Towards a Total Synthesis of Peloruside a and the Preparation of Selected Inositol Derivatives

Abstract

This thesis covers two broad areas of work under the general theme of the synthesis of bioactive and/or synthetically useful compounds based on natural products or deriving from the chiral pool. Chapters one, two and three focus on the marine secondary metabolite peloruside A (1), which has been shown to stabilise microtubules during mitosis and hence cause apoptosis (cell death) in a similar manner to the very successful anticancer drug Taxol® A synthetic program with the aim of devising a total synthesis was initiated at Victoria University of Wellington after peloruside A's discovery in 1999. Four synthetic disconnects were identified in the retrosynthetic analysis of peloruside A: to give the C-l to C-2 fragment; the C-3 to C-7 fragment; the C-8 to C-11 fragments; and the C-12 to C-24 fragment. The C-7 to C-8 bond was to be formed via an asymmetric aldol reaction to give the pyranose ring fragment (highlighted in blue). In this thesis, the synthesis of the C-3 to C-7 fragment is described. A1do1 reactions with the C-8 to C- 11 ketone have been investigated, and subsequent progress towards the assembly of the pyranose ring fragment is presented. Chapters four, five, six and seven describe the preparation of selected synthetically and biologically useful derivatives of the commercially available inositols, quebrachitol (L-chiro-inositol-2-methyl ether) and myo-inositol. The butane di-acetal (BDA) derivatives 293, 300, and 301 (as well as acetylated and methylated derivatives thereof) were prepared during work directed towards the synthesis of the inositol core of a phosphatidylinositol manno-oligosaccharide (PIM-6) isolated from Mycobacterium bovis and M. smegmatis. Quebrachitol derivatives 305, 306 and 307 were prepared and subsequently tested against myoinositol (the optimal competitor) in biological uptake assays of the microorganisms, Candida albicans and Leishmania donovani. For both microorganisms, the mono- and di-O-methylated L-chiro-inositol derivatives 307 and 305, as well as quebrachitol, gave significant inhibition results, with P values from P < 0.001 to P < 0.05 for paired-sample t-test analyses, i.e.99.9% to 95% confidence for significant inhibition, respectively. The benzoylated derivative 306 did not induce any inhibition of myo-inositol uptake. Myo-inositol is the most abundant of the inositols in nature and is readily available. However, as it is a meso compound, one of the key challenges in the use of myoinositol as a synthetic precursor is an efficient resolution method. The formation of myo-inositol camphanylidene acetal 269a is one successful solution, and work done in an attempt to better understand the selectivity of the reaction is reported here. Also, process development work was done to adapt the preparation so that it was suitable for scale-up, and a subsequent large scale synthesis of the acetal was undertaken. Previously unpublished X-ray crystal structures were obtained for 269a and, for two of the diastereomeric impurities of the reaction.