New routes to arylated azabicyclic systems from enaminones, and applications to alkaloid synthesis
Date
2009-04-09T12:41:30Z
Authors
Morgans, Garreth Llewellyn
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Abstract
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.