This is a renewal proposal that seeks to continue a productive research program directed toward the laboratory preparation of biologically active substances. Organic compounds isolated from Nature serve as fertile ground for the development of new therapeutic agents and as inspiration for the development of new strategies, reactions, catalysts, and reagents that can be used in their assembly. Certain natural products such as pactamycin exhibit favorable biological activities for which more in-depth exploration would be desirable;however, limitations in extant synthetic methods (or biotechnologies) preclude the efficient and practical preparation of advanced intermediates in quantities that would be useful for SAR studies. The general goal of this research program is to use natural products as an inspiration for new reaction and new reagent development. Complex bioactive natural products like pactamycin and echinosporin present a series of interesting synthetic challenges;their structures suggest to us methodologies that do not currently exist but would be exceptionally useful in efficient syntheses of these targets. The specific goals of this research proposal are to (i) achieve a concise asymmetric synthesis of the complex natural product pactamycin via a unique diastereoselective desymmetrization strategy;(ii) develop new techniques for C-N bond formation at the a-position of azomethines, thereby enabling rapid assembly of diverse diamines;(iii) create new methods for the assembly of functionally dense di- and triamines through the strategic application of a """"""""congested"""""""" Mannich addition;(iv) develop new polyfunctional reagents that will be applicable to the rapid construction of natural products like echinosporin, as well as a range of other useful chiral building blocks. Collectively the realization of these specific aims will advance the field of organic chemistry and be of use in biomedical endeavors by providing facile access to structures that were heretofore unknown or accessible only by virtue of methods that were inefficient and/or impractical.

Public Health Relevance

The molecules that are targeted for synthesis in this study 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 #
2R01GM084927-05
Application #
8436596
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2008-04-01
Project End
2017-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$275,181
Indirect Cost
$85,181
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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