(2R,4R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)tetrahydro-2H-pyran-2-carbaldehyde -Drug Synthesis Database

【结构式】

【分子编号】39419

【品名】(2R,4R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)tetrahydro-2H-pyran-2-carbaldehyde

【CA登记号】

【分子式】C₁₉H₄₀O₄Si₂

【分子量】388.6952

【元素组成】C 58.71% H 10.37% O 16.46% Si 14.45%

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：(XXVIII)

C10-C16 Fragment: The stereocontrolled reduction of ketoester (XIX) with Me4NHB(OAc)3 in acetonitrile/AcOH gives the dihydroxyester (XX), which is dehydrated to the lactone (XXI) with PPTS in refluxing benzene. The protection of (XXI) with triethylsilyl chloride as usual affords the fully silylated lactone (XXII), which is condensed with benzyloxymethyllithium in THF and reduced with BF3/Et2O and triethylsilane giving the benzyloxymethyl derivative (XXIII). The selective deprotection of (XXIII) with BF3/Et2O yields the 4-hydroxy derivative (XXIV), which is desilylated with TBAF in THF to give the diol (XXV). The silylation of (XXV) with TBDMS-OTf and lutidine in dichloromethane yields the fully protected compound (XXVI), which is debenzylated with H2 over Pd/C in acetic acid/ethyl acetate affording the carbinol (XXVII). Finally, this compound is oxidized with oxalyl chloride and triethylamine in DMSO to provide (XXVIII), the desired C10-C16 fragment.

参考文献中间体

合成目标

【1】 Lautens, M.; Prunet, J.A.; Carreira, E.M.; Carter, P.H.; Charette, A.B.; Evans, D.A.; Total synthesis of bryostatin 2. J Am Chem Soc 1999, 121, 33, 7540.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIX)	39410	methyl (5S)-5-hydroxy-3-oxo-6-[(triisopropylsilyl)oxy]hexanoate	C₁₆H₃₂O₅Si	详情	详情
(XX)	39411	methyl (3S,5S)-3,5-dihydroxy-6-[(triisopropylsilyl)oxy]hexanoate	C₁₆H₃₄O₅Si	详情	详情
(XXI)	39412	(4S,6S)-4-hydroxy-6-[[(triisopropylsilyl)oxy]methyl]tetrahydro-2H-pyran-2-one	C₁₅H₃₀O₄Si	详情	详情
(XXII)	39413	(4S,6S)-4-[(triethylsilyl)oxy]-6-[[(triisopropylsilyl)oxy]methyl]tetrahydro-2H-pyran-2-one	C₂₁H₄₄O₄Si₂	详情	详情
(XXIII)	39414	benzyl ((2R,4S,6S)-4-[(triethylsilyl)oxy]-6-[[(triisopropylsilyl)oxy]methyl]tetrahydro-2H-pyran-2-yl)methyl ether; ([(2S,4S,6R)-6-[(benzyloxy)methyl]-4-[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]methoxy)(triisopropyl)silane	C₂₉H₅₄O₄Si₂	详情	详情
(XXIV)	39415	(2R,4S,6S)-2-[(benzyloxy)methyl]-6-[[(triisopropylsilyl)oxy]methyl]tetrahydro-2H-pyran-4-ol	C₂₃H₄₀O₄Si	详情	详情
(XXV)	39416	(2R,4R,6S)-2-[(benzyloxy)methyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-4-ol	C₁₄H₂₀O₄	详情	详情
(XXVI)	39417	[((2S,4S,6R)-6-[(benzyloxy)methyl]-4-[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-2H-pyran-2-yl)methoxy](tert-butyl)dimethylsilane; benzyl [(2R,4S,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)tetrahydro-2H-pyran-2-yl]methyl ether	C₂₆H₄₈O₄Si₂	详情	详情
(XXVII)	39418	[(2R,4S,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)tetrahydro-2H-pyran-2-yl]methanol	C₁₉H₄₂O₄Si₂	详情	详情
(XXVIII)	39419	(2R,4R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)tetrahydro-2H-pyran-2-carbaldehyde	C₁₉H₄₀O₄Si₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXVIII)

Fragment coupling: Coupling of the C10-C16 fragment (XXVIII) with the C17-C27 fragment (XLIII) by means of BuLi, Ac2O and Mg in THF gives (XLVII), which is selectively deprotected with TBAF yielding the carbinol (XLVIII). The reaction of (XLVIII) with triflic anhydride and lutidine in CH2Cl2 affords the triflate (IL), which is coupled with the C1-C9 fragment (XVIII) by means of n-BuLi in THF giving the tricyclic intermediate (L). The opening of the lactol ring of (L) with triethylsilyl chloride and imidazole yields the silylated hydroxyketone (LI), which is treated first with tert-butoxycarbonyl anhydride and then with the lithium salt of benzyl alcohol in order to convert the phenylcarboxamide of (LI) into the benzyl ester (LII). The epoxidation of the dihydropyran double bond of (LII) with MCPBA followed by epoxide opening with MeOH and oxidation of the resulting alcohol with DMP in CH2Cl2 gives the oxoketal (LIII).

参考文献中间体

合成目标

【1】 Lautens, M.; Prunet, J.A.; Carreira, E.M.; Carter, P.H.; Charette, A.B.; Evans, D.A.; Total synthesis of bryostatin 2. J Am Chem Soc 1999, 121, 33, 7540.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
	40733	lithium phenylmethanolate	C₇H₇LiO	详情	详情
(IL)	39439	[(2S,4S,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[(E)-3-((2S)-2-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-3,4-dihydro-2H-pyran-6-yl)-3-methyl-1-butenyl]tetrahydro-2H-pyran-2-yl]methyl trifluoromethanesulfonate	C₄₁H₆₉F₃O₉SSi₂	详情	详情
(XXVIII)	39419	(2R,4R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)tetrahydro-2H-pyran-2-carbaldehyde	C₁₉H₄₀O₄Si₂	详情	详情
(XLIII)	39433	tert-butyl([(1R,2R)-1-([(2S)-6-[1,1-dimethyl-2-(phenylsulfonyl)ethyl]-3,4-dihydro-2H-pyran-2-yl]methyl)-2-[(4-methoxybenzyl)oxy]propyl]oxy)dimethylsilane; 2-((2S)-2-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-3,4-dihydro-2H-pyran-6-yl)-2-methylpropyl phenyl sulfone	C₃₃H₅₀O₆SSi	详情	详情
(XLVII)	39437	tert-butyl(dimethyl)silyl [(2S,4S,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[(E)-3-((2S)-2-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-3,4-dihydro-2H-pyran-6-yl)-3-methyl-1-butenyl]tetrahydro-2H-pyran-2-yl]methyl ether; tert-butyl([(2S,4S,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[(E)-3-((2S)-2-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-3,4-dihydro-2H-pyran-6-yl)-3-methyl-1-butenyl]tetrahydro-2H-pyran-2-yl]methoxy)dimethylsilane	C₄₆H₈₄O₇Si₃	详情	详情
(XLVIII)	39438	[(2S,4S,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[(E)-3-((2S)-2-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-3,4-dihydro-2H-pyran-6-yl)-3-methyl-1-butenyl]tetrahydro-2H-pyran-2-yl]methanol	C₄₀H₇₀O₇Si₂	详情	详情
(L)	39440		C₇₁H₁₁₅NO₁₂Si₃	详情	详情
(LI)	39441		C₇₇H₁₂₉NO₁₂Si₄	详情	详情
(LII)	39442		C₇₈H₁₃₀O₁₃Si₄	详情	详情
(LIII)	39443		C₇₉H₁₃₂O₁₅Si₄	详情	详情

Extended Information