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【结 构 式】

【药物名称】d-Thioctic acid, (R)-(+)-alpha-Lipoic acid, (R)-(+)-Thioctic acid, Dexlipotam

【化学名称】(+)-5-[1,2-Dithiolan-3(R)-yl]pentanoic acid

【CA登记号】1200-22-2

【 分 子 式 】C8H14O2S2

【 分 子 量 】206.32758

【开发单位】Asta Medica (Originator), Aventis Pharma (Licensee)

【药理作用】Antidiabetic Drugs, Diabetic Neuropathy, Agents for, ENDOCRINE DRUGS, Treatment of Diabetic Complications, Type 2 Diabetes Mellitus, Agents for, Pyruvate Dehydrogenase Activators

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20

合成路线1

Aldehyde (II), prepared by ozonolysis of cyclohexene (I), was ketalized with (S,S)-2,4-pentanediol (III) to afford dioxane (IV). Titanium chloride-mediated coupling of acetal (IV) with the ketene acetal (V) afforded diastereoselectively adduct (VI), which was subsequently hydrolyzed to carboxylic acid (VII) by means of trifluoroacetic acid. Removal of the pentanediol moiety to furnish the (R)-alcohol (IX) was accomplished via Jones oxidation of the secondary alcohol (VII) to ketone (VIII), followed by beta-elimination in the presence of piperidinium acetate. Reduction of the free carboxyl group by borane-tetrahydrofuran complex gave diol (X), which was further converted to dimesylate (XI). Disulfide displacement of the mesylate groups provided (+)-lipoic acid isopropyl ester (XII), which was finally hydrolyzed to the title acid using K2CO3 in MeOH/H2O.

参考文献 中间体
【1】 Elliott, J.D.; et al.; Asymmetric synthesis via acetal templates. 12. Highly diastereoselective coupling reactions with a ketene acetal. An efficient, asymmetric synthesis of R-(+)-alpha-lipoic acid. Tetrahedron Lett 1985, 26, 21, 2535.
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) 40446 1-cyclohexene 110-83-8 C6H10 详情 详情
(II) 57934 isopropyl 6-oxohexanoate C9H16O3 详情 详情
(III) 57935 (2S,4S)-2,4-pentanediol C5H12O2 详情 详情
(IV) 57936 isopropyl 5-[(4S,6S)-4,6-dimethyl-1,3-dioxan-2-yl]pentanoate C14H26O4 详情 详情
(V) 57937 {[1-(tert-butoxy)vinyl]oxy}(tert-butyl)dimethylsilane; 1-(tert-butoxy)vinyl tert-butyl(dimethyl)silyl ether C12H26O2Si 详情 详情
(VI) 57938 1-[tert-butyl(dimethyl)silyl] 8-isopropyl (3S)-3-{[(1S,3S)-3-hydroxy-1-methylbutyl]oxy}octanedioate C22H44O6Si 详情 详情
(VII) 57939 (3S)-3-{[(1S,3S)-3-hydroxy-1-methylbutyl]oxy}-8-isopropoxy-8-oxooctanoic acid C16H30O6 详情 详情
(VIII) 57940 (3S)-8-isopropoxy-3-{[(1S)-1-methyl-3-oxobutyl]oxy}-8-oxooctanoic acid C16H28O6 详情 详情
(IX) 57941 (3S)-3-hydroxy-8-isopropoxy-8-oxooctanoic acid C11H20O5 详情 详情
(X) 57942 isopropyl (6S)-6,8-dihydroxyoctanoate C11H22O4 详情 详情
(XI) 57943 isopropyl (6S)-6,8-bis[(methylsulfonyl)oxy]octanoate C13H26O8S2 详情 详情
(XII) 57944 isopropyl 5-[(3R)-1,2-dithiolan-3-yl]pentanoate C11H20O2S2 详情 详情

合成路线2

Alkylation of the lithio-dianion of propargyl alcohol (XIII) with 6-bromo-1-hexene (XIV), followed by in situ reduction of the resultant disubstituted acetylene with lithium metal gave the allylic alcohol (XV). Asymmetric Sharpless epoxidation of (XV) using tert-butyl hydroperoxide in the presence of L-(+)-diisopropyl tartrate afforded the (S,S)-epoxy alcohol (XVI). This was reduced to the chiral diol (XVII) employing Red-Al® in THF. After formation of the bis-mesylate (XVIII), oxidative cleavage of the terminal double bond by means of NaIO4 in the presence of ruthenium catalyst furnished the carboxylic acid (XIX). The mesylate groups were finally displaced by sodium disulfide to produce the desired cyclic disulfide compound.

参考文献 中间体
【1】 Page, P.C.B.; et al.; An enantioselective synthesis of R-(+)-alpha-lipoic acid. J Chem Soc - Perkins Trans I 1990, 6, 1615.
【2】 Bulman, P.C.; et al.; Enantioselective synthesis of R-(+)-alpha-lipoic acid. J Chem Soc Chem Commun 1986, 18, 1408.
【3】 Sutherland, I.O.; Page, P.C.B.; Rayner, C.M. (Asta Medica AG); Process for the preparation of pure enantiomers of R-(+)-alpha-lipoic acid and S-(-)-alpha-lipoic acid (thioctic acid), and nonene or mesyl derivs. as intermediates thereof. DE 3629116; EP 0261336 .
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) 16664 Propargyl Alcohol; 2-propyn-1-ol 107-19-7 C3H4O 详情 详情
(XIV) 37330 6-bromo-1-hexene 2695-47-8 C6H11Br 详情 详情
(XV) 57945 (2E)-2,8-nonadien-1-ol C9H16O 详情 详情
(XVI) 57946 [(2R,3S)-3-(5-hexenyl)oxiranyl]methanol C9H16O2 详情 详情
(XVII) 57947 (3S)-8-nonene-1,3-diol C9H18O2 详情 详情
(XVIII) 57948 (3S)-3-[(methylsulfonyl)oxy]-8-nonenyl methanesulfonate C11H22O6S2 详情 详情
(XIX) 57949 (6S)-6,8-bis[(methylsulfonyl)oxy]octanoic acid C10H20O8S2 详情 详情

合成路线3

An alternative route to (+)-lipoic acid used ethyl 4,6-di-O-acetyl-2,3-dideoxy-alpha-D-erythro-hexopyranoside (XX), prepared from triacetyl-D-glucal, as the chiral starting point. Deacetylation of (XX) with sodium methoxide under Zemplen conditions gave diol (XXI) which, after conventional benzylation, led to the 4,6-di-O-benzyl derivative (XXII). Ring opening of the cyclic acetal (XXII) with propanediol in the presence of boron trifluoride afforded the dithiane derivative (XXIII). The free hydroxyl group of (XXIII) was converted into xanthate (XXIV) by reaction with NaH and CS2, followed by methyl iodide. Reductive cleavage of the xanthate group by means of Bu3SnH and AIBN provided (XXV). Hydrolysis of the thioacetal function with HgO and BF3 provided aldehyde (XXVI). Chain homologation was performed by Wittig reaction of aldehyde (XXVI) with phosphorane (XXVII) to afford the unsaturated ester (XXVIII). Simultaneous double bond hydrogenation and benzyl ether cleavage in the presence of Raney nickel led to dihydroxy ester (XXIX). This was converted to the corresponding dimesylate (XXX), which was further cyclized to disulfide (XXXI) using the in situ generated sodium disulfide as in the precedent Schemes. Finally, basic hydrolysis of the ethyl ester (XXXI) yielded the title carboxylic acid.

参考文献 中间体
【1】 Rao, A.V.R.; et al.; Enantiospecific synthesis of (R)-(+)-alpha-lipoic acid from D-glucose. Carbohydr Res 1986, 148, 1, 51.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVI) 57956 (4S)-4,6-bis(benzyloxy)hexanal C20H24O3 详情 详情
(XX) 57950 [(2R,3S,6S)-3-(acetyloxy)-6-ethoxytetrahydro-2H-pyran-2-yl]methyl acetate C12H20O6 详情 详情
(XXI) 57951 (2R,3S,6S)-6-ethoxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol C8H16O4 详情 详情
(XXII) 57952 (2R,3S,6S)-3-(benzyloxy)-2-[(benzyloxy)methyl]-6-ethoxytetrahydro-2H-pyran; benzyl [(2R,3S,6S)-3-(benzyloxy)-6-ethoxytetrahydro-2H-pyran-2-yl]methyl ether C22H28O4 详情 详情
(XXIII) 57953 (2R,3S)-1,3-bis(benzyloxy)-5-(1,3-dithian-2-yl)-2-pentanol C23H30O3S2 详情 详情
(XXIV) 57954 O-[(1R,2S)-2-(benzyloxy)-1-[(benzyloxy)methyl]-4-(1,3-dithian-2-yl)butyl] S-methyl carbonodithioate C25H32O3S4 详情 详情
(XXV) 57955 benzyl (1S)-3-(benzyloxy)-1-[2-(1,3-dithian-2-yl)ethyl]propyl ether; 2-[(3S)-3,5-bis(benzyloxy)pentyl]-1,3-dithiane C23H30O2S2 详情 详情
(XXVII) 14182 ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane 1099-45-2 C22H21O2P 详情 详情
(XXVIII) 57957 ethyl (E,6S)-6,8-bis(benzyloxy)-2-octenoate C24H30O4 详情 详情
(XXIX) 57958 ethyl (6S)-6,8-dihydroxyoctanoate C10H20O4 详情 详情
(XXX) 57959 ethyl (6S)-6,8-bis[(methylsulfonyl)oxy]octanoate C12H24O8S2 详情 详情
(XXXI) 57960 ethyl 5-[(3R)-1,2-dithiolan-3-yl]pentanoate C10H18O2S2 详情 详情

合成路线4

A short synthetic strategy utilized the cyclic thioketal (XXXIII), derived from d-menthone (XXXII) and 1,3-propanedithiol, as the chiral template. Stereospecific oxidation of dithiane (XXXIII) employing NaIO4 produced sulfoxide (XXXIV). The carbanion generated from sulfoxide (XXXIV) was stereoselectively alkylated by 5-bromopentanoic acid (XXXV) in the presence of TMEDA to furnish the trans alkylated compound (XXXVI). Finally, acidic hydrolysis of (XXXVI) formed the intermediate mercapto sulfinic acid (XXXVII) which spontaneously cyclized to the desired dithiolane derivative.

参考文献 中间体
【1】 Menon, R.B.; et al.; Stereospecific synthesis of alpha-lipoic acid. Tetrahedron Lett 1987, 28, 44, 5313.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXII) 10208 L-Menthone; (2S,5R)-2-Isopropyl-5-methylcyclohexanone 14073-97-3 C10H18O 详情 详情
(XXXIII) 57961 (7R,10S)-7-isopropyl-10-methyl-1,5-dithiaspiro[5.5]undecane C13H24S2 详情 详情
(XXXIV) 57962 (6S,7R,10S)-7-isopropyl-10-methyl-5-thia-1-thioniaspiro[5.5]undecan-1-olate C13H24OS2 详情 详情
(XXXV) 57963 5-Bromo-n-valeric acid; 5-Bromopentanoic acid; 5-Bromovaleric acid 2067-33-6 C5H9BrO2 详情 详情
(XXXVI) 57964 (2R,6S,7R,10S)-2-(4-carboxybutyl)-7-isopropyl-10-methyl-5-thia-1-thioniaspiro[5.5]undecan-1-olate C18H32O3S2 详情 详情
(XXXVII) 57965 (6R)-6-(hydroxysulfanyl)-8-sulfanyloctanoic acid C8H16O3S2 详情 详情

合成路线5

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.

参考文献 中间体
【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6

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.

参考文献 中间体
【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7

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.

参考文献 中间体
【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8

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.

参考文献 中间体
【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9

Diisopropylidene mannitol (I) was first converted into the dibutyltin derivative (II), which was subsequently mono-benzylated to (III). Acetylation of (III) with acetic anhydride in pyridine gave (IV). After acidic hydrolysis of the isopropylidene ketals of (IV), the resultant tetraol (V) was converted into tetramesylate (VI). Reductive elimination in (VI) with Zn and NaI produced diene (VII). The acetate group of (VII) was then hydrolyzed to (VIII) using NaOMe. Intermediate (VIII) was reacted with triethyl orthoacetate in the presence of propionic acid to generate the allyl vinyl ether (IX), which underwent a Claisen rearrangement to the diene-ester (X). Selective hydroboration-oxidation of the terminal double bond of (X) yielded the primary alcohol (XI). Subsequent benzyl group hydrogenolysis in (XI) furnished the target intermediate diol (XII).

参考文献 中间体
【1】 Rao, A.V.R.; et al.; Synthesis of (3R,4R)-1,5-hexadien-3,4-diol and its unsymmetrical derivatives: Application to (R)-(+)-alpha-lipoic acid. Tetrahedron Lett 1987, 28, 19, 2183.
【2】 Yadav, J.S.; et al.; Synthesis of (3R,4R)-1,2-divinylglycol and its unsymmetrical derivatives: An application to the synthesis of R-(+)-alpha lipoic acid. J Carbohydr Chem 1990, 9, 2-3, 307.
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) 45944 (1S,2S)-1,2-bis[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,2-ethanediol 1707-77-3 C12H22O6 详情 详情
(II) 57998 (4R,5R)-2,2-dibutoxy-4,5-bis[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,3,2-dioxastannolane C20H38O8Sn 详情 详情
(III) 57999 (1S,2S)-2-(benzyloxy)-1,2-bis[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-ethanol C19H28O6 详情 详情
(IV) 58000 (1S,2R)-2-(benzyloxy)-1,2-bis[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl acetate C21H30O7 详情 详情
(V) 58001 (1R,2R,3R)-2-(benzyloxy)-1-[(1R)-1,2-dihydroxyethyl]-3,4-dihydroxybutyl acetate C15H22O7 详情 详情
(VI) 58002 (1S,2S,3R)-2-(benzyloxy)-1-{(1R)-1,2-bis[(methylsulfonyl)oxy]ethyl}-3,4-bis[(methylsulfonyl)oxy]butyl acetate C19H30O15S4 详情 详情
(VII) 58003 (1R,2R)-2-(benzyloxy)-1-vinyl-3-butenyl acetate C15H18O3 详情 详情
(VIII) 58004 (3R,4R)-4-(benzyloxy)-1,5-hexadien-3-ol C13H16O2 详情 详情
(IX) 58005 1-[({(1R,2R)-2-[(1-ethoxyvinyl)oxy]-1-vinyl-3-butenyl}oxy)methyl]benzene; benzyl (1R,2R)-2-[(1-ethoxyvinyl)oxy]-1-vinyl-3-butenyl ether C17H22O3 详情 详情
(X) 58006 ethyl (4E,6R)-6-(benzyloxy)-4,7-octadienoate C17H22O3 详情 详情
(XI) 58007 ethyl (E,6R)-6-(benzyloxy)-8-hydroxy-4-octenoate C17H24O4 详情 详情
(XII) 57958 ethyl (6S)-6,8-dihydroxyoctanoate C10H20O4 详情 详情

合成路线10

Alkylation of the dianion of octyl acetoacetate (XIII) with 4-iodobutyronitrile (XIV) provided the cyano keto ester (XV). Enantiospecific reduction of (XV) utilizing baker's yeast gave rise to the desired (S)-hydroxy ester (XVI) in high enantiomeric excess. Subsequent ester group reduction in (XVI) by means of LiBH4 provided diol (XVII). The target dihydroxy ester (XII) was then obtained by alcoholysis of nitrile (XVII) under acidic conditions.

参考文献 中间体
【1】 Jacobs, H.K.; Gopalan, A.S.; Stereochemical control of yeast reductions: Synthesis of R-(+)-alpha-lipoic acid. Tetrahedron Lett 1989, 30, 42, 5705.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 57958 ethyl (6S)-6,8-dihydroxyoctanoate C10H20O4 详情 详情
(XIII) 58008 octyl 3-oxobutanoate C12H22O3 详情 详情
(XIV) 58009 4-iodobutanenitrile C4H6IN 详情 详情
(XV) 58010 octyl 7-cyano-3-oxoheptanoate C16H27NO3 详情 详情
(XVI) 58011 octyl (3S)-7-cyano-3-hydroxyheptanoate C16H29NO3 详情 详情
(XVII) 58012 (6S)-6,8-dihydroxyoctanenitrile C8H15NO2 详情 详情

合成路线11

In a related method, keto ester (XX) was prepared by Claisen condensation of the lithium enolate of octyl acetate (XVIII) with 4-chlorobutanoyl chloride (XIX). Reduction of the beta-keto ester (XX) with baker's yeast gave rise to the (S)-alcohol (XXI). Subsequent ester group reduction in (XXI) with LiBH4 furnished diol (XXII), which was protected as the acetonide (XXIII) upon treatment with 2,2-dimethoxypropane under acidic conditions. Displacement of the chloride of (XXIII) with the sodium salt of diethyl malonate afforded the substituted malonate (XXIV). Decarbethoxylation of malonate (XXIV) to mono-ester (XXV) was accomplished employing NaCN in hot DMSO. The target dihydroxy ester (XII) was then obtained by acidic acetonide (XXV) hydrolysis.

参考文献 中间体
【1】 Jacobs, H.K.; Gopalan, A.S.; Bakers' yeast reduction of alkyl 6-chloro-3-oxohexanoates: Synthesis of (R)-(+)-alpha-lipoic acid. J Chem Soc - Perkins Trans I 1990, 7, 1897.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 57958 ethyl (6S)-6,8-dihydroxyoctanoate C10H20O4 详情 详情
(XVIII) 58013 octyl acetate C10H20O2 详情 详情
(XIX) 11265 4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride 4635-59-0 C4H6Cl2O 详情 详情
(XX) 58014 octyl 6-chloro-3-oxohexanoate C14H25ClO3 详情 详情
(XXI) 58015 octyl (3S)-6-chloro-3-hydroxyhexanoate C14H27ClO3 详情 详情
(XXII) 58016 (3S)-6-chloro-1,3-hexanediol C6H13ClO2 详情 详情
(XXIII) 58017 (4S)-4-(3-chloropropyl)-2,2-dimethyl-1,3-dioxolane C8H15ClO2 详情 详情
(XXIV) 58018 diethyl 2-{3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]propyl}malonate C15H26O6 详情 详情
(XXV) 58019 ethyl 5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]pentanoate C12H22O4 详情 详情

合成路线12

Esterification of diisopropylidene mannitol (I) with benzoyl chloride in pyridine afforded dibenzoate (II). Hydrolysis of the isopropylidene ketals of (II) with aqueous HOAc gave tetraol (III), which was further converted to tetramesylate (IV) on treatment with methanesulfonyl chloride and pyridine. Reductive elimination of the mesylate groups of (IV) using Zn dust and NaI yielded diene (V). The benzoate esters of (V) were then removed by treatment with sodium methoxide. The resultant divinylglycol (VI) was reacted with dibutyltin oxide to produce the tin derivative (VII), which was converted to the target intermediate, themono-benzyl ether (VIII), by treatment with benzyl bromide in hot DMF.

参考文献 中间体
【1】 Rao, A.V.R.; et al.; Synthesis of (3R,4R)-1,5-hexadien-3,4-diol and its unsymmetrical derivatives: Application to (R)-(+)-alpha-lipoic acid. Tetrahedron Lett 1987, 28, 19, 2183.
【2】 Yadav, J.S.; et al.; Synthesis of (3R,4R)-1,2-divinylglycol and its unsymmetrical derivatives: An application to the synthesis of R-(+)-alpha lipoic acid. J Carbohydr Chem 1990, 9, 2-3, 307.
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) 45944 (1S,2S)-1,2-bis[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,2-ethanediol 1707-77-3 C12H22O6 详情 详情
(II) 58020 (1R,2R)-2-(benzoyloxy)-1,2-bis[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl benzoate C26H30O8 详情 详情
(III) 58021 (1R,2R,3R)-2-(benzoyloxy)-1-[(1R)-1,2-dihydroxyethyl]-3,4-dihydroxybutyl benzoate C20H22O8 详情 详情
(IV) 58022 (1S,2S,3R)-2-(benzoyloxy)-1-{(1R)-1,2-bis[(methylsulfonyl)oxy]ethyl}-3,4-bis[(methylsulfonyl)oxy]butyl benzoate C24H30O16S4 详情 详情
(V) 58023 (1R,2R)-2-(benzoyloxy)-1-vinyl-3-butenyl benzoate C20H18O4 详情 详情
(VI) 58024 (3R,4R)-1,5-hexadiene-3,4-diol C6H10O2 详情 详情
(VII) 58025 (4R,5R)-2,2-dibutoxy-4,5-divinyl-1,3,2-dioxastannolane C14H26O4Sn 详情 详情
(VIII) 58004 (3R,4R)-4-(benzyloxy)-1,5-hexadien-3-ol C13H16O2 详情 详情

合成路线13

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.

参考文献 中间体
【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14

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).

参考文献 中间体
【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15

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).

参考文献 中间体
【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16

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).

参考文献 中间体
【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17

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).

参考文献 中间体
【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18

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.

参考文献 中间体
【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

合成路线19

The intermediate 6(S)-hydroxy-8-nonenoic acid methyl ester (III) has been obtained by enantioselective allylation of 6-oxohexanoic acid methyl ester (I) with allyltributylstannane (II) catalyzed by the chiral catalyst (R)-BINOL/Ti(O-iPr)4 in refluxing dichloromethane (other BINOL/metal catalysts have also been studied).

参考文献 中间体
【1】 Zimmer, R.; et al.; Enantioselective synthesis of (S)- and (R)-6-hydroxy-8-nonene-carboxylates by asymmetric catalysis: A formal synthesis of (R)-alpha-lipoic acid and its (S)-antipode. Tetrahedron Asymmetry 2000, 11, 4, 879.
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) 58067 Methyl 6-oxohexanoate C7H12O3 详情 详情
(II) 40599 Allyltributyltin; Tributyl-2-propenylstannane 24850-33-7 C15H32Sn 详情 详情
(III) 57996 methyl (6S)-6-hydroxy-8-nonenoate C10H18O3 详情 详情

合成路线20

1,6-Hexanediol (I) was protected as the mono-tetrahydropyranyl ether (II), and the free hydroxyl group was subsequently oxidized to aldehyde (III) under Swern conditions. Reformatskii reaction of aldehyde (III) with the organozinc reagent generated from ethyl bromoacetate yielded the racemic hydroxy ester (IV). The requisite (S)-enantiomer (VI) was obtained via oxidation of (IV) to oxo ester (V) using pyridinium chlorochromate, and then asymmetric hydrogenation in the presence of (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl dichlororuthenium complex. Oxo ester (V) was also prepared by SnCl2-catalyzed insertion of ethyl diazoacetate into aldehyde (III). The chiral hydroxy ester (VI) was then reduced to diol (VII) by means of NaBH4-CuSO4. After conversion of (VII) to the corresponding dimesylate (VIII), removal of the tetrahydropyranyl protecting group under acidic conditions gave alcohol (IX). This was sequentially oxidized with PCC to aldehyde, and then with Ag2O to furnish the target dimesylate acid intermediate (X).

参考文献 中间体
【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
(I) 58068 1,6 Hexanediol; 1,6-Dihydroxyhexane; Hexamethylene glycol 629-11-8 C6H14O2 详情 详情
(II) 58069 6-(tetrahydro-2H-pyran-2-yloxy)-1-hexanol C11H22O3 详情 详情
(III) 58070 6-(tetrahydro-2H-pyran-2-yloxy)hexanal C11H20O3 详情 详情
(IV) 58071 ethyl 3-hydroxy-8-(tetrahydro-2H-pyran-2-yloxy)octanoate C15H28O5 详情 详情
(V) 58072 ethyl 3-oxo-8-(tetrahydro-2H-pyran-2-yloxy)octanoate C15H26O5 详情 详情
(VI) 58073 ethyl (3S)-3-hydroxy-8-(tetrahydro-2H-pyran-2-yloxy)octanoate C15H28O5 详情 详情
(VII) 58074 (3S)-8-(tetrahydro-2H-pyran-2-yloxy)-1,3-octanediol C13H26O4 详情 详情
(VIII) 58075 (3S)-3-[(methylsulfonyl)oxy]-8-(tetrahydro-2H-pyran-2-yloxy)octyl methanesulfonate C15H30O8S2 详情 详情
(IX) 58076 (3S)-8-hydroxy-3-[(methylsulfonyl)oxy]octyl methanesulfonate C10H22O7S2 详情 详情
(X) 57949 (6S)-6,8-bis[(methylsulfonyl)oxy]octanoic acid C10H20O8S2 详情 详情
Extended Information