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【结 构 式】

【分子编号】17351

【品名】benzyl (2S,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(2R)oxiranyl]butyl ether; ([(1S,2R)-1-[(benzyloxy)methyl]-2-[(2R)oxiranyl]propyl]oxy)(tert-butyl)dimethylsilane

【CA登记号】

【 分 子 式 】C19H32O3Si

【 分 子 量 】336.54678

【元素组成】C 67.81% H 9.58% O 14.26% Si 8.35%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(IX)

The synthesis of the C16-C34 fragment of tacrolimus (FK-506), the key intermediate on the total synthesis of tacrolimus has been described: 1) The reaction of (Z)-2-butene (I) with (­)-beta-methoxydiisopinocamphenylborane (IPCB-OCH3; II) by means of potassium tert-butoxide and butyllithium in THF gives the butenyl borane (III), which is condensed with 2-benzyl-acetaldehyde (IV) by means of BF3 ethearate in ether to yield the monobenzylated diol (V). The silylation of (V) with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole affords the fully protected olefine (VI), which is oxidized with OsO4 and N-methylmorpholine N-oxide (NMO) in acetone/water/benzene to give a diastereomeric mixture of the diols (VII) and (VIII) separated by column chromatography. The epoxidation of (VII) with NaH and tosyl imidazole in THF afforded epoxide (IX), which was condensed with the protected furfuryl alcohol (X) by means of butyllithium and BF3 ethearate in THF giving the diol (XI). The oxidation of (XI) with m-chloroperbenzoic acid (MCPBA) with simultaneous trapping of the intermediate with 2-methoxypropene (XII) afforded the spiroenone (XIII), which was condensed with alkyne (XIV) by means of trimethylaluminum and a zircornium complex yielding the expected spiroketone (XV). 2) The alkyne intermediate (XIV) has been obtained by condensation of the chiral tosylate (XXVII) with lithium acetylide giving the chiral pentynol ether (XVIII). (XVIII) then was deprotected with p-toluenesulfonic acid and silylated with TBDMS-Cl. 3) The undesired diol (VIII) can also be converted into the epoxide (IX) by reaction with benzoyl chloride and dimethylaminopyridine (DMAP) to give the expected benzoate, which was subsequently treated with methanesulfonyl chloride and DMAP, and finally epoxidized with sodium methoxide in methanol. 4) The diol (VII) can be selectively obtained by reaction of methyl 5-O-benzyl-beta-D-ribofuranoside (XXIV) with methylmagnesium chloride and copper bromide giving methyl 5-O-benzyl-3-deoxy-3-C-methyl-beta-D-xylofuranoside (XXV). (XXV) was treated with ethanethiol and TBDMS-Cl in the presence of imidazole and a catalytic amount of DMAP affording the dithioacetal (XXVI). Finally, this compound is treated with HgCl2 and CaCO3, and reduced with NaBH4 in THF/methanol to afford the desired diol (VII). 5) The intermediate vinyl bromide (XXIII) has been obtained according to a previously reported method (Ragan, J.A. et al. J Org Chem 1989, 54(18): 4267) .

1 Liu, L.B.; Roper, T.D.; Ireland, R.E.; Total synthesis of FK-506. 1. Construction of the C16-C34 fragment. Tetrahedron 1997, 53, 39, 13221.
2 Liu, L.B.; Roper, T.D.; Gleason, J.L.; Ireland, R.E.; Total synthesis of FK-506. 2. Completion of the synthesis. Tetrahedron 1997, 53, 39, 13257.
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) 17343 2-Butene-cis; (Z)-2-butene 590-18-1 C4H8 详情 详情
(II) 63308 methyl 2,7,7-trimethylbicyclo[4.1.0]hept-3-yl(5,7,7-trimethylbicyclo[4.1.0]hept-3-yl)borinate C21H37BO 详情 详情
(III) 17345 2-butenyl(2,7,7-trimethylbicyclo[4.1.0]hept-3-yl)(5,7,7-trimethylbicyclo[4.1.0]hept-3-yl)borane C24H41B 详情 详情
(IV) 17346 Benzyloxyacetaldehyde; 2-(Benzyloxy)acetaldehyde 60656-87-3 C9H10O2 详情 详情
(V) 17347 (2S,3R)-1-(benzyloxy)-3-methyl-4-penten-2-ol C13H18O2 详情 详情
(VI) 17348 benzyl (2S,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-pentenyl ether; ([(1S,2R)-1-[(benzyloxy)methyl]-2-methyl-3-butenyl]oxy)(tert-butyl)dimethylsilane C19H32O2Si 详情 详情
(VII) 17349 (2S,3R,4S)-5-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-1,2-pentanediol C19H34O4Si 详情 详情
(VIII) 17350 (2R,3R,4S)-5-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-1,2-pentanediol C19H34O4Si 详情 详情
(IX) 17351 benzyl (2S,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(2R)oxiranyl]butyl ether; ([(1S,2R)-1-[(benzyloxy)methyl]-2-[(2R)oxiranyl]propyl]oxy)(tert-butyl)dimethylsilane C19H32O3Si 详情 详情
(X) 17352 2-[(1-methoxy-1-methylethoxy)methyl]furan; 1-(2-furylmethoxy)-1-methylethyl methyl ether C9H14O3 详情 详情
(XI) 17353 (2S,3R,4S)-5-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-[5-(hydroxymethyl)-2-furyl]-3-methyl-2-pentanol C24H38O5Si 详情 详情
(XII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(XIII) 17355 4-((1R,2S)-3-(benzyloxy)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methylpropyl)-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-10-en-9-one C27H42O6Si 详情 详情
(XIV) 17356 tert-butyl(dimethyl)[[(2S)-2-methyl-4-pentynyl]oxy]silane; tert-butyl(dimethyl)silyl (2S)-2-methyl-4-pentynyl ether C12H24OSi 详情 详情
(XV) 17357 4-((1R,2S)-3-(benzyloxy)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methylpropyl)-11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undecan-9-one C40H70O7Si2 详情 详情
(XVII) 17358 (2R)-3-methoxy-2-methylpropyl 4-methylbenzenesulfonate C12H18O4S 详情 详情
(XVIII) 17359 (4S)-5-methoxy-4-methyl-1-pentyne; methyl (2S)-2-methyl-4-pentynyl ether C7H12O 详情 详情
(XXIV) 17360 (1S,2R,4R,5R)-2-[(benzyloxy)methyl]-4-methoxy-3,6-dioxabicyclo[3.1.0]hexane; benzyl [(1S,2R,4R,5R)-4-methoxy-3,6-dioxabicyclo[3.1.0]hex-2-yl]methyl ether C13H16O4 详情 详情
(XXV) 17361 (2R,3R,4R,5S)-5-[(benzyloxy)methyl]-2-methoxy-4-methyltetrahydro-3-furanol C14H20O4 详情 详情
(XXVI) 17362 (2R,3R,4S)-5-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-1,1-bis(ethylsulfanyl)-3-methyl-2-pentanol C23H42O3S2Si 详情 详情
Extended Information