21-Hydroxyepothilone D, Desoxyepothilone F, dEpoF, -Drug Synthesis Database

【结构式】

【药物名称】21-Hydroxyepothilone D, Desoxyepothilone F, dEpoF

【化学名称】(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-[2-(hydroxymethyl)-4-thiazolyl]ethenyl]-1-oxacyclohexadec-13-ene-2,6-dione

【CA登记号】252981-50-3

【分子式】C₂₇H₄₁NO₆S

【分子量】507.69492

【开发单位】Sloan-Kettering Institute (Originator)

【药理作用】Oncolytic Drugs, Antimitotic Drugs, Epothilones, Microtubule-Stabilizing Agents

合成路线1 合成路线2 合成路线3

合成路线1

The intermediate iodovinyl compound (XI) has been obtained as follows: The reaction of 2-(hydroxymethyl)thiazole-4-carboxylic acid ethyl ester (I) with Troc-Cl and pyridine in dichloromethane gives the protected compound (II), which is reduced with DIBAL in the same solvent to yield the carbaldehyde (III). The condensation of aldehyde (III) with phosphorane (IV) in refluxing benzene affords the unsaturated aldehyde (V), which is asymmetrically allylated by means of (+)-diisopinocampheyl(allyl)borane in pentane to provide the chiral secondary alcohol (VI). The reaction of (VI) with Tbdms-Cl and lutidine in dichloromethane gives the silyl ether (VII), which is oxidized at the terminal double bond by means of OsO4 and Pb(OAc)4 to yield the aldehyde (VIII). The condensation of (VIII) with phosphorane (IX) and LiOH in THF affords the iodovinyl compound (X), which is finally treated with Troc-Cl and pyridine to provide the desired iodovinyl intermediate (XI).

参考文献中间体

【1】 Zhang, X.-G.; Chappell, M.D.; Lee, C.B.; Kuduk, S.D.; Danishefsky, S.J.; Chou, T.-C.; Wang, Z.-G.; Stachel, S.J.; Total synthesis and antitumor activity of 12,13-dexoxyepothilone F: An unexpected solvolysis problem at C15, mediated by remote substitution at C21. J Org Chem 2000, 65, 20, 6525.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	49350	ethyl 2-(hydroxymethyl)-1,3-thiazole-4-carboxylate	C₇H₉NO₃S	详情	详情
(II)	49351	ethyl 2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazole-4-carboxylate	C₁₀H₁₀Cl₃NO₅S	详情	详情
(III)	49352	(4-formyl-1,3-thiazol-2-yl)methyl 2,2,2-trichloroethyl carbonate	C₈H₆Cl₃NO₄S	详情	详情
(IV)	39940	2-(triphenylphosphoranylidene)propanal	C₂₁H₁₉OP	详情	详情
(V)	49353	[4-[(E)-2-methyl-3-oxo-1-propenyl]-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate	C₁₁H₁₀Cl₃NO₄S	详情	详情
(VI)	49354	[4-[(1E,3S)-3-hydroxy-2-methyl-1,5-hexadienyl]-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate	C₁₄H₁₆Cl₃NO₄S	详情	详情
(VII)	49355	[4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate	C₂₀H₃₀Cl₃NO₄SSi	详情	详情
(VIII)	49356	[4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-5-oxo-1-pentenyl)-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate	C₁₉H₂₈Cl₃NO₅SSi	详情	详情
(IX)	42754	(1-iodoethylidene)(triphenyl)phosphorane	C₂₀H₁₈IP	详情	详情
(X)	49357	[4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-heptadienyl)-1,3-thiazol-2-yl]methanol	C₁₈H₃₀INO₂SSi	详情	详情
(XI)	49358	[4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-heptadienyl)-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate	C₂₁H₃₁Cl₃INO₄SSi	详情	详情

合成路线2

The treatment of diketoester (XII) with trimethylsilyl diazomethane and DIEA gives enol ether (XIII), which is condensed with 2(S)-methyl-4-pentenal (XIV) by means of LDA to yield the aldol condensation product (XV) as the major isomer. The protection of the OH group of (XV) with Troc-Cl and pyridine affords the trichloroethyl carbonate (XVI), whose enol ether group is hydrolyzed with TsOH in acetone to provide the diketoester (XVII). The condensation of (XVII) with iodovinyl intermediate (XI) by means of BBN, (dppf)2PdCl2, AsPh3 and Cs2CO3 in THF/DMF/water gives adduct (XVIII), which is desilylated by means of HCl in methanol to yield the secondary alcohol (XIX). The asymmetric hydrogenation of (XIX) with H2 over a chiral Ru catalyst in acidic methanol affords the secondary diol (XX), which is silylated with Tes-OTf and lutidine to provide the bis-silyl ether (XXI). The selective desilylation of (XXI) with simultaneous hydrolysis of its tert-butyl ester by means of HCl in methanol gives the hydroxyacid (XXII) suitable for cyclization.

参考文献中间体

【1】 Zhang, X.-G.; Chappell, M.D.; Lee, C.B.; Kuduk, S.D.; Danishefsky, S.J.; Chou, T.-C.; Wang, Z.-G.; Stachel, S.J.; Total synthesis and antitumor activity of 12,13-dexoxyepothilone F: An unexpected solvolysis problem at C15, mediated by remote substitution at C21. J Org Chem 2000, 65, 20, 6525.
【2】 Harris, C.R.; et al.; New chemical synthesis of the promising cancer chemotherapeutic agent 12,13-desoxyepothilone B: Discovery of a surprising long-range effect on the diastereoselectivity of an aldol condensation. J Am Chem Soc 1999, 121, 30, 7050.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XI)	49358	[4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-heptadienyl)-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate	C₂₁H₃₁Cl₃INO₄SSi	详情	详情
(XII)	26239	tert-butyl 4,4-dimethyl-3,5-dioxoheptanoate	C₁₃H₂₂O₄	详情	详情
(XIII)	26240	tert-butyl (Z)-3-methoxy-4,4-dimethyl-5-oxo-2-heptenoate	C₁₄H₂₄O₄	详情	详情
(XIV)	26241	(2S)-2-methyl-4-pentenal	C₆H₁₀O	详情	详情
(XV)	26242	tert-butyl (2Z,6R,7S,8S)-7-hydroxy-3-methoxy-4,4,6,8-tetramethyl-5-oxo-2,10-undecadienoate	C₂₀H₃₄O₅	详情	详情
(XVI)	26243	tert-butyl (2Z,6R,7S,8S)-3-methoxy-4,4,6,8-tetramethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-2,10-undecadienoate	C₂₃H₃₅Cl₃O₇	详情	详情
(XVII)	26244	tert-butyl (6R,7S,8S)-4,4,6,8-tetramethyl-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-10-undecenoate	C₂₂H₃₃Cl₃O₇	详情	详情
(XVIII)	49359	tert-butyl (6R,7S,8S,12Z,15S,16E)-15-[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-17-[2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazol-4-yl]-12,16-heptadecadienoate	C₄₃H₆₅Cl₆NO₁₁SSi	详情	详情
(XIX)	49360	tert-butyl (6R,7S,8S,12Z,15S,16E)-15-hydroxy-4,4,6,8,12,16-hexamethyl-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-17-[2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazol-4-yl]-12,16-heptadecadienoate	C₃₇H₅₁Cl₆NO₁₁S	详情	详情
(XX)	49361	tert-butyl (3S,6R,7S,8S,12Z,15S,16E)-3,15-dihydroxy-4,4,6,8,12,16-hexamethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-17-[2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazol-4-yl]-12,16-heptadecadienoate	C₃₇H₅₃Cl₆NO₁₁S	详情	详情
(XXI)	49362	tert-butyl (3S,6R,7S,8S,12Z,15S,16E)-4,4,6,8,12,16-hexamethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-17-[2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazol-4-yl]-3,15-bis[(triethylsilyl)oxy]-12,16-heptadecadienoate	C₄₉H₈₁Cl₆NO₁₁SSi₂	详情	详情
(XXII)	49363	(3S,6R,7S,8S,12Z,15S,16E)-15-hydroxy-4,4,6,8,12,16-hexamethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-17-[2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazol-4-yl]-3-[(triethylsilyl)oxy]-12,16-heptadecadienoic acid	C₃₉H₅₉Cl₆NO₁₁SSi	详情	详情

合成路线3

The macrocyclization of (XXII) under Yamaguchi conditions (trichlorobenzoyl chloride, TEA and DMAP) in toluene gives the macrolactone (XXIII), which is treated with Zn and HOAc in THF or with NiI2/SmI2 in the same solvent to eliminate the two Troc protecting groups to yield the monosilylated intermediate (XXIV). Finally, this compound is desilylated by means of HF and pyridine in THF to afford the target 12,13-desoxyepothilone F.

参考文献中间体

【1】 Zhang, X.-G.; Chappell, M.D.; Lee, C.B.; Kuduk, S.D.; Danishefsky, S.J.; Chou, T.-C.; Wang, Z.-G.; Stachel, S.J.; Total synthesis and antitumor activity of 12,13-dexoxyepothilone F: An unexpected solvolysis problem at C15, mediated by remote substitution at C21. J Org Chem 2000, 65, 20, 6525.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXII)	49363	(3S,6R,7S,8S,12Z,15S,16E)-15-hydroxy-4,4,6,8,12,16-hexamethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-17-[2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazol-4-yl]-3-[(triethylsilyl)oxy]-12,16-heptadecadienoic acid	C₃₉H₅₉Cl₆NO₁₁SSi	详情	详情
(XXIII)	49364	[4-((E)-2-[(2S,9S,10S,11R,14S)-5,9,11,13,13-pentamethyl-12,16-dioxo-10-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-14-[(triethylsilyl)oxy]oxa-4-cyclohexadecen-2-yl]-1-propenyl)-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate	C₃₉H₅₇Cl₆NO₁₀SSi	详情	详情
(XXIV)	49365	(4S,7R,8S,9S,16S)-8-hydroxy-16-[(E)-2-[2-(hydroxymethyl)-1,3-thiazol-4-yl]-1-methylethenyl]-5,5,7,9,13-pentamethyl-4-[(triethylsilyl)oxy]oxa-13-cyclohexadecene-2,6-dione	C₃₃H₅₅NO₆SSi	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)