New routes to arylated azabicyclic systems from enaminones, and applications to alkaloid synthesis

Morgans, Garreth Llewellyn
Journal Title
Journal ISSN
Volume Title
This thesis describes the application of enaminones towards the construction of azabicyclic systems. After a brief survey of indolizidine alkaloids bearing aromatic substituents an overview of the general strategies developed in laboratories at this University for the synthesis of alkaloids is given in Chapter 1. More specifically, the use of the Eschenmoser sulfide contraction for the construction of vinylogous amides is central to the work presented in this thesis. Syntheses of nitrile containing indolizidine systems are described in chapter 2. Preliminary reactions towards this goal included the preparation of the vinylogous amide 3-{2-[(E)-2-oxo-2-phenylethylidene]-1-pyrrolidinyl}propanenitrile [157] by application of Eschenmoser’s sulfide contraction reaction to the appropriate thiolactam 3-(2-thioxo-1-pyrrolidinyl)propanenitrile [168A]. In addition, the vinylogous amide was reduced to afford the key amino-ketone 3-[2-(2-oxo-2-phenylethyl)-1-pyrrolidinyl]propanenitrile [160]. Cyclization of this intermediate afforded the vinylogous amides rel-(7R,8aS)-7-phenyl- 1,2,3,7,8,8a-hexahydro-6-indolizinecarbonitrile [179A] and rel-(7R,8aR)-7- phenyl-1,2,3,7,8,8a-hexahydro-6-indolizinecarbonitrile [179B] under specific reaction conditions. By altering the reaction conditions, an additional three products were isolated and characterized; a result that allowed for a step-bystep elucidation of the reaction mechanism for conversion of the aminoketone 3-{2-[(E)-2-oxo-2-phenylethylidene]-1-pyrrolidinyl}propanenitrile [157] into the vinylogous amides rel-(7R,8aS)-7-phenyl-1,2,3,7,8,8a-hexahydro-6- indolizinecarbonitrile [179A] and rel-(7R,8aR)-7-phenyl-1,2,3,7,8,8a-hexahydro- 6-indolizinecarbonitrile [179B]. In addition, approaches to sulfonecontaining indolizidine systems were explored. Approaches to the syntheses of the pyrrolidine 2-[1-(2-oxo-2-phenylethyl)-2- pyrrolidinyl]-1-phenyl-1-ethanone [172A], a key precursor for the construction Chapter 3. In trying to achieve this strategy, we found that synthesis of the intermediate pyrrolidine 2-[1-(2-oxo-2-phenylethyl)-2-pyrrolidinyl]-1-phenyl-1- ethanone [172A] proved to be non-trivial. Therefore the timing of reaction sequences and assembly of the N-alkyl chain was a necessary part of the strategy. A serendipitous discovery during this part of the research was the facile acid-induced cyclization of the vinylogous amides with an N-phenacyl group which lead to the formation of the pyrrolizine system. Therefore, Chapter 4 describes some of the approaches that were attempted in constructing this class of nitrogen-containing compound. More specifically, we explored the ambident nucleophilicity and electrophilicity of vinylogous amides towards the construction of the pyrrolizine system. The chapter ends by extending this approach towards the potential synthesis of the lamellarin class of alkaloids by application of this novel cyclization strategy.