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【结 构 式】 
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【分子编号】60143 【品名】(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-2-[(2S,3S)-2-hydroxy-3-methyl-6-heptynyl]-4-[(4-methoxybenzyl)oxy]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one 【CA登记号】 |
【 分 子 式 】C30H45NO5 【 分 子 量 】499.69104 【元素组成】C 72.11% H 9.08% N 2.8% O 16.01% |
合成路线1
该中间体在本合成路线中的序号：(L)Synthesis of the target Sanglifehrin A: The condensation of the chiral ketone (XXXVII) with aldehyde (XXXVIII) by means of Sn(OTf)2 and TEA in dichloromethane gives the beta-hydroxyketone (XXXIX), which is reduced with Me4NBH3CN to yield the diol (XL). The ketalization of (XL) by means of DDQ, followed by ration with Tes-Cl and imidazole affords the silylated ketal (XLI), which is cleaved with iBu2AlH and oxidized with (COCl)2 to provide the protected carbaldehyde (XLII). The stereocontrolled condensation of aldehyde (XLII) with the chiral acetylenic ketone intermediate (XXIV) by means of (+)-DIPCl and TEA in ethyl ether leads to the acetylenic ketone (XLIII). This is reduced with Me4NBH3CN and ketalized by means of 2,2-dimethoxypropane and PPTS (simultaneous desilylation takes place) to give the dihydroxy ozonide (XLIV). The protection of the primary OH group of (XLIV) by means of Piv-Cl, pyridine and DMAP yields the pivalate (XLV), which is silylated with Tes-Cl and imidazole and deprotected with iBu2AlH to afford the acetylenic alcohol (XLVI). The sequential oxidation of (XLVI) with DMP and with NaClO2, followed by methylation with diazomethane affords the methyl ester (XLVII), which is treated with Me2AlNH2 in dichloromethane to provide the corresponding amide (XLVIII). The desilylation of (XLVIII) by means of TBAF, followed by oxidation with DMP gives the delta-ketoester (XLIX), which is submitted to and acid ring closure with CSA to yield the spirolactam (L)
| 【1】 Duan, M.S.; Paquette, L.A.; Enantioselective total synthesis of the cyclophilin-binding immunosuppressive agent sanglifehrin A. Angew Chem. Int Ed 2001, 40, 19, 3632. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXVII) | 42614 | (2S)-1-[(4-methoxybenzyl)oxy]-2-methyl-3-pentanone | C14H20O3 | 详情 | 详情 | |
| (XXXVIII) | 60131 | (2S,4S)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-methylhexanal | C24H34O2Si | 详情 | 详情 | |
| (XXXIX) | 60132 | (2S,4R,5S,6S,8S)-8-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-hydroxy-1-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-3-decanone | C38H54O5Si | 详情 | 详情 | |
| (XL) | 60133 | (2S,3S,4R,5S,6S,8S)-8-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-3,5-decanediol | C38H56O5Si | 详情 | 详情 | |
| (XLI) | 60134 | (6S,8S,9S)-6,11,11-triethyl-9-{(1S)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl}-2,2,8-trimethyl-3,3-diphenyl-4,10-dioxa-3,11-disilatridecane; tert-butyl(diphenyl)silyl (2S,4S,5S,6S)-2-ethyl-6-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-methyl-5-[(triethylsilyl)oxy]heptyl ether | C44H68O5Si2 | 详情 | 详情 | |
| (XLII) | 60135 | (2R,3R,4S,5S,6S,8S)-8-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-5-[(triethylsilyl)oxy]decanal | C44H68O5Si2 | 详情 | 详情 | |
| (XLIII) | 60136 | (5S,8S,9S,10S,11S,12S,13S,15S)-15-({[tert-butyl(diphenyl)silyl]oxy}methyl)-8-hydroxy-10-[(4-methoxybenzyl)oxy]-5,9,11,13-tetramethyl-12-[(triethylsilyl)oxy]-1-(trimethylsilyl)-1-heptadecyn-6-one | C55H88O6Si3 | 详情 | 详情 | |
| (XLIV) | 60137 | (2S,4S,5S,6R,7R,8R)-8-{(4S,6S)-2,2-dimethyl-6-[(1S)-1-methyl-4-pentynyl]-1,3-dioxan-4-yl}-2-ethyl-7-[(4-methoxybenzyl)oxy]-4,6-dimethyl-1,5-nonanediol | C33H54O6 | 详情 | 详情 | |
| (XLV) | 60138 | (2S,4S,5S,6R,7R,8R)-8-{(4S,6S)-2,2-dimethyl-6-[(1S)-1-methyl-4-pentynyl]-1,3-dioxan-4-yl}-2-ethyl-5-hydroxy-7-[(4-methoxybenzyl)oxy]-4,6-dimethylnonyl pivalate | C38H62O7 | 详情 | 详情 | |
| (XLVI) | 60139 | (2S,4S,5S,6S,7S,8R)-8-{(4S,6S)-2,2-dimethyl-6-[(1S)-1-methyl-4-pentynyl]-1,3-dioxan-4-yl}-2-ethyl-7-[(4-methoxybenzyl)oxy]-4,6-dimethyl-5-[(triethylsilyl)oxy]-1-nonanol | C39H68O6Si | 详情 | 详情 | |
| (XLVII) | 60140 | methyl (2S,4S,5S,6S,7S,8R)-8-{(4S,6S)-2,2-dimethyl-6-[(1S)-1-methyl-4-pentynyl]-1,3-dioxan-4-yl}-2-ethyl-7-[(4-methoxybenzyl)oxy]-4,6-dimethyl-5-[(triethylsilyl)oxy]nonanoate | C40H68O7Si | 详情 | 详情 | |
| (XLVIII) | 60141 | (2S,4S,5S,6S,7S,8R)-8-{(4S,6S)-2,2-dimethyl-6-[(1S)-1-methyl-4-pentynyl]-1,3-dioxan-4-yl}-2-ethyl-7-[(4-methoxybenzyl)oxy]-4,6-dimethyl-5-[(triethylsilyl)oxy]nonanamide | C39H67NO6Si | 详情 | 详情 | |
| (XLIX) | 60142 | (2S,4S,6S,7S,8R)-8-{(4S,6S)-2,2-dimethyl-6-[(1S)-1-methyl-4-pentynyl]-1,3-dioxan-4-yl}-2-ethyl-7-[(4-methoxybenzyl)oxy]-4,6-dimethyl-5-oxononanamide | C33H51NO6 | 详情 | 详情 | |
| (L) | 60143 | (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-2-[(2S,3S)-2-hydroxy-3-methyl-6-heptynyl]-4-[(4-methoxybenzyl)oxy]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one | C30H45NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(L)The elimination of the Pmb protecting group of (L) by means of DDQ in dichloromethane affords compound (LI), which is brominated with NBS and AgNO3 in acetone to provide the bromoacetylene derivative (LII). The reaction of (LII) with tributyltin hydride, Pd2(dba)3 and PPh3 leads to the vinylstannane (LIII), which is condensed with the chiral tetracyclic macrolactone intermediate (XXXVI) by means of PdCl2(CH3CN)2 in DMF to give the cyclic precursor (LIV). Finally, this compound is submitted to an acidic hydrolysis by means of TsOH and BO3H3 in THF to provide the target Sanglifehrin A
| 【1】 Duan, M.S.; Paquette, L.A.; Enantioselective total synthesis of the cyclophilin-binding immunosuppressive agent sanglifehrin A. Angew Chem. Int Ed 2001, 40, 19, 3632. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXVI) | 32450 | (4R,7S,10S,16S,19S,25S,26R,27R)-10-(3-hydroxybenzyl)-19-[(E)-2-iodo-1-methylethenyl]-7-isopropyl-1,26-dimethyl-18,28,29-trioxa-6,9,12,30-tetraazatetracyclo[23.3.1.1(12,16).0(4,27)]triaconta-21,23-diene-5,8,11,17-tetrone; (4R,7S,10S,16S,19S,25S,26R,27R)-10-(3-hydroxybenzyl)-19-[(E)-2-iodo-1-methylethenyl]-7-isopropyl-1,26-dimethyl-18,28,29-trioxa-6,9,12,30-tetraazatetracyclo[23.3.1.1(12,16).0(4,27)]triaconta-21,23-diene-5,8,11,17-tetrone | C38H51IN4O8 | 详情 | 详情 | |
| (L) | 60143 | (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-2-[(2S,3S)-2-hydroxy-3-methyl-6-heptynyl]-4-[(4-methoxybenzyl)oxy]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one | C30H45NO5 | 详情 | 详情 | |
| (LI) | 35886 | (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S)-2-hydroxy-3-methyl-6-heptynyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one | C22H37NO4 | 详情 | 详情 | |
| (LII) | 32435 | (2S,3R,4S,5S,6R,9S,11S)-2-[(2S,3S)-7-bromo-2-hydroxy-3-methyl-6-heptynyl]-9-ethyl-4-hydroxy-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one | C22H36BrNO4 | 详情 | 详情 | |
| (LIII) | 35874 | (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S,6E)-2-hydroxy-3-methyl-7-(tributylstannyl)-6-heptenyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one | C34H65NO4Sn | 详情 | 详情 | |
| (LIV) | 32452 | (4R,7S,10S,16S,19S,25S,26R,27R)-19-{(1E,3E,7S,8S)-9-[(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl]-8-hydroxy-1,7-dimethyl-1,3-nonadienyl}-10-(3-hydroxybenzyl)-7-isopropyl-1,26-dimethyl-18,28,29-trioxa-6,9,12,30-tetraazatetracyclo[23.3.1.1~12,16~.0~4,27~]triaconta-21,23-diene-5,8,11,17-tetrone | C60H89N5O12 | 详情 | 详情 |