Access to enantioenriched molecules is crucial to modern biomedical research. Many of the most important reactions in organic synthesis rely on proton transfer as a key mechanistic step. As such, chiral Bronsted base catalysis has emerged as a promising strategy for the production of valuable molecular building blocks in enantioenriched form. This area of catalysis has been impeded, however, by the relatively limited basicity of established catalyst platforms, which has significantly curtailed the widespread application of these approaches. Thus, there exists a clear impetus for the invention of new catalysts with increased potency and effectiveness, which could provide a general solution to the challenge of enantioselective Bronsted base catalysis. Toward this end, we have developed a fundamentally new class of highly reactive and enantioselective chiral Bronsted base catalyst, based on 2,3-bis(dialkylamino)cyclopropenimines. Notably, cyclopropenimines possess significantly higher basicity than established catalytic platforms. Based on our early demonstrations, we envision that cyclopropenimines may emerge as the definitive platform for enantioselective Bronsted base catalysis. Cyclopropenimines offer unique advantages of: (1) high basicity and reactivity;(2) ease of preparation;(3) compatibility with aqueous and aerobic conditions;(4) catalyst modularity;and (5) amenability to scale. In each of the projects targeted herein, we aim to apply cyclopropenimine catalysis to address a prominent challenge in organic synthesis. The asymmetric transformations targeted in this grant are either currently unknown or suffer from significant limitations of substrate scope. Among the specific reactions that we aim to develop in the context of this grant are: enantioselective glycine Mannich and ?-thio Mannich reactions;?-arylations with quinones and benzene oxides;Michael additions with low acidity nucleophiles, including diazoesters;allylic alkylations;and enantioselective conjugate additions of phenols, amines, and nitrogen heterocycles. The development of these proposed transformations and the further establishment of the new cyclopropenimine catalyst platform will represent significant advances for the field of organic synthesis.

Public Health Relevance

One of the most significant impediments to the discovery of new medicinal agents is the inability to assemble complex molecules rapidly, efficiently, and with predictable outcomes. This proposal aims to address a number of major technological gaps in the field of organic synthesis, which will greatly accelerate the preparation of medicinal lead structures.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM102611-01A1
Application #
8458280
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2012-12-15
Project End
2017-11-30
Budget Start
2012-12-15
Budget End
2013-11-30
Support Year
1
Fiscal Year
2013
Total Cost
$292,239
Indirect Cost
$102,239
Name
Columbia University (N.Y.)
Department
Chemistry
Type
Other Domestic Higher Education
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
Bandar, Jeffrey S; Sauer, Gregory S; Wulff, William D et al. (2014) Transition state analysis of enantioselective Brønsted base catalysis by chiral cyclopropenimines. J Am Chem Soc 136:10700-7
Bandar, Jeffrey S; Lambert, Tristan H (2013) Cyclopropenimine-catalyzed enantioselective Mannich reactions of tert-butyl glycinates with N-Boc-imines. J Am Chem Soc 135:11799-802