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【结 构 式】 
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【分子编号】11491 【品名】(3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl-N,N,N',N'-tetramethylphosphonic diamide 【CA登记号】 |
【 分 子 式 】C28H61N2O4PS2Si 【 分 子 量 】612.994682 【元素组成】C 54.86% H 10.03% N 4.57% O 10.44% P 5.05% S 10.46% Si 4.58% |
合成路线1
该中间体在本合成路线中的序号：(XX)The total synthesis of FK-506 is described: This synthesis was performed by previously constructing three building fragments (XX), (XXXII) and (XLVI), which later were coupled sequentially. First the synthesis of these fragments will be presented, and afterwards their sequential coupling will be described. 1) (2RS,4R,6S,7R,8S,10R)-2-(Bis(dimethylamino)phosphono)-7-(tert-butyldimethylsilyloxy)-6,8-dimethoxy-10-(1,3-dithian-2-yl)-4-methylundecane (XX). The reaction of L-arabitol (I) with 2-acetoxyisobutyryl chloride in acetonitrile gives the diacetoxycompound (II), which by treatment with sodium methoxide in THF yields (2S,4S)-1,2:4,5-diepoxy-3-pentanol (III). The protection of (III) with TBS-Cl in THF affords the protected compound (IV), which is condensed with ethoxyacetylene (V) by means of butyllithium and boron trifluoride ethearate in THF giving the diacetylenic alcohol (VI). Cyclization of (VI) by means of HgCl2 and p-toluenesulfonic acid in refluxing ethanol yields the dilactone (VII), which is methylated by means of methyl iodide and lithium diisopropylamide in THF affording the methylated dilactone (VIII). The deprotection of (VIII) with HF in acetonitrile gives the hydroxydilactone (IX), which is benzylated with benzyl trichloroacetimidate and trifluoromethanesulfonic acid in dichloromethane-cyclohexane yielding the benzyl protected dilactone (X). The methanolysis of (X), followed by methylation with NaH and methyl iodide in DMF affords the nonanedioic ester (XI), which is debenzylated by hydrogenolysis with H2 over Pd/C in ethyl acetate giving the hydroxy diester (XII). The lactonization of (XII) with pyridinium p-toluenesulfonate in dichloromethane yields the lactone-methyl ester (XIII), which is selectively reduced with L-Selectride in THF affording the lactol-methyl ester (XIV). The reaction of (XIV) with propane-1,3-dithiol and boron trifluoride ethearate in dichloromethane gives the 1,3-dithiane derivative (XV), which by reduction of its lactone group with LiAlH4 in THF yields (2R,4S,5R,6S,8R)-8-(1,3-dithian-2-yl)-4,6-dimethoxy-2-methylnonane-1,5-diol (XVI). The reaction of (XVI) with I2, pyridine and triphenylphosphine in benzene affords the 1-iodo derivative (XVII), which is protected with TBS trifluoromethanesulfonate and triethylamine in dichloromethane giving the protected iodide (XVIII). Finally, this compound is condensed with ethylphosphonic acid bis(dimethylamide) (XIX) by means of butyllithium in THF to afford the first building fragment (XX).
| 【1】 Smith, D.B.; Schreiber, S.L.; Ragan, J.A.; Uehling, D.E.; Nakatsuka, M.; Sammakia, T.; Total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK5. J Am Chem Soc 1990, 112, 14, 5583. |
| 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) | 11442 | (2S,4S)-1,2,3,4,5-Pentanepentol; D-Arabinol | 488-82-4 | C5H12O5 | 详情 | 详情 |
| (II) | 11439 | [(3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-di[1,3]dioxolo[4,5-b:4,5-d]pyran-5-yl]methyl 4-methylbenzenesulfonate | C19H26O8S | 详情 | 详情 | |
| (III) | 11444 | Di[(2S)oxiranyl]methanol | C5H8O3 | 详情 | 详情 | |
| (IV) | 11445 | tert-Butyl(dimethyl)silyl di[(2S)oxiranyl]methyl ether; tert-Butyl[di[(2S)oxiranyl]methoxy]dimethylsilane | C11H22O3Si | 详情 | 详情 | |
| (V) | 11446 | 1-Ethoxyacetylene; Ethyl ethynyl ether.; Ethoxyethyne | 927-80-0 | C4H6O | 详情 | 详情 |
| (VI) | 11447 | (4S,6S)-5-[[tert-Butyl(dimethyl)silyl]oxy]-1,9-diethoxy-1,8-nonadiyne-4,6-diol | C19H34O5Si | 详情 | 详情 | |
| (VII) | 11448 | (5S)-5-[[[tert-Butyl(dimethyl)silyl]oxy][(2S)-5-oxotetrahydro-2-furanyl]methyl]dihydro-2(3H)-furanone | C15H26O5Si | 详情 | 详情 | |
| (VIII) | 11449 | (3R,5S)-5-[[[tert-Butyl(dimethyl)silyl]oxy][(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]methyl]-3-methyldihydro-2(3H)-furanone | C17H30O5Si | 详情 | 详情 | |
| (IX) | 11450 | (3R,5S)-5-[Hydroxy[(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]methyl]-3-methyldihydro-2(3H)-furanone | C11H16O5 | 详情 | 详情 | |
| (X) | 11451 | 5-(2-Bromophenyl)-1-(4-nitrophenyl)-1H-1,2,3,4-tetraazole | C13H8BrN5O2 | 详情 | 详情 | |
| (XI) | 11452 | dimethyl (2R,4S,6S,8R)-5-(benzyloxy)-4,6-dimethoxy-2,8-dimethylnonanedioate | C22H34O7 | 详情 | 详情 | |
| (XII) | 11453 | dimethyl (2R,4S,6S,8R)-5-hydroxy-4,6-dimethoxy-2,8-dimethylnonanedioate | C15H28O7 | 详情 | 详情 | |
| (XIII) | 11454 | methyl (2R,4S)-4-methoxy-4-[(2S,3S,5R)-3-methoxy-5-methyl-6-oxotetrahydro-2H-pyran-2-yl]-2-methylbutanoate | C14H24O6 | 详情 | 详情 | |
| (XIV) | 11455 | methyl (2R,4S)-4-[(2S,3S,5R)-6-hydroxy-3-methoxy-5-methyltetrahydro-2H-pyran-2-yl]-4-methoxy-2-methylbutanoate | C14H26O6 | 详情 | 详情 | |
| (XV) | 11456 | (3R,5S,6R)-6-[(1S,3R)-3-(1,3-Dithian-2-yl)-1-methoxybutyl]-5-methoxy-3-methyltetrahydro-2H-pyran-2-one | C16H28O4S2 | 详情 | 详情 | |
| (XVI) | 11457 | (2R,4S,5R,6S,8R)-8-(1,3-Dithian-2-yl)-4,6-dimethoxy-2-methyl-1,5-nonanediol | C16H32O4S2 | 详情 | 详情 | |
| (XVII) | 11458 | (2R,4S,5S,6S,8R)-8-(1,3-Dithian-2-yl)-1-iodo-4,6-dimethoxy-2-methyl-5-nonanol | C16H31IO3S2 | 详情 | 详情 | |
| (XVIII) | 11459 | tert-Butyl([(1S,2S,4R)-1-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-5-iodo-2-methoxy-4-methylpentyl]oxy)dimethylsilane; tert-Butyl(dimethyl)silyl (1S,2S,4R)-1-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-5-iodo-2-methoxy-4-methylpentyl ether | C22H45IO3S2Si | 详情 | 详情 | |
| (XIX) | 11460 | Ethyl-N,N,N',N'-tetramethylphosphonic diamide | C6H17N2OP | 详情 | 详情 | |
| (XX) | 11491 | (3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl-N,N,N',N'-tetramethylphosphonic diamide | C28H61N2O4PS2Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XX)5) A second coupling reaction was the addition of the phosphonamide (XX) to the aldehyde (LI) by means of butyllithium in THF to give the dithianylolefin (LII), which was treated first with TFIB and methanol and then with acetic acid, yielding the free aldeyde (LIII). The condensation of (LIII) with methyl 2-(2,4-dimethoxybenzyloxy)acetate (LIV) by means of lithium diisopropylamide in THF, followed by a treatment with LiOH affords the hydroxy acid (LV), which is protected with TES trifluoromethylsulfonate and treated with 2,6-dimethylpyridine to give the free amino acid (LVI), the open-chain precursor of FK-506.
| 【1】 Smith, D.B.; Schreiber, S.L.; Ragan, J.A.; Uehling, D.E.; Nakatsuka, M.; Sammakia, T.; Total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK5. J Am Chem Soc 1990, 112, 14, 5583. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 33696 | 3-[([1-[(1-[[(3-hydroxypropyl)amino]methyl]cyclohexyl)disulfanyl]cyclohexyl]methyl)amino]-1-propanol | C20H40N2O2S2 | 详情 | 详情 | ||
| (XX) | 11491 | (3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl-N,N,N',N'-tetramethylphosphonic diamide | C28H61N2O4PS2Si | 详情 | 详情 | |
| (LI) | 11490 | 1-(tert-butyl) 2-[(1S,2S,3S,5S,6S)-6-formyl-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2-methyl-3-[(triisopropylsilyl)oxy]-8-nonenyl] (2S)-1,2-piperidinedicarboxylate | C58H101NO9Si2 | 详情 | 详情 | |
| (LII) | 11492 | 2-[(1S,2S,3S,5S,6S,7E,10S,12S,13R,14S,16R)-6-allyl-16-(1,3-dithian-2-yl)-12,14-dimethoxy-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10-trimethyl-3,13-bis[(triisopropylsilyl)oxy]-7-heptadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C85H155NO11S2Si3 | 详情 | 详情 | |
| (LIII) | 11493 | 2-[(1S,2S,3S,5S,6S,7E,10S,12S,14R,15S,16R)-6-allyl-15-[[tert-butyl(dimethyl)silyl]oxy]-12,14-dimethoxy-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-17-oxo-3-[(triisopropylsilyl)oxy]-7-heptadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C79H143NO12Si3 | 详情 | 详情 | |
| (LIV) | 57274 | methyl 2-[(2,4-dimethoxybenzyl)oxy]acetate | C12H16O5 | 详情 | 详情 | |
| (LV) | 11494 | 2-[(1S,2S,3S,6S,7E,10S,12S,13R,14S,16R)-6-allyl-13-[[tert-butyl(dimethyl)silyl]oxy]-18-[(2,4-dimethoxybenzyl)oxy]-17-hydroxy-12,14,19-trimethoxy-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-19-oxo-3-[(triisopropylsilyl)oxy]-7-nonadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C91H159NO17Si3 | 详情 | 详情 | |
| (LVI) | 11495 | (4R,6S,7R,8S,10S,12E,14R,15S,17S,18S,19S,20E)-14-Allyl-7-[[tert-butyl(dimethyl)silyl]oxy]-2-[(2,4-dimethoxybenzyl)oxy]-6,8-dimethoxy-15-[(4-methoxybenzyl)oxy]-21-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,10,12,18,20-pentamethyl-19-[[(2S)piperidinylcarbonyl]oxy]-3-[(triethylsilyl)oxy]-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoic acid | C91H163NO16Si4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXXII)The intermediate chiral phosphonamide (XXXII) has been obtained as follows: The treatment of arabitol (XIX) with the Moffat reagent (alpha-acetoxy-isobutyric acyl chloride) (XX) gives the intermediate (XXI), which, without isolation, by treatment with NaOMe and with Tbdms-Cl yields the silylated diepoxide (XXII). The condensation of (XXII) with ethoxyethynyl lithium (XXIII) by means of BF3/Et2O, HgCl2 and Ts-OH affords the bis(lactone) (XXIV), which is methylated by means of methyl iodide and LDA to provide the dimethyl analogue (XXV). The hydrolysis and desilylation of (XXV) by means of HF, followed by reprotection with benzyl trichloroacetimidate, and exhaustive methylation with NaH and methyl iodide gives the chiral nonanedioic dimethyl ester (XXVI). The reductive cleavage of the benzyl ether group with H2 over Pd(OH)2, followed by cyclization by means of PPTS yields the lactone (XXVII). The reduction of (XXVII) with L-selectride, followed by protection with propane-1,3-dithiol and BF3/Et2O affords the 1,3-dithiane (XXVIII). The reduction of the lactone group of (XXVIII) with LiAlH4, followed by reaction with PPh3 and I2 provides the chiral nonyl iodide (XXIX). The protection of the OH group of (XXIX) by means of Tbdms-OTf gives the silyl ether (XXX), which is finally condensed with lithium derived ethylphosphonamide (XXXI) to yield the intermediate chiral phosphonamide (XXXII).
| 【1】 Ragan, J.A.; The total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK506. Diss Abstr Int B - Sci Eng 1991, 51, 8, 3849. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 11442 | (2S,4S)-1,2,3,4,5-Pentanepentol; D-Arabinol | 488-82-4 | C5H12O5 | 详情 | 详情 |
| (XX) | 32808 | 2-chloro-1,1-dimethyl-2-oxoethyl acetate | 40635-66-3 | C6H9ClO3 | 详情 | 详情 |
| (XXI) | 57258 | (1R,3R)-3-(acetyloxy)-4-chloro-1-(chloromethyl)-2-hydroxybutyl acetate | C9H14Cl2O5 | 详情 | 详情 | |
| (XXII) | 11445 | tert-Butyl(dimethyl)silyl di[(2S)oxiranyl]methyl ether; tert-Butyl[di[(2S)oxiranyl]methoxy]dimethylsilane | C11H22O3Si | 详情 | 详情 | |
| (XXIII) | 55241 | (2-ethoxyethynyl)lithium | C4H5LiO | 详情 | 详情 | |
| (XXIV) | 11448 | (5S)-5-[[[tert-Butyl(dimethyl)silyl]oxy][(2S)-5-oxotetrahydro-2-furanyl]methyl]dihydro-2(3H)-furanone | C15H26O5Si | 详情 | 详情 | |
| (XXV) | 11449 | (3R,5S)-5-[[[tert-Butyl(dimethyl)silyl]oxy][(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]methyl]-3-methyldihydro-2(3H)-furanone | C17H30O5Si | 详情 | 详情 | |
| (XXVI) | 11452 | dimethyl (2R,4S,6S,8R)-5-(benzyloxy)-4,6-dimethoxy-2,8-dimethylnonanedioate | C22H34O7 | 详情 | 详情 | |
| (XXVII) | 11454 | methyl (2R,4S)-4-methoxy-4-[(2S,3S,5R)-3-methoxy-5-methyl-6-oxotetrahydro-2H-pyran-2-yl]-2-methylbutanoate | C14H24O6 | 详情 | 详情 | |
| (XXVIII) | 11456 | (3R,5S,6R)-6-[(1S,3R)-3-(1,3-Dithian-2-yl)-1-methoxybutyl]-5-methoxy-3-methyltetrahydro-2H-pyran-2-one | C16H28O4S2 | 详情 | 详情 | |
| (XXIX) | 11458 | (2R,4S,5S,6S,8R)-8-(1,3-Dithian-2-yl)-1-iodo-4,6-dimethoxy-2-methyl-5-nonanol | C16H31IO3S2 | 详情 | 详情 | |
| (XXX) | 11459 | tert-Butyl([(1S,2S,4R)-1-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-5-iodo-2-methoxy-4-methylpentyl]oxy)dimethylsilane; tert-Butyl(dimethyl)silyl (1S,2S,4R)-1-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-5-iodo-2-methoxy-4-methylpentyl ether | C22H45IO3S2Si | 详情 | 详情 | |
| (XXXI) | 57259 | {1-[bis(dimethylamino)phosphoryl]ethyl}lithium | C6H16LiN2OP | 详情 | 详情 | |
| (XXXII) | 11491 | (3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl-N,N,N',N'-tetramethylphosphonic diamide | C28H61N2O4PS2Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXXII)The condensation of carbaldehyde (XLVIII) with the chiral intermediate phosphonamide (XXXII), by means of BuLi, gives the adduct (XLIX), which is treated with phenyliodonium trifluoroacetate and AcOH to cleave the 1,3-dithiane ring and yield the carbaldehyde (L). The cyclocondensation of (L) with 2-(2,4-dimethoxybenzyloxy)acetic acid methyl ester (LI) by means of LDA, LiOH, TesOTf and 2-chloro-1-methylpyridinium iodide (CMPI) affords the macrolactone (LII), which is submitted to a sequence of deprotection (DDQ), oxidation (DMP), deprotection (TFA) and oxidation (DMP) to provide the tricarbonyl compound (LIII). A similar sequence (TFA, DMP, DDQ, and DMP) can also be used to obtain the tricarbonyl compound (LIII). Finally this compound is fully desilylated by means of HF in acetonitrile to provide the target FK-506.
| 【1】 Ragan, J.A.; The total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK506. Diss Abstr Int B - Sci Eng 1991, 51, 8, 3849. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXII) | 11491 | (3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl-N,N,N',N'-tetramethylphosphonic diamide | C28H61N2O4PS2Si | 详情 | 详情 | |
| (XLVIII) | 57271 | 1-(tert-butyl) 2-{(1S,2S,3S,5S,6S)-6-formyl-5-[(4-methoxybenzyl)oxy]-1-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-2-methyl-3-[(triisopropylsilyl)oxy]-8-nonenyl} (2S)-1,2-piperidinedicarboxylate | C58H101NO10Si2 | 详情 | 详情 | |
| (XLIX) | 57272 | 2-{(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R)-6-allyl-13-{[tert-butyl(dimethyl)silyl]oxy}-16-(1,3-dithian-2-yl)-12,14-dimethoxy-5-[(4-methoxybenzyl)oxy]-1-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-2,8,10-trimet | C82H149NO12S2Si3 | 详情 | 详情 | |
| (L) | 57273 | 2-{(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R)-6-allyl-13-{[tert-butyl(dimethyl)silyl]oxy}-12,14-dimethoxy-5-[(4-methoxybenzyl)oxy]-1-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-2,8,10,16-tetramethyl-17-oxo-3-[(tr | C79H143NO13Si3 | 详情 | 详情 | |
| (LI) | 57274 | methyl 2-[(2,4-dimethoxybenzyl)oxy]acetate | C12H16O5 | 详情 | 详情 | |
| (LII) | 57275 | (3S,4S,5S,7S,8R,12S,14S,15R,16S,18R,26aS)-8-allyl-15-{[tert-butyl(dimethyl)silyl]oxy}-20-[(2,4-dimethoxybenzyl)oxy]-14,16-dimethoxy-7-[(4-methoxybenzyl)oxy]-3-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-4,10,12,18-tetramethyl-19-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,19,20,24,25,26,26a-octadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,21(4H,23H)-dione | C91H161NO15Si4 | 详情 | 详情 | |
| (LIII) | 11499 | (3S,4S,5S,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-15-[[tert-butyl(dimethyl)silyl]oxy]-14,16-dimethoxy-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,11,12,13,14,15,16,17,18,24,25,26,26a-tetradecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,7,19,20,21(4H,8H,23H)-pentone | C68H123NO12Si3 | 详情 | 详情 |