A Highly Efficient and Commercially Important Synthesis of the Antitumor Catharanthus Alkaloids Vinblastine and Leurosidine from Catharanthine and Vindoline

Abstract

Extensive studies of various reaction parameters for the chemical coupling of catharanthine (1) and vindollne (2) followed by evaluation of highly unstable intsrmsdiatcn by careful reaction control have provided essentially a quantitative yiald in thia coupling reaction.Subsequent regloselective reduction of the resultant intermediate 3 by selcst NADH models afford.a high yield of an enamins (5) which.without isolation, is ~sleetively oxidlrad to unstable iminivm intermediates 6 and 7 and the latter, again without isolation.are finally reduced to vinblastins (8, 401).laurosidine (10.161).and 3',4'-enhydrovinblastine (4.121).The entire process of five steps ( 1 4 1 1 + 2-+3 -+5 -+6,7-+8,10,4) can be achisvsd in a one-pot operation and the high overall yield of vinblsstine (8) requires that each reaction must proceed in yields in excess of 801.hlr .USECIS in the biomimetic conversion of 3'.4'-anhydrovinbla.tins(4) to the important anticancer drug, vinblastins (8).as described in the pracedlng publlcationl, ha.prompted u8 to investigate the adaptation of such a synthetic sequence towards an efficient aynth~sis of 8, and in a manner which may be applied subsequently for industrial production (Scheme 1).The important features of the above biomimetlc synthesis include: (a) the established pivotal role of the conjugated iminium intermediate 3 between the two mnomeric alkaloids, catharanthine (1) end vindoline ( 2 ) , and the vinblastlne family of bisindolc alkaloids: (b) rsgiooelective 1.4-reduction of 3 to the key enmine intermediate 5 by 8-NADH; ' C to 20° C.