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【结 构 式】 
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【分子编号】57977 【品名】methyl (6S)-6,8-dihydroxyoctanoate 【CA登记号】 |
【 分 子 式 】C9H18O4 【 分 子 量 】190.23952 【元素组成】C 56.82% H 9.54% O 33.64% |
合成路线1
该中间体在本合成路线中的序号：(XLVIII)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：(XLVIII)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：(XLVIII)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 |
合成路线4
该中间体在本合成路线中的序号：(XIII)Racemic tetrahydro-2-furylmethanol (I) was converted to tosylate (II), which was further displaced by KCN to yield nitrile (III). Basic hydrolysis of nitrile (III), followed by Fischer esterification of the resultant carboxylic acid (IV) provided ethyl ester (V). Enzymatic resolution of racemic ester (V) by means of the lipase from Candida cylindracea generated a mixture of the (R)-acid (VI) and the unreacted (S)-ester (VII), which were separated by column chromatography. The desired (S) ester (VII) was then reduced to alcohol (VIII) with LiAlH4 in cold Et2O. Regioselective opening of the cyclic ether (VIII) with iodotrimethylsilane in acetone furnished the acetonide of 6-iodo-1,3-hexanediol (IX). Alkylation of benzyl methyl malonate (X) with iodide (IX) provided malonate (XI). Hydrogenolysis of the benzyl ester group of (XI), followed by thermal decarboxylation led to ester (XII). The target dihydroxy ester precursor (XIII) was then obtained by acid-catalyzed hydrolysis of the acetonide function.
| 【1】 Laxmi, Y.R.S.; Iyengar, D.S.; Chemoenzymatic synthesis of methyl (6S)-(-)-6,8-dihydroxyoctanoate: A precursor to (R)-(+)-alpha-lipoic acid. Synthesis (Stuttgart) 1996, 5, 594. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 58026 | 2-(Hydroxymethyl)tetrahydrofuran; Tetrahydro-2-furancarbinol; Tetrahydro-2-furanmethanol; Tetrahydrofurfural alcohol; Tetrahydrofurfuryl alcohol | 97-99-4 | C5H10O2 | 详情 | 详情 |
| (II) | 58027 | Toluene-4-sulfonic acid tetrahydrofuran-2-ylmethyl ester | C12H16O4S | 详情 | 详情 | |
| (III) | 58028 | 2-tetrahydro-2-furanylacetonitrile | C6H9NO | 详情 | 详情 | |
| (IV) | 58029 | 2-tetrahydro-2-furanylacetic acid | C6H10O3 | 详情 | 详情 | |
| (V) | 58030 | methyl 2-tetrahydro-2-furanylacetate | C7H12O3 | 详情 | 详情 | |
| (VI) | 58031 | 2-[(2R)tetrahydro-2-furanyl]acetic acid | C6H10O3 | 详情 | 详情 | |
| (VII) | 58032 | methyl 2-[(2S)tetrahydro-2-furanyl]acetate | C7H12O3 | 详情 | 详情 | |
| (VIII) | 58033 | 2-[(2S)tetrahydro-2-furanyl]-1-ethanol | C6H12O2 | 详情 | 详情 | |
| (IX) | 58034 | (4S)-4-(3-iodopropyl)-2,2-dimethyl-1,3-dioxane | C9H17IO2 | 详情 | 详情 | |
| (X) | 58035 | 1-benzyl 3-methyl malonate | C11H12O4 | 详情 | 详情 | |
| (XI) | 58036 | 1-benzyl 3-methyl 2-{3-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]propyl}malonate | C20H28O6 | 详情 | 详情 | |
| (XII) | 58037 | methyl 5-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]pentanoate | C12H22O4 | 详情 | 详情 | |
| (XIII) | 57977 | methyl (6S)-6,8-dihydroxyoctanoate | C9H18O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIII)Addition of vinylmagnesium bromide to 2-nitrocyclohexanone (XIV) afforded the nitro alcohol (XV). Ring cleavage of (XVI) in the presence of anhydrous CuSO4 absorbed on silica gel gave the nitro ketone (XVI). Nitro group hydrolysis in (XVI) by successive treatment with NaOMe and H2SO4 in MeOH furnished oxo ester (XVII) as the main product. This was enantiospecifically reduced with baker's yeast to yield the (S)-alcohol (XVIII). Selective methyl ether cleavage with tetrabutylammonium iodide and BF3 provided the dihydroxy ester precursor (XIII).
| 【1】 Bezbarua, M.S.; et al.; A short enantioselective formal synthesis of methyl (S)-(-)-6,8-dihydroxyoctanoate: A key intermediate for the synthesis of R-(+)-alpha-lipoic acid. Synthesis (Stuttgart) 1996, 11, 1289. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 57977 | methyl (6S)-6,8-dihydroxyoctanoate | C9H18O4 | 详情 | 详情 | |
| (XIV) | 58038 | 2-Nitrocyclohexanone | C6H9NO3 | 详情 | 详情 | |
| (XV) | 58039 | 2-nitro-1-vinylcyclohexanol | C8H13NO3 | 详情 | 详情 | |
| (XVI) | 58040 | 8-nitro-1-octen-3-one | C8H13NO3 | 详情 | 详情 | |
| (XVII) | 58041 | methyl 8-methoxy-6-oxooctanoate | C10H18O4 | 详情 | 详情 | |
| (XVIII) | 58042 | methyl (6S)-6-hydroxy-8-methoxyoctanoate | C10H20O4 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XIII)A further procedure for the preparation of the key intermediate (XIII) utilized the chiral starting material (S)-4-benzyloxy-1,2-butanediol (XIX), easily accessible from (S)-malic acid. Inversion of the configuration of (XIX) was accomplished via formation of dimesylate (XX), followed by displacement with potassium acetate in refluxing Ac2O. The resultant diacetate (XXI) was hydrolyzed to the required (R)-diol (XXII) by treatment with K2CO3 in MeOH. Conversion of (XXII) into epoxide (XXIV) was performed through the benzylidene ketal (XXIII), following the reported procedure for the corresponding (S)-enantiomer. Copper(I)-catalyzed addition of 3-butenylmagnesium bromide (XXV) to epoxide (XXIV) furnished alcohol (XXVI), which was further protected as the benzyl ether (XXVII). Hydroboration of olefin (XXVII) with in situ generated disiamylborane, followed by oxidative work-up gave rise to the primary alcohol (XXVIII). This was oxidized with pyridinium dichromate to the carboxylic acid (XXIX), which was further esterified by means of methanolic HCl to afford ester (XXX). Then, catalytic hydrogenolysis of the di(benzyloxy) ester (XXX) yielded the target intermediate dihydroxyester (XIII).
| 【1】 Brookes, M.H.; et al.; Syntheses of alpha-(R)- and alpha-(S)-lipoic acid from (S)-malic acid. J Chem Soc - Perkins Trans I 1988, 1, 9. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 57977 | methyl (6S)-6,8-dihydroxyoctanoate | C9H18O4 | 详情 | 详情 | |
| (XIX) | 58043 | (2S)-4-(benzyloxy)-1,2-butanediol | C11H16O3 | 详情 | 详情 | |
| (XX) | 58044 | (2S)-4-(benzyloxy)-2-[(methylsulfonyl)oxy]butyl methanesulfonate | C13H20O7S2 | 详情 | 详情 | |
| (XXI) | 58045 | (2R)-2-(acetyloxy)-4-(benzyloxy)butyl acetate | C15H20O5 | 详情 | 详情 | |
| (XXII) | 58052 | (2R)-4-(benzyloxy)-1,2-butanediol | C11H16O3 | 详情 | 详情 | |
| (XXIII) | 58046 | (4R)-4-[2-(benzyloxy)ethyl]-2-phenyl-1,3-dioxolane; benzyl 2-[(4R)-2-phenyl-1,3-dioxolan-4-yl]ethyl ether | C18H20O3 | 详情 | 详情 | |
| (XXIV) | 42367 | benzyl 2-[(2S)oxiranyl]ethyl ether; (2S)-2-[2-(benzyloxy)ethyl]oxirane | C11H14O2 | 详情 | 详情 | |
| (XXV) | 35896 | bromo(3-butenyl)magnesium | 7103-09-5 | C4H7BrMg | 详情 | 详情 |
| (XXVI) | 58047 | (3S)-1-(benzyloxy)-7-octen-3-ol | C15H22O2 | 详情 | 详情 | |
| (XXVII) | 58048 | 1-({[(3S)-3-(benzyloxy)-7-octenyl]oxy}methyl)benzene; benzyl (1S)-1-[2-(benzyloxy)ethyl]-5-hexenyl ether | C22H28O2 | 详情 | 详情 | |
| (XXVIII) | 58049 | (6S)-6,8-bis(benzyloxy)-1-octanol | C22H30O3 | 详情 | 详情 | |
| (XXIX) | 58050 | (6S)-6,8-bis(benzyloxy)octanoic acid | C22H28O4 | 详情 | 详情 | |
| (XXX) | 58051 | methyl (6S)-6,8-bis(benzyloxy)octanoate | C23H30O4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XIII)A further procedure utilized the (S)-keto ester (XXXI) as the chiral starting material. Baeyer-Villiger oxidation of cyclohexanone (XXXI) with m-CPBA in the presence of a phosphate buffer at pH 8 provided two regioisomeric chiral lactones (XXXII) and (XXXIII), which were separated by column chromatography. The major isomer (XXXII) was subsequently reduced with LiAlH4 to furnish triol (XXXIV). The 1,3-dihydroxy moiety of (XXXIV) was then protected as the acetonide derivative (XXXV) employing 2,2-dimethoxypropane. The requisite ester (XXXVII) was prepared by stepwise oxidation of the primary alcohol (XXXV) to the aldehyde (XXXVI) using pyridinium dichromate, and then to the corresponding carboxylic acid with m-CPBA, followed by esterification with ethereal diazomethane to (XXXVII). Hydrolysis of the acetonide (XXXVII) by means of p-toluenesulfonic acid in methanol led to the target intermediate, the dihydroxy ester (XIII).
| 【1】 Ganaha, M.; et al.; Synthesis of methyl (S)-(-)-6,8-dihydroxyoctanoate as a precursor of (R)-(+)-alpha-lipoic acid. Biosci Biotechnol Biochem 1999, 63, 11, 2025. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 57977 | methyl (6S)-6,8-dihydroxyoctanoate | C9H18O4 | 详情 | 详情 | |
| (XXXI) | 58053 | methyl 2-[(1S)-2-oxocyclohexyl]acetate | C9H14O3 | 详情 | 详情 | |
| (XXXII) | 58054 | methyl 2-[(2S)-7-oxooxepanyl]acetate | C9H14O4 | 详情 | 详情 | |
| (XXXIII) | 58055 | methyl 2-[(3S)-2-oxooxepanyl]acetate | C9H14O4 | 详情 | 详情 | |
| (XXXIV) | 58056 | (3S)-1,3,8-octanetriol | C8H18O3 | 详情 | 详情 | |
| (XXXV) | 58057 | 5-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-1-pentanol | C11H22O3 | 详情 | 详情 | |
| (XXXVI) | 58058 | 5-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]pentanal | C11H20O3 | 详情 | 详情 | |
| (XXXVII) | 58037 | methyl 5-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]pentanoate | C12H22O4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XIII)The olefinic diester (XXXVIII) was subjected to OsO4-catalyzed asymmetric dihydroxylation using hydroquinidine 1,4-phthalazinediyl diether [(DHQD)2-PHAL] as chiral ligand to afford diol (XXXIX). This was converted to the cyclic sulfate (XL) by treatment with SOCl2, followed by RuCl3-catalyzed NaIO4 oxidation of the intermediate sulfite. Regioselective reduction of sulfate (XL) at the alpha position with NaBH4 in DMA led to the (3S)-alcohol (XLI). Further selective reduction of the ethyl ester group of (XLI) was achieved by treatment with NaBH4-Et3N in MeOH-DMF, yielding the target intermediate dihydroxy ester (XIII).
| 【1】 Upadhya, T.T.; et al.; Asymmetric dihydroxylation and hydrogenation approaches to the enantioselective synthesis of R-(+)-alpha-lipoic acid. Tetrahedron Lett 2001, 42, 29, 4891. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 57977 | methyl (6S)-6,8-dihydroxyoctanoate | C9H18O4 | 详情 | 详情 | |
| (XXXVIII) | 58059 | 1-ethyl 8-methyl (E)-2-octenedioate | C11H18O4 | 详情 | 详情 | |
| (XXXIX) | 58060 | 1-ethyl 8-methyl (2R,3S)-2,3-dihydroxyoctanedioate | C11H20O6 | 详情 | 详情 | |
| (XL) | 58061 | ethyl (4R,5S)-5-(5-methoxy-5-oxopentyl)-2,2-dioxo-1,3,2lambda~6~-dioxathiolane-4-carboxylate | C11H18O8S | 详情 | 详情 | |
| (XLI) | 58062 | 1-ethyl 8-methyl (3S)-3-hydroxyoctanedioate | C11H20O5 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XIII)The key dihydroxy ester intermediate (XIII) was also obtained by asymmetric hydrogenation of hydroxy ketoester (XLIII) in the presence of (S)-BINAP-dichlororuthenium catalyst. The precursor hydroxy ketoester (XLIII) was prepared by two alternative procedures. In one method, the racemic dihydroxy ester (XLII) was selectively oxidized to (XLIII) by means of NaOCl. In another method, the unsaturated keto ester (XLIV) was epoxidized by means of sodium percarbonate, and the resultant epoxide (XLV) was then reduced to the hydroxy ketoester (XLIII) by catalytic hydrogenation over PtO2.
| 【1】 Gewald, R. (Asta Medica AG); Method for producing enantiomer-free 6,8-dihydroxyoctanoic acid esters by means of asymmetric, catalytic hydrogenation. DE 10036516; WO 0210113 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 57977 | methyl (6S)-6,8-dihydroxyoctanoate | C9H18O4 | 详情 | 详情 | |
| (XLII) | 58066 | methyl 6,8-dihydroxyoctanoate | C9H18O4 | 详情 | 详情 | |
| (XLIII) | 58063 | methyl 8-hydroxy-6-oxooctanoate | C9H16O4 | 详情 | 详情 | |
| (XLIV) | 58064 | methyl 6-oxo-7-octenoate | C9H14O3 | 详情 | 详情 | |
| (XLV) | 58065 | methyl 6-(2-oxiranyl)-6-oxohexanoate | C9H14O4 | 详情 | 详情 |