The research and development of new drug therapies is reliant upon synthetic methods that are able to deliver diverse drug-like molecules in a straightforward manner. One common motif found in numerous pharmaceuticals and biologically active natural products are 5- and 7-membered carbocyclic frameworks. As a result, new synthetic methods that allow direct access to these types of scaffolds is necessary for facilitatin the development of these types compounds as therapeutic agents. Cycloaddition reactions are one of the most effective routes for carbocycle synthesis, with [4+2] cycloadditions in particular being a key route for diverse cyclohexane synthesis. However, [3+2] and [4+3] cycloaddition methods for pentacyclic and heptacyclic ring construction remain limited due to the difficulty associated with forming reactive 3-carbon intermediates. Recently, visible light photocatalysis has emerged as a way of mediating cycloaddition reactions through the formation of reactive radical cation intermediates. Unlike other methods for radical cation generation, visible light photocatalysis proceeds under mild conditions and with high efficiency. This proposal aims to utilize visible light photocatalysis as a new approach to [3+2] and [4+3] cycloaddition reactions through the photocatalyzed ring opening of cyclopropyl sulfides to 3-carbon radical cation intermediates. In these transformations the sulfide serves as a "redox auxiliary" by facilitating the formation and participation of the requisite 3-carbon radical cation intermediate in cycloaddition reactions between alkenes and dienes. In a subsequent step, the sulfide handle can be easily removed under reductive conditions to liberate the desired 5- or 7-membered carbocyclic product. Due to the unique reactivity of radical cation intermediates, these transformations will allow entry into pentacyclic and heptacyclic scaffolds with diverse substitution patterns that would otherwise be challenging to access. In contrast to traditional photochemical methods that require strong UV light and special photoreactors, the proposed transformations will be practical to carry out, requiring standard glassware and a household light bulb to induce photoactivation. In the end, the methods developed in this proposal will provide medicinal and organic chemists a novel strategy-level disconnection for synthesizing biologically active targets that posses pentacyclic and heptacyclic scaffolds. In addition, the findings from this research will lend insight into the development of other useful ring opening transformations that proceed through visible light photoredox catalysis.

Public Health Relevance

The ability to treat a wide variety of diseases through the development of new and improved pharmaceuticals is important for the wellbeing of society;however, this progress can be hindered by the synthetic methods available for making new drugs. As a result, the design of new synthetic methods that are able to produce drug-like molecules in a straightforward manner would greatly aid in the process of bringing new medicines to the public.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32GM105149-01
Application #
8454047
Study Section
Special Emphasis Panel (ZRG1-F04-A (09))
Program Officer
Lees, Robert G
Project Start
2013-03-15
Project End
2016-03-14
Budget Start
2013-03-15
Budget End
2014-03-14
Support Year
1
Fiscal Year
2013
Total Cost
$49,214
Indirect Cost
Name
University of Wisconsin Madison
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Du, Juana; Skubi, Kazimer L; Schultz, Danielle M et al. (2014) A dual-catalysis approach to enantioselective [2 + 2] photocycloadditions using visible light. Science 344:392-6