(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 -Drug Synthesis Database

【结构式】

【分子编号】64650

【品名】(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

【CA登记号】

【分子式】C₅₅H₇₈O₁₂SSi

【分子量】991.36862

【元素组成】C 66.64% H 7.93% O 19.37% S 3.23% Si 2.83%

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：(LXIII)

Spiranic phenylsulfone intermediate (LXIII). The cyclization of the dithiane derivative (LIII) by means of HCL and Hg(ClO4)2/CaCO3 in acetonitrile/water gives a mixture of the desired spiroketal compound (LV) along with its isomer (LIV) that can be converted to (LV) by treatment with HClO4. The reaction of (LV) with Piv-Cl and TEA, followed by silylation with Tbdms-Cl and imidazole allows the selective silylation of the secondary OH group yielding (LVI). The cleavage of the Piv group of (LVI) by means of DIBAL in dichloromethane, followed by treatment with I2, PPh3 and imidazole in benzene affords the iodomethyl compound (LVII). The condensation of (LVII) with the dithiane intermediate (LII) by means of BuLi in THF/HMPA provides compound (LVIII), which is treated with Hg(ClO4)2 and CaCO3 and reduced with NaBH4 to cleave the dithiane auxiliary and yield alcohol (LIX). The protection of the OH group of (LIX) with Bom-Cl and DIEA affords compound (LX), which is reduced with DIBAL to cleave the cyclic ketal group and provide the primary alcohol (LXI). The reaction of (LXI) with I2, PPh3 and imidazole in benzene/acetonitrile gives the iodo derivative (LXII), which is finally treated with sodium phenylsulfinate in hot DMF to yield the desired spiranic phenylsulfone derivative (LXIII).

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
(LII)	64639	(4S,5R)-2-(3,4-dimethylphenyl)-4-[(1S)-1-(1,3-dithian-2-yl)ethyl]-5-methyl-1,3-dioxane	C₁₉H₂₈O₂S₂	详情	详情
(LIII)	64640	(5R,7S)-5-[(benzyloxy)methyl]-7-[(2-{(2S)-3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-methoxypropyl}-1,3-dithian-2-yl)methyl]-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane; benzyl (2R,4S)-2,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(2-{(2S)-3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-methoxypropyl}-1,3-dithian-2-yl)pentyl ether	C₃₇H₆₈O₆S₂Si₂	详情	详情
(LIV)	64641	(2R,4S,6R,8S,10S)-2-[(benzyloxy)methyl]-8-(hydroxymethyl)-10-methoxy-1,7-dioxaspiro[5.5]undecan-4-ol	C₁₉H₂₈O₆	详情	详情
(LV)	64642	(2R,4S,6S,8S,10S)-2-[(benzyloxy)methyl]-8-(hydroxymethyl)-10-methoxy-1,7-dioxaspiro[5.5]undecan-4-ol	C₁₉H₂₈O₆	详情	详情
(LVI)	64643	((2S,4S,6S,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)methyl pivalate	C₃₀H₅₀O₇Si	详情	详情
(LVII)	64644	benzyl [(2R,4S,6S,8S,10S)-4-{[tert-butyl(dimethyl)silyl]oxy}-8-(iodomethyl)-10-methoxy-1,7-dioxaspiro[5.5]undec-2-yl]methyl ether; {[(2R,4S,6S,8S,10S)-2-[(benzyloxy)methyl]-8-(iodomethyl)-10-methoxy-1,7-dioxaspiro[5.5]undec-4-yl]oxy}(tert-butyl)dimethylsilane	C₂₅H₄₁IO₅Si	详情	详情
(LVIII)	64645	benzyl {(2R,4S,6R,8S,10S)-4-{[tert-butyl(dimethyl)silyl]oxy}-8-[(2-{(1S)-1-[(4S,5R)-2-(3,4-dimethylphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl}-1,3-dithian-2-yl)methyl]-10-methoxy-1,7-dioxaspiro[5.5]undec-2-yl}methyl ether; ({(2R,4S,6R,8S,10S)-2-[(benzyloxy)methyl]-8-[(2-{(1S)-1-[(4S,5R)-2-(3,4-dimethylphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl}-1,3-dithian-2-yl)methyl]-10-methoxy-1,7-dioxaspiro[5.5]undec-4-yl}oxy)(tert-butyl)dimethylsilane	C₄₄H₆₈O₇S₂Si	详情	详情
(LIX)	64646	(2R,3R)-1-((2R,4S,6R,8R,10S)-8-[(benzyloxy)methyl]-10-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)-3-[(4S,5R)-2-(3,4-dimethylphenyl)-5-methyl-1,3-dioxan-4-yl]-2-butanol	C₄₁H₆₄O₈Si	详情	详情
(LX)	64647	({(2R,4S,6R,8S,10S)-8-{(2R,3R)-2-[(benzyloxy)methoxy]-3-[(4S,5R)-2-(3,4-dimethylphenyl)-5-methyl-1,3-dioxan-4-yl]butyl}-2-[(benzyloxy)methyl]-10-methoxy-1,7-dioxaspiro[5.5]undec-4-yl}oxy)(tert-butyl)dimethylsilane; benzyl ((2R,4S,6R,8S,10S)-8-{(2R,3R)-2-[(benzyloxy)methoxy]-3-[(4S,5R)-2-(3,4-dimethylphenyl)-5-methyl-1,3-dioxan-4-yl]butyl}-4-{[tert-butyl(dimethyl)silyl]oxy}-10-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)methyl ether	C₄₉H₇₂O₉Si	详情	详情
(LXI)	64648	(2R,3S,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)-3-[(2,4-dimethoxybenzyl)oxy]-2,4-dimethyl-1-hexanol	C₄₉H₇₄O₁₁Si	详情	详情
(LXII)	64649	({(2R,4S,6R,8S,10S)-8-{(2R,3S,4R,5S)-2-[(benzyloxy)methoxy]-4-[(2,4-dimethoxybenzyl)oxy]-6-iodo-3,5-dimethylhexyl}-2-[(benzyloxy)methyl]-10-methoxy-1,7-dioxaspiro[5.5]undec-4-yl}oxy)(tert-butyl)dimethylsilane; benzyl ((2R,4S,6R,8S,10S)-8-{(2R,3S,4R,5S)-2-[(benzyloxy)methoxy]-4-[(2,4-dimethoxybenzyl)oxy]-6-iodo-3,5-dimethylhexyl}-4-{[tert-butyl(dimethyl)silyl]oxy}-10-methoxy-1,7-dioxaspiro[5.5]undec-2-yl)methyl ether	C₄₉H₇₃IO₁₀Si	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

合成路线2

该中间体在本合成路线中的序号：(LXIII)

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

Extended Information