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.
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Kutney et al. (1988) studied this question.