The development of effective methods for the selective synthesis of compounds having mirror asymmetry (chirality) is of significant economic and biomedical importance. In the pharmaceutical industry, single chiral-form (enantiomer) drugs constitute over half of the total drug market, and the key components in 9 of the top 10 drugs are chiral. The biomedical importance of chiral compounds has spurred intense research efforts from leading laboratories-indeed the founding of several companies. Moreover, the societal and scientific importance of this endeavor has been recognized through two separate Nobel prizes. In this renewal proposal, we outline plans for the development and use of novel catalysts for enantioselective synthesis of chiral compounds. Unlike traditional metal-based catalysts, the catalysts being developed and studied in this program are organic molecules that, like enzymes, are capable of activating a reactant through the formation of one or more hydrogen bonds. This metal-free acceleration of reactions is not only of fundamental interest, but is also of industrial importance, since metal impurities, especially transition metals, are undesirable in pharmaceutical drugs. The research efforts will focus on three major areas: (a) development, application, and mechanistic studies of chiral taddols and related compounds as enantioselective catalysts, (b) the development and application of chiral squaramides and related compounds, and (c) the design and study of novel hydrogen bond donor scaffolds. The central hypothesis driving this work is that the development of new and distinct classes of hydrogen bond donor scaffolds is expected to greatly expand the classes of reactions that can be rendered enantioselective and lead to improvements in the effectiveness and substrate-scope of existing reactions. The range of projects that have been selected for the next funding period represents a balance between feasibility and novelty. Some known reactions will be examined using the newly developed catalysts so as to allow calibration of these catalysts with established methodology. Much of the effort, however, will be on the discovery of new enantioselective reactions using the newly developed catalysts. Many of the subprojects are supported by promising preliminary results, whereas others represent new directions in either catalyst or methodology development. Mechanistic, crystallographic, and computational studies will provide an understanding of the catalytic processes and steer the development of more effective catalysts. Overall, the investigations proposed for the next funding period are expected to lead to the development of broadly useful asymmetric catalysis methodologies that will impact many facets of chemical synthesis, including the synthesis of biologically active natural products and pharmaceutical drugs. Additionally, the effort will provide excellent training in synthetic methodology development to undergraduate, graduate and postdoctoral students interested in a research career in the pharmaceutical industry or academia.

Public Health Relevance

Most new pharmaceutical drugs are chiral compounds-that is, they are produced in one of two possible mirror image forms. The chemical synthesis of chiral intermediates to these drugs presents a significant scientific challenge. The overall goal of this project is to develop new catalysts and new methods-based on environmentally-friendly hydrogen bond-based activation-for the synthesis of diverse classes of chiral molecules, many of which could prove useful for the development of pharmaceutical drugs.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
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University of Chicago
Schools of Arts and Sciences
United States
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Kagawa, Natsuko; Nibbs, Antoinette E; Rawal, Viresh H (2016) One-Carbon Homologation of Primary Alcohols to Carboxylic Acids, Esters, and Amides via Mitsunobu Reactions with MAC Reagents. Org Lett 18:2363-6
Montgomery, Thomas D; Rawal, Viresh H (2016) Palladium-Catalyzed Modular Synthesis of Substituted Piperazines and Related Nitrogen Heterocycles. Org Lett 18:740-3
Nibbs, Antoinette E; Montgomery, Thomas D; Zhu, Ye et al. (2015) Access to Spirocyclized Oxindoles and Indolenines via Palladium-Catalyzed Cascade Reactions of Propargyl Carbonates with 2-Oxotryptamines and Tryptamines. J Org Chem 80:4928-41
Yang, Kin S; Rawal, Viresh H (2014) Synthesis of ?-amino acid derivatives and peptides via enantioselective addition of masked acyl cyanides to imines. J Am Chem Soc 136:16148-51
Montgomery, Thomas D; Nibbs, Antoinette E; Zhu, Ye et al. (2014) Rapid access to spirocyclized indolenines via palladium-catalyzed cascade reactions of tryptamine derivatives and propargyl carbonate. Org Lett 16:3480-3
Sumaria, Chintan S; Türkmen, Yunus E; Rawal, Viresh H (2014) Non-precious metals catalyze formal [4 + 2] cycloaddition reactions of 1,2-diazines and siloxyalkynes under ambient conditions. Org Lett 16:3236-9
Türkmen, Yunus E; Sen, Saikat; Rawal, Viresh H (2013) Stacks and clips: Uncanny similarities in the modes of self-assembly in tenary Ag(I) complexes with 1,2-diazines and chelating heteroarenes. CrystEngComm 2013:4221-4224
Yang, Kin S; Nibbs, Antoinette E; Turkmen, Yunus E et al. (2013) Squaramide-catalyzed enantioselective Michael addition of masked acyl cyanides to substituted enones. J Am Chem Soc 135:16050-3
Türkmen, Yunus E; Rawal, Viresh H (2013) Exploring the potential of diarylacetylenediols as hydrogen bonding catalysts. J Org Chem 78:8340-53
Hutson, Gerri E; Turkmen, Yunus E; Rawal, Viresh H (2013) Salen promoted enantioselective Nazarov cyclizations of activated and unactivated dienones. J Am Chem Soc 135:4988-91

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