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【结 构 式】 
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【分子编号】17343 【品名】2-Butene-cis; (Z)-2-butene 【CA登记号】590-18-1 |
【 分 子 式 】C4H8 【 分 子 量 】56.10752 【元素组成】C 85.63% H 14.37% |
合成路线1
该中间体在本合成路线中的序号：(I)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 |
合成路线2
该中间体在本合成路线中的序号：2) The condensation of 5,7-dihydroxy-4-propyl-2H-1-benzopyran-2-one (III) with N-methylformanilide (XII) by means of POCl3 in hot dichloromethane gives the carbaldehyde (XIII), which is cyclized with 3-chloro-3-methyl-1-butyne (XIV) by means of ZnCl2 /K2CO3 in hot 2-butanone/DMF, yielding the benzodipyran-carbaldehyde (XV). The enantioselective reaction of (XV) with 2(E)-butene and the chiral borane (+)-(E)-crotyldiisopinocamphenylborane (XVI) affords the single (R, R)-enatiomer (XVII). The selective silylation of (XVII) with TBDMS-Cl as usual gives the monosilyl ether (XVIII), which is cyclized by means of mercuric acetate and NaBH4 in THF, yielding the silylated (10R,11R,12R)-benzotripyran (XIX). The desilylation of (XIX) with tetrabutylammonium fluoride in THF gives the (10R,11S,12R)-benzotripyran (XX) (calanolide B), which is converted into calanolide A by inversion of the C-12 OH-group carried out with a modified Mitsunobu reaction with dimethyl azodicarboxylate (DEAD)/trimethylphosphine/chloroacetic acid in toluene/THF, followed by treatment with NH4OH in methanol.
| 【1】 Tagliaferri, F.; Deshpande, P.P.; Yan, S.; Victory, S.F.; Baker, D.C.; Synthesis of optically active calanoides A and B. J Org Chem 1995, 60, 10, 2964. |
| 【2】 Castañer, J.; Leeson, P.; Sorbera, L.A.; Calanolide A. Drugs Fut 1999, 24, 3, 235. |
| 【3】 Tagliaferri, F.; Yan, S.; Deshpande, P.P.; Baker, D.C.; Victory, S.F. (University of Tennessee, Knoxville); Synthesis of optically active calanolides A and B . US 5608085; WO 9626934 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17343 | 2-Butene-cis; (Z)-2-butene | 590-18-1 | C4H8 | 详情 | 详情 | |
| (III) | 22405 | 5,7-dihydroxy-4-propyl-2H-chromen-2-one | C12H12O4 | 详情 | 详情 | |
| (XII) | 20360 | methyl(phenyl)formamide;N-Methylformanilide;N-Formyl-N-methylaniline;Methylphenylformamide;N-methyl-N-phenylformamide;N-Methyl-N-formylaniline;N-Formyl-N-methylaniline | 93-61-8 | C8H9NO | 详情 | 详情 |
| (XIII) | 22415 | 5,7-dihydroxy-2-oxo-4-propyl-2H-chromene-8-carbaldehyde | C13H12O5 | 详情 | 详情 | |
| (XIV) | 22416 | 3-chloro-3-methyl-1-butyne | 1111-97-3 | C5H7Cl | 详情 | 详情 |
| (XV) | 22417 | 5-hydroxy-2,2-dimethyl-8-oxo-10-propyl-2H,8H-pyrano[2,3-f]chromene-6-carbaldehyde | C18H18O5 | 详情 | 详情 | |
| (XVI) | 22418 | (E)-2-butenyl[bis(2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)]borane | C24H41B | 详情 | 详情 | |
| (XVII) | 22419 | 5-hydroxy-6-[(1R,2R)-1-hydroxy-2-methyl-3-butenyl]-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one | C22H26O5 | 详情 | 详情 | |
| (XVIII) | 22420 | 6-((1R,2R)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-3-butenyl)-5-hydroxy-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one | C28H40O5Si | 详情 | 详情 | |
| (XIX) | 22421 | (10R,11R,12R)-12-[[tert-butyl(dimethyl)silyl]oxy]-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2H,6H,10H-dipyrano[2,3-f:2,3-h]chromen-2-one | C28H40O5Si | 详情 | 详情 | |
| (XX) | 22413 | (10R,11S,12R)-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2H,6H,10H-dipyrano[2,3-f:2,3-h]chromen-2-one | C22H26O5 | 详情 | 详情 |