This thesis describes the development of chiral auxiliary based methodologies for the
asymmetric synthesis of hydroxylated !-lactones and "-lactones containing multiple contiguous
stereocentres. The first chapter introduces the concept of chirality and provides a general
overview of the range of strategies available for the preparation of chiral molecules in
enantiomerically pure forms. The second chapter critically reviews the range of synthetic
methodology that is currently available for the asymmetric synthesis of chiral #-lactones that
are either natural products or useful chiral building blocks for synthesis. The third chapter
describes the development of novel methodology for the epoxidation/lactonisation of a range of
$-vinyl-syn-aldols to directly afford !-lactones containing up to four contiguous stereocentres in
high de. These reactions were shown to proceed via a mechanism whereby hydroxyl-directed
diastereoselective epoxidation is followed by intramolecular attack of their !-acyl-oxazolidin-2-
one fragment, to directly afford the desired chiral !-lactone. The ‘self-cleavage’ aspect of these
reactions was exploited to enable this methodology to be transferred to polymer-support using
an immobilised Evans’-oxazolidin-2-one for asymmetric synthesis.
Chapter 4 describes the development of a complementary methodology for the asymmetric
synthesis of this type of hydroxylated !-lactone based on a strategy involving dihydroxylation of
N-acyl-oxazolidin-2-one-$-vinyl-syn-aldols using catalytic amounts of osmium tetroxide. This
methodology was developed as part of a reinvestigation of previously reported dihydroxylation
reactions by Dias and coworkers, where we have clearly shown that the stereochemistry of thelactones reported in their paper have been incorrectly assigned. This diastereoselective dihydroxylation methodology has been successfully applied to the asymmetric synthesis of the
natural product deoxyribonolactone.
Finally, Chapter 5 describes the development of methodology for the asymmetric synthesis of
chiral "-lactones containing four contiguous stereocentres of use as potential chiral building
blocks for the synthesis of polyketide natural products. In this approach, cyclopropanation of
N-acyl-oxazolidin-2-one-$-vinyl-syn-aldols occurs under the sterodirecting effect of the $-
hydroxyl group to afford cyclopropyl-aldols in very high de. These cyclopropyl-aldols are then
ring opened in the presence of mercuric ions, with their N-acyl-oxazolidin-2-one fragment
acting as an internal nucleophile, to afford highly functionalised alkyl-mercury species that may
be subsequently reduced to afford their corresponding "-lactones in high de.
Date of Award | 1 Nov 2009 |
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Original language | English |
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Awarding Institution | |
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Supervisor | Steven Bull (Supervisor) |
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- mercury dihydroxylation
- Assymetric synthesis
- aldol
- lactones
- cyclopropanation
- epoxidation
Chiral auxiliaries and substrate directable reactions to access highly functionalised chiral lactones
Davies, I. (Author). 1 Nov 2009
Student thesis: Doctoral Thesis › PhD