The Use of Abiotic Strategies and C–H Functionalization Toward Natural Product Total Synthesis and Studies Toward CNS-Penetrant Drug Derivatives

Research in the Stoltz group focuses primarily on total synthesis endeavors and the development of new methodologies for the asymmetric formation of stereocenters in organic chemistry. Herein we describe our efforts in natural product total synthesis campaigns and investigations on the synthesis of small molecule steroid derivatives for the purposes of central nervous system (CNS) targeting treatments. Chapter 1 encompasses our completed and asymmetric total synthesis of (–)-cylindrocyclophane A facilitated by Rh-catalyzed C–H functionalization methodology. We report the use of both a stepwise and a one-pot regio- , enantio-, and diastereoselective macrocyclization to forge a 22-membered paracyclophane framework. Chapter 2 describes the synthesis of bufalin and digitoxigenin derivatives in aim to develop compounds with greater CNS-penetrative properties. We disclose the synthesis of pyridine and pyridone derivatives of bufalin, and stereochemical modifications of the steroid scaffold. Chapter 3 outlines our progress toward a total synthesis of antitumor, antibiotic (+)-cyanocycline A utilizing a modular and convergent approach. We report the exploration of several different synthetic routes toward the natural product, efficient cross-coupling transformations, and current directions toward the naphthyridinomycin alkaloid skeleton.