Synthetic studies on molecules related to the azinothricin family and allopumiliotoxin 339A

• Main Author: LeFranc, Amandine A. H.
• Published: University College London (University of London) 2008
• Subjects: 547.7
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487205

The Azinothricin family of compounds are based on a cyclodepsipeptide core and were first encountered in the late 1980s. Most of the members exhibit potent antitumour and antibiotic activities. In 1997, the Hale group synthesised A83586C through a chemoselective coupling strategy between an unprotected cyclohexadepsipeptide and a fully elaborated pyran activated ester. In this thesis, the asymmetric synthesis of two cyclodepsipeptides analogues are investigated, the L-proline analogue of GE3 cyclodepsipeptide and the (3S.5S)- 5-hydroxypiperazic acid analogue of A83586C cyclodepsipeptide. The synthesis of analogues may be of value for elucidating the mode of action of these natural products. Furthermore, it might allow the identification of a considerably simplified structure for industrial purposes. In a second project, a new approach to the synthesis of (+)-allopumiliotoxin 339A was studied. The pumiliotoxin and allopumiliotoxin class of amphibian alkaloids displays significant cardiotonic activity. Allopumiliotoxin 339A is one of the most potent compounds of the family its activity is due to an interaction with a modulatory site on the voltage-dependent sodium channel. Our strategy to (+)-allopumiliotoxin 339A was based on the synthesis of two main fragments, an a-alkoxyaldehyde and a functionalised side chain fragment. Our initial research to the a-alkoxyaldehyde involved a Sharpless Asymmetric Aminohydroxylation reaction. However, this reaction proved not to be feasible on the trisubstituted alkene precursor. Eventually the a-alkoxyaldehyde was successfully prepared using a Trost's opening of an epoxide followed by an asymmetric induction of chiral sulfinimine to access the desired stereochemistry. The synthesis of the side chain segment was achieved via an O-directed hydrostannation strategy developed in the Hale group. This strategy allowed the stereoselective synthesis of the trisubstituted alkene moiety of the side chain.