The importance of methods for the synthesis of chiral compounds in high enantiomeric purity cannot be overstated. In 2001, single enantiomer drugs comprised 36% ($147 billion) of the total market of $410 billion. This number is projected to increase steadily, such that chiral drugs will constitute a market of over $200 billion by 2008. The growing economic importance of chiral compounds has spurred major research efforts from many laboratories, academic and industrial, directed at the selective preparation of chiral compounds. A recent report from the PI's laboratory described the development of chiral metal-salen complexes that are exceptional catalysts for enantioselective Diels-AIder (DA) reactions, one of the most useful reactions for organic synthesis. A major focus of the proposed activity will be to investigate these catalysts and to develop related complexes for use in DA and other C-C bond forming reactions. The high efficiency of these catalysts (record low catalyst loading) makes them attractive for various applications in complex molecule synthesis, even for industrial uses. In conjunction with this work, additional heteroatom-substituted dienes will be developed for use in DA reactions. Also presented in the proposal are plans for the development of metal-free catalysts that use hydrogen bonding rather than Lewis acids to promote the enantioselective process. This metal-free acceleration of reactions is not only of fundamental interest, but is also of potential industrial importance, since metal impurities, especially transition metals, are undesirable in precious chemicals such as pharmaceutical drugs. Effort will be directed at the use of hydrogen bonding for the enantioselective catalysis of various C-C bond-forming reactions. The asymmetric catalysis capabilities of numerous chiral alcohols as well as other hydrogen bond donors will be examined. Both of the major subprojects (metal salen complexes and hydrogen bonding catalysis) will integrate crystallographic studies and computational modeling in order to develop models to rationalize the observed enantioselectivities. Overall, the investigations described in this proposal are expected to lead to useful new methodology advances for the asymmetric synthesis of complex molecules. The projects described herein will provide excellent training for undergraduate students, graduate students, and postdoctoral associates in asymmetric catalysis methodology development and complex molecule synthesis, experience that will prepare them well for independent research careers, either in industry or academics. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM069990-04
Application #
7162142
Study Section
Special Emphasis Panel (ZRG1-SSS-B (01))
Program Officer
Schwab, John M
Project Start
2004-01-01
Project End
2007-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
4
Fiscal Year
2007
Total Cost
$212,107
Indirect Cost
Name
University of Chicago
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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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