(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S)-2-hydroxy-3-methyl-6-heptynyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one -Drug Synthesis Database

【结构式】

【分子编号】35886

【品名】(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S)-2-hydroxy-3-methyl-6-heptynyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one

【CA登记号】

【分子式】C₂₂H₃₇NO₄

【分子量】379.54012

【元素组成】C 69.62% H 9.83% N 3.69% O 16.86%

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：(XXIX)

The regiocontrolled condensation of (spirolactam (XVII) with the chiral borane (+)(Z)-crotyl-diisopinocampheylborane (XX) in THF gives the diol (XXI), which is silylated with TBDMS-OTf and lutidine in dichloromethane yielding the bis(silyloxy) compound (XXII). The ozonolysis of the terminal double bond of (XXII) with O3 in dichloromethane affords the aldehyde (XXIII), which is condensed with the silyl aldimine (XXIV) by means of LDA in THF giving the unsaturated aldehyde (XXV). Hydrogenation of the double bond of (XXV) yields aldehyde (XXVI), which is condensed with the diazo phosphonate (XXVII) by means of K2CO3 in methanol providing the terminal acetylenic compound (XXVIII). The reaction of (XXVIII) with TBAF in THF gives the desilylated acetylenic compound (XXIX), which is brominated with NBS and AgNO3 in acetone yielding the omega-bromoacetylenic compound (XXX). Finally, this compound is treated with tributyltin hydride, Pd2(dba)3 and PPh3 in chloroform to afford the desired tributyl stannane intermediate (I).

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; Total synthesis of the novel immunosuppressant Sanglifehrin A. J Am Chem Soc 2000, 122, 16, 3830.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	35874	(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S,6E)-2-hydroxy-3-methyl-7-(tributylstannyl)-6-heptenyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one	C₃₄H₆₅NO₄Sn	详情	详情
(XVII)	32424	2-[(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl]acetaldehyde	C₁₆H₂₇NO₄	详情	详情
(XXI)	35879	(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S)-2-hydroxy-3-methyl-4-pentenyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one	C₂₀H₃₅NO₄	详情	详情
(XXII)	35880	(2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-((2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-pentenyl)-9-ethyl-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one	C₃₂H₆₃NO₄Si₂	详情	详情
(XXIII)	35881	(2R,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-((2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-9-ethyl-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl)-2-methylbutanal	C₃₁H₆₁NO₅Si₂	详情	详情
(XXV)	35882	(E,4S,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-((2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-9-ethyl-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl)-4-methyl-2-hexenal	C₃₃H₆₃NO₅Si₂	详情	详情
(XXVI)	35883	(4S,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-((2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-9-ethyl-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl)-4-methylhexanal	C₃₃H₆₅NO₅Si₂	详情	详情
(XXVII)	35884	diethyl 1-diazo-2-oxopropylphosphonate	C₇H₁₃N₂O₄P	详情	详情
(XXVIII)	35885	(2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-((2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-6-heptynyl)-9-ethyl-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one	C₃₄H₆₅NO₄Si₂	详情	详情
(XXIX)	35886	(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S)-2-hydroxy-3-methyl-6-heptynyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one	C₂₂H₃₇NO₄	详情	详情
(XXX)	32435	(2S,3R,4S,5S,6R,9S,11S)-2-[(2S,3S)-7-bromo-2-hydroxy-3-methyl-6-heptynyl]-9-ethyl-4-hydroxy-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one	C₂₂H₃₆BrNO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(LI)

The elimination of the Pmb protecting group of (L) by means of DDQ in dichloromethane affords compound (LI), which is brominated with NBS and AgNO3 in acetone to provide the bromoacetylene derivative (LII). The reaction of (LII) with tributyltin hydride, Pd2(dba)3 and PPh3 leads to the vinylstannane (LIII), which is condensed with the chiral tetracyclic macrolactone intermediate (XXXVI) by means of PdCl2(CH3CN)2 in DMF to give the cyclic precursor (LIV). Finally, this compound is submitted to an acidic hydrolysis by means of TsOH and BO3H3 in THF to provide the target Sanglifehrin A

参考文献中间体

合成目标

【1】 Duan, M.S.; Paquette, L.A.; Enantioselective total synthesis of the cyclophilin-binding immunosuppressive agent sanglifehrin A. Angew Chem. Int Ed 2001, 40, 19, 3632.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXXVI)	32450	(4R,7S,10S,16S,19S,25S,26R,27R)-10-(3-hydroxybenzyl)-19-[(E)-2-iodo-1-methylethenyl]-7-isopropyl-1,26-dimethyl-18,28,29-trioxa-6,9,12,30-tetraazatetracyclo[23.3.1.1(12,16).0(4,27)]triaconta-21,23-diene-5,8,11,17-tetrone; (4R,7S,10S,16S,19S,25S,26R,27R)-10-(3-hydroxybenzyl)-19-[(E)-2-iodo-1-methylethenyl]-7-isopropyl-1,26-dimethyl-18,28,29-trioxa-6,9,12,30-tetraazatetracyclo[23.3.1.1(12,16).0(4,27)]triaconta-21,23-diene-5,8,11,17-tetrone	C₃₈H₅₁IN₄O₈	详情	详情
(L)	60143	(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-2-[(2S,3S)-2-hydroxy-3-methyl-6-heptynyl]-4-[(4-methoxybenzyl)oxy]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one	C₃₀H₄₅NO₅	详情	详情
(LI)	35886	(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S)-2-hydroxy-3-methyl-6-heptynyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one	C₂₂H₃₇NO₄	详情	详情
(LII)	32435	(2S,3R,4S,5S,6R,9S,11S)-2-[(2S,3S)-7-bromo-2-hydroxy-3-methyl-6-heptynyl]-9-ethyl-4-hydroxy-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one	C₂₂H₃₆BrNO₄	详情	详情
(LIII)	35874	(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S,6E)-2-hydroxy-3-methyl-7-(tributylstannyl)-6-heptenyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one	C₃₄H₆₅NO₄Sn	详情	详情
(LIV)	32452	(4R,7S,10S,16S,19S,25S,26R,27R)-19-{(1E,3E,7S,8S)-9-[(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl]-8-hydroxy-1,7-dimethyl-1,3-nonadienyl}-10-(3-hydroxybenzyl)-7-isopropyl-1,26-dimethyl-18,28,29-trioxa-6,9,12,30-tetraazatetracyclo[23.3.1.1~12,16~.0~4,27~]triaconta-21,23-diene-5,8,11,17-tetrone	C₆₀H₈₉N₅O₁₂	详情	详情

Extended Information