The objective of this research proposal is to invent new catalytic synthetic methods or strategies that allow enantioselective access to structural and stereochemical motifs, which although common among anti-viral, anti-cancer anti- bacterial and anti-inflammatory medicinal agents, cannot be readily accessed using conventional methods. In this endeavor, we target processes that are readily applied within the related discipline of enantioselective catalysis and therefore will have a direct and immediate impact on the production of single enantiomer drugs with established biological importance. Our intent is to develop synthetic methods of broad utility and function that will ultimately provide new chemical tools for the diverse range of biomedical researchers that utilize molecule construction. As a consequence, this core research will prove valuable to a number of wide-ranging therapeutical areas. 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, relatively few asymmetric transformations have been reported which employ organic molecules as reaction catalysts (organocatalysis) despite 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 organocatalysis that enables simple chiral amines to function as asymmetric catalysts for a wide range of transformations that traditionally utilize Lewis acids. We further describe a catalyst design endeavor that should provide an inexpensive, robust amine catalyst that provides high levels of asymmetric induction across a broad spectrum of chemical processes. During the tenure of this granting period we hope to demonstrate the value of this new chemical strategy in the context of the first examples of enantioselective organocatalytic (1) intermolecular Diels-Alder reactions, (2) intramolecular Diels-Alder reactions, (3) 1,3-dipolar cycloadditions, (4) Benzene alkylations, (5) Pyrrole alkylations, (6) Indole alkylations, (7) Furan alkylations, (8) Michael Additions, (9) Mukaiyama-Michael Additions, (10) Vinylogous Michael Additions and (10) Intramolecular Ene reactions. The pyrroloindolines and bispyrroloindolines represent a diverse family of structurally complex polyindoline alkaloids that exhibit remarkable biological properties across a broad spectrum of pharmacological screens (anti-cancer, anti-inflammatory, neuroactivity receptors: cholecystokinin, substance P and neurokinin 1). This proposal outlines an innovative application of our iminium activation strategy towards the one step enantioselective cascade synthesis of bispyrroloindoline architecture. Having demonstrated the feasibility of this transformation, we hope to determine the scope of this catalytic tandem reaction methodology for the production of a range of bispyrroloindoline alkaloids. To exemplify the value of this innovative asymmetric catalytic methodology we will pursue the highly expeditious synthesis of (+)-pseudophrynamine A; a constituent of the dendrobatid amphibians. This new chemical tool will be further employed for the five step asymmetric synthesis of (+)-chimonanthine, a complex alkaloid that will serve as an architectural template to launch a variety of subsequent complex target syntheses endeavors.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066142-03
Application #
6748617
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2002-06-01
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
3
Fiscal Year
2004
Total Cost
$355,573
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Engineering
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Storer, R Ian; Carrera, Diane E; Ni, Yike et al. (2006) Enantioselective organocatalytic reductive amination. J Am Chem Soc 128:84-6
Tuttle, Jamison B; Ouellet, Stephane G; MacMillan, David W C (2006) Organocatalytic transfer hydrogenation of cyclic enones. J Am Chem Soc 128:12662-3
Chen, Young K; Yoshida, Masanori; MacMillan, David W C (2006) Enantioselective organocatalytic amine conjugate addition. J Am Chem Soc 128:9328-9
Wilson, Rebecca M; Jen, Wendy S; Macmillan, David W C (2005) Enantioselective organocatalytic intramolecular Diels-Alder reactions. The asymmetric synthesis of solanapyrone D. J Am Chem Soc 127:11616-7
Beeson, Teresa D; Macmillan, David W C (2005) Enantioselective organocatalytic alpha-fluorination of aldehydes. J Am Chem Soc 127:8826-8
Mangion, Ian K; MacMillan, David W C (2005) Total synthesis of brasoside and littoralisone. J Am Chem Soc 127:3696-7
Huang, Yong; Walji, Abbas M; Larsen, Catharine H et al. (2005) Enantioselective organo-cascade catalysis. J Am Chem Soc 127:15051-3
Ouellet, Stephane G; Tuttle, Jamison B; MacMillan, David W C (2005) Enantioselective organocatalytic hydride reduction. J Am Chem Soc 127:32-3
Kunz, Roxanne K; MacMillan, David W C (2005) Enantioselective organocatalytic cyclopropanations. The identification of a new class of iminium catalyst based upon directed electrostatic activation. J Am Chem Soc 127:3240-1
Mangion, Ian K; Northrup, Alan B; MacMillan, David W C (2004) The importance of iminium geometry control in enamine catalysis: identification of a new catalyst architecture for aldehyde-aldehyde couplings. Angew Chem Int Ed Engl 43:6722-4

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