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【结 构 式】 
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【分子编号】42650 【品名】(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 【CA登记号】 |
【 分 子 式 】C37H69NO5Si2 【 分 子 量 】664.1296 【元素组成】C 66.92% H 10.47% N 2.11% O 12.05% Si 8.46% |
合成路线1
该中间体在本合成路线中的序号：(XLI)The target compound has been obtained as follows: The condensation of ester intermediate (XI) with aldehyde intermediate (XXI) by means of lithium 2,2,6,6-tetramethylpiperidide (Li-TMP) gives the addition compound (XXXI), which is reduced at the ester group with LiAlH4, yielding the carbinol (XXXII). The reduction of this carbinol by sulfonation with mesitylenesulfonyl chloride, followed by reduction with LiAlH4, affords the corresponding methyl derivative (XXXIII), which is silylated at the secondary OH group with TBDMS-Otf, providing the fully protected compound (XXXIV). Elimination of the Pmb protecting groups of (XXXIV) with DDQ yields the diol (XXXV), which is selectively oxidized at the primary OH group to the corresponding aldehyde (XXXVI) by means of TEMPO. The Wittig condensation of (XXXVI) with phosphonate (XXXVII) by means of K2CO3 and 18-C-6 affords the octadecatetraenoic ester (XXXVIII), which is treated with trichloroacetyl isocyanate and K2CO3 to provide the carbamate (XXXIX). The reduction of the ester group of (XXXIX) by means of DIBAL gives the primary alcohol (XL), which is finally oxidized with DMP to the expected intermediate aldehyde (XLI).
| 【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 |
|---|---|---|---|---|---|---|
| (XI) | 42622 | 2,6-dimethylphenyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C34H52O5Si | 详情 | 详情 | |
| (XXI) | 42632 | (2R,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienal | C18H24O3 | 详情 | 详情 | |
| (XXXI) | 42641 | 2,6-dimethylphenyl (2S,3S,4S,5S,6S,7Z)-2-[(Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl]-3-hydroxy-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadienoate | C52H76O8Si | 详情 | 详情 | |
| (XXXII) | 42642 | (2R,3R,4S,5S,6S,7Z)-2-[(Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl]-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadiene-1,3-diol | C44H70O7Si | 详情 | 详情 | |
| (XXXIII) | 42643 | (3Z,5S,6S,7S,8R,9S,11Z,13S,14R,15S)-14-[[tert-butyl(dimethyl)silyl]oxy]-6,16-bis[(4-methoxybenzyl)oxy]-5,7,9,11,13,15-hexamethyl-1,3,11-hexadecatrien-8-ol | C44H70O6Si | 详情 | 详情 | |
| (XXXIV) | 42644 | (5R,6S,7Z,10S,11R)-11-[(1R,2S,3S,4Z)-2-[(4-methoxybenzyl)oxy]-1,3-dimethyl-4,6-heptadienyl]-5-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2,2,3,3,6,8,10,13,13,14,14-undecamethyl-4,12-dioxa-3,13-disila-7-pentadecene; (2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienyl 4-methoxybenzyl ether | n/a | C50H84O6Si2 | 详情 | 详情 |
| (XXXV) | 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 |
| (XXXVI) | 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 |
| (XXXVII) | 41856 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate | 88738-78-7 | C7H9F6O5P | 详情 | 详情 |
| (XXXVIII) | 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 |
| (XXXIX) | 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 |
| (XL) | 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 | |
| (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 |
合成路线2
该中间体在本合成路线中的序号：(XLI)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：(IV)The Grignard reaction of the chiral pentanamide (I) with methylmagnesium bromide in ether gives the hydroxyhexanamide (II), which is oxidized with SO3/pyridine in DMSO to yield the oxohexanamide (III). The aldol condensation of the oxohexanamide (III) with the chiral aldehyde (IV) by means of (+)-beta-chlorodiisopinocampheylborane and TEA in ethyl ether affords the aldol (V), which is reduced with tetramethylammonium triacetoxyborohydride in acetonitrile/acetic acid to provide the dihydroxyamide (VI). Finally, this compound is deprotected and lactonized by treatment with HCl in THF/water to furnish the target discodermolide.
| 【1】 Kinder, F.R. (Novartis AG; Novartis-Erfindungen VmbH); Process for preparing discodermolide and analogues thereof. WO 0212220 . |
| 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) | 52184 | (2R,3S,4R)-3-{[tert-Butyl(dimethyl)silyl]oxy}-N-methoxy-2,4-dimethyl-5-oxopentanamide | C14H29NO4Si | 详情 | 详情 | |
| (II) | 52185 | (2R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-N-methoxy-2,4-dimethylhexanamide | C15H33NO4Si | 详情 | 详情 | |
| (III) | 52186 | (2R,3S,4R)-3-{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-2,4-dimethyl-5-oxohexanamide | C15H31NO4Si | 详情 | 详情 | |
| (IV) | 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 | |
| (V) | 52187 | (1S,2R,3R,4S,6Z,8S,9S,10S,11Z,13S,16R,17S,18R)-3,9,17-tris{[tert-butyl(dimethyl)silyl]oxy}-13-hydroxy-19-(methoxyamino)-2,4,6,8,10,16,18-heptamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-15,19-dioxo-6,11-nonadecadienyl carbamate | C52H100N2O9Si3 | 详情 | 详情 | |
| (VI) | 52188 | (1S,2R,3R,4S,6Z,8S,9S,10S,11Z,13S,15S,16S,17S,18R)-3,9,17-tris{[tert-butyl(dimethyl)silyl]oxy}-13,15-dihydroxy-19-(methoxyamino)-2,4,6,8,10,16,18-heptamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-19-oxo-6,11-nonadecadienyl carbamate | C52H102N2O9Si3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(LV)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 |