methyl (2R,3S,4R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dimethyl-5-oxopentanoate -Drug Synthesis Database

【结构式】

【分子编号】62859

【品名】methyl (2R,3S,4R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dimethyl-5-oxopentanoate

【CA登记号】

【分子式】C₁₄H₂₈O₄Si

【分子量】288.45942

【元素组成】C 58.29% H 9.78% O 22.19% Si 9.74%

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：(XI)

Synthesis of the chiral 5-oxopentanoic ester intermediate (XI): The reaction of 3-hydroxy-2(S)-methylpentanoic acid methyl ester (I) with 4-methoxybenzyl trichloroacetimidate gives the aryl ether (II), which is treated with ethylmagnesium bromide to yield the ketone (III). The condensation of (III) with formaldehyde by means of (c-Hex)2B-Cl and H2O2 affords the hydroxypentanone (IV), which is reduced by means of NaBH(OAc)3 in THF/AcOH to provide the diol (V). The regioselective oxidation of the primary alcohol of (V) with TEMPO and BAIB in dichloromethane gives the beta-hydroxyaldehyde (VI), which is further oxidized with NaClO2 yielding the carboxylic acid (VII). The esterification of (VII) by means of Me-I and K2CO3, or with TMS-CHN2 affords the methyl ester (VIII), which is treated with Tbdms-OTf and lutidine to provide the silyl ether (IX). The selective deprotection of (IX) by means of DDQ in dichloromethane furnishes the omega-hydroxyester (X), which is finally submitted to a Swern oxidation to yield the chiral 5-oxopentanoic ester intermediate (XI).

参考文献中间体

合成目标

【1】 Paterson, I.; Delgado, O.; Florence, G.J.; Lyothier, I.; Scott, J.P.; Sereinig, N.; 1,6-asymmetric induction in boron-mediated aldol reactions: Application to a practical total synthesis of (+)-discodermolide. Org Lett 2003, 5, 1, 35.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	17128	Methyl (2S)-3-hydroxy-2-methylpropanoate	72657-23-9	C₅H₁₀O₃	详情	详情
(II)	42654	methyl (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanoate		C₁₃H₁₈O₄	详情	详情
(III)	42614	(2S)-1-[(4-methoxybenzyl)oxy]-2-methyl-3-pentanone		C₁₄H₂₀O₃	详情	详情
(IV)	62852	(2S,4S)-1-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethyl-3-pentanone		C₁₅H₂₂O₄	详情	详情
(V)	62853	(2S,3R,4S)-5-[(4-methoxybenzyl)oxy]-2,4-dimethyl-1,3-pentanediol		C₁₅H₂₄O₄	详情	详情
(VI)	62854	(2R,3S,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanal		C₁₅H₂₂O₄	详情	详情
(VII)	62855	(2R,3S,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanoic acid		C₁₅H₂₂O₅	详情	详情
(VIII)	62856	methyl (2R,3S,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanoate		C₁₆H₂₄O₅	详情	详情
(IX)	62857	methyl (2R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanoate		C₂₂H₃₈O₅Si	详情	详情
(X)	62858	methyl (2R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-2,4-dimethylpentanoate		C₁₄H₃₀O₄Si	详情	详情
(XI)	62859	methyl (2R,3S,4R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dimethyl-5-oxopentanoate		C₁₄H₂₈O₄Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

Synthesis of the target (+)-Discodermolide: The selective oxidation of the chiral hexadecatrien-1,11-diol derivative (XII) with TEMPO and BAIB gives the hydroxyaldehyde (XIII), which is condensed with the phosphonate (XIV) by means of K2CO3 and 18-C-6 in toluene to yield the methyl ketone (XV). The reaction of the free OH group of (XV) with trichloroacetyl isocyanate and neutral alumina affords the carbamate (XVI), which is condensed with the chiral 5-oxopentanoic ester intermediate (XI) by means of (c-Hex)2B-Cl and TEA in ethyl ether to provide the chiral 5-hydroxy-7-oxotetracosatetraenoic ester (XVII). The cyclization of (XVII) by means of Ac-OH in aqueous THF furnishes the oxo- lactone (XVIII), which is reduced with K-Selectride in toluene/THF to give the hydroxy lactone (XIX). Finally, this compound is deprotected by means of HCl in methanol to provide the target (+)-Discodermolide.

参考文献中间体

合成目标

【1】 Paterson, I.; Delgado, O.; Florence, G.J.; Lyothier, I.; Scott, J.P.; Sereinig, N.; 1,6-asymmetric induction in boron-mediated aldol reactions: Application to a practical total synthesis of (+)-discodermolide. Org Lett 2003, 5, 1, 35.
【2】 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)	62859	methyl (2R,3S,4R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dimethyl-5-oxopentanoate		C₁₄H₂₈O₄Si	详情	详情
(XII)	42645	(2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatriene-1,11-diol	n/a	C₃₄H₆₈O₄Si₂	详情	详情
(XIII)	42646	(2R,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienal	n/a	C₃₄H₆₆O₄Si₂	详情	详情
(XIV)	62860	bis(2,2,2-trifluoroethyl) 2-oxopropylphosphonate		C₇H₉F₆O₄P	详情	详情
(XV)	62861	(3Z,5S,6S,7S,8Z,11S,12R,13R,14S,15S,16Z)-6,12-bis{[tert-butyl(dimethyl)silyl]oxy}-14-hydroxy-5,7,9,11,13,15-hexamethyl-3,8,16,18-nonadecatetraen-2-one		C₃₇H₇₀O₄Si₂	详情	详情
(XVI)	62862	(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-tetradecadienyl carbamate		C₃₈H₇₁NO₅Si₂	详情	详情
(XVII)	62863	methyl (2R,3S,4S,5S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-3,11,17-tris{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-2,4,10,12,14,16,18,20-octamethyl-7-oxo-8,13,21,23-tetracosatetraenoate		C₅₂H₉₉NO₉Si₃	详情	详情
(XVIII)	62864	(1S,2R,3R,4S,6Z,8S,9S,10S,11Z)-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)-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-13-oxo-6,11-tetradeca		C₅₁H₉₅NO₈Si₃	详情	详情
(XIX)	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

Extended Information