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【结 构 式】 
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【分子编号】42640 【品名】methyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-oxohexanoate 【CA登记号】 |
【 分 子 式 】C15H30O4Si 【 分 子 量 】302.4863 【元素组成】C 59.56% H 10% O 21.16% Si 9.28% |
合成路线1
该中间体在本合成路线中的序号：(XXX)The intermediate (XXX) has been obtained as follows: The condensation of benzylated hydroxypentanone (XXII) with acetaldehyde (XXIII) by means of DCHBCl gives the hydroxyhexanone (XXIV), which is reduced with LiBH4, yielding the diol (XXV). The silylation of (XXV) with Tbdms-OTf affords the disilyl ether (XXVI), which is regioselectively monodesilylated with CSA, providing the alcohol (XXVII). The hydrogenolysis of (XXVII) with H2 over Pd/C gives the primary alcohol (XXVIII), which is treated with (COCl)2 and NaClO2 in order to oxidize the primary alcohol to carboxylic acid and the secondary alcohol to ketone to furnish the ketoacid (XXIX). Finally, this compound is esterified with diazomethane to afford the desired ester intermediate (XXX).
| 【1】 Paterson, I.; Florence, G.J.; Synthesis of (+)-discodermolide and analogues by control of asymmetric induction in aldol reactions of gamma-chiral (Z)-enals. Tetrahedron Lett 2000, 41, 35, 6935. |
| 【2】 Paterson, I.; et al.; Total synthesis of the antimicrotubule agent (+)-discodermolide using boron-mediated aldol reactions of chiral ketones. Angew Chem. Int Ed Engl 2000, 39, 2, 377. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXII) | 42633 | (2S)-1-(benzyloxy)-2-methyl-3-pentanone | C13H18O2 | 详情 | 详情 | |
| (XXIII) | 11974 | Acetaldehyde | 75-07-0 | C2H4O | 详情 | 详情 |
| (XXIV) | 42634 | (2S,4S,5S)-1-(benzyloxy)-5-hydroxy-2,4-dimethyl-3-hexanone | C15H22O3 | 详情 | 详情 | |
| (XXV) | 42635 | (2S,3S,4R,5S)-6-(benzyloxy)-3,5-dimethyl-2,4-hexanediol | C15H24O3 | 详情 | 详情 | |
| (XXVI) | 42636 | benzyl (2S,3R,4S,5S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethylhexyl ether; (5R,6S,7S)-5-[(1S)-2-(benzyloxy)-1-methylethyl]-2,2,3,3,6,7,9,9,10,10-decamethyl-4,8-dioxa-3,9-disilaundecane | n/a | C27H52O3Si2 | 详情 | 详情 |
| (XXVII) | 42637 | (2S,3S,4R,5S)-6-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-2-hexanol | n/a | C21H38O3Si | 详情 | 详情 |
| (XXVIII) | 42638 | (2S,3R,4S,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1,5-hexanediol | C14H32O3Si | 详情 | 详情 | |
| (XXIX) | 42639 | (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-oxohexanoic acid | C14H28O4Si | 详情 | 详情 | |
| (XXX) | 42640 | methyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-oxohexanoate | C15H30O4Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXX)The condensation of aldehyde (XLI) with the intermediate ketoester (XXX) by means of chloro-(+)-disopinocampheylborane ((+)-IPCBCl) gives the 5-oxotetracosatetraenoic ester (XLII), which is submitted to reduction of the 5-oxo group with Me3N-BH(OAc)3, yielding a mixture of the 5-hydroxyester (XLIV) and the corresponding lactone (XLIII). Finally, this mixture, without separation of its components, is submitted to desilylation, with simultaneous lactonization, by treatment with HF and pyridine in THF.
| 【1】 Paterson, I.; et al.; Total synthesis of the antimicrotubule agent (+)-discodermolide using boron-mediated aldol reactions of chiral ketones. Angew Chem. Int Ed Engl 2000, 39, 2, 377. |
| 【2】 Paterson, I.; Florence, G.J.; Synthesis of (+)-discodermolide and analogues by control of asymmetric induction in aldol reactions of gamma-chiral (Z)-enals. Tetrahedron Lett 2000, 41, 35, 6935. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXX) | 42640 | methyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-oxohexanoate | C15H30O4Si | 详情 | 详情 | |
| (XLI) | 42650 | (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-tridecadienyl carbamate | C37H69NO5Si2 | 详情 | 详情 | |
| (XLII) | 42651 | methyl (2R,3S,4R,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-2,4,10,12,14,16,18,20-octamethyl-5-oxo-8,13,21,23-tetracosatetraenoate | C52H99NO9Si3 | 详情 | 详情 | |
| (XLIII) | 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 | |
| (XLIV) | 42653 | methyl (2R,3S,4S,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7-dihydroxy-2,4,10,12,14,16,18,20-octamethyl-8,13,21,23-tetracosatetraenoate | C52H101NO9Si3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)Chiral 5-oxohexanoic ester intermediate (XI): The reaction of 3-hydroxy-2(S)-methylpropionic acid methyl ester (I) with benzyl trichloroacetimidate gives the benzyl ether (II), which is condensed with ethylmagnesium bromide in THF to yield the chiral ketone (III). The reaction of (III) with (c-hexyl)2B-Cl ad TEA affords the boron enolate (IV), which is condensed with acetaldehyde to provide the intermediate boron aldolate (V). The reduction of (V) with LiBH4 and H2O2 in aqueous methanol gives the chiral diol (VI), which is silylated by means of Tbdms-OTf to yield the bis-silyl ether (VII). The selective deprotection of (VII) by means of CSA in methanol/dichloromethane affords the alcohol (VIII), which is debenzylated by means of H2 over Pd/C in ethanol to provide the diol (IX). The oxidation of (IX) with (COCl)2 and DMSO in dichloromethane gives the intermediate oxoaldehyde that is oxidized with NaClO2 to yield the 5-oxohexanoic acid (X). Finally, this compound is methylated with diazomethane in ethyl ether to afford the target, chiral 5-oxohexanoic ester intermediate (XI).
| 【1】 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 |
|---|---|---|---|---|---|---|
| (I) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 62835 | methyl (2S)-3-(benzyloxy)-2-methylpropanoate | C12H16O3 | 详情 | 详情 | |
| (III) | 42633 | (2S)-1-(benzyloxy)-2-methyl-3-pentanone | C13H18O2 | 详情 | 详情 | |
| (IV) | 62836 | (E)-1-[(1S)-2-(benzyloxy)-1-methylethyl]-1-propenyl dicyclohexylborinate | C25H39BO2 | 详情 | 详情 | |
| (V) | 62837 | C27H43BO3 | 详情 | 详情 | ||
| (VI) | 42635 | (2S,3S,4R,5S)-6-(benzyloxy)-3,5-dimethyl-2,4-hexanediol | C15H24O3 | 详情 | 详情 | |
| (VII) | 42636 | benzyl (2S,3R,4S,5S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethylhexyl ether; (5R,6S,7S)-5-[(1S)-2-(benzyloxy)-1-methylethyl]-2,2,3,3,6,7,9,9,10,10-decamethyl-4,8-dioxa-3,9-disilaundecane | n/a | C27H52O3Si2 | 详情 | 详情 |
| (VIII) | 42637 | (2S,3S,4R,5S)-6-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-2-hexanol | n/a | C21H38O3Si | 详情 | 详情 |
| (IX) | 42638 | (2S,3R,4S,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1,5-hexanediol | C14H32O3Si | 详情 | 详情 | |
| (X) | 42639 | (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-oxohexanoic acid | C14H28O4Si | 详情 | 详情 | |
| (XI) | 42640 | methyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-oxohexanoate | C15H30O4Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)The reaction of the OH group of (LII) with trichloroacetyl isocyanate and K2CO3 in methanol gives the carbamate (LIII). The reduction of the ester group of (LIII) with DIBAL in dichloromethane yields the primary alcohol (LIV), which is oxidized with DMP to afford the aldehyde (LV). The condensation of (LV) with the boron enolate (LVI), (obtained by reaction of the 5-oxohexanoic ester intermediate (XI) with (c-Hex)2B-Cl), provides the chiral 5-oxotetracosatetraenoic ester (LVII), which is reduced with Me4HBH(OAc)3 in acetonitrile/AcOH to give the dihydroxyester (LVIII). Finally, this compound is lactonized and simultaneously deprotected by means of HF/pyridine in THF or HCl in methanol giving rise to the target (+)-Discodermolide.
| 【1】 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) | 42640 | methyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-oxohexanoate | C15H30O4Si | 详情 | 详情 | |
| (LII) | 42647 | methyl (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-5,11-bis[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenoate | n/a | C37H70O5Si2 | 详情 | 详情 |
| (LIII) | 42648 | methyl (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-13-[(aminocarbonyl)oxy]-5,11-bis[[tert-butyl(dimethyl)silyl]oxy]-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenoate | n/a | C38H71NO6Si2 | 详情 | 详情 |
| (LIV) | 42649 | (1S,2R,3R,4S,6Z,8S,9S,10S,11Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-6,11-tridecadienyl carbamate | C37H71NO5Si2 | 详情 | 详情 | |
| (LV) | 42650 | (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-tridecadienyl carbamate | C37H69NO5Si2 | 详情 | 详情 | |
| (LVI) | 62851 | methyl (2R,3S,4R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(dicyclohexylboryl)oxy]-2,4-dimethyl-5-hexenoate | C27H51BO4Si | 详情 | 详情 | |
| (LVII) | 42651 | methyl (2R,3S,4R,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-2,4,10,12,14,16,18,20-octamethyl-5-oxo-8,13,21,23-tetracosatetraenoate | C52H99NO9Si3 | 详情 | 详情 | |
| (LVIII) | 42653 | methyl (2R,3S,4S,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7-dihydroxy-2,4,10,12,14,16,18,20-octamethyl-8,13,21,23-tetracosatetraenoate | C52H101NO9Si3 | 详情 | 详情 |