Seeking Innovation and Efficiency in Natural Product Synthesis

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With the support of the Chemical Synthesis (SYN) program in the Division of Chemistry, Professor Erik Sorensen of Princeton University will develop new synthetic methods toward the synthesis of natural products that possess architecturally novel and challenging scaffolds. The ideas and methods of organic synthesis being established in these studies have the potential to contribute to broader advances at the chemistry/biology interface and in materials science and polymer chemistry. This project seeks to demonstrate how the intricate structural elements of the cyclobutastellettolide and curvularol classes of natural products may be formed in a relatively small number of steps from simple starting materials. Professor Sorensen and his students are developing synthetic strategies based upon reactive intermediates that may be induced to undergo cascades of bond-forming reactions. Such cascade processes are desirable because they directly form substantial fractions of the target compounds and yield laboratory syntheses that are efficient. This research is expected to produce new bond-forming reactions, provide knowledge about the scope and limitations of these transformations and provide access to a wide range of novel molecular structures, some of which are expected to have therapeutic potential. Additional societal benefits include the recruitment and participation of under-represented college students from non-R1 institutions in summer research experiences that teach students how to approach challenging problems in organic synthesis and help them to discover that they can do science. Professor Sorensen and his students will harness the reactivities of high-energy carbon radicals, carbenes, and organometallic species in controlled constructions of crowded carbon–carbon bonds, a longstanding problem in the field of organic synthesis. On the foundation of a powerful free radical cascade cyclization that directly generates three of the four rings of the cyclobutastellettolide natural products, they will determine if a reactive carbene can insert into a nearby carbon–hydrogen bond to form the last remaining carbon–carbon bond. Should it succeed, this transformation would produce one of the most crowded carbon–carbon bonds ever constructed via a rhodium carbene C–H insertion reaction. In the course of this project, a new reaction for trapping tertiary radicals in nickel-catalyzed acylations will also be developed and new insights into the capabilities of the Norrish-Yang photochemical cyclization process will be gained. The feasibility of a distinctly direct strategy for synthesizing the anticancer natural product curvularol will also be evaluated. At the heart of this approach is an innovative reductive cleavage of an oxetane heterocycle as a prelude to a Barbier cyclization to establish the challenging curvularol ring system and pattern of relative stereochemistry. In all of these undertakings, new methods and ideas for forming chemical bonds are being developed with potentially far-ranging scientific impact.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.