Synthetic approaches to quinolizidine alkaloids.

Abstract

An outline of reported synthetic routes to the Lupine alkaloids, epilamprolobine [2] and lamprolobine [3] and a review of the use of vinylogous amides and urethanes as precursors for the synthesis of alkaloids are presented in Chapter 1. This is followed by a presentation of our strategy for synthesis of the two Lupine alkaloids. Vinylogous cyanamide intermediate 1- (3-hydroxypropyl) -2- cyanomethylenepiperidine [68] plays a key role in this strategy, since exploitation of its ambident nucleophilicity forms the central theme of this project,

The successful route to the intermediate [68] involved the preliminary preparation of the tertiary thiolactam, 1-(2- ethoxycarbonylethyl)piperidine-2-thione [83][ by thiation of the secondary lactam 2-piperidinone [72] and conjugate addition at nitrogen with ethyl acrylate in a Michael reaction. Sulphur extrusion of the salt made from [83] and bromoacetonitrile and subsequent reduction of the ester group provided the pivotal vinylogous cyanamide intermediate. A number; of alternative routes based on 5- bromopentanoic acid [80], 1-allyl-2-piperidinone [73] and thiolactams [84J and [105] were unsuccessful.

Cyclisation of the intermediate [68] was achieved by an intramolecular c-alkylative ring closure via the corresponding tosylate [l16] to forln an unsaturated functionalised quinolizidine [69]. Stereoselective carboncarbon double bond reduction and nitrile reduction resulted in the synthesis of two quinolizidines. lupinamine [11] and epilupinamine [112]. Further transformations led to the formation of the derivatives, N-acetyllupinamine [113] and N-acetylepilupinamine [114], and also to the target alkaloids, epilamprolcbine [2] and lamprolobine [3].