Stereoselective Construction of Challenging C – C Bonds: Total Synthesis of Complex Bioactive Agents

Abstract

The central premise of the research in my group focuses on developing novel synthetic transformations that permit the expeditious total synthesis of complex bioactive natural products. A unique and striking feature of the program is the ability to access new chemical reactivity, which in conjunction with detailed mechanistic studies, permits the development of sophisticated multi-component processes for the stereoselective construction of complex molecular architectures.

One of the group’s ongoing goals is developing allylic coupling reactions using rhodium-allyl electrophiles with an array of carbon and heteroatom pronucleophiles. Indeed, this process now represents a powerful and highly regio- and stereoselective sp3 cross-coupling reaction for target-directed  synthesis.  In recent work, we have focused on the alternative umpolung reaction paradigm, which probes the merit of the corresponding allylic metal anions in the context of novel dynamic kinetic resolution reactions of a,b-unsaturated aldehydes that function as both acyl anions and homoenolates in novel cross-coupling reactions.

In the context of total synthesis, we have recently developed a concise, efficient and scalable total synthesis of the complex bioactive sesquiterpene natural product, Thapsigargin. This agent was isolated from the Mediterranean plant Thapsia garganica and provided a highly selective subnanomolar inhibitor of intracellular calcium ion transport enzymes, which induces apoptosis, leading to cell death. Mipsagargin, a prodrug of Thapsigargin, is currently in the late-stage clinical trials to treat liver, brain, prostate and kidney cancer. The seminar will outline the evolution of these useful developments and their impact on synthetic and medicinal chemistry.

Speaker bio

Andrew Evans is the Alfred  R. Bader Chair of Organic Chemistry and a Tier 1 Canada Research Chair in Organic and Organometallic Chemistry in the Department of Chemistry at Queen’s University. He received a B.Sc. with honors in Applied Chemistry at Newcastle Polytechnic in 1987 and a Ph.D. at the University of Cambridge in 1991 under the supervision of Andrew B. Holmes, FRS. He then completed postdoctoral studies with Philip D. Magnus, FRS, at the University of Texas at Austin as a NATO Postdoctoral Fellow. In 1993, he initiated his independent career at the University of Delaware, where he rose through the ranks to Professor before moving to Indiana University in 2001. In 2006, he moved to the University of Liverpool, where he was the Heath Harrison Chair of Organic Chemistry, before moving to his current position in July 2012.

His research accomplishments have been globally recognized, including the Changjiang Scholar Award, ACS Cope Scholar Award, ACS Fellow, RSC Pedler Award, the Royal Society Wolfson Research Merit Award, Pfizer Award for Creativity in Organic Chemistry, Johnson and Johnson Focused Giving Award, GlaxoWellcome Chemistry Scholar Award, Camille Dreyfus Teacher-Scholar Award, Eli Lilly Grantee Award and Zeneca Excellence in Chemistry Award. He has also served on ACS Division of Organic Chemistry as a Member-at-Large, National Organic Symposium Executive Officer, Councilor and Division Chair. He currently serves as one of the co-chairs of the highly acclaimed ACS-DOC Graduate Research Symposium. Additionally, he is an Associate Editor for the Thieme journal, Synthesis and the Editor-in- Chief for Organic Reactions.