I.Total Syntheses and Biological Studies of Largazole and Brasilibactin A. II.Stereoselective Synthesis of 2,6-Cis- and 2,6-Trans-Piperidines through an Organocatalytic Aza-Michael Reaction.

Abstract

The dissertation focuses on three main projects which complement the studies towards the total syntheses of biologically active natural products as well as the development of stereoselective synthesis of 2,6-disubstituted piperidines. The first project introduced the first total synthesis of largazole, which is a marine natural product isolated from cyanobacterium of genus Symploca sp. in 2008. It consists of an unusual 16-membered macrocycle incorporating a 4-methylthiazoline linearly fused to a thiazole and an ester of 3-hydroxy-7-mercaptohept-4-enoic acid unit, part of which has been identified to be essential for the potent histone deacetylase (HDAC) inhibitory and consequently antiproliferative activities. Structure-activity relationship (SAR) studies suggest that thiol group generated by hydrolysis of the thioester moiety is the warhead and is critical for its HDAC inhibitory and antiproliferative activity. The biological evaluation of the analogues focusing on macrocycle and linker chain between sulfur atom and macrocycle suggests that the four-atom linker between the macrocycle and the octanoyl group in the side chain and the (S)-configuration at C17-position are critical to potent HDAC inhibitory activity of largazole. In contrast, the valine residue in the macrocycle can be replaced with alanine without compromising activity to a large extent. These SAR results would provide insights into structural requirements for HDAC inhibitory activity including the observed HDAC selectivity of largazole and help in the design of isoform-specific HDAC inhibitors based on largazole. The second project involved the synthesis of cytotoxic mycobactin-like siderophore-brasilibactin A and its unnatural diastereomers, which are then identified to unambiguously confirm that brasilibactin A possesses the 17S, 18R absolute stereochemistry at β-hydroxy acid fragment. The convergent synthetic strategy has been applied to the synthesis of a more water-soluble analogue-Bbtan, iron-binding studies of which suggest brasilibactin A may play an important role in the iron-uptake mechanism in mycobacteria and related organisms. The third project elucidated a convergent stereoselective synthesis of 2,6-cis- and 2,6-trans-piperidines through a reagent-controlled organocatalytic aza-Michael reaction promoted by the gem-disubstituent effect introduced by 1,3-dithiane. The reaction was applicable to a broad range of substrates and proceeded with good stereoselectivities (up to 20:1 dr) and yields. The 1,3-dithiane group allowed for rapid access to substrates, promoted the intramolecular aza-Michael reaction via the gem-disubstituent effect, and improved the yield of the reaction. This synthetic method should be broadly applicable to the efficient synthesis of a diverse set of bioactive natural products with 2,6-disubstituted piperidines.