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【结 构 式】

【药物名称】Khafrefungin

【化学名称】2(S),3(S),5-Trihydroxy-4(R)-[11(R)-hydroxy-2,4(R),6,8,10(S),12(S)-hexamethyl-5-oxodocosa-2(E),6(E),8(E)-trienoyloxy]pentanoic acid

【CA登记号】180992-28-3

【 分 子 式 】C33H56O9

【 分 子 量 】596.80887

【开发单位】Merck & Co. (Originator)

【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY

合成路线1

The condensation of decanal (I) with silyl enol ether (II) by means of a chiral catalyst and Sn(OTf)2 in dichloromethane gives the chiral thiocarboxylic ester (III), which is treated with chlorothioformate (IV) and pyridine in refluxing dichloroethane to yield the thiocarbonic ester (V). The reduction of (V) with Bu3SnH and AIBN in refluxing toluene affords the chiral thioester (VI), which is reduced with LiAlH4 in THF to provide the alcohol (VII). The oxidation of (VII) with oxalyl chloride in DMSO/dichloromethane gives the corresponding aldehyde (VIII), which is condensed with phosphorane (IX) to yield the unsaturated ester (X). The reduction of the ester group of (X) with DIBAL in dichloromethane affords the allyl alcohol (XI), which is submitted to a Sharpless epoxidation with tert-butyl hydroperoxide (TBHP) and Ti(O-iPr)4 in the presence of diethyl D-tartrate, providing the chiral epoxide (XII). Methylation of the epoxide ring of (XII) with MeLi and CuI in ethyl ether gives the diol (XIII), which is treated with the dimethyl acetal (XIV) and Ts-OH in dichloromethane to yield the 1,3-dioxane (XV). The reductive cleavage of (XV) with DIBAL in the same solvent affords the Pmb ether (XVI), whose primary alcohol is oxidized with oxalyl chloride in DMSO/dichloromethane to provide the aldehyde (XVII). The condensation of (XVII) with phosphorane (XVIII) in refluxing THF gives the unsaturated ester (XIX).

1 Wakabayashi, T.; Mori, K.; Kobayashi, S.; Total synthesis and structural elucidation of khafrefungin. J Am Chem Soc 2001, 123, 7, 1372.
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) 31059 decanal 112-31-2 C10H20O 详情 详情
(II) 47158 (Z)-1-(propylsulfanyl)-1-propenyl trimethylsilyl ether; trimethyl[[(Z)-1-(propylsulfanyl)-1-propenyl]oxy]silane C9H20OSSi 详情 详情
(III) 47159 S-propyl (2S,3R)-3-hydroxy-2-methyldodecanethioate C16H32O2S 详情 详情
(IV) 25805 1-[(chlorocarbothioyl)oxy]benzene; Phenylchlorothioformate 1005-56-7 C7H5ClOS 详情 详情
(V) 47160 S-propyl (2S,3R)-2-methyl-3-[(phenoxycarbothioyl)oxy]dodecanethioate C23H36O3S2 详情 详情
(VI) 47161 S-propyl (2S)-2-methyldodecanethioate C16H32OS 详情 详情
(VII) 47162 (2S)-2-methyl-1-dodecanol C13H28O 详情 详情
(VIII) 47163 (2S)-2-methyldodecanal C13H26O 详情 详情
(IX) 47164 propyl 2-(triphenylphosphoranylidene)acetate C23H23O2P 详情 详情
(X) 47165 propyl (E,4S)-4-methyl-2-tetradecenoate C18H34O2 详情 详情
(XI) 47166 (E,4S)-4-methyl-2-tetradecen-1-ol C15H30O 详情 详情
(XII) 47167 [(2S,3R)-3-[(1S)-1-methylundecyl]oxiranyl]methanol C15H30O2 详情 详情
(XIII) 47168 (2S,3R,4S)-2,4-dimethyl-1,3-tetradecanediol C16H34O2 详情 详情
(XIV) 26485 1-(dimethoxymethyl)-4-methoxybenzene 2186-92-7 C10H14O3 详情 详情
(XV) 47169 (4R,5S)-2-(4-methoxyphenyl)-5-methyl-4-[(1S)-1-methylundecyl]-1,3-dioxane; methyl 4-[(4R,5S)-5-methyl-4-[(1S)-1-methylundecyl]-1,3-dioxan-2-yl]phenyl ether C24H40O3 详情 详情
(XVI) 47170 (2S,3R,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-1-tetradecanol C24H42O3 详情 详情
(XVII) 47171 (2R,3R,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyltetradecanal C24H40O3 详情 详情
(XVIII) 47172 propyl 2-(triphenylphosphoranylidene)propanoate C24H25O2P 详情 详情
(XIX) 47173 propyl (E,4S,5R,6S)-5-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-hexadecenoate C30H50O4 详情 详情

合成路线2

The reduction of the ester group of (XIX) with DIBAL in dichloromethane gives the alcohol (XX), which is oxidized with TPAP and NMO in the same solvent, yielding the corresponding aldehyde (XXI). The condensation of (XXI) with phosphorane (XVIII) in refluxing THF affords the diunsaturated ester (XXII), which is reduced with DIBAL as before to provide the alcohol (XXIII). The oxidation of (XXIII) with TPAP and NMO as before gives the aldehyde (XXIV), which is condensed with the silyl enol ether (II) by means of Sn(OTf)2, Bu2Sn(OAc)2 and a chiral catalyst to yield the unsaturated thioester (XXV). The reaction of the OH group of (XXV) with Tes-OTf and lutidine in dichloromethane affords the silyl ether (XXVI), which is reduced with DIBAL in the same solvent to provide the corresponding aldehyde (XXVII).

1 Wakabayashi, T.; Mori, K.; Kobayashi, S.; Total synthesis and structural elucidation of khafrefungin. J Am Chem Soc 2001, 123, 7, 1372.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 47158 (Z)-1-(propylsulfanyl)-1-propenyl trimethylsilyl ether; trimethyl[[(Z)-1-(propylsulfanyl)-1-propenyl]oxy]silane C9H20OSSi 详情 详情
(XI) 47175 (E,4S,5R,6S)-5-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-hexadecenal C27H44O3 详情 详情
(XVIII) 47172 propyl 2-(triphenylphosphoranylidene)propanoate C24H25O2P 详情 详情
(XIX) 47173 propyl (E,4S,5R,6S)-5-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-hexadecenoate C30H50O4 详情 详情
(XX) 47174 (E,4S,5R,6S)-5-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-hexadecen-1-ol C27H46O3 详情 详情
(XXII) 47176 ethyl (2E,4E,6S,7R,8S)-7-[(4-methoxybenzyl)oxy]-2,4,6,8-tetramethyl-2,4-octadecadienoate C32H52O4 详情 详情
(XXIII) 47177 (2E,4E,6S,7R,8S)-7-[(4-methoxybenzyl)oxy]-2,4,6,8-tetramethyl-2,4-octadecadien-1-ol C30H50O3 详情 详情
(XXIV) 47178 (2E,4E,6S,7R,8S)-7-[(4-methoxybenzyl)oxy]-2,4,6,8-tetramethyl-2,4-octadecadienal C30H48O3 详情 详情
(XXV) 47179 S-propyl (2S,3S,4E,6E,8S,9R,10S)-3-hydroxy-9-[(4-methoxybenzyl)oxy]-2,4,6,8,10-pentamethyl-4,6-icosadienethioate C36H60O4S 详情 详情
(XXVI) 47180 S-propyl (2S,3S,4E,6E,8S,9R,10S)-9-[(4-methoxybenzyl)oxy]-2,4,6,8,10-pentamethyl-3-[(triethylsilyl)oxy]-4,6-icosadienethioate C42H74O4SSi 详情 详情
(XXVII) 47181 (2S,3S,4E,6E,8S,9R,10S)-9-[(4-methoxybenzyl)oxy]-2,4,6,8,10-pentamethyl-3-[(triethylsilyl)oxy]-4,6-icosadienal C39H68O4Si 详情 详情

合成路线3

The condensation of aldehyde (XXVII) with phosphorane (XVIII) in refluxing THF gives the triunsaturated ester (XXVIII), which is reduced with DIBAL in dichloromethane to yield the primary alcohol (XXIX), which is oxidized with TPAP and NMO, affording the aldehyde (XXX). Further oxidation of (XXX) with NaClO2 in tert-butanol/water provides the carboxylic acid (XXXI), which is esterified with the chiral alcohol (XXXII) by means of DCC and DMAP in refluxing dichloromethane to give the ester (XXXIII). Elimination of the silyl protecting groups of (XXXIII) with HCl in THF yields the dihydroxy compound (XXXIV). Oxidation of the secondary and primary OH groups of (XXXIV) with DMP and NaClO2 affords the corresponding oxo acid (XXXV), which is finally treated with BCl3 in dichloromethane to eliminate the Pmb protecting groups and afford the target compound.

1 Wakabayashi, T.; Mori, K.; Kobayashi, S.; Total synthesis and structural elucidation of khafrefungin. J Am Chem Soc 2001, 123, 7, 1372.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVIII) 47172 propyl 2-(triphenylphosphoranylidene)propanoate C24H25O2P 详情 详情
(XXVII) 47181 (2S,3S,4E,6E,8S,9R,10S)-9-[(4-methoxybenzyl)oxy]-2,4,6,8,10-pentamethyl-3-[(triethylsilyl)oxy]-4,6-icosadienal C39H68O4Si 详情 详情
(XXVIII) 47182 ethyl (2E,4R,5S,6E,8E,10S,11R,12S)-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-5-[(triethylsilyl)oxy]-2,6,8-docosatrienoate C44H76O5Si 详情 详情
(XXIX) 47183 (2E,4R,5S,6E,8E,10S,11R,12S)-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-5-[(triethylsilyl)oxy]-2,6,8-docosatrien-1-ol C42H74O4Si 详情 详情
(XXX) 47184 (2E,4R,5S,6E,8E,10S,11R,12S)-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-5-[(triethylsilyl)oxy]-2,6,8-docosatrienal C42H72O4Si 详情 详情
(XXXI) 47185 (2E,4R,5S,6E,8E,10S,11R,12S)-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-5-[(triethylsilyl)oxy]-2,6,8-docosatrienoic acid C42H72O5Si 详情 详情
(XXXII) 47186 (2R,3R,4R)-5-[[tert-butyl(dimethyl)silyl]oxy]-1,3,4-tris[(4-methoxybenzyl)oxy]-2-pentanol C35H50O8Si 详情 详情
(XXXIII) 47187 (1R,2S,3R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2,3-bis[(4-methoxybenzyl)oxy]-1-[[(4-methoxybenzyl)oxy]methyl]butyl (2E,4R,5S,6E,8E,10S,11R,12S)-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-5-[(triethylsilyl)oxy]-2,6,8-docosatrienoate C77H120O12Si2 详情 详情
(XXXIV) 47188 (1R,2S,3R)-4-hydroxy-2,3-bis[(4-methoxybenzyl)oxy]-1-[[(4-methoxybenzyl)oxy]methyl]butyl (2E,4R,5S,6E,8E,10S,11R,12S)-5-hydroxy-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-2,6,8-docosatrienoate C65H92O12 详情 详情
(XXXV) 47189 (2S,3S,4R)-2,3,5-tris[(4-methoxybenzyl)oxy]-4-([(2E,4R,6E,8E,10S,11R,12S)-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-5-oxo-2,6,8-docosatrienoyl]oxy)pentanoic acid C65H88O13 详情 详情

合成路线4

Synthesis of intermediates: Iodinated pivalate (X): The condensation of 3-iodo-2-methyl-2-propenal (I) with the silylated enol ether (II) by means of Zr(O-tBu)4 and 3,3'-I2-BINOL in toluene gives the iodopentenoic acid (III), which is treated with Tips-Cl and imidazole to yield the silyl ether (IV). The reduction of (IV) by means of DIBAL in dichloromethane affords the 5-iodopenten-1-ol (V), which is oxidized by means of (COCl)2 in DMSO/dichloromethane to provide the aldehyde (VI). The Wittig condensation of (VI) with phosphorane (VII) in refluxing THF leads to the heptadienoic ester (VIII), which is reduced with DIBAL in dichloromethane giving the primary alcohol (IX). Finally this alcohol is esterified pivaloyl chloride and pyridine to affords the target iodinated pivalate (X).

1 Kobayashi, S.; Mori, K.; Wakabayashi, T.; Yasuda, S.; Hanada, K.; Convergent total synthesis of khafrefungin and its inhibitory activity of fungal sphigolipid syntheses. J Org Chem 2001, 66, 16, 5580.
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) 37952 (E)-3-iodo-2-methyl-2-propenal C4H5IO 详情 详情
(II) 60333 phenyl 1-[(trimethylsilyl)oxy]-1-propenyl ether; trimethyl{[1-(phenyloxy)-1-propenyl]oxy}silane C12H18O2Si 详情 详情
(III) 60334 phenyl 3-hydroxy-5-iodo-2,4-dimethyl-4-pentenoate C13H15IO3 详情 详情
(IV) 60335 phenyl 5-iodo-2,4-dimethyl-3-{[tris(1-methylethyl)silyl]oxy}-4-pentenoate C22H35IO3Si 详情 详情
(V) 60336 5-iodo-2,4-dimethyl-3-{[tris(1-methylethyl)silyl]oxy}-4-penten-1-ol C16H33IO2Si 详情 详情
(VI) 60337 5-iodo-2,4-dimethyl-3-{[tris(1-methylethyl)silyl]oxy}-4-pentenal C16H31IO2Si 详情 详情
(VII) 47172 propyl 2-(triphenylphosphoranylidene)propanoate C24H25O2P 详情 详情
(VIII) 60338 propyl 7-iodo-2,4,6-trimethyl-5-{[tris(1-methylethyl)silyl]oxy}-2,6-heptadienoate C22H41IO3Si 详情 详情
(IX) 60339 7-iodo-2,4,6-trimethyl-5-{[tris(1-methylethyl)silyl]oxy}-2,6-heptadien-1-ol C19H37IO2Si 详情 详情
(X) 60340 7-iodo-2,4,6-trimethyl-5-{[tris(1-methylethyl)silyl]oxy}-2,6-heptadienyl 2,2-dimethylpropanoate C24H45IO3Si 详情 详情

合成路线5

Alkenylboronic acid (XV): The intermediate tetradecyl aldehyde derivative (XII) has been obtained by an already reported sequence (see scheme no. 23979101a, intermediates (I) to (XVII)) starting from decanal (XI). The reaction of aldehyde (XII) with CBr4 and PPh3 in dichloromethane gives the dibromovinyl derivative (XIII), which is treated with BuLi and Me-I in THF to yield the alkyne (XIV). Finally, this compound is condensed with catecholborane to provide the target alkenylboronic acid (XV).

1 Kobayashi, S.; Mori, K.; Wakabayashi, T.; Yasuda, S.; Hanada, K.; Convergent total synthesis of khafrefungin and its inhibitory activity of fungal sphigolipid syntheses. J Org Chem 2001, 66, 16, 5580.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 31059 decanal 112-31-2 C10H20O 详情 详情
(XII) 47171 (2R,3R,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyltetradecanal C24H40O3 详情 详情
(XIII) 60341 1-({[4,4-dibromo-2-methyl-1-(1-methylundecyl)-3-butenyl]oxy}methyl)-4-(methyloxy)benzene; 4,4-dibromo-2-methyl-1-(1-methylundecyl)-3-butenyl [4-(methyloxy)phenyl]methyl ether C25H40Br2O2 详情 详情
(XIV) 60342 1-({[2-methyl-1-(1-methylundecyl)-3-pentynyl]oxy}methyl)-4-(methyloxy)benzene; methyl 4-({[2-methyl-1-(1-methylundecyl)-3-pentynyl]oxy}methyl)phenyl ether C26H42O2 详情 详情
(XV) 60343 1,3,5-trimethyl-4-({[4-(methyloxy)phenyl]methyl}oxy)-1-pentadecenylboronic acid C26H45BO4 详情 详情

合成路线6

Synthesis of the target compound: The condensation of the iodinated pivalate (X) with the alkenylboronic acid (XV) by means of TlOEt and Pd(PPh3)4 in hot THF gives the adduct (XVI), which is treated with DIBAL in dichloromethane to eliminate the pivaloyl group and yield the primary alcohol (XVII). The oxidation of (XVII) with MnO2 affords the aldehyde (XVIII), which is oxidized to the carboxylic acid (XIX) by means of NaClO2 in tert-butanol/water. The esterification of acid (XIX) with alcohol (XX) by means of DCC and DMAP in refluxing dichloromethane affords the ester (XXI), which is desilylated by means of HCl in THF to provide the dihydroxy compound (XXII). The oxidation of diol (XXII) first with DMP and then with NaClO2 leads to the ketoacid (XXIII), which is finally debenzylated by a treatment with BCl3 in dichloromethane to give the target Khafrefungin.

1 Kobayashi, S.; Mori, K.; Wakabayashi, T.; Yasuda, S.; Hanada, K.; Convergent total synthesis of khafrefungin and its inhibitory activity of fungal sphigolipid syntheses. J Org Chem 2001, 66, 16, 5580.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XV) 60343 1,3,5-trimethyl-4-({[4-(methyloxy)phenyl]methyl}oxy)-1-pentadecenylboronic acid C26H45BO4 详情 详情
(XVI) 60344 7-iodo-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-2,6-heptadienyl 2,2-dimethylpropanoate C33H39IO3Si 详情 详情
(XVII) 60345 2,4,6,8,10,12-hexamethyl-11-({[4-(methyloxy)phenyl]methyl}oxy)-5-[(triphenylsilyl)oxy]-2,6,8-docosatrienyl 2,2-dimethylpropanoate C59H82O5Si 详情 详情
(XVIII) 60347 2,4,6,8,10,12-hexamethyl-11-({[4-(methyloxy)phenyl]methyl}oxy)-5-[(triphenylsilyl)oxy]-2,6,8-docosatrienal C54H72O4Si 详情 详情
(XIX) 60348 2,4,6,8,10,12-hexamethyl-11-({[4-(methyloxy)phenyl]methyl}oxy)-5-[(triphenylsilyl)oxy]-2,6,8-docosatrienoic acid C54H72O5Si 详情 详情
(XX) 47186 (2R,3R,4R)-5-[[tert-butyl(dimethyl)silyl]oxy]-1,3,4-tris[(4-methoxybenzyl)oxy]-2-pentanol C35H50O8Si 详情 详情
(XXI) 60350 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2,3-bis({[4-(methyloxy)phenyl]methyl}oxy)-1-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]butyl 2,4,6,8,10,12-hexamethyl-11-({[4-(methyloxy)phenyl]methyl}oxy)-5-[(triphenylsilyl)oxy]-2,6,8-docosatrienoate C89H120O12Si2 详情 详情
(XXII) 60349 4-hydroxy-2,3-bis({[4-(methyloxy)phenyl]methyl}oxy)-1-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]butyl 5-hydroxy-2,4,6,8,10,12-hexamethyl-11-({[4-(methyloxy)phenyl]methyl}oxy)-2,6,8-docosatrienoate C65H92O12 详情 详情
(XXIII) 60347 2,4,6,8,10,12-hexamethyl-11-({[4-(methyloxy)phenyl]methyl}oxy)-5-[(triphenylsilyl)oxy]-2,6,8-docosatrienal C54H72O4Si 详情 详情
Extended Information