methyl (Z)-4-{(2R,6R)-6-[(2R)-2-methyl-4-oxopentyl]-5,6-dihydro-2H-pyran-2-yl}-2-butenoate -Drug Synthesis Database

【结构式】

【分子编号】61169

【品名】methyl (Z)-4-{(2R,6R)-6-[(2R)-2-methyl-4-oxopentyl]-5,6-dihydro-2H-pyran-2-yl}-2-butenoate

【CA登记号】

【分子式】C₁₆H₂₄O₄

【分子量】280.36416

【元素组成】C 68.55% H 8.63% O 22.83%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

The butenoic ester intermediate (VIII) has been obtained as follows: The condensation of the known aldehyde (I) with phosphonate (II) by means of KHMDS in THF gives the unsaturated ester (III), which is selectively hydrolyzed at its benzoate group by means of K2CO3 in methanol to yield the ethanol derivative (IV). The oxidation of (IV) by means of DMP affords the acetaldehyde (V), which is condensed with the phosphorane (VI) by means of DBU and LiCl in acetonitrile to provide the methyl ketone (VII) (1). Finally, this compound is methylated by means of Me2Zn and Ni(acac)2 in ethyl ether to give the target butenoic ester intermediate (VIII)

参考文献中间体

合成目标

【1】 Paterson, I.; et al.; Total synthesis of the microtubule-stabilizing agent (-)-laulimalide. Org Lett 2001, 3, 20, 3149.
【2】 Paterson, I.; et al.; Synthesis of the macrocyclic core of laulimalide. Org Lett 2001, 3, 2, 213.

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)	61164	2-[(2S,6R)-6-(2-oxoethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl benzoate		C₁₆H₁₈O₄	详情	详情
(II)	41856	methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate	88738-78-7	C₇H₉F₆O₅P	详情	详情
(III)	61165	2-{(2S,6R)-6-[(Z)-4-methoxy-4-oxo-2-butenyl]-3,6-dihydro-2H-pyran-2-yl}ethyl benzoate		C₁₉H₂₂O₅	详情	详情
(IV)	61166	methyl (Z)-4-[(2R,6S)-6-(2-hydroxyethyl)-5,6-dihydro-2H-pyran-2-yl]-2-butenoate		C₁₂H₁₈O₄	详情	详情
(V)	59559	Dimethyl acetonylphosphonate; Acetylmethylphosphonic acid dimethyl ester; Dimethyl (2-oxopropyl)phosphonate	4202-14-6	C₅H₁₁O₄P	详情	详情
(VI)	61167	methyl (Z)-4-[(2R,6S)-6-(2-oxoethyl)-5,6-dihydro-2H-pyran-2-yl]-2-butenoate		C₁₂H₁₆O₄	详情	详情
(VII)	61168	methyl (Z)-4-{(2R,6S)-6-[(E)-4-oxo-2-pentenyl]-5,6-dihydro-2H-pyran-2-yl}-2-butenoate		C₁₅H₂₀O₄	详情	详情
(VIII)	61169	methyl (Z)-4-{(2R,6R)-6-[(2R)-2-methyl-4-oxopentyl]-5,6-dihydro-2H-pyran-2-yl}-2-butenoate		C₁₆H₂₄O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Synthesis of the target compound: The condensation of the butenoic ester intermediate (VIII) with the intermediate octadienal derivative (XXXI) by means of (+)-Ipc2BCl , TEA and H2O2 in ethyl ether gives the linear adduct (XXXII), which is silylated with Tbdms-OTf and lutidine to yield the fully protected intermediate (XXXIII). The reduction of the ester group of (XXXIII) with DIBAL gives the alcohol (XXXIV), which is oxidized with DMP and NaClO2 to yield the carboxylic acid (XXXV). The selective deprotection of the Pmb ether of (XXXV) by means of DDQ in dichloromethane affords the hydroxyacid (XXXVI), which is submitted to cyclization by means of DEAD and PPh3 in benzene to provide the macrolactone (XXXVII). The methylenation of the ketonic group of (XXXVII) by reaction with Zn, PbI2, TiCl4 and CH2I2 in THF gives the exomethylene derivative (XXXVIII), which is desilylated by treatment with HF and pyridine in THF to yield the immediate precursor (XXXIX). Finally, this compound is selectively epoxidized by reaction with (+)-DIPT, tBuOOH and Ti(OiPr)4 in dichloromethane to afford the target Laulimalide

参考文献中间体

合成目标

【1】 Paterson, I.; et al.; Total synthesis of the microtubule-stabilizing agent (-)-laulimalide. Org Lett 2001, 3, 20, 3149.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VIII)	61169	methyl (Z)-4-{(2R,6R)-6-[(2R)-2-methyl-4-oxopentyl]-5,6-dihydro-2H-pyran-2-yl}-2-butenoate	C₁₆H₂₄O₄	详情	详情
(XXXI)	61189	(2E,5R,6S,7E)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadienal	C₂₈H₄₂O₅Si	详情	详情
(XXXII)	61190	methyl (Z)-4-((2R,6R)-6-{(2R,7E,10R,11S,12E)-11-{[tert-butyl(dimethyl)silyl]oxy}-6-hydroxy-10-[(4-methoxybenzyl)oxy]-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-oxo-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butenoate	C₄₄H₆₆O₉Si	详情	详情
(XXXIII)	61191	methyl (Z)-4-((2R,6R)-6-{(2R,7E,10R,11S,12E)-6,11-bis{[tert-butyl(dimethyl)silyl]oxy}-10-[(4-methoxybenzyl)oxy]-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-oxo-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butenoate	C₅₀H₈₀O₉Si₂	详情	详情
(XXXIV)	61192	(2R,7E,10R,11S,12E)-6,11-bis{[tert-butyl(dimethyl)silyl]oxy}-1-{(2R,6R)-6-[(Z)-4-hydroxy-2-butenyl]-3,6-dihydro-2H-pyran-2-yl}-10-[(4-methoxybenzyl)oxy]-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-7,12-tridecadien-4-one	C₄₉H₈₀O₈Si₂	详情	详情
(XXXV)	61193	(Z)-4-((2R,6R)-6-{(2R,7E,10R,11S,12E)-6,11-bis{[tert-butyl(dimethyl)silyl]oxy}-10-[(4-methoxybenzyl)oxy]-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-oxo-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butenoic acid	C₄₉H₇₈O₉Si₂	详情	详情
(XXXVI)	61194	(Z)-4-((2R,6R)-6-{(2R,7E,10R,11S,12E)-6,11-bis{[tert-butyl(dimethyl)silyl]oxy}-10-hydroxy-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-oxo-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butenoic acid	C₄₁H₇₀O₈Si₂	详情	详情
(XXXVII)	61195	(1R,7S,11S,15R,17R)-11-{[tert-butyl(dimethyl)silyl]oxy}-7-{(1S,2E)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-15-methyl-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-triene-5,13-dione	C₄₁H₆₈O₇Si₂	详情	详情
(XXXVIII)	61196	(1R,7S,11S,15S,17R)-11-{[tert-butyl(dimethyl)silyl]oxy}-7-{(1S,2E)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-15-methyl-13-methylene-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-trien-5-one	C₄₂H₇₀O₆Si₂	详情	详情
(XXXIX)	61197	(1R,7S,11S,15S,17R)-11-hydroxy-7-{(1S,2E)-1-hydroxy-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-15-methyl-13-methylene-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-trien-5-one	C₃₀H₄₂O₆	详情	详情

Extended Information