Synthesis of amphibean indolizidine alkaloids and related compounds from enaminone precursors
Date
2008-06-20T09:11:57Z
Authors
Riley, Darren Lyall
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
The work discussed in this thesis is centered on the synthetic protocol developed for the
synthesis of alkaloids in the organic chemistry laboratories at the University of the
Witwatersrand. The alkaloids of interest in this thesis are the 5,8-disubstituted indolizidines
(-)-209I [185] and (-)-223V [174], the piperidine alkaloid (±)-thalictroidine [257] as well as
several 5-monosubstituted indolizidines including (±)-tashiromine [330a] and (±)-5-epitashiromine
[330b]. The work is put into perspective in two parts. The first part is a review of
all the classes of alkaloids that have currently been isolated and identified from the skin
extracts of amphibians, in particular the Dendrobatidae family of neotropical frogs. The
second part gives a chronological review of all previous racemic and enantioselective
syntheses of the 5,8-disubstituted indolizidines. This is followed by an overview of the
general synthetic approach used in the syntheses of alkaloids in the “Wits” laboratories.
Particular emphasis is placed on the enantioselective synthetic strategies, developed by
Gravestock, for the synthesis of 5,8-disubstituted indolizidine alkaloids. The aims and
strategies to be used in the present project are then introduced.
The racemic synthesis of (±)-thalictroidine [257], used in model studies in order to practice
fundamental functional group transformations for the preparation of piperidine systems is
reported. The key reactions introduced in this section were the preparation of
bromoacetamides, thiolactams and enaminones, the latter by the application of Eschenmoser’s
sulfide contraction, as well as the reduction of exocyclic carbon-carbon double bonds in six
membered vinylogous urethanes. The synthesis of (±)-thalictroidine [257], is the first reported
synthesis of the natural product, and spectroscopic and crystallographic data are in agreement
with the structure proposed by Kennelly et al.125
The synthesis of several 5-monosubstituted indolizidines, used in model studies in order to
establish fundamental skeletal and functional group transformations for 5,8-disubstituted
indolizidines are then shown. Key reactions include the preparation of several enaminones
including a vinylogous urethane [312] and a Weinreb amide [314] from thiolactam [304].
These enaminones were cyclised under alkylative conditions to afford 5-substituted
indolizidines [320] and [322] respectively. The synthetic utility of the Weinreb amide for the
introduction of unbranched alkyl substituents at the 5-position is introduced, and the utility of the vinylogous urethane [320] is shown by a three step conversion into (±)-tashiromine [330a]
and (±)-5-epi-tashiromine [330b].
The formal enantioselective synthesis of indolizidine (-)-209I [185] is reported. In order to
begin the enantioselective synthesis of (-)-209I [185], methodology developed by Gravestock
was adapted to the preparation and utilization of vinylogous ureas containing the Weinreb
amide functionality. Conjugate addition of the secondary amine N-benzyl-N-(1R)-1-
phenylethylamine [243] to tert-butyl (2E)-2-hexenoate [267] gave optically pure tertiary
amine [268]. Debenzylation of this amine gave primary amine [336]. Subsequent lactam
formation, thionation and sulfide contraction with N-methoxy-N-methyl-2-bromoacetamide
[271] yielded vinylogous urea [272]. The reduction of tert-butyl ester [272] to liberate alcohol
[273] was low yielding and an alternative method was used, which involved the reduction of
the tert-butyl ester at an early stage of the synthesis, protecting it as a silyl ether, and then
liberating the free alcohol at an appropriate stage in the synthesis. The silyl ether was not
compatible with the thionation step and was swapped at the lactam stage for an acetate
protecting group. Subsequent reactions included an acylative cyclisation to form the
indolizidine skeleton and a stereoselective reduction of the carbon-carbon double bond to
yield (5R,8S,8aS)-N-methoxy-N-methyl-5-propyloctahydro-8-indolizinecarboxamide [275].
Mono-alkylation of the Weinreb amide functionality and epimerization to 1-[(5R,8R,8aS)-5-
propyloctahydro-8-indolizinyl]-1-propanone [191] represented a formal synthesis of
indolizidine (-)-209I [185].
Approaches towards the synthesis of a late stage common intermediate [259] which could
have the substituents at both the 5- and 8-positions modified independent of each other at or
near the end of the synthesis are discussed. Finally an alternative synthetic approach negating
the need for several of the protection and deprotection steps is shown with regards to the
synthesis of the structurally related 1,4-disubstituted quinolizidines