TOTAL SYNTHESIS AND ANTIMICROBIAL ACTIVITY EVALUATION OF NATURAL PRODUCTS AND THEIR ANALOGUES

The need to develop new antimicrobials remains a major driving force as microorganisms continue to develop resistance against existing antibiotics. Natural products are large reservoirs of new biologically active substances and most of the currently used antimicrobials have been developed from naturally occurring lead compounds. Aim of the PhD work was the study of new naturally derived antimicrobial compounds and the development of synthetic sequences which might, in principle, have value in the preparation of the natural products themselves as well as in synthesizing various analogues. Among a number of possible candidates we have selected three natural products, Leopolic acid A, Promysalin and Resormicyn. During the PhD period the synthesis of these natural products has been carried out, and the biological activity of the compounds has been evaluated. Key steps of the synthetic approach to Promysalin encompass an organocatalytic asymmetric α-hydroxylation of carbonyl compounds employed to fabricate the myristamide framework, and Superhydride® mediated reductive elimination of lactam to obtain the salicyldehydroproline fragment. Crucial steps for the leopolic acid synthetic strategy include a Dieckmann cyclization to obtain the 2,3-pyrrolidinedione ring and a Wittig olefination to install the polymethylene chain. Finally, the key steps in resormicyn synthetic approach include the late stage stereospecific dehydration of alcohol to install the Z-olefin and palladium catalyzed one-pot deprotection of allyl and alloc groups. The straightforward and modular nature of the developed syntheses has given easy access to the preparation of structurally related analogues and the biological activity of the compounds has been evaluated. Preliminary SAR have emerged for promysalin and leopolic acid.