This research proposal seeks to invent and develop broad new asymmetric catalytic strategies, which will provide enantioselective access to a range of privileged functional motifs not readily available through current approaches. Each of the methods to be pursued in this grant addresses a prominent and long-standing challenge in synthetic organic chemistry. A main focus of this proposal is the invention of new asymmetric methods based on the powerful multicatalytic strategy of """"""""synergistic catalysis."""""""" This concept envisions the productive merger of two simultaneous catalytic cycles, which operate in concert to separately activate each reactant, culminating in a single bond- forming event. Because of its enormous potential to enable the development of previously inconceivable chemical transformations, and to dramatically improve the selectivity of existing reactions, we anticipate that asymmetric synergistic catalysis will emerge as a transformative synthetic paradigm. The research to be pursued in Aim I of this grant is directed toward the development of new synergistic methods based on the merger of organocatalysis and copper catalysis.
Aims II and III of this proposal outline the development and application of a novel asymmetric catalytic activation mode, recently identified in our laboratory, that utilizes ligated copper catalysis with iodonium salts, to effect the asymmetric functionalization of nucleophilic substrates. Specifically Aim I envisions the development, through the synergistic merger of organocatalysis and copper catalysis, of a collection of powerful new asymmetric methods, namely: -arylation of aldehydes;-vinylation of aldehydes using either vinyl iodonium salts or vinyl borane coupling partners;-methylation of aldehydes;and -arylation of aldehydes.
Aim II outlines the development, through application of a novel ligated copper catalysis platform, of a series of new asymmetric transformations by which to achieve: -arylation of carbonyls;-vinylation of carbonyls;and dearomatizing arylation of tryptamine and tryptophol substrates, to deliver pyrroloindoline and furanoindoline motifs. Finally, in Aim III of this proposal, we will demonstrate the ability of our newly developed asymmetric dearomatizing arylation protocol to facilitate the construction of complex target systems, through a convergent asymmetric synthesis of the 3- arrylpyrroloindoline natural product, naseseazine A.

Public Health Relevance

The objective of this research is to establish a new catalytic strategy for chemical synthesis whereby natural products, bioactive compounds and medicinal agents can be generated in a highly accelerated fashion from cheap, inexpensive and readily available starting materials.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM103558-02
Application #
8519481
Study Section
Special Emphasis Panel (ZRG1-BCMB-U (02))
Program Officer
Lees, Robert G
Project Start
2012-08-01
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$287,272
Indirect Cost
$103,922
Name
Princeton University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Noble, Adam; McCarver, Stefan J; MacMillan, David W C (2015) Merging photoredox and nickel catalysis: decarboxylative cross-coupling of carboxylic acids with vinyl halides. J Am Chem Soc 137:624-7
Cuthbertson, James D; MacMillan, David W C (2015) The direct arylation of allylic sp(3) C-H bonds via organic and photoredox catalysis. Nature 519:74-7
Jin, Jian; MacMillan, David W C (2015) Alcohols as alkylating agents in heteroarene C-H functionalization. Nature 525:87-90
Jin, Jian; MacMillan, David W C (2015) Direct α-arylation of ethers through the combination of photoredox-mediated C-H functionalization and the Minisci reaction. Angew Chem Int Ed Engl 54:1565-9
Hager, Dominik; MacMillan, David W C (2014) Activation of C-H bonds via the merger of photoredox and organocatalysis: a coupling of benzylic ethers with Schiff bases. J Am Chem Soc 136:16986-9
Peifer, Manuel; Berger, Raphaëlle; Shurtleff, Valerie W et al. (2014) A general and enantioselective approach to pentoses: a rapid synthesis of PSI-6130, the nucleoside core of sofosbuvir. J Am Chem Soc 136:5900-3
Chu, Lingling; Ohta, Chisa; Zuo, Zhiwei et al. (2014) Carboxylic acids as a traceless activation group for conjugate additions: a three-step synthesis of (±)-pregabalin. J Am Chem Soc 136:10886-9
Noble, Adam; MacMillan, David W C (2014) Photoredox α-vinylation of α-amino acids and N-aryl amines. J Am Chem Soc 136:11602-5
Zuo, Zhiwei; Ahneman, Derek T; Chu, Lingling et al. (2014) Dual catalysis. Merging photoredox with nickel catalysis: coupling of α-carboxyl sp³-carbons with aryl halides. Science 345:437-40
Qvortrup, Katrine; Rankic, Danica A; MacMillan, David W C (2014) A general strategy for organocatalytic activation of C-H bonds via photoredox catalysis: direct arylation of benzylic ethers. J Am Chem Soc 136:626-9

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