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New synthetic approaches to indolizidine and pyrrolidine alkaloids

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

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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 alanine.
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
Authors/Creators:Gourlay, BS
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Copyright 2010 the Author

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No access or viewing until January 2012. Thesis (PhD)--University of Tasmania, 2010. Includes bibliographical references

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