This proposal focuses on new metal-catalyzed hydroacylation and hydroarylation reactions to form biologically active molecules, such as chiral amines, differentially substituted hydrazines, isoindolones, and indazolones. Previously reported metal-catalyzed hydroacylation processes generally involve the addition of an acyl and hydride group across the face of all carbon ?-systems. There has been limited work of hydroacylation reactions where the ?-acceptor contains a heteroatom. The emphasis of this proposal is the investigation of the metal-catalyzed hydroacylation and hydroarylation of ?-systems that contain one more heteroatoms (ketimines and diazenes). Following the successful achievement of these reactions we will explore a C-H activation strategy to convert the generated chiral amines and hydrazides to the corresponding cyclic isoindolones, and indazolones, respectively. In addition to exploring the hydroacylation of ketimines, we will examine the decarbonylation pathway to achieve the hydroarylation of ketimines. Successful establishment of these methodologies would find wide application in the fields of medicinal chemistry, drug discovery, and pharmaceutical research by allowing for the direct rapid assembly of important nitrogen containing biologically active molecules.

Public Health Relevance

This proposal focuses on the development of efficient metal-catalyzed hydroacylation and hydroarylation processes to make new carbon-nitrogen and carbon-carbon bonds. More specifically these proposed methods will allow for the construction of biologically active molecules such as chiral amines, substituted hydrazines, isoindolones, and indazolones.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM108294-02
Application #
8729350
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Barski, Oleg
Project Start
2013-09-01
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Cohen, Daniel T; Zhang, Chi; Pentelute, Bradley L et al. (2015) An Umpolung Approach for the Chemoselective Arylation of Selenocysteine in Unprotected Peptides. J Am Chem Soc 137:9784-7
Cohen, Daniel T; Buchwald, Stephen L (2015) Mild palladium-catalyzed cyanation of (hetero)aryl halides and triflates in aqueous media. Org Lett 17:202-5