Design and Synthesis of Guaianolide Analogs

Our team designs and synthesizes guaianolide analogs with muted thiol reactivity as a way to gain access to meaningful SAR data for this class of bioactive compounds. Our approach uses an allylboration/cyclization process and an allenic Pauson–Khand reaction (APKR) to rapidly assemble the 5,7,5-ring system. Additionally, we exchange the highly reactive α-methylene-γ-lactone with an α-methylene-γ-lactam–a covalent reactive group with thiol reactivity that can be regulated in predictable ways. We are testing our hypothesis in the rational design of covalent inhibitors with low reactivity and high affinity for the kinase and protease enzyme targets, VASH1 and SARS-CoV-2 main protease.

Asymmetric Allenic Pauson-Khand Reaction (APKR)

Our team designs and synthesizes transition-metal catalysts to control reaction outcomes such as product selectivity and yield. Our approach uses a deep mechanistic understanding informed by a real-time collaboration between experimental and computational organic chemists. In this way, we have synthesized 5,7-ring systems with high enantioselectivity enabled through a stereoconvergent Rh(I)-catalyzed allenic Pauson–Khand reaction. We are applying these findings to the enantioselective synthesis of thapsigargin and we are extending this mechanistic approach to other systems including the PKR of enynes.  

Dearomative Cycloaddition Reactions

Our team identifies factors that govern reactivity and product selectivity in the dearomative didehydro-Diels–Alder (DDDA) reaction of heteroarenes. Our approach uses an iterative, real-time collaboration between experimental and computational organic chemists to gain mechanistic insight. We expect that revealing the key reactivity factors will inform other cyclization and cycloaddition reactions involving de-aromatization and re-aromatization processes. Additionally, we are applying these findings to the synthesis of novel ladder-type heteroarene compounds for use in high performing organic photovoltaic materials.