4-((2R,6R)-6-{(2S,6S,7E,10S,11S,12E)-10-hydroxy-11-[(4-methoxybenzyl)oxy]-6-(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butynoic acid -Drug Synthesis Database

【结构式】

【分子编号】63149

【品名】4-((2R,6R)-6-{(2S,6S,7E,10S,11S,12E)-10-hydroxy-11-[(4-methoxybenzyl)oxy]-6-(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butynoic acid

【CA登记号】

【分子式】C₄₀H₅₄O₉

【分子量】678.86336

【元素组成】C 70.77% H 8.02% O 21.21%

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：(LV)

The condensation of carbaldehyde (XLVII) with the intermediate Pmb-protected phenyl sulfone (XXIII) by means of BuLi, Ac2O and Na/Hg gives the linear adduct (XLVIII), which is protected at its free OH group by means of DHP and PPTS, and selectively deprotected with TBAF yielding the primary alcohol (XLIX). The oxidation of (XLIX) with DMP affords the acetaldehyde derivative (L), which is condensed with CBr4 and PPh3 to provide the dibromovinyl derivative (LI). The condensation of (LI) with methyl chloroformate (LII) by means of BuLi gives the acetylenic ester (LIII), which is treated with CSA to eliminate the THP protecting group and yield the hydroxy ester (LIV). The hydrolysis of the ester (LIV) with LiOH in THF/water affords the hydroxyacid (LV).

参考文献中间体

合成目标

【1】 Ghosh, A.K.; Wang, Y.; Kim, J.T.; Total synthesis of microtubule-stabilizing agent (-)-laulimalide. J Org Chem 2001, 66, 26, 8973.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXIII)	63121	(3S,4S,5E)-4-[(4-methoxybenzyl)oxy]-6-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1-(phenylsulfonyl)-5-hexen-3-ol		C₂₆H₃₂O₆S	详情	详情
(XLVII)	63142	(2S)-4-{(2S)-3-[(2R,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-2-(methoxymethoxy)-4-pentenal		C₂₄H₄₄O₅Si	详情	详情
(XLVIII)	63143	(1E,3S,4S,6E,8S)-10-{(2S)-3-[(2R,6R)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-3-[(4-methoxybenzyl)oxy]-8-(methoxymethoxy)-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1,6,10-undecatrien-4-ol		C₄₄H₇₀O₈Si	详情	详情
(XLIX)	63144	2-{(2R,6R)-6-[(2S,6S,7E,10S,11S,12E)-11-[(4-methoxybenzyl)oxy]-6-(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-10-(tetrahydro-2H-pyran-2-yloxy)-7,12-tridecadienyl]-5,6-dihydro-2H-pyran-2-yl}-1-ethanol		C₄₃H₆₄O₉	详情	详情
(L)	63145	2-{(2R,6R)-6-[(2S,6S,7E,10S,11S,12E)-11-[(4-methoxybenzyl)oxy]-6-(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-10-(tetrahydro-2H-pyran-2-yloxy)-7,12-tridecadienyl]-5,6-dihydro-2H-pyran-2-yl}acetaldehyde		C₄₃H₆₂O₉	详情	详情
(LI)	63146	(1S,3E,5S)-7-{(2S)-3-[(2R,6R)-6-(3,3-dibromo-2-propenyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-1-{(1S,2E)-1-[(4-methoxybenzyl)oxy]-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-5-(methoxymethoxy)-3,7-octadienyl tetrahydro-2H-pyran-2-yl ether 2-{[(1S,3E,5S)-7-{(2S)-3-[(2R,6R)-6-(3,3-dibromo-2-propenyl)-3,6-dihydro-2H-pyran-2-yl]-2-methylpropyl}-1-{(1S,2E)-1-[(4-methoxybenzyl)oxy]-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-5-(methoxymethoxy)-3,7-octadienyl]oxy}tetrahydro-2H-pyran		C₄₄H₆₂Br₂O₈	详情	详情
(LII)	16993	methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate	79-22-1	C₂H₃ClO₂	详情	详情
(LIII)	63147	methyl 4-{(2R,6R)-6-[(2S,6S,7E,10S,11S,12E)-11-[(4-methoxybenzyl)oxy]-6-(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-10-(tetrahydro-2H-pyran-2-yloxy)-7,12-tridecadienyl]-5,6-dihydro-2H-pyran-2-yl}-2-butynoate		C₄₆H₆₄O₁₀	详情	详情
(LIV)	63148	methyl 4-((2R,6R)-6-{(2S,6S,7E,10S,11S,12E)-10-hydroxy-11-[(4-methoxybenzyl)oxy]-6-(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butynoate		C₄₁H₅₆O₉	详情	详情
(LV)	63149	4-((2R,6R)-6-{(2S,6S,7E,10S,11S,12E)-10-hydroxy-11-[(4-methoxybenzyl)oxy]-6-(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butynoic acid		C₄₀H₅₄O₉	详情	详情

合成路线2

该中间体在本合成路线中的序号：(LV)

The cyclization of the hydroxyacid (LV) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF/benzene gives the acetylenic macrolactone (LVI), which is reduced with Lindlar catalyst and 1-hexene in ethyl acetate to yield the cis-macrolactone (LVII). The Mom-protecting group of (LVII) is selectively removed by means of PPTS in tert-butanol to afford the allylic alcohol (LVIII), which is submitted to a Sharpless epoxidation with t-BuOOH, (+)-DET and Ti(OiPr)4 in dichloromethane providing the epoxide (LIX). Finally, the Pmb-protecting group of (LIX) is removed by means of DDQ in dichloromethane to furnish the target Laulimalide.

参考文献中间体

合成目标

【1】 Ghosh, A.K.; Wang, Y.; Kim, J.T.; Total synthesis of microtubule-stabilizing agent (-)-laulimalide. J Org Chem 2001, 66, 26, 8973.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(LV)	63149	4-((2R,6R)-6-{(2S,6S,7E,10S,11S,12E)-10-hydroxy-11-[(4-methoxybenzyl)oxy]-6-(methoxymethoxy)-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-methylene-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butynoic acid	C₄₀H₅₄O₉	详情	详情
(LVI)	63150	15-methyl-7-[3-(4-methyl-3,6-dihydro-2H-pyran-2-yl)-1-({[4-(methyloxy)phenyl]methyl}oxy)-2-propenyl]-13-methylidene-11-{[(methyloxy)methyl]oxy}-6,21-dioxabicyclo[15.3.1]henicosa-9,19-dien-3-yn-5-one	C₄₀H₅₂O₈	详情	详情
(LVII)	63151	15-methyl-7-[3-(4-methyl-3,6-dihydro-2H-pyran-2-yl)-1-({[4-(methyloxy)phenyl]methyl}oxy)-2-propenyl]-13-methylidene-11-{[(methyloxy)methyl]oxy}-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-trien-5-one	C₄₀H₅₄O₈	详情	详情
(LVIII)	63152	11-hydroxy-15-methyl-7-[3-(4-methyl-3,6-dihydro-2H-pyran-2-yl)-1-({[4-(methyloxy)phenyl]methyl}oxy)-2-propenyl]-13-methylidene-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-trien-5-one	C₃₈H₅₀O₇	详情	详情
(LIX)	63153	7-hydroxy-3-methyl-12-[3-(4-methyl-3,6-dihydro-2H-pyran-2-yl)-1-({[4-(methyloxy)phenyl]methyl}oxy)-2-propenyl]-5-methylidene-9,13,22-trioxatricyclo[16.3.1.0~8,10~]docosa-15,19-dien-14-one	C₃₈H₅₀O₈	详情	详情

Extended Information