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【结 构 式】

【分子编号】14183

【品名】ethyl (E,5R,6R)-5,6-bis[[tert-butyl(dimethyl)silyl]oxy]-2-heptenoate

【CA登记号】

【 分 子 式 】C21H44O4Si2

【 分 子 量 】416.74896

【元素组成】C 60.52% H 10.64% O 15.36% Si 13.48%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(VI)

An asymmetric synthesis of the C(17)-C(27)-segment of bryostatin 1 has been described: The asymmetric dihydroxylation of 1,4(E)-hexadiene (I) with AD-mix-beta in tert-butanol gives the diol (II), which is protected with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole in DMF, yielding the bis(silyl) ether (III). The oxidation of (III) with OsO4 and NaIO4 affords the aldehyde (IV), which is condensed with triphenylphosphoranylideneacetic acid ethyl ester (V) in dichloromethane to give 5(R),6(R)-bis(tert-butyldimethylsilyloxy)-2(E)-heptenoic acid ethyl ester (VI). The reduction of (VI) with dibutylaluminum hydride (DIBAL-H) yields the primary alcohol (VII), which is epoxidized with (-)-DET, Ti(OPr)4 and tert-butyl peroxide in dichloromethane to the epoxy-alcohol (VIII). The reductive opening of the epoxide ring of (VIII) with REDAL affords the diol (IX), which by reaction with 4-methoxybenzaldehyde dimethylacetal [PMB(OMe)2] and PPTS in DMF is converted to the acetal (X). The reductive cleavage of (X) with DIBAL-H in dichloromethane affords 5(R),6(R)-bis(tert-butyldimethylsilyloxy)-3(S)-(4-methoxybenzyloxy)-1-h eptanol (XI), which is oxidized with oxalyl chloride to the corresponding aldehyde (XII). The condensation of (XII) with phosphorane (V) in dichloromethane gives 7(R),8(R)-bis(tert-butyldimethylsilyloxy)-5(S)-(4-methoxybenzyloxy)-2(E)-nonenoic acid ethyl ester (XIII), which is asymmetrically dihydroxylated with AD-mix-beta as before to the dihydroxy ester (XIV). The protection of (XIV) by reaction with 2,2-dimethoxypropane and PPTS yields the isopropylidene ketal (XV), which is submitted to a Claisen condensation with the lithium enolate of methyl isobutyrate, affording the keto ester (XVI). Selective deprotection of (XVI) with HF.pyridine affords the diol (XVII), which is acylated with pivaloyl chloride (Pv-Cl) and pyridine in dichloromethane, giving the bispivaloyloxy derivative (XVIII). A new selective deprotection of (XVIII) with DDQ in dichloromethane yields the hydroxy ester (XIX), which is submitted to cyclization with Amberlyst-15 H+ and acetyl chloride in methanol to afford the perhydrofuropyran derivative (XX). The oxidation of the hydroxy group of (XX) with RuCl3 and NaIO4 in acetonitrile/CCl4 gives the corresponding ketonic compound (XXI), which is finally submitted to a condensation with triphenylphosphoranylideneacetic acid methyl ester in dichloromethane to afford 2(E)-[5(S)-[2(R),3(R)-bis(pivaloyloxy)butyl]-3a(S)-methoxy-2,2-dimethyl-7a(S)-perhydrofuro[3,2-a]pyran-7-ylidene]acetic acid methyl ester (XXII), which includes the C(17)-C(27)-fragment of bryostatin 1 with the correct stereochemistry.

1 Manaviazar, S.; Lennon, J.A.; Javaid, M.H.; Hobbs, C.J.; Hale, K.J.; Asymmetric synthesis of the C17-C27 segment of the antineoplastic macrolide bryostatin 1. Tetrahedron Lett 1995, 36, 8, 1359.
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) 14178 (4E)-1,4-Hexadiene; 1,4-Hexadiene 592-45-0 C6H10 详情 详情
(II) 14179 (2R,3R)-5-Hexene-2,3-diol C6H12O2 详情 详情
(III) 14180 tert-Butyl(dimethyl)silyl (1R)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-butenyl ether; (5R,6R)-5-Allyl-2,2,3,3,6,8,8,9,9-nonamethyl-4,7-dioxa-3,8-disiladecane C18H40O2Si2 详情 详情
(IV) 14181 (3R,4R)-3,4-Bis[[tert-butyl(dimethyl)silyl]oxy]pentanal C17H38O3Si2 详情 详情
(V) 14182 ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane 1099-45-2 C22H21O2P 详情 详情
(VI) 14183 ethyl (E,5R,6R)-5,6-bis[[tert-butyl(dimethyl)silyl]oxy]-2-heptenoate C21H44O4Si2 详情 详情
(VII) 14184 (E,5R,6R)-5,6-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-hepten-1-ol C19H42O3Si2 详情 详情
(VIII) 14185 [(2R,3R)-3-((2R,3R)-2,3-Bis[[tert-butyl(dimethyl)silyl]oxy]butyl)oxiranyl]methanol C19H42O4Si2 详情 详情
(IX) 14186 (3S,5R,6R)-5,6-Bis[[tert-butyl(dimethyl)silyl]oxy]-1,3-heptanediol C19H44O4Si2 详情 详情
(X) 14187 (5R,6R)-5-[[(4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]methyl]-2,2,3,3,6,8,8,9,9-nonamethyl-4,7-dioxa-3,8-disiladecane; 4-[(4S)-4-((2R,3R)-2,3-Bis[[tert-butyl(dimethyl)silyl]oxy]butyl)-1,3-dioxan-2-yl]phenyl methyl ether C27H50O5Si2 详情 详情
(XI) 14188 (3S,5R,6R)-5,6-Bis[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]-1-heptanol C27H52O5Si2 详情 详情
(XII) 14189 (3R,5R,6R)-5,6-Bis[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]heptanal C27H50O5Si2 详情 详情
(XIII) 14190 ethyl (E,5S,7R,8R)-7,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5-[(4-methoxybenzyl)oxy]-2-nonenoate C31H56O6Si2 详情 详情
(XIV) 14191 ethyl (2S,3R,5S,7R,8R)-7,8-bis[[tert-butyl(dimethyl)silyl]oxy]-2,3-dihydroxy-5-[(4-methoxybenzyl)oxy]nonanoate C31H58O8Si2 详情 详情
(XV) 14192 ethyl (4S,5R)-5-[(2S,4R,5R)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-[(4-methoxybenzyl)oxy]hexyl]-2,2-dimethyl-1,3-dioxolane-4-carboxylate C34H62O8Si2 详情 详情
(XVI) 14193 methyl 3-((4S,5R)-5-[(2S,4R,5R)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-[(4-methoxybenzyl)oxy]hexyl]-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-3-oxopropanoate C37H66O9Si2 详情 详情
(XVII) 14194 methyl 3-((4S,5R)-5-[(2R,4R,5R)-4,5-dihydroxy-2-[(4-methoxybenzyl)oxy]hexyl]-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-3-oxopropanoate C25H38O9 详情 详情
(XVIII) 14195 methyl 3-((4S,5R)-5-[(2S,4R,5R)-4,5-bis[(2,2-dimethylpropanoyl)oxy]-2-[(4-methoxybenzyl)oxy]hexyl]-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-3-oxopropanoate C35H54O11 详情 详情
(XIX) 14196 methyl 3-((4S,5R)-5-[(2S,4R,5R)-4,5-bis[(2,2-dimethylpropanoyl)oxy]-2-hydroxyhexyl]-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-3-oxopropanoate C27H46O10 详情 详情
(XX) 14197 (1R,2R)-3-[(3aS,5S,7R,7aS)-7-hydroxy-3a-methoxy-3,3-dimethyl-2-oxohexahydro-2H-furo[3,2-b]pyran-5-yl]-2-[(2,2-dimethylpropanoyl)oxy]-1-methylpropyl pivalate C24H40O9 详情 详情
(XXI) 14198 (1R,2R)-3-[(3aS,5R,7aS)-3a-methoxy-3,3-dimethyl-2,7-dioxohexahydro-2H-furo[3,2-b]pyran-5-yl]-2-[(2,2-dimethylpropanoyl)oxy]-1-methylpropyl pivalate C24H38O9 详情 详情
(XXII) 14199 (1R,2R)-3-[(3aS,5S,7aS)-3a-methoxy-7-[(E)-2-methoxy-2-oxoethylidene]-3,3-dimethyl-2-oxohexahydro-2H-furo[3,2-b]pyran-5-yl]-2-[(2,2-dimethylpropanoyl)oxy]-1-methylpropyl pivalate C27H42O10 详情 详情
Extended Information