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【结 构 式】 
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【分子编号】57976 【品名】methyl 5-[(3R)-1,2-dithiolan-3-yl]pentanoate 【CA登记号】 |
【 分 子 式 】C9H16O2S2 【 分 子 量 】220.35684 【元素组成】C 49.06% H 7.32% O 14.52% S 29.1% |
合成路线1
该中间体在本合成路线中的序号：(L)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：(L)Both enantiomers of racemic 8-chloro-6-hydroxyoctanoic acid (LX) were separated employing either (+)- or (-)-alpha-methylbenzylamine. Esterification of the (R)-(-)-enantiomer with HCl-MeOH provided the chloro hydroxy ester (LXI). Further chlorination of (LXI) with SOCl2 and pyridine proceeded with inversion of configuration at C-6 to furnish the (S)-dichloro derivative (LXII). The cyclic disulfide (L) was then prepared by treatment of chloride (LXII) with sulfur and sodium sulfide in boiling EtOH. Basic hydrolysis of the methyl ester group of (LXII) then afforded (R) alpha lipoic acid. The title compound was also obtained from the (S)-(+)-acid (LXIII). Reaction of hydroxy acid (LXIII) with methanesulfonyl chloride produced the chloro mesylate (LXIV), which was then cyclized to the target disulfide in the presence of sulfur and Na2S.
| 【2】 Villani, F.; Nardi, A.; Salvi, A.; Falabella, G.; Synthesis of R(+)alpha-lipoic acid. WO 0230919 . |
| 【1】 Laban, G.; Beisswenger, T.; Gewald, R. (AWD.pharma GmbH & Co. KG); Preparation and use of the pure enantiomers of 8-chloro-6-sulfonyloxy-octanoic acid and its alkyl esters and of the pure enantiomers of 6,8-dichloro-octanoic acid and its alkyl esters. DE 19533881; EP 0763533; US 5731448 . |
| 【3】 Laban, G.; Beisswenger, T.; Gewald, R. (AWD.pharma GmbH & Co. KG); Preparation and utilisation of pure enantiomers of 8-halogen-6-hydroxyoctanoic acid, their alkyl esters and their salts with pure enantiomers of alpha-methyl-benzylamines. DE 19533882; EP 0763516; US 5869713 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (L) | 57976 | methyl 5-[(3R)-1,2-dithiolan-3-yl]pentanoate | C9H16O2S2 | 详情 | 详情 | |
| (LX) | 57985 | 8-chloro-6-hydroxyoctanoic acid | C8H15ClO3 | 详情 | 详情 | |
| (LXI) | 57986 | methyl (6R)-8-chloro-6-hydroxyoctanoate | C9H17ClO3 | 详情 | 详情 | |
| (LXII) | 57988 | methyl (6S)-6,8-dichlorooctanoate | C9H16Cl2O2 | 详情 | 详情 | |
| (LXIII) | 57987 | (6S)-8-chloro-6-hydroxyoctanoic acid | C8H15ClO3 | 详情 | 详情 | |
| (LXIV) | 57989 | (6S)-8-chloro-6-[(methylsulfonyl)oxy]octanoic acid | C9H17ClO5S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(L)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 |