【结 构 式】 |
【分子编号】22756 【品名】(1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-12-[(E)-2-[(1R,3R,4R)-4-(allyloxy)-3-methoxycyclohexyl]-1-methylethenyl]-14-[[tert-butyl(dimethyl)silyl]oxy]-17-ethyl-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone 【CA登记号】 |
【 分 子 式 】C52H87NO12Si 【 分 子 量 】946.34782 【元素组成】C 66% H 9.27% N 1.48% O 20.29% Si 2.97% |
合成路线1
该中间体在本合成路线中的序号:(V)Ascomycin (I) was protected as the C24,C32-bis(tert-butyldimethyl- silyl)ether (II), and then was selectively desilylated at the C32 position with p-toluenesulfonic acid in MeOH-CH2Cl2. The resulting monosilylated compound (III) was treated with allyl trichloroacetimidate (IV) and trifluoromethanesulfonic acid to provide the C32 allyl ether (V). Subsequent dihydroxylation of the allyl group of (V) using N-methylmorpholine-N-oxide in the presence of a catalytic amount of OsO4 afforded glycol (VI), and further oxidative cleavage of (VI) with sodium metaperiodate produced aldehyde (VII).
【1】 Goulet, M.; Wyvratt, M.J.; Sinclair, P.J.; Wong, F. (Merck & Co., Inc.); Imidazolidyl macrolides having immunosuppressive activity. EP 0536896; JP 1994510303; US 5247076; WO 9305059 . |
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) | 14951 | (1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-ethyl-1,14-dihydroxy-12-[(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetron | C43H69NO12 | 详情 | 详情 | |
(II) | 22753 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-14-[[tert-butyl(dimethyl)silyl]oxy]-12-[(E)-2-((1R,3R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methoxycyclohexyl)-1-methylethenyl]-17-ethyl-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone | C55H97NO12Si2 | 详情 | 详情 | |
(III) | 22754 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-14-[[tert-butyl(dimethyl)silyl]oxy]-17-ethyl-1-hydroxy-12-[(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone | C49H83NO12Si | 详情 | 详情 | |
(IV) | 22755 | allyl 2,2,2-trichloroethanimidoate | 51479-73-3 | C5H6Cl3NO | 详情 | 详情 |
(V) | 22756 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-12-[(E)-2-[(1R,3R,4R)-4-(allyloxy)-3-methoxycyclohexyl]-1-methylethenyl]-14-[[tert-butyl(dimethyl)silyl]oxy]-17-ethyl-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone | C52H87NO12Si | 详情 | 详情 | |
(VI) | 22757 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-14-[[tert-butyl(dimethyl)silyl]oxy]-12-[(E)-2-[(1R,3R,4R)-4-(2,3-dihydroxypropoxy)-3-methoxycyclohexyl]-1-methylethenyl]-17-ethyl-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone | C52H89NO14Si | 详情 | 详情 | |
(VII) | 22758 | 2-([(1R,2R,4R)-4-[(E)-2-((1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-14-[[tert-butyl(dimethyl)silyl]oxy]-17-ethyl-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-2,3,10,16-tetraoxo-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-en-12-yl)-1-propenyl]-2-methoxycyclohexyl]oxy)acetaldehyde | C51H85NO13Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(V)Protection of ascomycin (I) by means of tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of 2,6-lutidine provided the 14,4''-disilylated derivative (II). Selective removal of the 4''-silyl group of (II) with para-toluenesulfonic acid in MeOH-CH2Cl2 yielded the 14-protected compound (III). This was converted to allyl ether (V) upon treatment with allyl trichloroacetimidate (IV) and trifluoromethanesulfonic acid. Dihydroxylation of the allyl double bond of (V) with OsO4 and N-methylmorpholine-N-oxide, followed by oxidative cleavage of the resulting diol (VI) with sodium metaperiodate furnished aldehyde (VII).
【1】 Sinclair, P.J.; Goulet, J.; Wong, F.; Goulet, M.; Parsons, W.H.; Wyvratt, Matthew, J.; O-Heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroarylmacrolides having immunosuppressive activity. US 5349061 . |
【2】 Sinclair, P.J.; Organ, H.M.; Wong, F.; Goulet, M.; Parsons, W.H.; Wyvratt, Matthew, J.; O-Aryl, O-alkyl, O-alkenyl and O-alkynylmacrolides having immunosuppressive activity. US 5565560 . |
【3】 Wong, F.; Holmes, M.A.; Armstrong, H.M.; et al.; Potent immunosuppressive C32-O-arylethyl ether derivatives of ascomycin with reduced toxicity. Bioorg Med Chem Lett 1999, 9, 14, 2089-94. |
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) | 14951 | (1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-ethyl-1,14-dihydroxy-12-[(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetron | C43H69NO12 | 详情 | 详情 | |
(II) | 33687 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-14-[[tert-butyl(dimethyl)silyl]oxy]-12-[(E)-2-((1R,3R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methoxycyclohexyl)-1-methylethenyl]-17-ethyl-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone | C55H97NO12Si2 | 详情 | 详情 | |
(III) | 22754 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-14-[[tert-butyl(dimethyl)silyl]oxy]-17-ethyl-1-hydroxy-12-[(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone | C49H83NO12Si | 详情 | 详情 | |
(IV) | 22755 | allyl 2,2,2-trichloroethanimidoate | 51479-73-3 | C5H6Cl3NO | 详情 | 详情 |
(V) | 22756 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-12-[(E)-2-[(1R,3R,4R)-4-(allyloxy)-3-methoxycyclohexyl]-1-methylethenyl]-14-[[tert-butyl(dimethyl)silyl]oxy]-17-ethyl-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone | C52H87NO12Si | 详情 | 详情 | |
(VI) | 22757 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-14-[[tert-butyl(dimethyl)silyl]oxy]-12-[(E)-2-[(1R,3R,4R)-4-(2,3-dihydroxypropoxy)-3-methoxycyclohexyl]-1-methylethenyl]-17-ethyl-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone | C52H89NO14Si | 详情 | 详情 | |
(VII) | 22758 | 2-([(1R,2R,4R)-4-[(E)-2-((1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-14-[[tert-butyl(dimethyl)silyl]oxy]-17-ethyl-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-2,3,10,16-tetraoxo-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-en-12-yl)-1-propenyl]-2-methoxycyclohexyl]oxy)acetaldehyde | C51H85NO13Si | 详情 | 详情 |