Synthetic approaches to quinolizidine alkaloids.

[摘要] An outline of reported synthetic routes to the Lupinealkaloids, epilamprolobine [2] and lamprolobine [3] and areview of the use of vinylogous amides and urethanes asprecursors for the synthesis of alkaloids are presented inChapter 1. This is followed by a presentation of ourstrategy for synthesis of the two Lupine alkaloids.Vinylogous cyanamide intermediate 1- (3-hydroxypropyl) -2-cyanomethylenepiperidine [68] plays a key role in thisstrategy, since exploitation of its ambident nucleophilicity forms the central theme of this project,The successful route to the intermediate [68] involved thepreliminary preparation of the tertiary thiolactam, 1-(2-ethoxycarbonylethyl)piperidine-2-thione [83][ by thiationof the secondary lactam 2-piperidinone [72] and conjugateaddition at nitrogen with ethyl acrylate in a Michaelreaction. Sulphur extrusion of the salt made from [83] andbromoacetonitrile and subsequent reduction of the estergroup provided the pivotal vinylogous cyanamide intermediate.A number; of alternative routes based on 5-bromopentanoic acid [80], 1-allyl-2-piperidinone [73] andthiolactams [84J and [105] were unsuccessful.Cyclisation of the intermediate [68] was achieved by anintramolecular c-alkylative ring closure via thecorresponding tosylate [l16] to forln an unsaturatedfunctionalised quinolizidine [69]. Stereoselective carboncarbondouble bond reduction and nitrile reduction resultedin the synthesis of two quinolizidines. lupinamine [11] andepilupinamine [112]. Further transformations led to theformation of the derivatives, N-acetyllupinamine [113] andN-acetylepilupinamine [114], and also to the targetalkaloids, epilamprolcbine [2] and lamprolobine [3].

[发布机构] University of the Witwatersrand