E-7389, B-1939, NSC-707389, ER-086526

艾日布林Chemical Name: (1S,3S,6S,9S,12S,14R,16R,18S,20R,21R,22S,26R,29S,31R,32S,35R,36S)-20-[3-Amino-2(S)-hydroxypropyl]-21-methoxy-14-methyl-8,15-dimethylene-2,19,30,34,37,39,40,41-octaoxanonacyclo[24.9.2.1(3,32).1(3,33).1(6,9).1(12,16).0(18,22).0(29,36).0(31,35)]hentetracontan-24-one; (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-2-[3-Amino-2(S)-hydroxypropyl]-3-methoxy-26-methyl-20,27-bis(methylene)-11,15:18,21:24,28-triepoxy-7,9-ethano-12,15-methanoperhydro-9H,15H-furo[3,2-i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5-one
CAS No. 253128-41-5
项目整合开发状态: Phase I
项目研究机构: Eisai (Originator), National Cancer Institute (Codevelopment)
合成路线:Treatment of L-arabinose (I) with tert-butyldiphenylsilyl chloride and imidazole provided the mono-silylated furanose (II).The free hydroxyl groups of (II) were subsequently acylated with Ac2O,yielding the triacetate (III).Introduction of an allyl group in (III) by using the silyl reagent (IV) and boron trifluoride produced the allyl derivative (V) as a diastereomeric mixture.After basic hydrolysis of the acetate esters of (V),the required diastereoisomer (VI) was isolated by means of flash chromatography.Regioselective silylation of diol (VI) with tert-butyldiphenylsilyl chloride furnished (VII).Following methylation of the remaining free hydroxyl,the resultant methyl ether (VIII) was desilylated with methanolic HCl,giving diol (IX).Protection of the primary alcohol of (IX) was accomplished by acylation with pivaloyl chloride in pyridine,yielding (X).The secondary alcohol group of (X) was then converted to the benzyl ether (XI).Subsequent Sharpless asymmetric dihydroxylation of the allyl moiety of (XI) produced glycol (XII).

合成路线:After silylation of diol (XII) to give (XIII),the O-benzyl group of (XIII) was removed by hydrogenolysis in the presence of Pearlman抯 catalyst,yielding alcohol (XIV).Oxidation of alcohol (XIV) to the corresponding ketone (XV) was carried out by means of N-methylmorpholine-N-oxide in the presence of a catalytic amount of tetrapropylammonium perruthenate (TPAP).Ketone (XV) was then converted to the methylene derivative (XVI) by treatment with Tebbe's reagent,generated from bis(cyclopentadienyl)titanium and trimethylaluminum.Olefin (XVI) hydroboration by means of 9-borabicyclononane,followed by oxidative work-up with sodium perborate,provided the primary alcohol (XVII) as the undesired diastereoisomer.Configuration of alcohol (XVII) was inverted via Swern oxidation to the corresponding aldehyde,which was epimerized to (XVIII) under basic conditions.Further,aldehyde (XVIII) reduction with NaBH4 at 0 C generated alcohol (XIX).This was protected as the methoxybenzyl ether (XXI) by condensation with p-methoxybenzyl trichloroacetimidate (XX).The pivaloyl ester of (XXI) was then removed by reductive cleavage with LiAlH4,affording alcohol (XXII).

合成路线:Homologation of alcohol (XXII) was effected by Swern oxidation to aldehyde (XXIII),which was then converted to the vinyl derivative (XXIV) by Wittig reaction with methylene triphenylphosphorane.Hydroboration of olefin (XXIV),followed by oxidative work-up,furnished alcohol (XXV).This was subjected to a further Swern oxidation to aldehyde (XXVI).Coupling of aldehyde (XXVI) with the known vinyl iodide (XXVII) produced a mixture of pyran derivative (XXVIII) and some uncyclized intermediate.Cyclization to (XXVIII) was completed by subsequent treatment of the reaction mixture with potassium hexamethyldisilazide.The p-methoxybenzyl protecting group of (XXVIII) was removed by oxidative treatment with DDQ.The desired diastereomer (XXIX) was then isolated by column chromatography.

合成路线:Alcohol (XXIX) was converted to the corresponding tosylate (XXX) employing p-toluenesulfonyl chloride and pyridine.Replacement of the pivaloyl protecting group of (XXX) for a mono-methoxytrityl group,yielding (XXXII),was effected by reductive cleavage of the pivaloyl ester of (XXX) and then treatment of alcohol (XXXI) with methoxytrityl chloride.Displacement of the tosylate group of (XXXII) by NaI in refluxing acetone provided the alkyl iodide (XXXIII).

合成路线:The aldehyde building block (XXXV) was obtained by DIBAL reduction of the previously described methyl ester (XXXIV).Lithiation of alkyl iodide (XXXIII) by means of tert-BuLi and then addition to aldehyde (XXXV) furnished the carbinol adduct (XXXVI).The methoxytrityl protecting group of (XXXVI) was then removed by acidic treatment,yielding (XXXVII).Oxidation of both free hydroxyl groups of (XXXVII) with Dess-Martin periodinane reagent gave rise to the keto aldehyde (XXXVIII).

合成路线:An alternative,more convenient preparation of intermediate (XXXVIII) from (XXIX) was also reported.Activation of alcohol (XXIX) as the triflate (XXXIX) by means of trifluoromethanesulfonic anhydride,followed by condensation with thiophenol,gave the phenyl thioether (XL).This was oxidized to sulfone (XLI) using N-methylmorpholine-N-oxide in the presence of TPAP.The pivaloyl protecting group of (XLI) was reductively cleaved with DIBAL,giving (XLII).The lithium anion generated from sulfone (XLII) in the presence of n-BuLi was then condensed with aldehyde (XXXV) to furnish the carbinol adduct (XLIII).