Utility and Application of Chiral, Unsaturated Acylammoniums

Texas A&M University, College Station TX

Investigators

Abstract

Through this award, funded by the Chemical Synthesis Program, Prof. Daniel Romo from Texas A&M University is turning to bioinspired organocascade or domino processes that generate multiple bonds and stereocenters in a single operation, significantly increasing the efficiency of bioactive natural product and pharmaceutical synthesis. Organocatalysis involves the use of small, chiral organic molecules to activate substrates and initiate various bond constructions. Generic substrate activation modes, and their implementation in reaction design, have led to an explosion in covalent organocatalysts over the past decade, using judicious combinations of catalytic activation modes. However, there is a paucity of general substrate activation modes, with only limited types revealing multiple reactive sites in a single catalytic cycle. This research will explore a new activation mode that could prove broadly useful for the development of novel organocascade reactions. Undergraduates, working in the Texas A&M Undergraduate MiniPharma Program, will study certain aspects of the proposed methods gaining teamwork and leadership experience, a taste of various aspects of pharmaceutical research, new research skills, and experience with state-of-the-art equipment ultimately contributing to publishable research. This research pursues a novel and broad design principle based on readily generated chiral unsaturated acylammonium salts, significantly impacting the growing field of scaleable, asymmetric organocatalysis. The organocascade processes focus on cycloadditions, enabling highly practical, enantioselective synthetic routes to carbocycles and heterocycles commonly found in bioactive natural products and pharmaceuticals. In addition, the synthesis of recyclable, supported-isothiourea catalysts and mechanistic studies of unsaturated acylammonium intermediates, given their established and increasing importance for organocascade catalysis, are undertaken in collaboration with Prof. Dean Tantillo (UC Davis). The utility of the developed synthetic methods is demonstrated by targeting the synthesis of natural products with compelling bioactivities enabling further fundamental studies at the chemistry/biology interface with Prof. Stephan Sieber (Tech Univ of Munich, Germany). Hypothesis-driven, novel reaction development and empirical laboratory synthetic methods for reaction discovery are employed to reach these objectives.