Over the last 30 years, enantioselective catalysis has become one of the most important frontiers in exploratory organic synthetic research with widespread application in biomedical settings. Surprisingly, however, the research area of organocatalysis (the use of small organic molecules as reaction catalysts) has become a field of central importance in chemical synthesis in only the last ten years. This is quite remarkable given the widespread availability of organic chemicals in enantiopure form and the attendant potential for savings in cost, time, energy, operational complexity and chemical waste. This proposal outlines the development of an innovative and general strategy for enantioselective organocatalysis that enables simple aldehydes to participate in a variety of a-functionalization reactions that were previously unknown. As part of these studies, we describe a catalyst design endeavor that should provide inexpensive, robust amine catalysts that engender high levels of asymmetric induction for a broad spectrum of enamine-mediated reactions. During the tenure of this granting period we hope to demonstrate the value of this new enamine activation strategy in the context of the first examples of enantioselective organocatalytic (1) aldehyde-aldehyde cross aldol reactions, (2) a-chlorination reactions, (3) a-aminotosylation reactions, and (4) a-alkylation reactions. ? We also hope to introduce three new strategies for chemical synthesis that are founded upon enamine organocatalysis that will allow accelerated access to bioarchitectures and functionalities that are not readily available by conventional methods. The first strategy involves a conceptually novel approach to the production of polyol-differentiated carbohydrates in only two chemical transformations (both aldol reactions). This modularity of this sequence will allow the construction of natural and non-natural carbohydrates that can incorporate carbon, nitrogen, halogen or sulfur substituents within the saccharide framework. The second strategy involves the enantioselective catalytic synthesis of reactive intermediates that are suitably versatile to undergo in situ, asymmetric bond transfer. This powerful strategy should enable the production of a diverse range of synthons such as aziridines, epoxides and amino acids (amongst others) from simple aldehydes using the same catalytic induction step in each protocol. Last, we introduce a new activation concept for organocatalysis that we term SOMO activation. This new approach to organocatalysis is based upon the transient formation of aldehyde derived radical cations (the one-electron intermediate that bridges the fields of iminium and enamine catalysis) that can enantioselectively intercept a range of p-nucleophiles. Specifically, we propose that SOMO catalysis will allow the first enantioselective intramolecular a-alkylation of aldehydes, a long standing goal for the field of asymmetric catalysis. Having demonstrated the feasibility of SOMO activation, we hope to launch this new organocatalysis area in the context of several important transforms including intramolecular oxidative cyclizations. ? ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Schwab, John M
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Princeton University
Schools of Arts and Sciences
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