The Development of Pot-Economical Strategies for the Synthesis of Natural Products and Analogs

Abstract

The development of atom-, redox-, step-, and pot-economical methods for the efficient synthesis of medicinal drugs, bioactive natural products and their synthetic analogs stands at the forefront of modern day organic synthesis and drug discovery. In particular, one-pot sequential operations are of prime importance due to their efficiency, versatility, and expediency in constructing advanced intermediates, polycyclic scaffolds and bioactive natural products. One-pot sequential protocols enable the formation of several bonds and stereocenters in a single reaction vessel, and minimize the need for workup and chromatographic procedures between intermediary steps, thus saving time and reducing chemical waste generation in multistep syntheses of bioactive target molecules. Previous studies in our group have focused on the development and utilization of one-pot sequential protocols for the synthesis of (–)-tetrahydrolipstatin and strictifolione. The focus of this dissertation is the development and implementation of one-pot sequential operations for the streamlined syntheses of α,β-unsaturated macrocycles, bioactive natural products and their synthetic analogs. Chapter-1 is a literature review focused on recent application of one-pot sequential protocols in natural product and drug synthesis. Chapter-2 is work carried out in the course of this dissertation that is focused on the synthesis of functionalized and structurally diverse α,β-unsaturated 14- membered macrocycles. A series of one-pot sequential protocols was developed for the synthesis of novel macrocycles bearing α,β-unsaturated chemotypes. The method highlights a phosphate tether-mediated approach to establish asymmetry, and consecutive one-pot sequential processes to access the macrocycles with minimal purification procedures. This library amenable strategy provided diverse macrocycles containing α,β-unsaturated carbon-, sulfur-, or phosphorus-based warheads. Chapter-3 outlines our work on a pot-economical total synthesis of antifungal natural product Sch-725674 and structural analogs. The approach takes advantage of a number of one-pot sequential transformations, including a phosphate tethermediated one-pot sequential RCM/CM/ chemoselective hydrogenation protocol, a one-pot tosylation/ acrylation sequence, and a one-pot sequential Finkelstein reaction/Boord olefination/ acetonide deprotection procedure to streamline the synthesis route by reducing isolation and purification procedures, thus saving time. Overall, an asymmetric route has been developed that is efficiently accomplished in seven pots from phosphate (S,S)-triene and with minimal purification. Chapter 4 describes our ongoing efforts toward the asymmetric total synthesis of (–)-13-desmetnyl-lyngbouilloside an unnatural analog of lyngbouilloside. The key reactions involved in the synthesis of 13-desmethyl-lyngbouilloside are one-pot sequential RCM/CM/ chemoselective hydrogenation, regio- and diastereoselective cuprate addition followed by tether removal, Pd-catalyzed reductive allylic transposition, Roskamp homologation, Boeckaman acylketen cyclization, Julia olefination and glycosylation. Thus far, we were able to accomplish the synthesis of macrolactone core of (–)-13-desmetnyl-lyngbouilloside. Further studies towards the completion of the molecule are underway. Chapter 5 is a compilation of the experimental work carried out in this dissertation.