Given their wide availability, chiral oxazolidinones are potentially useful but ignored substrates for catalysis. Using transition metal catalysts, CO2 extrusion from oxazolidinones could be envisioned to afford reactive aza-metallacyclobutane intermediates that can be taken to a variety of complex nitrogenous products. The Ni-catalyzed transformation of chiral oxazolidinones to small chiral heterocycles, such as aziridines and ?-lactams, will be developed. Following Ni-mediated alkyl C-O insertion into a chiral oxazolidinone, decarboxylation will afford the aza-metallacyclobutane intermediate. Reductive elimination will afford chiral aziridines. Alternatively, under a carbon monoxide atmosphere, highly substituted chiral ?-lactams can be constructed. Many natural products containing chiral aziridine or ?-lactam functionality exhibit medicinally important properties, such as anticancer and antibiotic activity;however, due to the scarcity of methods toward the synthesis of these chiral heterocycles, they present formidable synthetic challenges. The Ni-catalyzed method outlined in this proposal would offer a convenient, facile, and divergent approach to these pharmacophores from readily available chiral precursors. Importantly, this method can be used combinatorially to construct libraries of potentially bioactive molecules. Reaction screening will be carried out on a simple, unsubstituted oxazolidinone model substrate to optimize reaction conditions, including ligands and solvent. Substrates of higher-substitution will then be evaluated in this transformation. Mechanistic and spectroscopic studies, including radical trap experiments, are proposed to determine whether a Ni0/NiII or NiI/NiIII cycle operates, and whether deleterious loss of stereochemical information occurs via a radical intermediate. In addition, hypothesized intermediates will be synthesized and subjected to reaction conditions to determine whether or not they lie along the catalytic cycle. By gaining insight into the mechanism of the proposed transformation, further optimization can be rationalized, and the method made general.

Public Health Relevance

Synthetically-challenging nitrogen-containing rings are found in countless medicinally-active molecules. In this proposal, a novel nickel-catalyzed reaction will be developed to allow the fast, convenient construction of these functionalities from readily available starting material. This approach uses cheap, abundant catalysts and precursor, and may potentially be amenable to the large-scale production of pharmaceuticals in industry.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM103238-02
Application #
8588792
Study Section
Special Emphasis Panel (ZRG1-F04-D (20))
Program Officer
Barski, Oleg
Project Start
2012-11-16
Project End
2015-11-15
Budget Start
2013-11-16
Budget End
2014-11-15
Support Year
2
Fiscal Year
2014
Total Cost
$49,214
Indirect Cost
Name
University of California Berkeley
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
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Wolf, William J; Winston, Matthew S; Toste, F Dean (2014) Exceptionally fast carbon-carbon bond reductive elimination from gold(III). Nat Chem 6:159-64