This project seeks to develop and implement new tactics for the total synthesis of complex natural products that exhibit promising biological activities. Targeted structures that will be synthesized under the aegis of this grant are: 1) zaragozic acid C, a squalene synthase inhibitor;2) pactamycin, an antibiotic;3) leustroducsin B, a colony-stimulating factor inducer. These three structurally unique natural products share a high level of functional group and stereochemical complexity that renders them attractive platforms for new reaction discovery. An underlying principle of the proposed research is that buildup of the carbon skeleton must coincide with introduction of stereochemical information for maximum efficiency;therefore, cascade reactions are a staple of the projected synthetic routes. The strategies in particular seek to harness the unique reactivity of a newly developed reagent: tert-butyl tert-butyldimethylsilyl glyoxylate. This is a coupling reagent that conjoins complementary nucleophilic and electrophilic reaction partners, often with high levels of stereocontrol for the stereogenic centers that are concomitantly built up with the carbon skeleton. In each proposed synthesis, the key step is a new, mechanistically guided poly-addition reaction that introduces a significant fraction of the molecular complexity in a single operation. The reactions are configured such that the key functional groups are introduced in the proper oxidation state, minimizing wasteful downstream operations.

Public Health Relevance

The molecules that are targeted for synthesis in this study all exhibit potent biological activities that could hold significance in the development of small molecule therapeutics. The efficient preparation of these compounds is a necessary precondition for any future biomedical applications.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084927-04
Application #
8265929
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2009-03-01
Project End
2013-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$250,937
Indirect Cost
$74,519
Name
University of North Carolina Chapel Hill
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Boyce, Gregory R; Johnson, Jeffrey S (2016) An Asymmetric Vinylogous Michael Cascade of Silyl Glyoximide, Vinyl Grignard, and Nitroalkenes via Long Range Stereoinduction. J Org Chem 81:1712-7
Steward, Kimberly M; Gentry, Emily C; Johnson, Jeffrey S (2015) Correction to ""Dynamic kinetic resolution of α-keto esters via asymmetric transfer hydrogenation"". J Am Chem Soc 137:3715
Sharpe, Robert J; Johnson, Jeffrey S (2015) A global and local desymmetrization approach to the synthesis of steroidal alkaloids: stereocontrolled total synthesis of paspaline. J Am Chem Soc 137:4968-71
Krabbe, Scott W; Johnson, Jeffrey S (2015) Asymmetric total syntheses of megacerotonic acid and shimobashiric acid A. Org Lett 17:1188-91
Sharpe, Robert J; Malinowski, Justin T; Sorana, Federico et al. (2015) Preparation and biological evaluation of synthetic and polymer-encapsulated congeners of the antitumor agent pactamycin: insight into functional group effects and biological activity. Bioorg Med Chem 23:1849-57
Sharpe, Robert J; Johnson, Jeffrey S (2015) Asymmetric Total Synthesis of the Indole Diterpene Alkaloid Paspaline. J Org Chem 80:9740-66
Sharpe, Robert J; Portillo, Maribel; Vélez, Robert A et al. (2015) A Scalable Protocol for the Regioselective Alkylation of 2-Methylcyclohexane-1,3-dione with Unactivated sp(3) Electrophiles. Synlett 26:2293-2295
Corbett, Michael T; Johnson, Jeffrey S (2014) Dynamic kinetic asymmetric transformations of *-stereogenic *-ketoesters by direct aldolization. Angew Chem Int Ed Engl 53:255-9
Malinowski, Justin T; Sharpe, Robert J; Johnson, Jeffrey S (2013) Enantioselective synthesis of pactamycin, a complex antitumor antibiotic. Science 340:180-2
Sharpe, Robert J; Malinowski, Justin T; Johnson, Jeffrey S (2013) Asymmetric synthesis of the aminocyclitol pactamycin, a universal translocation inhibitor. J Am Chem Soc 135:17990-8

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