triisopropylsilyl 2-{(2S,4S,6R,8S,10S)-10-(acetyloxy)-2-{2-[(1R,2S,3R,4R)-2-(acetyloxy)-4-[(benzyloxy)methoxy]-5-((2S,4S,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-1,3-dimethylpentyl]-2-propenyl}-4-methyl-4-[(triethylsilyl)oxy]-1-oxaspiro[5.5]undec-8-yl}acetate -Drug Synthesis Database

【结构式】

【分子编号】64656

【品名】triisopropylsilyl 2-{(2S,4S,6R,8S,10S)-10-(acetyloxy)-2-{2-[(1R,2S,3R,4R)-2-(acetyloxy)-4-[(benzyloxy)methoxy]-5-((2S,4S,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-1,3-dimethylpentyl]-2-propenyl}-4-methyl-4-[(triethylsilyl)oxy]-1-oxaspiro[5.5]undec-8-yl}acetate

【CA登记号】

【分子式】C₇₄H₁₂₄O₁₅Si₃

【分子量】1338.04606

【元素组成】C 66.43% H 9.34% O 17.94% Si 6.3%

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：(LXIX)

Assembly of the target compound. The condensation of the iodomethyl tetrahydropyran intermediate (XLVII) with the spiranic phenylsulfone derivative (LXIII) by means of BuLi in toluene gives the adduct (LXIV), which is desulfurized by methylenation with CH2I2 and i-PrMgCl in THF/HMPA to yield (LXV). The reaction of (LXV) with TBAF, followed by selective resilylation with Tbdms-Cl and imidazole and cleavage of the acetonide group with concomitant spiroketalization by means of HClO4 affords the bis spiroketal compound (LXVI). The cleavage of the benzyl ether group of (LXVI) by means of DDQ, followed by selective acetylation of the secondary OH group provides acetate (LXVII), which is silylated with Tes-OTf and lutidine, and selectively deprotected by means of HF and pyridine to give the primary alcohol (LXVIII). The oxidation of (LXVIII) with DMP and NaClO2, followed by silylation with Tips-Cl and TEA yields the silyl ester (LXIX).

参考文献中间体

合成目标

【1】 Smith, A.B.; et al.; The spongistatins: Architecturally complex natural products - Part one: A formal synthesis of (+)-spongistatin 1 by construction of an advanced ABCD fragment. Angew Chem. Int Ed 2001, 40, 1, 191.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XLVII)	64635	tert-butyl(dimethyl)silyl (2R,4S,6R)-2-{[(4S,6S)-6-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2,2-dimethyl-1,3-dioxan-4-yl]methyl}-6-(iodomethyl)-2-methoxy-4-methyltetrahydro-2H-pyran-4-yl ether; tert-butyl[2-((4S,6S)-6-{[(2R,4S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(iodomethyl)-2-methoxy-4-methyltetrahydro-2H-pyran-2-yl]methyl}-2,2-dimethyl-1,3-dioxan-4-yl)ethoxy]diphenylsilane	C₃₉H₆₃IO₆Si₂	详情	详情
(LXIII)	64650	(2S,3R,4S,5R)-5-[(benzyloxy)methoxy]-6-((2S,4S,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-3-[(2,4-dimethoxybenzyl)oxy]-2,4-dimethylhexyl phenyl sulfone; ({(2R,4S,8S,10S)-8-[(2R,3S,4R,5S)-2-[(benzyloxy)methoxy]-4-[(2,4-dimethoxybenzyl)oxy]-3,5-dimethyl-6-(phenylsulfonyl)hexyl]-2-[(benzyloxy)methyl]-10-methoxy-1,7-dioxaspiro[5.5]undec-4-yl}oxy)(tert-butyl)dimethylsilane	C₅₅H₇₈O₁₂SSi	详情	详情
(LXIV)	64651	(2S,3R,4S,5R)-5-[(benzyloxy)methoxy]-6-((2S,4S,6R,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-1-[((2R,4S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-{[(4S,6S)-6-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2,2-dimethyl-1,3-dioxan-4-yl]methyl}-6-methoxy-4-methyltetrahydro-2H-pyran-2-yl)methyl]-3-[(2,4-dimethoxybenzyl)oxy]-2,4-dimethylhexyl phenyl sulfone; ({(2R,4S,6R,8S,10S)-8-[(2R,3S,4R,5S)-2-[(benzyloxy)methoxy]-7-((2R,4S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-{[(4S,6S)-6-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2,2-dimethyl-1,3-dioxan-4-yl]methyl}-6-methoxy-4-methyltetrahydro-2H-pyran-2-yl)-4-[(2,4-dimethoxybenzyl)oxy]-3,5-dimethyl-6-(phenylsulfonyl)heptyl]-2-[(benzyloxy)methyl]-10-methoxy-1,7-dioxaspiro[5.5]undec-4-yl}oxy)(tert-butyl)dimethylsilane	C₉₄H₁₄₀O₁₈SSi₃	详情	详情
(LXV)	64652	({(2R,4S,8S,10S)-8-{(2R,3S,4S,5R)-2-[(benzyloxy)methoxy]-6-[((2S,4S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-{[(4S,6S)-6-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2,2-dimethyl-1,3-dioxan-4-yl]methyl}-6-methoxy-4-methyltetrahydro-2H-pyran-2-yl)methyl]-4-[(2,4-dimethoxybenzyl)oxy]-3,5-dimethyl-6-heptenyl}-2-[(benzyloxy)methyl]-10-methoxy-1,7-dioxaspiro[5.5]undec-4-yl}oxy)(tert-butyl)dimethylsilane; benzyl ((2R,4S,8S,10S)-8-{(2R,3S,4S,5R)-2-[(benzyloxy)methoxy]-6-[((2S,4S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-{[(4S,6S)-6-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2,2-dimethyl-1,3-dioxan-4-yl]methyl}-6-methoxy-4-methyltetrahydro-2H-pyran-2-yl)methyl]-4-[(2,4-dimethoxybenzyl)oxy]-3,5-dimethyl-6-heptenyl}-4-{[tert-butyl(dimethyl)silyl]oxy}-10-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)methyl ether	C₈₉H₁₃₆O₁₆Si₃	详情	详情
(LXVI)	64653	(2S,4S,6R,8S,10S)-2-(2-{(1R,2S,3S,4R)-4-[(benzyloxy)methoxy]-5-((2S,4S,6S,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-2-[(2,4-dimethoxybenzyl)oxy]-1,3-dimethylpentyl}-2-propenyl)-10-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-methyl-1-oxaspiro[5.5]undecane-4,8-diol	C₇₀H₁₁₂O₁₄Si₂	详情	详情
(LXVII)	64654	(2S,4S,6R,8S,10S)-2-{2-[(1R,2S,3R,4R)-2-(acetyloxy)-4-[(benzyloxy)methoxy]-5-((2S,4S,6S,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-1,3-dimethylpentyl]-2-propenyl}-10-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-hydroxy-4-methyl-1-oxaspiro[5.5]undec-8-yl acetate	C₆₅H₁₀₆O₁₄Si₂	详情	详情
(LXVIII)	64655	(2S,4S,6R,8S,10S)-2-{2-[(1R,2S,3R,4R)-2-(acetyloxy)-4-[(benzyloxy)methoxy]-5-((2S,4S,6S,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-1,3-dimethylpentyl]-2-propenyl}-10-(2-hydroxyethyl)-4-methyl-4-[(triethylsilyl)oxy]-1-oxaspiro[5.5]undec-8-yl acetate	C₆₅H₁₀₆O₁₄Si₂	详情	详情
(LXIX)	64656	triisopropylsilyl 2-{(2S,4S,6R,8S,10S)-10-(acetyloxy)-2-{2-[(1R,2S,3R,4R)-2-(acetyloxy)-4-[(benzyloxy)methoxy]-5-((2S,4S,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-1,3-dimethylpentyl]-2-propenyl}-4-methyl-4-[(triethylsilyl)oxy]-1-oxaspiro[5.5]undec-8-yl}acetate	C₇₄H₁₂₄O₁₅Si₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(LXIX)

The cleavage of the Bom and benzyl protecting groups of (LXIX) by means of 1-methyl-1,4-cyclohexadiene and Pd(OH)2/C in ethanol, followed by oxidation with DMP gives the ketonic carbaldehyde compound (LXX) (4), which is condensed with the advanced intermediate phosphonium salt (XLI) by means of NaHMDS in toluene to yield the adduct (LXXI). The selective deprotection of the Tms silyl ester groups of (LXXI) with KF in methanol affords the dihydroxyacid (LXXII), which is submitted to macrolactonization by means of 2,4,6-trichlorobenzoyl chloride, DIEA and DMAP in toluene to provide the macrolactone (LXXIII). The fully desilylation of (LXXIII) by means of HF in acetonitrile/water gives rise to a 1:3 mixture of spongistatin 2 and its epimer (LXXIV) with the unnatural configuration being predominant. Perchloric acid mediated epimerization of (LXXIV) in the presence of calcium perchlorate leads to a 3.9-2.3:1 mixture (with the natural configuration being predominant), along with some degradation products (2).

参考文献中间体

合成目标

【2】 Smith, A.B. III; Lin, Q.; Doughty, V.A.; Zhuang, L.; McBriar, M.D.; Kerns, J.K.; Brook, C.S.; Murase, N.; Nakayama, K.; The spongistatins: Architecturally complex natural products - Part two: Synthesis of the C(29-51) subunit, fragment assembly, and final elaboration to (+)-spongistatin 2. Angew Chem. Int Ed 2001, 40, 1, 196.
【1】 Smith, A.B.; et al.; The spongistatins: Architecturally complex natural products - Part one: A formal synthesis of (+)-spongistatin 1 by construction of an advanced ABCD fragment. Angew Chem. Int Ed 2001, 40, 1, 191.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XLI)	64629	[4-((2R,3S,4S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-{(S)-{(2R,3S,4R,5R,6R)-6-((4S,5E)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-methylene-5,7-octadienyl)-3-methyl-4,5-bis[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}[(triethylsilyl)oxy]methyl}-6-methoxy-3-methyltetrahydro-2H-pyran-2-yl)butyl](triphenyl)phosphonium iodide	C₆₉H₁₁₈IO₈PSi₅	详情	详情
(LXIX)	64656	triisopropylsilyl 2-{(2S,4S,6R,8S,10S)-10-(acetyloxy)-2-{2-[(1R,2S,3R,4R)-2-(acetyloxy)-4-[(benzyloxy)methoxy]-5-((2S,4S,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-1,3-dimethylpentyl]-2-propenyl}-4-methyl-4-[(triethylsilyl)oxy]-1-oxaspiro[5.5]undec-8-yl}acetate	C₇₄H₁₂₄O₁₅Si₃	详情	详情
(LXX)	64657	triisopropylsilyl 2-{(2S,4S,6R,8S,10S)-10-(acetyloxy)-2-{2-[(1R,2S,3S)-2-(acetyloxy)-5-((2S,4S,6R,8R,10S)-10-{[tert-butyl(dimethyl)silyl]oxy}-8-formyl-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-1,3-dimethyl-4-oxopentyl]-2-propenyl}-4-methyl-4-[(triethylsilyl)oxy]-1-oxaspiro[5.5]undec-8-yl}acetate	C₅₉H₁₀₆O₁₄Si₃	详情	详情
(LXXI)	64658		C₁₁₀H₂₀₈O₂₁Si₈	详情	详情
(LXXII)	64659		C₉₅H₁₇₂O₂₁Si₅	详情	详情
(LXXIII)	64660	(1R,3S,5S,6R,9R,10R,11R,13R,14S,15R,17S,18S,19R,25R,27S,29S,31S,33S,36S,37S,38R,41S,43S,49S)-3,37-bis(acetyloxy)-17,27-bis{[tert-butyl(dimethyl)silyl]oxy}-11-((4S,5E)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-methylene-5,7-octadienyl)-10-hydroxy-15,31-dimethoxy-18,36,38,43,49-pentamethyl-39-methylene-7,35-dioxo-14,43-bis[(triethylsilyl)oxy]-8,12,45,46,47,48-hexaoxaheptacyclo[39.3.1.1~1,5~.1~9,13~.1~15,19~.1~25,29~.1~29,33~]	C₉₆H₁₇₀O₂₂Si₅	详情	详情
(LXXIV)	64661	(1R,3S,5S,6R,9R,10R,11R,13R,14S,15R,17S,18R,19R,25R,27S,29S,31S,33S,36S,37S,38R,41S,43S,49S)-3,37-bis(acetyloxy)-10,14,17,27,43-pentahydroxy-11-[(4S,5E)-4-hydroxy-2-methylene-5,7-octadienyl]-15,31-dimethoxy-18,36,38,43,49-pentamethyl-39-methylene-7,35-dioxo-8,12,45,46,47,48-hexaoxaheptacyclo[39.3.1.1~1,5~.1~9,13~.1~15,19~.1~25,29~.1~29,33~]	C₆₆H₁₀₀O₂₂	详情	详情

Extended Information