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【结 构 式】 
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【分子编号】57975 【品名】methyl (6S)-6,8-bis[(methylsulfonyl)oxy]octanoate 【CA登记号】 |
【 分 子 式 】C11H22O8S2 【 分 子 量 】346.42288 【元素组成】C 38.14% H 6.4% O 36.95% S 18.51% |
合成路线1
该中间体在本合成路线中的序号：(XLIX)A different strategy was based on the enantioselective oxidation of a cyclohexanone derivative by enzymic Baeyer-Villiger reaction. Keto ester (XXXVIII) was protected as the ethylene ketal (XXXIX) and subsequently reduced to alcohol (XL) using LiAlH4. Acetylation of alcohol (XL) to acetate (XLI), followed by acidic ketal hydrolysis afforded cyclohexanone (XLII) (9,10). The racemic ketone (XLII) was then subjected to oxidative cleavage by monooxigenase 2 obtained from Pseudomonas putida to furnish the (R)-lactone (XLIV) along with unreacted (S)-cyclohexanone (XLIII) (9-11). The use of cyclohexanone monooxigenase from Acinetobacter NCIMB 9871 has also been reported for this reaction (12). Methanolysis of lactone (XLIV) in the presence of NaOMe gave rise to the (R)-dihydroxy ester (XLV). Inversion of the configuration of (XLV) was accomplished by Mitsunobu coupling with p-nitrobenzoic acid (XLVI) to produce the (S)-p-nitrobenzoate ester (XLVII). Smooth hydrolysis of ester (XLVII) provided methyl (S)-6,8-dihydroxyoctanoate (XLVIII), which was processed through intermediates (XLIX) and (L), as for the isopropyl (X) (Scheme 29605101a) and ethyl (XXIX) (Scheme 29605103a) homologues, to afford the title compound.
| 【1】 Adger, B.; et al.; The synthesis of (R)-(+)-lipoic acid using a monooxygenase-catalysed biotransformation as the key step. Bioorg Med Chem 1997, 5, 2, 253. |
| 【2】 Adger, B.; et al.; Application of enzymatic Baeyer-Villiger oxidations of 2-substituted cycloalkanones to the total synthesis of (R)-(+)-lipoic acid. J Chem Soc Chem Commun 1995, 15, 1563. |
| 【3】 McCague, R.; Roberts, S.M.; Adger, B.M. (Celltech Group plc); Process for the production of lipoic acid. WO 9638437 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXVIII) | 57966 | Ethyl 2-cyclohexanone acetate; Ethyl 2-oxocyclohexane acetate | 24731-17-7 | C10H16O3 | 详情 | 详情 |
| (XXXIX) | 57967 | ethyl 2-(1,4-dioxaspiro[4.5]dec-6-yl)acetate | C12H20O4 | 详情 | 详情 | |
| (XL) | 57968 | 2-(1,4-dioxaspiro[4.5]dec-6-yl)-1-ethanol | C10H18O3 | 详情 | 详情 | |
| (XLI) | 57969 | 2-(1,4-dioxaspiro[4.5]dec-6-yl)ethyl acetate | C12H20O4 | 详情 | 详情 | |
| (XLII) | 57970 | 2-(2-oxocyclohexyl)ethyl acetate | C10H16O3 | 详情 | 详情 | |
| (XLIII) | 57971 | 2-[(1S)-2-oxocyclohexyl]ethyl acetate | C10H16O3 | 详情 | 详情 | |
| (XLIV) | 57972 | 2-[(2R)-7-oxooxepanyl]ethyl acetate | C10H16O4 | 详情 | 详情 | |
| (XLV) | 57973 | methyl (6R)-6,8-dihydroxyoctanoate | C9H18O4 | 详情 | 详情 | |
| (XLVI) | 18119 | 4-nitrobenzoic acid; p-nitrobenzoic acid | 62-23-7 | C7H5NO4 | 详情 | 详情 |
| (XLVII) | 57974 | (1S)-6-methoxy-1-{2-[(4-nitrobenzoyl)oxy]ethyl}-6-oxohexyl 4-nitrobenzoate | C23H24N2O10 | 详情 | 详情 | |
| (XLVIII) | 57977 | methyl (6S)-6,8-dihydroxyoctanoate | C9H18O4 | 详情 | 详情 | |
| (XLIX) | 57975 | methyl (6S)-6,8-bis[(methylsulfonyl)oxy]octanoate | C11H22O8S2 | 详情 | 详情 | |
| (L) | 57976 | methyl 5-[(3R)-1,2-dithiolan-3-yl]pentanoate | C9H16O2S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XLIX)A synthetic route based on the asymmetric reduction of oxo diesters has been reported. Meldrum's acid (LII) was acylated by methyl adipoyl chloride (LI) in the presence of pyridine to produce the intermediate (LIII) which, upon alcoholysis with isobutanol, led to oxo diester (LIV). Enantioselective reduction of (LIV) by means of baker's yeast furnished the (S)-hydroxy diester (LV). Alternatively, the analogous oxo diester (LVI) was prepared by acylation of methyl acetoacetate with methyl adipoyl chloride (LI), followed by deacetylation in the presence of ammonium hydroxide. Then, asymmetric chemical reduction of (LVI) by hydrogenation in the presence of the chiral catalyst Ru2Cl4[(S)-BINAP]2 provided the (S)-hydroxy diester (LVII). Regioselective reduction of either diester (LV) or (LVII) by means of NaBH4 in refluxing THF furnished dihydroxy ester (XLVIII). After conversion of (XLVIII) to the dimesylate (XLIX), displacement with potassium thioacetate afforded the bis(acetylthio) derivative (LVIII), which was further hydrolyzed with KOH to provide dihydrolipoic acid (LIX). In a related procedure, dihydrolipoic acid (LIX) was prepared by reaction of dimesylate (XLIX) with sodium disulfide, followed by reductive treatment with NaBH4 and NaOH. The title cyclic disulfide was then obtained by oxidation of the dithiol (LIX) using oxygen in the presence of FeCl3.
| 【1】 Bringmann, G.; et al.; A short and productive synthesis of (R)-alpha-lipoic acid. Z Naturforsch B - J Chem Sci 1999, 54, 5, 655. |
| 【2】 Laban, G.; Gewald, R. (Asta Medica AG); Process for the preparation of enantiomerically pure diesters of 3-hydroxyoctandioic acid by asymmetric catalytic hydrogenation. DE 19709069; EP 0863125; US 6013833 . |
| 【3】 Paust, J.; Klatt, M.J.; Niebel, M. (BASF AG); Method for producing lipoic acid and dihydrolipoic acid. WO 0210151 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XLVIII) | 57977 | methyl (6S)-6,8-dihydroxyoctanoate | C9H18O4 | 详情 | 详情 | |
| (XLIX) | 57975 | methyl (6S)-6,8-bis[(methylsulfonyl)oxy]octanoate | C11H22O8S2 | 详情 | 详情 | |
| (LI) | 49228 | methyl 6-chloro-6-oxohexanoate | C7H11ClO3 | 详情 | 详情 | |
| (LII) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (LIII) | 57978 | methyl 6-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-6-hydroxyhexanoate | C13H18O7 | 详情 | 详情 | |
| (LIV) | 57979 | 1-isobutyl 8-methyl 3-oxooctanedioate | C13H22O5 | 详情 | 详情 | |
| (LV) | 57980 | 1-isobutyl 8-methyl (3S)-3-hydroxyoctanedioate | C13H24O5 | 详情 | 详情 | |
| (LVI) | 57981 | dimethyl 3-oxooctanedioate | C10H16O5 | 详情 | 详情 | |
| (LVII) | 57982 | dimethyl (3S)-3-hydroxyoctanedioate | C10H18O5 | 详情 | 详情 | |
| (LVIII) | 57983 | methyl (6R)-6,8-bis(acetylsulfanyl)octanoate | C13H22O4S2 | 详情 | 详情 | |
| (LIX) | 57984 | (6R)-6,8-disulfanyloctanoic acid | C8H16O2S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XLIX)The reaction of the chiral dibenzoyloxy-dihydropyran (LXV) with H2SO4 and HgSO4 gives the unsaturated aldehyde (LXVI), which is condensed with the phosphorane (LXVII) to yield the hepatdienoic ester (LXVIII). The hydrogenation of (LXVIII) with H2 over Pd/C affords the heptanoic ester (LXIX), which is treated with Ts-Cl and pyridine to provide the tosyloxy derivative (LXX). The cyclization of (LXX) by means of K2CO3 gives the chiral epoxide (LXXI), which is condensed with vinylmagnesium bromide (LXXII) to yield 6(S)-hydroxy-8-nonenoic acid methyl ester (LXXIII). The oxidation of the terminal double bond of (LXXIII) with ozone affords the carbaldehyde (LXXIV), which is reduced with NaBH4 to provide 6(S),8-dihydroxyoctanoic acid methyl ester (XLVIII). The reaction of (XLVIII) with Ms-Cl and pyridine gives the dimesylate (XLIX), which is treated with Na2S2 to yield the lipoic acid methyl ester (L), which is hydrolyzed to the target acid with KOH in H2O.
| 【1】 Adger, B.; et al.; The synthesis of (R)-(+)-lipoic acid using a monooxygenase-catalysed biotransformation as the key step. Bioorg Med Chem 1997, 5, 2, 253. |
| 【2】 Adger, B.; et al.; Application of enzymatic Baeyer-Villiger oxidations of 2-substituted cycloalkanones to the total synthesis of (R)-(+)-lipoic acid. J Chem Soc Chem Commun 1995, 15, 1563. |
| 【3】 McCague, R.; Roberts, S.M.; Adger, B.M. (Celltech Group plc); Process for the production of lipoic acid. WO 9638437 . |
| 【4】 Villani, F.; Nardi, A.; Salvi, A.; Falabella, G.; Synthesis of R(+)alpha-lipoic acid. WO 0230919 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XLVIII) | 57977 | methyl (6S)-6,8-dihydroxyoctanoate | C9H18O4 | 详情 | 详情 | |
| (XLIX) | 57975 | methyl (6S)-6,8-bis[(methylsulfonyl)oxy]octanoate | C11H22O8S2 | 详情 | 详情 | |
| (L) | 57976 | methyl 5-[(3R)-1,2-dithiolan-3-yl]pentanoate | C9H16O2S2 | 详情 | 详情 | |
| (LXV) | 57990 | (3R,4S)-4-(benzoyloxy)-3,4-dihydro-2H-pyran-3-yl benzoate | C19H16O5 | 详情 | 详情 | |
| (LXVI) | 57991 | (1S,2E)-1-(hydroxymethyl)-4-oxo-2-butenyl benzoate | C12H12O4 | 详情 | 详情 | |
| (LXVII) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (LXVIII) | 57992 | (1S,2E,4E)-1-(hydroxymethyl)-6-methoxy-6-oxo-2,4-hexadienyl benzoate | C15H16O5 | 详情 | 详情 | |
| (LXIX) | 57993 | (1S)-1-(hydroxymethyl)-6-methoxy-6-oxohexyl benzoate | C15H20O5 | 详情 | 详情 | |
| (LXX) | 57994 | (1S)-6-methoxy-1-({[(4-methylphenyl)sulfonyl]oxy}methyl)-6-oxohexyl benzoate | C22H26O7S | 详情 | 详情 | |
| (LXXI) | 57995 | methyl 5-[(2S)oxiranyl]pentanoate | C8H14O3 | 详情 | 详情 | |
| (LXXII) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (LXXIII) | 57996 | methyl (6S)-6-hydroxy-8-nonenoate | C10H18O3 | 详情 | 详情 | |
| (LXXIV) | 57997 | methyl (6S)-6-hydroxy-8-oxooctanoate | C9H16O4 | 详情 | 详情 |