methyl (2R,3S,4R,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-2,4,10,12,14,16,18,20-octamethyl-5-oxo-8,13,21,23-tetracosatetraenoate -Drug Synthesis Database

【结构式】

【分子编号】42651

【品名】methyl (2R,3S,4R,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-2,4,10,12,14,16,18,20-octamethyl-5-oxo-8,13,21,23-tetracosatetraenoate

【CA登记号】

【分子式】C₅₂H₉₉NO₉Si₃

【分子量】966.6159

【元素组成】C 64.61% H 10.32% N 1.45% O 14.9% Si 8.72%

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：(XLII)

The condensation of aldehyde (XLI) with the intermediate ketoester (XXX) by means of chloro-(+)-disopinocampheylborane ((+)-IPCBCl) gives the 5-oxotetracosatetraenoic ester (XLII), which is submitted to reduction of the 5-oxo group with Me3N-BH(OAc)3, yielding a mixture of the 5-hydroxyester (XLIV) and the corresponding lactone (XLIII). Finally, this mixture, without separation of its components, is submitted to desilylation, with simultaneous lactonization, by treatment with HF and pyridine in THF.

参考文献中间体

合成目标

【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	分子式	供应商	用于合成
(XXX)	42640	methyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-oxohexanoate	C₁₅H₃₀O₄Si	详情	详情
(XLI)	42650	(1S,2R,3R,4S,6Z,8S,9S,10S,11Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-13-oxo-6,11-tridecadienyl carbamate	C₃₇H₆₉NO₅Si₂	详情	详情
(XLII)	42651	methyl (2R,3S,4R,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-2,4,10,12,14,16,18,20-octamethyl-5-oxo-8,13,21,23-tetracosatetraenoate	C₅₂H₉₉NO₉Si₃	详情	详情
(XLIII)	42652	(1S,2R,3R,4S,6Z,8S,9S,10S,11Z,13S)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-14-((2S,3S,4S,5R)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-oxotetrahydro-2H-pyran-2-yl)-13-hydroxy-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-6,11-t	C₅₁H₉₇NO₈Si₃	详情	详情
(XLIV)	42653	methyl (2R,3S,4S,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7-dihydroxy-2,4,10,12,14,16,18,20-octamethyl-8,13,21,23-tetracosatetraenoate	C₅₂H₁₀₁NO₉Si₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(LVII)

The reaction of the OH group of (LII) with trichloroacetyl isocyanate and K2CO3 in methanol gives the carbamate (LIII). The reduction of the ester group of (LIII) with DIBAL in dichloromethane yields the primary alcohol (LIV), which is oxidized with DMP to afford the aldehyde (LV). The condensation of (LV) with the boron enolate (LVI), (obtained by reaction of the 5-oxohexanoic ester intermediate (XI) with (c-Hex)2B-Cl), provides the chiral 5-oxotetracosatetraenoic ester (LVII), which is reduced with Me4HBH(OAc)3 in acetonitrile/AcOH to give the dihydroxyester (LVIII). Finally, this compound is lactonized and simultaneously deprotected by means of HF/pyridine in THF or HCl in methanol giving rise to the target (+)-Discodermolide.

参考文献中间体

合成目标

【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
(XI)	42640	methyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-oxohexanoate		C₁₅H₃₀O₄Si	详情	详情
(LII)	42647	methyl (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-5,11-bis[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenoate	n/a	C₃₇H₇₀O₅Si₂	详情	详情
(LIII)	42648	methyl (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-13-[(aminocarbonyl)oxy]-5,11-bis[[tert-butyl(dimethyl)silyl]oxy]-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenoate	n/a	C₃₈H₇₁NO₆Si₂	详情	详情
(LIV)	42649	(1S,2R,3R,4S,6Z,8S,9S,10S,11Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-6,11-tridecadienyl carbamate		C₃₇H₇₁NO₅Si₂	详情	详情
(LV)	42650	(1S,2R,3R,4S,6Z,8S,9S,10S,11Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-13-oxo-6,11-tridecadienyl carbamate		C₃₇H₆₉NO₅Si₂	详情	详情
(LVI)	62851	methyl (2R,3S,4R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(dicyclohexylboryl)oxy]-2,4-dimethyl-5-hexenoate		C₂₇H₅₁BO₄Si	详情	详情
(LVII)	42651	methyl (2R,3S,4R,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-2,4,10,12,14,16,18,20-octamethyl-5-oxo-8,13,21,23-tetracosatetraenoate		C₅₂H₉₉NO₉Si₃	详情	详情
(LVIII)	42653	methyl (2R,3S,4S,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7-dihydroxy-2,4,10,12,14,16,18,20-octamethyl-8,13,21,23-tetracosatetraenoate		C₅₂H₁₀₁NO₉Si₃	详情	详情

Extended Information