hexane were added, and the mixture was stirred at room temperature for 30 min to give white crystals. Thus, 115 g of the desired product was obtained in almost quantitative yield and 99.5% purity by filtration and drying, which had m.p. 166.1 °C (Lit. 165 °C) and [α] D 20 = -21.18 0 (c 0.7% CHCl3). The NMR spectrum was consistent with the literature data (ChemCatChem [Catalytic Chemistry], 7[6] 907 (2015) Supporting Information).

[0101] Example 2.

[0102] To a 1 L reactor equipped with a mechanical stirrer and a reflux condenser was added (-)-α-cadinene (110 g, 91% purity, 0.49 mol, [α] D 20 = -84.2 0 , pure), isobutanol (200 g), potassium osmate dihydrate (1 g, 2.68 mmol, 0.54 mol%), and N-methylmorpholine N-oxide 50 wt% in water (200 g, 0.853 mol). The reaction mixture was heated to 93 °C - 95 °C and maintained at gentle reflux at this temperature for 24 h. GC analysis showed that only 3% - 4% of the unreacted α-cadinene remained and only a single diastereoisomer of cis-cadinane diol was obtained.

[0103] The reaction mixture was cooled to 10 °C over a 1 h period to obtain a crystalline product, which was filtered on a Büchner funnel and washed with water. The crystals were transferred to a reactor, to which 3 portions of hexane were added, and the mixture was stirred at room temperature for 30 min to give white crystals. Thus, 95 g of the desired product was obtained in 81% yield and 99.5% purity by filtration and drying, which had m.p. 166.1 °C (Lit. 165 °C).

[0104] Example 3.

[0105] To a 1 L reactor equipped with a mechanical stirrer and a reflux condenser was added α-cadinene (110 g, 91% purity, 0.49 mol, [α] D 20 =-84.2 0 , pure), isopentyl alcohol (100 g, a mixture of isomers, Merck b.p. 131 °C), potassium osmate dihydrate (0.7 g, 0.39 mol %), and NMO 50 wt% in water (235 g, 1.0 mol). The reaction mixture was heated to 93 °C - 95 °C and maintained at gentle reflux at this temperature for 24 h. GC analysis showed that only 3% - 4% of unreacted α-cadinene remained and only a single diastereomer of cis-cadinane diol was obtained.

[0106] The reaction mixture was cooled to 10 °C over a 1 h period and filtered to obtain the crystalline product, which was collected on a Büchner funnel and washed with water. The crystals were transferred to a reactor, 3 portions of hexane were added thereto, and the mixture was stirred at room temperature for 30 min. A white crystalline product was obtained in 81% yield (95 g) and 99.5% purity, m.p. 166.1 °C (Lit. 165 °C).

[0107] Example 4.

[0108] To a 1 L reactor equipped with a mechanical stirrer and a reflux condenser was added valencene (117.8 g, 85% purity, 0.49 mol), isobutyl alcohol (100 g), potassium osmate dihydrate (0.7 g, 0.39 mol %), and NMO 50 wt% in water (235 g, 1.0 mol). The mixture was heated to 93 °C - 95 °C and maintained at gentle reflux at this temperature for 24 h. GC analysis showed that valencene was completely converted to valencene-11,12-diol. The reaction mixture was treated with an aqueous solution of sodium dithionite and filtered. The filtrate was acidified to pH 2 with 12 N H2SO4 to convert N-methylmorpholine to its hydrogen sulfate. The phases were separated, the aqueous phase was extracted with isobutyl alcohol, and the combined organic phases were washed with 25% aqueous NaCl solution. Isobutyl alcohol was distilled off under reduced pressure. The residue was fractionated under vacuum to yield the desired product as a pale yellow oil. The yield was 95%.

[0109] Example 5.

[0110] To a 1 L reactor equipped with a mechanical stirrer and a reflux condenser were added (-)-isopulegol (76 g, 99.5% purity, 0.49 mol), isobutanol (100 g), potassium osmate dihydrate (0.7 g, 0.39 mol %), and NMO 50 wt% in water (235 g, 1.0 mol). The reaction mixture was heated to 93 °C - 95 °C and maintained at gentle reflux at this temperature for 12 h. GC analysis showed complete conversion of (-)-isopulegol to a single diastereomer of p-menthane-3,8,9-triol. Conventional workup of the reaction mixture gave the desired product as an oil. Fractionation gave pure p-menthane-3,8,9-triol, boiling at 140 °C - 145 °C / 0.08 Torr. The yield was 93%.

[0111] Example 6.

[0112] To a 1 L reactor equipped with a mechanical stirrer and a reflux condenser were added (+)-α-pinene (100 g, 92% purity, 0.67 mol), isobutanol (25 g), isoamyl alcohol (75 g, isomer mixture, b.p. 131 °C), potassium osmate dihydrate (0.20 g, 0.08 mol %), and NMO 50 wt% in water (175 g, 0.744 mol). The reaction mixture was heated to 92 °C and maintained at gentle reflux at this temperature for 14 h. GC analysis showed complete conversion of (+)-α-pinene to a single diastereomer of (+)-pinanediol. The reaction mixture was diluted with 250 mL of water and extracted with hexane (2 x 200 mL). The combined organic phases were washed with 100 mL of water. Evaporation of the solvent gave a white solid. The yield based on an internal standard was 96%.

[0113] For all purposes, all publications cited herein are incorporated by reference in their entirety. Although several embodiments have been described in the above examples, those of ordinary skill in the art will understand that various changes in form and detail may be made therein without departing from the spirit and scope of the disclosure as defined by the following claims.

Claims

1. A method for preparing a diol compound from an olefin, the method comprising oxidizing the olefin with an oxidant at a high temperature in one or more solvents in the presence of a catalytic amount of an osmate (VI), wherein the oxidation composition consists of an olefin, an oxidant, an osmate (VI) and one or more solvents, the one or more solvents consist of isobutanol, isoamyl alcohol, mixtures thereof and mixtures thereof with water, and the osmate (VI) has the general formula M j OsO4, M j OsO 4· 2H2O or M j OsO2(OH)4, where M is potassium (K), sodium (Na) or an ammonium ion, and j is 2, and the oxidant is a tertiary amine N-oxide having the general formula R 1 R 2 R 3 N + -O - , where R 1 is a C1-C 10 alkyl group, and R 2 and R 3 together with the N atom to which they are attached form a 5- to 7-membered heterocyclic group optionally containing 1 or 2 additional heteroatoms selected from O and N, and the olefin is selected from the group consisting of: cedrene, valencene, isopulegol, thujopsene, sclareol, α and β-pinene, camphene, myrcene, ocimene, D-limonene, dipentene, squalene, (2E,4E)-hex-2,4-diene, 6-methyl-1,5-heptadiene, 2,6-dimethylhepta-1,5-diene, 1,5,9-cyclododecatriene, terpinolene, α-terpineol, β-terpineol, δ-terpineol, allyl alcohol, allyl chloride, β-citronellol, hydroxycitronellol, linalool, dehydrolinalool, geraniol, eugenol, β-phellandrene, α-thujene, Δ 3 -carene, nerolidol, trans-β-farnesene, dihydrofarnesol, farnesol, homofarnesol β-caryophyllene, α-bisabolol, 2,4-decadien-1-al, 1-acetylcyclohexene, 1-[(1R,2S)-2,6,6-trimethylcyclohex-3-en-1-yl]ethanone, 6-methyl-5-hepten-2-one, ethyl sorbate and (Z)-hex-3-en-1-ol.

2. The method according to claim 1, wherein, The osmate(VI) is K2OsO 4· 2H2O or K2OsO2(OH)4.

3. The method according to claim 1, wherein, The oxidizing agent is N-methylmorpholine N-oxide.

4. The method according to claim 1, wherein, The high temperature is in the range from 35 °C to the reflux temperature of the one or more solvents.

5. The method according to claim 1, wherein, The solvent is a mixture of water and isobutanol and / or isoamyl alcohol, and the high temperature is the azeotropic temperature of the mixture.

6. The method according to claim 1, wherein, The solvent is isobutanol.

7. The method according to claim 1, wherein, Based on the olefin, the catalytic amount of osmate(VI) is in the range of about 0.05 mol% to about 5 mol%.

8. The method according to claim 1, wherein, Based on the olefin, the catalytic amount of osmate(VI) is in the range of about 0.1 mol% to about 2 mol%.

9. The method according to claim 1, wherein, Based on the olefin, the catalytic amount of osmate(VI) is in the range of about 0.2 to about 1 mol%.

10. The method according to claim 1, wherein, Based on the olefin, the catalytic amount of osmate(VI) is in the range of about 0.3 to about 0.5 mol%.

11. The method according to claim 1, wherein, The high temperature is in the range from about 35 °C to about 150 °C.

12. The method according to claim 1, wherein, The high temperature is in the range from about 50 °C to about 125 °C.

13. The method according to claim 1, wherein, The high temperature is in the range from about 75 °C to about 115 °C.

14. The method according to claim 1, wherein, The solvent is a mixture of water and isobutanol, and the high temperature is 93 °C - 95 °C.

15. The method according to claim 1, wherein, The olefin is cedrene, and the diol compound is α,α-cedrane diol.

16. The method according to claim 15, wherein, The weight ratio of isobutanol:cedrene is in the range of about 0.5 to about 4.

17. The method according to claim 15, wherein, The weight ratio of isobutanol:cedrene is about 2.

18. The method according to claim 1, further comprising post-treatment of the reaction and separation of the diol compound.

19. The method according to claim 18, wherein, The separation includes crystallization, fractional distillation or chromatography.

20. A method for preparing α,α-cedrane diol, the method comprising oxidizing cedrene with an oxidant at a high temperature in one or more solvents in the presence of a catalytic amount of osmate(VI), wherein the oxidation composition comprises an alkene, an oxidant, osmate(VI) and one or more solvents, the one or more solvents are isobutanol, isoamyl alcohol, mixtures thereof and mixtures thereof with water, the osmate(VI) has the general formula M j OsO4, M j OsO 4· 2H2O or M j OsO2(OH)4, M is potassium (K) or sodium (Na), and j is 2, and the oxidant is a tertiary amine N-oxide having the general formula R 1 R 2 R 3 N + -O - wherein R 1 is C1-C 10 alkyl, and R2 and R 3 together with the N atom to which they are attached form a 5- to 7-membered heterocyclic group optionally containing 1 or 2 additional heteroatoms selected from O and N.

21. The method according to claim 20, wherein, The osmate(VI) is potassium osmate dihydrate K2OsO 4· 2H2O.

22. The method according to claim 20 or 21, wherein, The oxidizing agent is N-methylmorpholine N-oxide.

23. The method according to claim 20, wherein, The solvent is isobutanol, and the high temperature is 93 °C - 95 °C.

24. The method according to claim 20, further comprising separating the α,α-cedrane diol by crystallizing from the reaction mixture by cooling the reaction mixture and filtering to collect the crystalline product.

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