|
【结 构 式】 
|
【分子编号】11439 【品名】[(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 【CA登记号】 |
【 分 子 式 】C19H26O8S 【 分 子 量 】414.47664 【元素组成】C 55.06% H 6.32% O 30.88% S 7.74% |
合成路线1
该中间体在本合成路线中的序号：(I)G-6-M is prepared as shown. All secondary hydroxyl groups of D-galactopyranose were protected by vicinal capping into bis(acetonides) yielding 1,2:3,4-di-O-isopropylidene-D-galactopyranose. This was tosylated at 6-CH2OH and alkylated at C-6 with diethanolamine. The hydroxyethyl groups of compound (II) were chlorinated and the acetonides deblocked with dilute aqueous acid to give 6-bis(2-chloroethyl)amino-6-deoxy-D-galactopyranose hydrochloride in an overall conversion of ca. 42%.
| 【1】 Plasee, T.F.; Galamustine Hydrochloride. Drugs Fut 1991, 16, 3, 205. |
| 【2】 Hammer, C.F.; Talebian, A.; Green, D.; McPherson, E.; Schein, P.S.; 6-bis-(2-Chloroethyl)amino-6-deoxy-D-galactopyranose hydrochloride: Synthesis, chemical characterization, murine P388 antitumor activity, and bone marrow toxicity. J Pharm Sci 1989, 78, 11, 918-21. |
| 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) | 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 | |
| (II) | 11440 | 2-[[[(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](2-hydroxyethyl)amino]-1-ethanol | C16H29NO7 | 详情 | 详情 | |
| (III) | 11441 | N-[[(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]-2-chloro-N-(2-chloroethyl)-1-ethanaminium | C16H28Cl2NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)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 |