Total Synthesis of Imidazole-Containing β-Carboline Alkaloids and Pyrrole-Imidazole Alkaloids

Abstract

The first part in this dissertation focuses on the development of an enantioselective total synthesis of villagorgin A, from another natural product haploscleridamine. Haploscleridamine was targeted first as it was thought that a successful approach to this family member would permit access to the other congeners through minor modifications, including conversion to villagorgin A. Moreover, villagorgin A has just one additional carbon atom compared to haploscleridamine, the introduction of which can be envisioned through a Pictet-Spengler reaction with formaldehyde. On completion of the haploscleridamine synthesis, attention was turned to the brominated congener, lissoclin C. Lissoclin C can be accessed from the same intermediate 3-piperidinone used en route to haploscleridamine by reaction with a different hydrazone derivative. The second part of this dissertation illustrates an approach, which relied on ring closing metathesis (RCM) to afford the key intermediate piperidinone which in turn was constructed from a protected histidine derivative. The RCM precursor was accessed by N-allylation and Grignard chemistry. Reduction followed by the installation of the indole moiety, put the finishing touches on the core framework. Deprotection then gave haploscleridamine. A subsequent hexafluroisopropanol-mediated Pictet-Spengler reaction provided villagorgin A. The third part of this dissertation describes the development of a synthetic route to assess the stereochemical purity of both haploscleridamine and villagorgin A. First the same synthetic sequence was conducted but with racemic histidine. Samples of racemic and non-racemic haploscleridamine and villagorgin A were assessed by HPLC using chiral column, they essentially gave indistinguishable results; each showed essentially a 1:1 mixture of both enantiomers. These results implied that our nominally asymmetric syntheses had delivered almost racemic products. An approach includes to minimize epimerization was developed avoiding the use of DIBAL-H in the reduction step. Repetition of the prior sequence delivered scalemic haploscleridamine and villagorgin A in 30% ee. The fourth part of this dissertation addresses the total synthesis of a pyrrole-imidazole alkaloids named ageliferin. It describes a method to construct the complete framework of ageliferin via a stereoselective intramolecular Diels Alder reaction and a detailed discussion of the problems that arise during the attempted installation of 2-amino group on the imidazole ring. Two different approaches were pursued for incorporation of the C2 amine to complete total synthesis of ageliferin either via C2 amination pre-Diels-Alder or C2 amination post Diels-Alder.