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New synthetic approaches to indolizidine and pyrrolidine alkaloids

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Gourlay, BS (2010) New synthetic approaches to indolizidine and pyrrolidine alkaloids. PhD thesis, University of Tasmania.

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Abstract

This thesis describes synthetic approaches towards indolizidine and pyrrolidine alkaloids.
The total synthesis of indolizidine 167B, and its epi-analogue was achieved from D-norvaline,
which was converted to an a-pyrrolic ester through a refined Clauson-Kaas
pyrrole synthesis. The method was developed by investigating the reaction requirements
for pyrrole synthesis, and it was found that a two-step, one pot procedure is far superior to
current methods. Chain homologation gave the y-pyrrolic analogue, which underwent
cyclisation to form the 5-propy1-6,7-dihydro indolizin-8(5H)-one core, which represented a
formal synthesis of (-)-indolizidine 167B. An alternate reduction strategy of this derivative
was developed using a dissolving metal reduction, which allowed access to epi-indolizidine
167B, allowing synthesis of both diastereomers from a common intermediate. This
research was extended to the synthesis of higher homologues of the 5-alkyl indolizidines by
using homoserine as the starting material. Pyrrole formation, chain homologation and
mesylation gave an intermediate which was elaborated to give a formal synthesis of
indolizidine 209D through cuprate chemistry.
The synthesis of pyrrolidine alkaloids was also investigated using a [3+2] azomethine ylide
cycloaddition as the ring-forming step. Investigation into diastereoselective pyrrolidine
synthesis through lithium bromide mediated generation of stabilised azomethine ylides
from imines and subsequent cycloaddition showed a lack of reactivity. Therefore
pyrrolidine formation was achieved by in situ generation of a non-stabilised ylide through
decarboxylation and subsequent cycloaddition with a dipolarophile. The non-stabilised
ylide formed from N-methyl alanine and anisaldehyde underwent cycloaddition with 1,2-
trans-bisphenylsulfonyl ethylene to give a pyrrolidine in a three component coupling
reaction. Reductive desulfonation, epoxidation and ring-opening then yielded a C3-C4 cis
diol isomer of the alkaloid codonopsinine. A formal synthesis of (±)-codonopsinine was also
achieved from N-benzyl ala nine.
The azomethine ylide chemistry was further elaborated with the use of the chiral
dipolarophile (-)-8-phenylmenthyl acrylate allowing the formal synthesis of β-proline.

Item Type: Thesis (PhD)
Copyright Holders: The Author
Copyright Information:

Copyright 2010 the Author

Additional Information:

No access or viewing until January 2012. After that date, available for use in the Library and copying in accordance with the Copyright Act 1968, as amended. Thesis (PhD)--University of Tasmania, 2010. Includes bibliographical references

Date Deposited: 09 Dec 2014 00:14
Last Modified: 17 May 2016 01:24
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