CAREER: Chemoenzymatic Synthesis of Complex Polycyclic Alkaloids Enabled by A-Ketoglutarate Dependent Iron Enzymes

Brandeis University, Waltham MA

Investigators

Abstract

With support of the Chemical Synthesis program in the Division of Chemistry, Chi Ting of Brandeis University is studying the development of new strategies for the synthesis of a class of naturally occurring molecules that are referred to as alkaloids. Many of these molecules are challenging to isolate from natural sources, resulting in limited quantities being available to study. Specifically, this work will couple organic synthesis with enzymology (biocatalysis) to prepare alkaloids in sufficient quantities for their further study, particularly their study for therapeutic purposes. The biocatalysis that the Ting group is examining modifies relatively complex molecular intermediates and by doing so, allows them to directly access the alkaloids. In addition to the research plan, outreach activities are planned to introduce organic chemistry to middle school students in Waltham, Massachusetts. These activities will showcase the presence of natural products in everyday life, and introduce students to molecular structure. The overarching goal of these activities is to engage students early on in chemistry and especially organic chemistry in so doing, initiate interest in pursuing science professionally. The Ting lab is enabling the total synthesis of complex, polycyclic alkaloids by incorporating enzyme-catalyzed reactions at a late stage into their total synthesis efforts. Their approach is not only conceptually different than traditional total synthesis efforts because of the importance of biocatalysis in the synthetic design. The approach also differs from most chemoenzymatic synthetic methods in that these typically involve the biocatalyst-facilitated synthesis of earlier stage synthetic building blocks, often with control of absolute stereochemistry. There is currently great interest in chemical biology and medicinal chemistry circles in expanding the use of late stage functionalization into the repertoire of chemoenzymatic synthesis. Much activity has been directed at late stage enzymatic halogenation, for example. The work proposed here goes beyond such transformations to develop more fully the area of late stage peroxidation. This strategy has the potential to be highly enabling for the generation of complex, bioactive molecules, especially those that contain relatively sensitive peroxide functionalities. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.