Event

Dr. Edwin Alfonzo

California Institute of Technology

Monday, January 13, 2025

10:30 AM

Carolyn Hoff Lynch Lecture Hall

Chemistry Complex

231 South 34th Street

Biomimetic Strategies for Lignan Synthesis and New-to-Nature Nitrene Transfer Reactions 

Classical lignan (CL) natural products are of significant interest due to their broad spectrum of potent biological activities, leading to FDA-approved agents like etoposide and podophyllotoxin and multiple clinical candidates. The chief source for CLs, however, remains natural sources, constraining medicinal chemists to semi-synthetic modifications and limiting deeper biological studies. The first part of my talk will describe a de novo synthetic approach inspired by Nature’s biosynthetic blueprints toward CLs. By leveraging designer photoredox catalysts, a highly selective, convergent, and modular [3+2] dipolar cycloaddition was developed, providing access to a key intermediate that was advanced to all eight CLs. The developed synthetic approach provides efficient access to CL analogs, enabling structure-activity relationship studies and library synthesis for biological testing. 

The second part of my talk will describe efforts in repurposing and evolving natural heme proteins into biocatalysts capable of catalyzing new-to-nature nitrene transfer reactions. Specifically, the development of enantiodivergent enzymes that allow access to L- and D-noncanonical amino acids, critical in developing modern therapeutics, will be described. The discovery of enantiodivergent enzymes was facilitated by creating a high-throughput experimentation workflow that connected sequence-activity-selectivity data, enabling the identification of highly active and selective enzymes. I will close by sharing our discovery that nitrene transferases could process abiotic boronic acids into their corresponding amines through a stereospecific 1, 2-metallate shift mechanism. This finding opens new opportunities in biocatalysis by demonstrating that boronic acids, commonly used as precursors in transition-metal-catalyzed cross-coupling reactions, can play a similar role with metalloenzymes. 

Bio: Edwin Alfonzo, a native of the Commonwealth of Massachusetts, received his BS in chemistry from the University of Massachusetts Lowell in 2014. He completed his doctoral research in the laboratory of Aaron B. Beeler at Boston University, where he achieved the first unified synthesis of classical lignan natural products. Inspired by nature's strategies for complex molecule synthesis, Edwin joined the Frances H. Arnold laboratory at the California Institute of Technology in 2021 as an NIH postdoctoral fellow. Currently a K99/R00 early-career awardee, he focuses on engineering proteins to address outstanding challenges in chemical synthesis.