DIHYDROXYLATION OF OLEFINS USING OSMATE (VI) SALTS

Abstract

A highly efficient synthesis of cis-diol compounds through cis-dihydroxylation of olefins using osmate (VI) salt as catalysts is disclosed, which has found important application in efficient large-scale preparation of, among others, α,α-cedranediol from α-cedrene.

Claims

1. A method of preparing a diol compound from an olefin, the method comprising oxidation of the olefin with an oxidant in the presence of a catalytic amount of an osmate (VI) salt in one or more solvent(s) at an elevated temperature.

2. The method of claim 1, wherein the osmate (VI) salt has a general formula M.sub.jOsO.sub.4, M.sub.jOsO.sub.4.2H.sub.2O, or M.sub.jOsO.sub.2(OH).sub.4, wherein M is a metal ion or ammonium ion, and j is 1 or 2.

3. The method of claim 2, wherein M is potassium (K) or sodium (Na), and j is 2.

4. The method of claim 1, wherein the osmate (VI) salt is K.sub.2OsO.sub.4.2H.sub.2O or K.sub.2OsO.sub.2(OH).sub.4.

5. The method of claim 1, wherein the oxidant is a tertiary amine N-oxide, having a general formula R.sup.1R.sup.2R.sup.3N.sup.+—O.sup.−, wherein R.sup.1, R.sup.2, and R.sup.3 are each independently C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.8 cycloalkyl, or 3- to 10-membered heterocyclyl; or wherein R.sup.1 is a C.sub.1-C.sub.10 alkyl, and R.sup.2 and R.sup.3 together with the N atom to which they are attached form a 5- to 7-membered heterocyclyl optionally containing 1 or 2 additional heteroatoms selected from O and N.

6. The method of claim 1, wherein the oxidant is N-methylmorpholine N-oxide.

7. The method of claim 1, wherein the solvent comprises an aliphatic alcohol.

8. The method of claim 7, wherein the aliphatic alcohol is selected from the group consisting of C.sub.1-C.sub.6 alcohol, isomers thereof, and mixtures thereof.

9-11. (canceled)

12. The method of claim 1, wherein the solvent comprises isobutanol.

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

14-18. (canceled)

19. The method of claim 1, wherein the elevated temperature is in the range of from about 75° C. to about 115° C.

20. (canceled)

21. The method of claim 1, wherein the solvent is a mixture of water and isobutanol, and the elevated temperature is 93-95° C.

22. The method of claim 1, wherein the olefin is selected from the group consisting of cedrene, valencene, isopulegol, manool, sclareol, α and β-pinene, camphene, myrcene, ocimene, D-limonene, dipentene, squalene, (2E,4E)-hexa-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-citranellol, hydroxycitronellol, linalool, dehydrolinalool, geraniol, eugenol, β-fellandrene, α-thujene, Δ.sup.3-carene, nerolidol, trans-β-farnesene, dihydro farnesol, 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-Methyl-5-hepten-2-one, ethyl sorbate, and (Z)-hex-3-en-1-ol (leaf alcohol).

23-26. (canceled)

27. A method of preparing α,α-cedranediol, comprising oxidation of cedrene with an oxidant in the presence of a catalytic amount of an osmate (VI) salt in one or more solvent(s) at an elevated temperature.

28. The method of claim 27, wherein the osmate (VI) salt is potassium osmate dihydrate K.sub.2OsO.sub.4.2H.sub.2O.

29. The method of claim 27, wherein the oxidant is N-methylmorpholine N-oxide.

30. The method of claim 27, wherein the solvent comprises a C.sub.1-C.sub.6 aliphatic alcohol.

31. The method of claim 27, wherein the solvent comprises isobutanol.

32. (canceled)

Description

DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention is based on a surprising discovery that osmate (VI) salts, e.g., potassium osmate (VI) dihydrate (K.sub.2OsO.sub.4.2H.sub.2O), can be used as a safe alternative to OsO.sub.4 in dihydroxylation of olefins, which is particularly useful for preparation of α,α-cedranediol, the precursor in the synthesis of (4aR,5R,7aS,9R)-octahydro-2,2,5,8,8,9α-hexamethyl-4H-4a,9-methanoazuleno(5,6-d)-1,3-dioxole (Ambrocenide®), through dihydroxylation of α-cedrene.

[0027] In one aspect, the present invention provides a method of preparing a diol compound from an olefin, the method comprising oxidation of the olefin with an oxidant in the presence of a catalytic amount of an osmate (VI) salt in one or more solvent(s) at an elevated temperature.

[0028] In one embodiment, the osmate (VI) salt has a general formula M.sub.jOsO.sub.4, wherein M is a metal ion or ammonium ion and j is 1 or 2, which may exist in the form of hydrate M.sub.jOsO.sub.4xH.sub.2O, wherein x is selected from 1 to 6, preferably 2 when j is 1 or 2, e.g., M.sub.jOsO.sub.4.2H.sub.2O or M.sub.jOsO.sub.2(OH).sub.4.

[0029] In another embodiment, in the osmate salt of formula M.sub.jOsO.sub.4, M.sub.jOsO.sub.4.2H.sub.2O, or M.sub.jOsO.sub.2(OH).sub.4, M is potassium (K) or sodium (Na), and j is 2.

[0030] In another embodiment, sometimes preferred, the osmate (VI) salt is K.sub.2OsO.sub.4.2H.sub.2O or K.sub.2OsO.sub.2(OH).sub.4.

[0031] In one embodiment, the oxidant is a tertiary amine N-oxide.

[0032] In one embodiment, the tertiary amine N-oxide has a general formula R.sup.1R.sup.2R.sup.3N.sup.+—O.sup.−, wherein R.sup.1, R.sup.2, and R.sup.3 are each independently C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.8 cycloalkyl, or 3- to 10-membered heterocyclyl; or wherein R.sup.1 is a C.sub.1-C.sub.10 alkyl, and R.sup.2 and R.sup.3 together with the N atom to which they are attached form a 5- to 7-membered heterocyclyl optionally containing 1 or 2 additional heteroatoms selected from O and N.

[0033] In another embodiment, sometimes preferred, the oxidant is N-methylmorpholine N-oxide (NMO), sometimes more preferably an aqueous solution of NMO.

[0034] In another embodiment, the solvent comprises an aliphatic alcohol, and sometimes preferably a mixture of an aliphatic alcohol and water.

[0035] In another embodiment, the aliphatic alcohol is selected from C.sub.1-C.sub.8 alcohol, isomers thereof, and mixtures thereof, sometimes preferably C.sub.4-C.sub.5 alcohol, and sometimes more preferably isobutanol.

[0036] In another embodiment, the elevated temperature is in the range from 35° C. to reflux temperature of the solvent(s).

[0037] In another embodiment, the solvent is a mixture of water and one or more C.sub.1-C.sub.10 aliphatic alcohols, and the elevated temperature is azeotrope temperature of the mixture.

[0038] In another embodiment, the alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, amyl alcohol, iso-amyl alcohol, and mixtures thereof.

[0039] In another embodiment, sometimes preferably, the solvent is isobutanol.

[0040] In another embodiment, the catalytic amount of osmate (VI) salt is in the range of about 0.05 mol % to about 5 mol % based on the olefin.

[0041] In another embodiment, the catalytic amount of osmate (VI) salt is in the range of about 0.1 mol % to about 2 mol % based on the olefin.

[0042] In another embodiment, the catalytic amount of osmate (VI) salt is in the range of about 0.2 to about 1 mol % based on the olefin.

[0043] In another embodiment, sometimes preferably, the catalytic amount of osmate (VI) salt is in the range of about 0.3 to about 0.5 mol % based on the olefin.

[0044] In another embodiment, the elevated temperature is in the range from about 35° C. to about 150° C.

[0045] In another embodiment, the elevated temperature is in the range from about 50° C. to about 125° C.

[0046] In another embodiment, the elevated temperature is in the range from about 75° C. to about 115° C.

[0047] In another embodiment, the elevated temperature is the boiling point of the water-alcohol azeotrope.

[0048] In another embodiment, sometimes preferably, the solvent is a mixture of water and isobutanol, and the elevated temperature is 93-95° C.

[0049] In another embodiment, the olefin is selected from the group consisting of cedrene, valencene, isopulegol, manool, sclareol, α and β-pinene, camphene, myrcene, ocimene, D-limonene, dipentene, 1-methylcyclohexene, vinylcyclohexane, guaiacol allyl ether, phenyl allyl sulfide, vinyltrimethylsilane, 3-(tert-butyldimethyl silyloxy)-2-methylindene, 3-ethenyl-1,5-dihydro-2,4-benzodioxepin, stilbene, squalene, (2E,4E)-hexa-2,4-diene, 6-methyl-1,5-heptadiene, 2,6-dimethylhepta-1,5-diene, 1,5,9-cyclododecatriene, terpinolene, α-terpineol, β-terpineol, 6-terpineol, allyl alcohol, allyl acetate, allyl chloride, β-citranellol, hydroxycitronellol, linalool, dehydrolinalool, geraniol, eugenol, β-fellandrene, α-thujene, Δ.sup.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-methyl-5-hepten-2-one, ethyl acrylate, ethylsorbate, (Z)-hex-3-en-1-ol (leaf alcohol).

[0050] In another embodiment, sometimes preferably, the olefin is cedrene, and the diol compound is α,α-cedranediol

[0051] In another embodiment, sometimes preferably, the olefin is cedrene, and the isobutanol:cedrene ratio by weight is in the range of about 0.5 to about 4, preferably about 2.

[0052] In another embodiment, the method further includes work-up of the reaction and isolation of the diol compound.

[0053] In another embodiment, the isolation comprises crystallization, fractional distillation, or chromatography.

[0054] In one particular aspect, the present invention provides a method of preparing α,α-cedranediol, comprising oxidation of cedrene with an oxidant in the presence of a catalytic amount of an osmate (VI) salt in one or more solvent(s) at an elevated temperature.

[0055] In one embodiment of this particular aspect, the osmate (VI) salt is potassium osmate dihydrate K.sub.2OsO.sub.4.2H.sub.2O.

[0056] In one embodiment of this particular aspect, the oxidant is N-methylmorpholine N-oxide.

[0057] In one embodiment of this particular aspect, the solvent comprises water and a C.sub.1-C.sub.6 aliphatic alcohol, and the elevated temperature is in the range of about 75° C. to 115° C.

[0058] In one embodiment of this particular aspect, the solvent is isobutanol, and the elevated temperature is 93-95° C.

[0059] In one embodiment of this particular aspect, the method further includes isolating the α,α-cedranediol through crystallization from reaction mixture by cooling down the reaction mixture and filtering to collect crystalline product.

[0060] To illustrate, when used under Upjohn dihydroxylation conditions on α-cedrene using 0.3-0.4 mol % K.sub.2OsO.sub.4.2H.sub.2O and commercial 50% aq NMO in a mixture of tert-butanol and acetone, a slow reaction was observed at room temperature, giving only 10% of the desired diol, yet in high selectivity. Increasing the temperature to 50° C. raised the conversion up to 23% after 48 hours. Use of DMF or N,N-dimethylacetamide as solvents and heating to 85-90° C. greatly improved the conversion, affording 85% of the desired diol accompanied by the corresponding undesired ketol after 20 hours.

[0061] When various aliphatic alcohols were used as the reaction solvents, varying results were observed. For example, use of boiling ethanol or isopropanol gave clean reactions, but only partial conversion was observed after 24 hours.

[0062] When tert-butanol was used as the sole solvent, the reaction gave 68% conversion after boiling at 85° C. for 74 hours and about 18% by-products were observed.

[0063] Surprisingly, when isobutanol was used as the solvent, heating to 93-95° C. for 24 hours gave a highly selective reaction in 96-97% conversion. In fact, α,α-cedranediol was formed exclusively, with no traces of β,β-cedranediol detected as shown by gas chromatography results. That is, the osmium catalyst approaches α,α-cedrene only from the less hindered, bottom side (alpha attack):

##STR00006##

[0064] Similar results were obtained when boiling amyl alcohol (mixed isomers) was used. With this solvent mixture, the reaction was completed after 24 hours. The boiling point of the reaction mixture is dictated by the particular water-alcohol azeotrope. This appears to be the first report on the beneficial use of primary aliphatic alcohols as reaction solvents for osmium-catalyzed dihydroxylation of olefins.

[0065] 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 conversion of the catalyst to the less reactive OsO.sub.3.2Py.

[0066] The desired crystalline α,α-cedranediol was obtained in 81% yield by cooling the reaction mixture to 10° C. for 1 hr. When the temperature was lowered to 2° C. for 3 hours the crystalline product was filtered and stirred with hexane at room temperature for 30 minutes. α,α-Cedranediol was obtained in quantitative yield having a melting point of 166.7° C.

[0067] Suitable solvents are butanol, isobutanol, sec-butanol, isobutanol and amyl alcohol (mixture of isomers). The preferred solvent is isobutanol.

[0068] The isobutanol:cedrene ratio could vary from 0.5 to 4, with a preferred ratio of 2. The loading of K.sub.2OsO.sub.4.2H.sub.2O could vary from 0.1 mol % to 2 mole %, a more preferred range is 0.2 to 0.6 mole %, and still preferred range is 0.38 mol %.

[0069] The temperature range vary from 75 to 115° C., the preferred range is the boiling point of the water-alcohol azeotrope, namely 93-95° C.

[0070] We applied the new reaction conditions on two other substrates. When valencene having a purity of 85% was dihydroxylated in boiling isobutanol according to the new reaction conditions, valencene-11,12-diol was obtained in quantitative yield after 24 hours.

##STR00007##

[0071] The dihydroxylation of valencene was reported (WO2006128126A1) to proceed in aqueous acetone at room temperature in presence of 1 mol % OsO.sub.4 and NMO as reoxidant. The conversion was complete with unspecified yield.

##STR00008##

[0072] When the new dihydroxylation was applied on isopulegol, p-menthan-3,8,9-triol was obtained as a single isomer in quantitative yield after refluxing for only 12 hours. According to Helv. Chim. Acta, 87[10], 2602 (2004), application of Sharpless AD-mix dihydroxylation on isopulegol was unsatisfactory, giving a mixture of epimers at C8.

[0073] The new dihydroxylation conditions were applied on (+)-α-pinene using a refluxing mixture of isobutanol/isoamylalcohol. The reaction was completed in 14 hours to afford (+)-pinandiol quantitatively as single isomer.

##STR00009##

[0074] Any terms in the present application, unless specifically defined, will take the ordinary meanings as understood by a person of ordinary skill in the art.

[0075] As used herein, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise.

[0076] 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 of 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.

[0077] All parts, percentages and proportions refer to herein and in the claims are by weight unless otherwise indicated.

[0078] As disclosed herein, a number of ranges of numeric values are provided. It is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed.

[0079] The phrase “reactor” refers to a device where the reaction actually is conducted.

[0080] “Alkyl” refers to a saturated aliphatic hydrocarbon group including C.sub.1-C.sub.12 straight chain and branched chain groups. Preferably an alkyl group is an alkyl 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, or the like.

[0081] “Cycloalkyl” refers to a saturated and/or partially unsaturated monocyclic hydrocarbon group having 3 to 8 carbon atoms, sometimes preferably 3 to 6 carbon atoms. Representative examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, or the like.

[0082] “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, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or the like.

[0083] The following non-limiting examples serve to illustrate certain aspects of the invention.

EXAMPLES

Example 1

[0084] To a 1 L reactor equipped with a mechanical stirrer and a reflux condenser were added technical grade (−)-alpha-cedrene (110 g, 91% purity, 0.49 mol, [α].sub.D.sup.20=−84.2°, neat), isobutyl alcohol (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 93-95° C., at which gentle reflux was maintained for 24 hours. GC analysis indicated that only 3-4% unreacted alpha-cedrene remained and only single diastereoisomer of cis-cedranediol was obtained.

[0085] The reaction mixture was cooled for 3 hr at 2° C. to obtain a crystalline product, which was filtered and washed with water. The crystals were transferred to the reactor, to which 3 parts of hexane were added, and the mixture was stirred at room temperature for 30 min to afford white crystals. Thus, 115 g of the desired product was obtained in nearly quantitative yield and 99.5% purity by filtration and drying, having m. p. 166.1° C. (Lit. 165° C.) and [α].sub.D.sup.20=−21.18.sup.0 (c 0.7% CHCl.sub.3). The NMR spectrum matches the literature data (ChemCatChem, 7[6] 907 (2015) Supporting Information).

Example 2

[0086] To a 1 L reactor equipped with a mechanical stirrer and a reflux condenser were added (−)-alpha-cedrene (110 g, 91% purity, 0.49 mol, [α].sub.D.sup.20=−84.2°, neat), isobutyl alcohol (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 93-95° C., at which gentle reflux was maintained for 24 hours. GC analysis indicated that only 3-4% unreacted alpha-cedrene remained and only single diastereoisomer of cis-cedranediol was obtained.

[0087] The reaction mixture was cooled down during 1 hr to 10° C. to obtain a crystalline product, which was filtered on a Buchner funnel and washed with water. The crystals were transferred to the reactor, to which 3 parts of hexane were added and the mixture was stirred at room temperature for 30 min to afford white crystals. Thus, 95 g of the desired product was obtained by filtration and drying in 81% yield and 99.5% purity, having m. p. 166.1° C. (Lit. 165° C.).

Example 3

[0088] To a 1 L reactor equipped with a mechanical stirrer and a reflux condenser were added alpha-cedrene (110 g, 91% purity, 0.49 mol, [α].sub.D.sup.20=−84.2°, neat), isoamyl alcohol (100 g, 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 93-95° C., at which gentle reflux was maintained for 24 hours. GC analysis indicated that only 3-4% unreacted alpha-cedrene remained and only single diastereoisomer of cis-cedranediol was obtained.

[0089] The reaction mixture was cooled during 1 hr to 10° C. and filtered to obtain a crystalline product, which was collected on a Buchner funnel and washed with water. The crystals were transferred to the reactor, to which 3 parts of hexane were added, 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.).

Example 4

[0090] To a 1 L reactor equipped with a mechanical stirrer and a reflux condenser were 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 93-95° C., at which gentle reflux was maintained for 24 hours. GC analysis indicated a complete conversion of valencene to valencene-11,12-diol. The reaction mixture was treated by aqueous sodium hydrosulfite and Celite®, followed by filtration. The filtrate was acidified to pH 2 with 12N H.sub.2SO.sub.4 to convert the N-methyl morpholine to its hydrosulfate salt. The phases were separated, the aqueous phase was extracted with isobutanol, and the combined organic phases were washed with 25% aq. NaCl. The isobutanol was distilled under reduced pressure. The residue was fractionally distilled under vacuum to give the desired product as a light yellow oil. The yield was 95%.

Example 5

[0091] 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), 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 reaction mixture was heated to 93-95° C., at which gentle reflux was maintained for 12 hours. GC analysis indicated a complete conversion of (−)-Isopulegol to a single diastereomer of p-menthan-3,8.9-triol. Usual workup of the reaction mixture gave the desired product as an oil. Fractional distillation gave pure p-menthan-3,8.9-triol boiling at 140-145° C./0.08 torr. The yield was 93%.

Example 6

[0092] 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), isobutyl alcohol (25 g), isoamyl alcohol (75 g, mixture of isomers, 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., at which gentle reflux was maintained for 14 hours. GC analysis indicated a complete conversion of (+)-α-pinene to a single diastereoisomer of (+)-Pinanediol. The reaction mixture was diluted with 250 mL water and extracted with hexane (2×200 mL). The combined organic phases were washed with 100 mL water. The solvent was evaporated to give white solid. The yield according to internal standard was 96%.

[0093] All publications cited herein are incorporated by reference in their entirety for all purposes. While several embodiments have been described in the Examples above, it will be understood by those of ordinary skill in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the following claims.