The synthesis of open chain pancratistatin analogues
Date
2010-07-09T12:06:05Z
Authors
Thompson, Warren
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Abstract
(+)-Pancratistatin is a medicinally useful compound which has been isolated from plants
belonging to the Amaryllidaceae plant family. The deceptively simple looking
pancratistatin is in fact a complicated molecule; it has six contiguous stereocenters of
which four belong to alcohol groups and the other two make up a trans B-C ring junction.
In addition, it consists of three fused rings. The medicinal properties and the synthetic
challenges set by pancratistatin have attracted the attentions of many synthetic groups.
Herein are reported approaches to the synthesis of C-seco pancratistatin analogues. D(-)-
tartaric acid was used as the starting material as it contains two of the four stereocenters
found in pancratistatin.
Organocuprate and rhodium-catalyzed reactions were successfully employed to install
one of the two stereocenters required for the trans B-C junction. The rhodium catalysed
addition reactions were found to be more efficient: they were easier to set up, the work up
was a simple filtration, high conversions and anti-selectivity were observed. The antiselective
addition was proved by means of obtaining a crystal structure of 3-((4R,5R)-5-
(benzyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-phenylpropanoic acid -
a carboxylic acid derivative of an addition product.
Confirmation of the resulting compound, resulting from the attempted ring closure via an
isocyanate intermediate - formed through a Curtius rearrangement of an azide - to
complete the trans B-C junction has proved, through NMR analysis, to be inconclusive.
Unfortunately, this result meant that the synthesis was halted one step away from the
formation of a protected open chain pancratistatin analogue. Good progress was made towards the synthesis of open chain pancratistatin analogues
and it is said with great optimism that the analogues will eventually be made.