During the last two funding cycles our research program has made significant progress in the development of asymmetric base catalysis, as well as acid-base and iminium-base bifunctional catalysis by organic catalysts as broadly applicable concepts for the development of asymmetric reactions. In our previous studies the catalysts afford activity, enantioselectivity and diastereoselectivity through their involvement in a single transition state of stereochemical consequences. Our proposed studies focus on the invention and development of new reaction cascades. Building on preliminary results revealing the ability of cinchona alkaloids to serve as efficient chiral proton donors, the development of asymmetric dual-functional cooperative organocatalysis becomes a common theme underlying our proposed studies. In this mode of catalysis the organic catalysts act as a bifunctional catalyst to promote two different individual steps in the reaction cascades by activating and orienting the two participating reactants or intermediates.
The specific aims are: 1) Development of enantioselective and diastereoselective conjugate addition-protonation reactions of ???-disubstituted nitroalkenes for asymmetric synthesis of chiral amino compounds. 2) Development of biomimetic proton transfer catalysis for enantioselective isomerizations of ???-unsaturated carbonyl to chiral ???-unsaturated carbonyl compounds via tandem deprotonation-protonation reactions. 3) Development of asymmetric peroxidations via enantioselective and chemo-controlled conjugate addition-protonation reactions with hydroperoxides. By establishing a broad range of synthetically important asymmetric transformations that currently represent unmet challenges for existing catalysts, our studies will provide unique entries into and achieve efficient asymmetric syntheses of chiral molecules of biological and therapeutic interest that are either inaccessible or difficult to prepare in a concise and useful manner by existing synthetic methods.

Public Health Relevance

Small molecules constitute one of the most important forms of therapeutic agents and play an increasingly important role in biomedical research. The goal of this work is to develop new and efficient synthetic methods that will greatly enhance our ability to rapidly create molecules of diverse structures with defined configuration, thereby providing biomedical researchers with powerful tools to accelerate the discovery of small molecules possessing biologically interesting and therapeutically desirable properties. These synthetic methods will also provide the foundation for the development of cost-effective processes for the sustainable manufacturing of therapeutic agents with significant implications to public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061591-13
Application #
8588335
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2000-07-01
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
13
Fiscal Year
2014
Total Cost
$305,730
Indirect Cost
$112,230
Name
Brandeis University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
616845814
City
Waltham
State
MA
Country
United States
Zip Code
02454
Lu, Xiaojie; Deng, Li (2014) Catalytic asymmetric peroxidation of ?,?-unsaturated nitroalkenes by a bifunctional organic catalyst. Org Lett 16:2358-61
Provencher, Brian A; Bartelson, Keith J; Liu, Yan et al. (2011) Structural study-guided development of versatile phase-transfer catalysts for asymmetric conjugate additions of cyanide. Angew Chem Int Ed Engl 50:10565-9
Liu, Yan; Provencher, Brian A; Bartleson, Keith J et al. (2011) Highly Enantioselective Asymmetric Darzens Reactions with a Phase Transfer Catalyst. Chem Sci 2:1301-1304
Wu, Yongwei; Singh, Ravi P; Deng, Li (2011) Asymmetric olefin isomerization of butenolides via proton transfer catalysis by an organic molecule. J Am Chem Soc 133:12458-61
Bartelson, Keith J; Singh, Ravi P; Foxman, Bruce M et al. (2011) Catalytic Asymmetric [4 + 2] Additions with Aliphatic Nitroalkenes. Chem Sci 2:1940-1944
Li, Hongming; Liu, Xiaofeng; Wu, Fanghui et al. (2010) Elucidation of the active conformation of cinchona alkaloid catalyst and chemical mechanism of alcoholysis of meso anhydrides. Proc Natl Acad Sci U S A 107:20625-9
Singh, Ravi P; Foxman, Bruce M; Deng, Li (2010) Asymmetric vinylogous aldol reaction of silyloxy furans with a chiral organic salt. J Am Chem Soc 132:9558-60
Liu, Yan; Sun, Bingfeng; Wang, Baomin et al. (2009) Catalytic asymmetric conjugate addition of simple alkyl thiols to alpha,beta-unsaturated N-acylated oxazolidin-2-ones with bifunctional catalysts. J Am Chem Soc 131:418-9
Li, Hongming; Song, Jun; Deng, Li (2009) Catalytic enantioselective conjugate additions with alpha,beta-unsaturated sulfones. Tetrahedron 65:3139-3148
Sun, Bing-Feng; Hong, Ran; Kang, Yan-Biao et al. (2009) Asymmetric total synthesis of (-)-plicatic acid via a highly enantioselective and diastereoselective nucleophilic epoxidation of acyclic trisubstitued olefins. J Am Chem Soc 131:10384-5

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