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【结 构 式】

【分子编号】42620

【品名】(7S,8R)-8-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5,7-dimethyl-3,4,7,8-tetrahydro-2H-oxocin-2-one

【CA登记号】

【 分 子 式 】C20H28O4

【 分 子 量 】332.43992

【元素组成】C 72.26% H 8.49% O 19.25%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(VIII)

The intermediate (XI) has been obtained as follows: The condensation of the chiral ketone (I) with unsaturated aldehyde (II) by means of chlorodicyclohexylborane (DCHBCl) gives the chiral heptenone (III), which is esterified with propanal and SmI3, yielding the ester (IV). The ketalization of (IV) with 2-(phenylselanyl)acetaldehyde diethyl acetal (V) by means of pyridinium p-toluenesulfonate (PPTS) affords the cyclic ketal (VI), which is oxidized with NaIO4 and condensed with the silylated enol ether (VII), providing the lactone (VIII). Methanolysis of the lactone (VII) with MeONa and silylation of the hydroxyester gives methyl ester (IX), which is hydrolyzed with KOH and reesterified with 2,6-dimethylphenol (X) and DCC, yielding the desired intermediate, the aryl ester (XI).

1 Paterson, I.; et al.; Total synthesis of the antimicrotubule agent (+)-discodermolide using boron-mediated aldol reactions of chiral ketones. Angew Chem. Int Ed Engl 2000, 39, 2, 377.
2 Paterson, I.; Florence, G.J.; Synthesis of (+)-discodermolide and analogues by control of asymmetric induction in aldol reactions of gamma-chiral (Z)-enals. Tetrahedron Lett 2000, 41, 35, 6935.
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) 42614 (2S)-1-[(4-methoxybenzyl)oxy]-2-methyl-3-pentanone C14H20O3 详情 详情
(II) 11387 2-Methylacrylaldehyde; Methacrylaldehyde 78-85-3 C4H6O 详情 详情
(III) 42615 (2S,4S,5R)-5-hydroxy-1-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-6-hepten-3-one C18H26O4 详情 详情
(IV) 42616 (1R)-1-[(1R,2S,3S)-2-hydroxy-4-[(4-methoxybenzyl)oxy]-1,3-dimethylbutyl]-2-methyl-2-propenyl propionate C21H32O5 详情 详情
(V) 42617 1-[(2,2-diethoxyethyl)selanyl]benzene; 1-ethoxy-2-(phenylselanyl)ethyl ethyl ether C12H18O2Se 详情 详情
(VI) 42618 (4R,5S,6S)-4-isopropenyl-6-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxane; (2S)-2-[(4S,5S,6R)-6-isopropenyl-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxan-4-yl]propyl 4-methoxybenzyl ether C26H34O4Se 详情 详情
(VII) 42619 tert-butyl[(1-methoxyvinyl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl 1-methoxyvinyl ether C9H20O2Si 详情 详情
(VIII) 42620 (7S,8R)-8-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5,7-dimethyl-3,4,7,8-tetrahydro-2H-oxocin-2-one C20H28O4 详情 详情
(IX) 42621 methyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate C27H46O5Si 详情 详情
(X) 37388 2,6-dimethylphenol 576-26-1 C8H10O 详情 详情
(XI) 42622 2,6-dimethylphenyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate C34H52O5Si 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XXXIV)

Synthesis of the target (+)-Discodermolide: The reaction of 3-hydroxy-2(S)-methylpropionic acid methyl ester (I) with p-methoxybenzyl trichloroacetimidate gives the benzyl ether (XXVI), which is condensed with ethylmagnesium bromide in THF to yield the chiral ketone (XXVII). The reaction of (XXVII) with 2-methylpropenal (XXVIII) by means of (c-Hex)2B-Cl and TEA in ethyl ether affords the chiral hydroxyketone (XXIX), which is reduced with SmI2 and propanal to provide the beta-diol monoester (XXX). The methanolysis of (XXX) by means of K2CO3 furnishes the diol (XXXI), which can also be obtained directly by reduction of (XXIX) with Me4NBH(OAc)3 in acetonitrile/AcOH. The reaction of (XXXI) with the diethylacetal (XXXII) and PPTS in refluxing toluene gives the phenylselenoacetal (XXXIII), which is oxidized with NaIO4 and treated with DBU to achieve a Claisen rearrangement and yield the eight member lactone (XXXIV). The hydrolysis of (XXXIV) with KOH in refluxing aqueous methanol affords the hydroxyacid (XXXV), which is esterified with 2,6-dimethylphenol (XXXVI) by means of DCC and DMAP in dichloromethane to provide the phenyl ester (XXXVII). The reaction of (XXXVII) with Tbdms-OTf and lutidine gives the silylated ester (XXXVIII). Alternatively, the methanolysis of the lactone (XXXIV) with NaOMe in methanol gives the hydroxyester (XXXIX), which is treated with Tbdms-OTf as before to yield the silylated ester (XL). The hydrolysis of the ester (XL) with KOH in refluxing aqueous methanol affords the silylated hydroxyacid (XLI), which is esterified with 2,6-dimethylphenol (XXXVI) by means of DCC and DMAP to provide the already reported phenyl ester (XXXVIII).

1 Paterson, I.; Florence, G.J.; Gerlach, K.; Scott, J.P.; Sereinig, N.; A practical synthesis of (+)-discodermolide and analogues: Fragment union by complex aldol reactions. J Am Chem Soc 2001, 123, 39, 9535.
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) 17128 Methyl (2S)-3-hydroxy-2-methylpropanoate 72657-23-9 C5H10O3 详情 详情
(XXVI) 42654 methyl (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanoate C13H18O4 详情 详情
(XXVII) 42614 (2S)-1-[(4-methoxybenzyl)oxy]-2-methyl-3-pentanone C14H20O3 详情 详情
(XXVIII) 11387 2-Methylacrylaldehyde; Methacrylaldehyde 78-85-3 C4H6O 详情 详情
(XXIX) 42615 (2S,4S,5R)-5-hydroxy-1-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-6-hepten-3-one C18H26O4 详情 详情
(XXX) 62842 (1R)-1-{(1R,2S,3S)-2-hydroxy-4-[(4-methoxybenzyl)oxy]-1,3-dimethylbutyl}-2-methyl-2-propenyl butyrate C22H34O5 详情 详情
(XXXI) 62843 (3R,4R,5S,6S)-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-1-heptene-3,5-diol C18H28O4 详情 详情
(XXXII) 62844 1-[(2,2-dipropoxyethyl)selanyl]benzene; 2-(phenylselanyl)-1-propoxyethyl propyl ether C14H22O2Se 详情 详情
(XXXIII) 42618 (4R,5S,6S)-4-isopropenyl-6-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxane; (2S)-2-[(4S,5S,6R)-6-isopropenyl-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxan-4-yl]propyl 4-methoxybenzyl ether C26H34O4Se 详情 详情
(XXXIV) 42620 (7S,8R)-8-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5,7-dimethyl-3,4,7,8-tetrahydro-2H-oxocin-2-one C20H28O4 详情 详情
(XXXV) 62845 (Z,6S,7R,8S)-7-hydroxy-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoic acid C20H30O5 详情 详情
(XXXVI) 37388 2,6-dimethylphenol 576-26-1 C8H10O 详情 详情
(XXXVII) 62847 2,6-dimethylphenyl (Z,6S,7R,8S)-7-hydroxy-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate C28H38O5 详情 详情
(XXXVIII) 42622 2,6-dimethylphenyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate C34H52O5Si 详情 详情
(XXXIX) 62846 methyl (Z,6S,7R,8S)-7-hydroxy-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate C21H32O5 详情 详情
(XL) 42621 methyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate C27H46O5Si 详情 详情
(XLI) 62848 (Z,6S,7R,8S)-7-{[tert-butyl(dimethyl)silyl]oxy}-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoic acid C26H44O5Si 详情 详情
Extended Information