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【结 构 式】 
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【分子编号】57325 【品名】(1R,6R,10S,12S,13R,14S,16R,17R,25S,28S,29R,30R)-28-[(E)-2-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-12,14-dimethoxy-8,10,16,29,32,32-hexamethyl-2,27,31,33,35-pentaoxa-20-azapentacyclo[28.3.1.1~13,17~.0~1,6~.0~20,25~]pentatriacont-7-ene-4,18,19,26-tetrone 【CA登记号】 |
【 分 子 式 】C63H91NO13Si 【 分 子 量 】1098.49998 【元素组成】C 68.88% H 8.35% N 1.28% O 18.93% Si 2.56% |
合成路线1
该中间体在本合成路线中的序号：(XXX)The selective desilylation of (XXV) by means of TBAF gives the diol (XXVI), which is oxidized by means of NaClO and NaClO2 to yield the hydroxyacid (XXVII), which is methylated with diazomethane to afford the methyl ester (XXVIII). The cyclization of (XXVIII) by means of LiOH and Tes-OTf provides the macrocyclic alpha-hydroxy ketonic intermediate (XXIX), which is oxidized with DMP to the alpha diketonic intermediate (XXX).
| 【1】 Gleason, J.L.; The total synthesis of FK-506 and its spiroketal analogs. Diss Abstr Int B - Sci Eng 1994, 54, 12, Part 1, 6206. |
| 【2】 Ireland, R.E.; et al.; A total synthesis of FK-506. J Org Chem 1996, 61, 20, 6856. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXV) | 57320 | 2-[(1S,2E)-1-[(1R)-1-((4S,6R,11R)-11-{(E,4S,6S)-6-[(2R,3S,5R,6R)-6-((1S)-1,2-bis{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-methoxy-5-methyltetrahydro-2H-pyran-2-yl]-6-methoxy-2,4-dimethyl-1-hexenyl}-2,2-dimethyl-9-oxo-1,3,7-trioxaspiro[5.5]undec-4-yl)ethyl]-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-2-methyl-2-propenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C80H133NO15Si3 | 详情 | 详情 | |
| (XXVI) | 57321 | 1-(tert-butyl) 2-((1S,2E)-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-{(1R)-1-[(4S,6R,11R)-11-((E,4S,6S)-6-{(2R,3S,5R,6R)-6-[(1S)-1,2-dihydroxyethyl]-3-methoxy-5-methyltetrahydro-2H-pyran-2-yl}-6-methoxy-2,4-dimethyl-1-hexenyl)-2,2-dimethyl-9-oxo-1,3,7-trioxaspiro[5.5]undec-4-yl]ethyl}-2-methyl-2-propenyl) (2S)-1,2-piperidinedicarboxylate | C68H105NO15Si | 详情 | 详情 | |
| (XXVII) | 57322 | (2R)-2-[(2R,3R,5S,6R)-6-((1S,3S,5E)-6-{(4S,6R,11R)-4-[(1R,2S,3E)-2-({[(2S)-1-(tert-butoxycarbonyl)piperidinyl]carbonyl}oxy)-4-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1,3-dimethyl-3-butenyl]-2,2-dimethyl-9-oxo-1,3,7-trioxaspiro[5.5]undec-11-yl}-1-methoxy-3,5-dimethyl-5-hexenyl)-5-methoxy-3-methyltetrahydro-2H-pyran-2-yl]-2-hydroxyethanoic acid | C68H103NO16Si | 详情 | 详情 | |
| (XXVIII) | 57323 | 1-(tert-butyl) 2-((1S,2E)-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-{(1R)-1-[(4S,6R,11R)-11-((E,4S,6S)-6-{(2R,3S,5R,6R)-6-[(1R)-1-hydroxy-2-methoxy-2-oxoethyl]-3-methoxy-5-methyltetrahydro-2H-pyran-2-yl}-6-methoxy-2,4-dimethyl-1-hexenyl)-2,2-dimethyl-9-oxo-1,3,7-trioxaspiro[5.5]undec-4-yl]ethyl}-2-methyl-2-propenyl) (2S)-1,2-piperidinedicarboxylate | C69H105NO16Si | 详情 | 详情 | |
| (XXIX) | 57324 | (1R,6R,10S,12S,13R,14S,16R,17R,18R,25S,28S,29R,30R)-28-[(E)-2-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-18-hydroxy-12,14-dimethoxy-8,10,16,29,32,32-hexamethyl-2,27,31,33,35-pentaoxa-20-azapentacyclo[28.3.1.1~13,17~.0~1,6~.0~20,25~]pentatriacont-7-ene-4,19,26-trione | C63H93NO13Si | 详情 | 详情 | |
| (XXX) | 57325 | (1R,6R,10S,12S,13R,14S,16R,17R,25S,28S,29R,30R)-28-[(E)-2-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-12,14-dimethoxy-8,10,16,29,32,32-hexamethyl-2,27,31,33,35-pentaoxa-20-azapentacyclo[28.3.1.1~13,17~.0~1,6~.0~20,25~]pentatriacont-7-ene-4,18,19,26-tetrone | C63H91NO13Si | 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 reduction of the tetrahydropyranone group of (XXX) by means of Li(s-Bu)3BH gives the tetrahydropyranol (XXXI), which is iodinated by means of PPh3 and iodine to give the iodo derivative (XXXII). The reaction of the alpha diketonic group of (XXXII) with KHMDS and TesCl yields the silyl enol ether (XXXIII). The fragmentation of the iodinated spiroketal group of (XXXIII) was achieved using a Zn-Ag couple, that was prepared in situ by reduction of ZnCl2 and AgOAc by means of C8K (a mixture of graphite and potassium heated at 150 C under argon) to provide the silylated precursor (XXXIV). Finally the silylated enol ether group of (XXXIV) is hydroxylated by means of dimethyldioxirane and desilylated by means of HF to afford the target FK-506.
| 【1】 Gleason, J.L.; The total synthesis of FK-506 and its spiroketal analogs. Diss Abstr Int B - Sci Eng 1994, 54, 12, Part 1, 6206. |
| 【2】 Ireland, R.E.; et al.; A total synthesis of FK-506. J Org Chem 1996, 61, 20, 6856. |
| 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) | 57325 | (1R,6R,10S,12S,13R,14S,16R,17R,25S,28S,29R,30R)-28-[(E)-2-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-12,14-dimethoxy-8,10,16,29,32,32-hexamethyl-2,27,31,33,35-pentaoxa-20-azapentacyclo[28.3.1.1~13,17~.0~1,6~.0~20,25~]pentatriacont-7-ene-4,18,19,26-tetrone | C63H91NO13Si | 详情 | 详情 | |
| (XXXI) | 57326 | (1R,4R,6R,10S,12S,13R,14S,16R,17R,25S,28S,29R,30R)-28-[(E)-2-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-4-hydroxy-12,14-dimethoxy-8,10,16,29,32,32-hexamethyl-2,27,31,33,35-pentaoxa-20-azapentacyclo[28.3.1.1~13,17~.0~1,6~.0~20,25~]pentatriacont-7-ene-18,19,26-trione | C63H93NO13Si | 详情 | 详情 | |
| (XXXII) | 57327 | (1R,4S,6R,10S,12S,13R,14S,16R,17R,25S,28S,29R,30R)-28-[(E)-2-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-4-iodo-12,14-dimethoxy-8,10,16,29,32,32-hexamethyl-2,27,31,33,35-pentaoxa-20-azapentacyclo[28.3.1.1~13,17~.0~1,6~.0~20,25~]pentatriacont-7-ene-18,19,26-trione | C63H92INO12Si | 详情 | 详情 | |
| (XXXIII) | 57328 | (1R,4S,6R,10S,12S,13R,14S,16R,25S,28S,29R,30R)-28-[(E)-2-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-4-iodo-12,14-dimethoxy-8,10,16,29,32,32-hexamethyl-18-[(triethylsilyl)oxy]-2,27,31,33,35-pentaoxa-20-azapentacyclo[28.3.1.1~13,17~.0~1,6~.0~20,25~]pentatriaconta-7,17-diene-19,26-dione | C69H106INO12Si2 | 详情 | 详情 | |
| (XXXIV) | 57329 | (9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-allyl-12-[(E)-2-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-14-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-2-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0~4,9~]octacosa-1,18-diene-3,10,16-trione | C66H101NO11Si2 | 详情 | 详情 |