The ability to prepare functionalized organic molecules rationally and predictably, whether individually or in libraries, is central to organic synthesis, medicinal chemistry and the pharmaceutical industry.
The aims of this work are to develop new and/or improved methods for the formation of carbon-carbon and carbon-fluorine bonds. Included in this work is the development of new strategies and techniques for the preparation of complex heterocycles, which are the building blocks of medicinal chemistry and the pharmaceutical industry, via cross-coupling methodology. Also included are methods directed to the construction of sp3C- sp2C bonds both in racemic form and with absolute stereocontrol. We are also proposing to develop new methods for the preparation of selectively fluorinated organic molecules and those that are selectively substituted with trifluoromethyl groups. Further, information gained from this work will help to understand the mechanism of the processes that are being developed in order to increase the rate of improvement of the techniques that we are studying. The development of new methods for organic synthesis is key to the development of the field of organic chemistry as a whole. These reactions are of critical importance to the pharmaceutical industry. Methods for the selective fluorination of complex molecules are of great significance for positron emission tomography (PET) for imaging applications. The chemistry we are proposing has the possibility to improve access to selectively labeled compounds for PET applications. Cross-coupling methods for carbon-carbon bond formation are regularly used by those in the pharmaceutical industry for the preparation of analogues with increased potency and reduced side effects. Moreover, the methods can be employed for the preparation of quantities of new substances for preclinical and clinical testing and for the actual manufacture of a pharmaceutical agent. The techniques that are being developed allow for these important functions to be carried out in a more rapid and efficient fashion than previously possible. Moreover, they allow for the preparation of new substances, which have previously been inaccessible. These new compounds have the possibilities of having physiological properties of great importance in medicinal chemistry and the pharmaceutical industry.

Public Health Relevance

The chemistry we are proposing has the possibility to improve access to selectively labeled compounds for PET applications. The cross-coupling methods we are developing for carbon- carbon bond formation are regularly used by those in the pharmaceutical industry for the preparation of analogues with increased potency and reduced side effects. Moreover, the methods can be employed for the preparation of quantities of new substances for preclinical and clinical testing and for the actual manufacture of a pharmaceutical agent.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM046059-21
Application #
8308435
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
1992-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
21
Fiscal Year
2012
Total Cost
$882,280
Indirect Cost
$336,762
Name
Massachusetts Institute of Technology
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Yang, Yang; Buchwald, Stephen L (2014) Copper-catalyzed regioselective ortho C-H cyanation of vinylarenes. Angew Chem Int Ed Engl 53:8677-81
Lee, Hong Geun; Milner, Phillip J; Buchwald, Stephen L (2014) Pd-catalyzed nucleophilic fluorination of aryl bromides. J Am Chem Soc 136:3792-5
Zou, Yekui; Spokoyny, Alexander M; Zhang, Chi et al. (2014) Convergent diversity-oriented side-chain macrocyclization scan for unprotected polypeptides. Org Biomol Chem 12:566-73
Lee, Hong Geun; Milner, Phillip J; Colvin, Michael T et al. (2014) Structure and Reactivity of [(L•Pd)n•(1,5-cyclooctadiene)] (n=1-2) Complexes Bearing Biaryl Phosphine Ligands. Inorganica Chim Acta 422:188-192
Yang, Yang; Niedermann, Katrin; Han, Chong et al. (2014) Highly selective palladium-catalyzed cross-coupling of secondary alkylzinc reagents with heteroaryl halides. Org Lett 16:4638-41
Bruno, Nicholas C; Niljianskul, Nootaree; Buchwald, Stephen L (2014) N-substituted 2-aminobiphenylpalladium methanesulfonate precatalysts and their use in C-C and C-N cross-couplings. J Org Chem 79:4161-6
Milner, Phillip J; Kinzel, Tom; Zhang, Yong et al. (2014) Studying regioisomer formation in the Pd-catalyzed fluorination of aryl triflates by deuterium labeling. J Am Chem Soc 136:15757-66
Friis, Stig D; Skrydstrup, Troels; Buchwald, Stephen L (2014) Mild Pd-catalyzed aminocarbonylation of (hetero)aryl bromides with a palladacycle precatalyst. Org Lett 16:4296-9
Bruno, Nicholas C; Buchwald, Stephen L (2013) Synthesis and application of palladium precatalysts that accommodate extremely bulky di-tert-butylphosphino biaryl ligands. Org Lett 15:2876-9
Spokoyny, Alexander M; Zou, Yekui; Ling, Jingjing J et al. (2013) A perfluoroaryl-cysteine S(N)Ar chemistry approach to unprotected peptide stapling. J Am Chem Soc 135:5946-9

Showing the most recent 10 out of 83 publications