The past decade has seen intense interest in the characterization, synthesis and medicinal development of polyketide/macrolide natural products such as the bryostatins, discodermolides, spongistatins, epothilones, etc. as extraordinarily potent anti-cancer agents. In many cases, only exceedingly limited quantities of these (often marine) natural products are available from natural sources/fermentation, and this has greatly hampered efforts to more fully evaluate their biological/medicinal profile. The recent synthesis of ~60 g of discodermolide by a large group of Novartis chemists with enormous effort, time, and expense both underscores the need for large amounts of these compounds and provides a useful benchmark as to the state of the art in terms of synthetic accessibility. It is imperative, therefore, that synthetic organic chemists continue to provide significantly simpler methods for the synthesis of such compounds. Success toward this ambitious goal would impact not just the supply of these compounds, but efforts to develop analogs with improved pharmacological profiles as well. The present proposal details the development of reactions that will establish high levels of structural and stereochemical complexity in operationally trivial, environmentally sound, and scalable processes. This will be achieved through the orchestration of tandem reactions that assemble simple, principally hydrocarbon fragments into large segments of the target natural products that contain as many as three stereocenters. Importantly, the conceptual foundation for these methods involves the use of Lewis acidic silanes, compounds that are extraordinarily straightforward and inexpensive to synthesize on large scales. Following the development of these methodologies, we will demonstrate their effectiveness by accomplishing brief and efficient syntheses of important natural products such as zincophorin, dictyostatin, and the C(1)-C(28) ABCD fragment and the C(29)-C(51) EF fragment of the spongistatins. The targets have been selected for their biological importance and because it is our goal to improve the step economy with which such structures may be prepared.

Public Health Relevance

Polyketide natural products are a rich source of biologically active compounds with extraordinary medicinal potential as antibiotics and as anti-cancer agents. However, very often they are available from natural sources in only minute quantities, insufficient for their full biological profile to be investigated. This proposal seeks to develop efficient methods for the synthesis of gram-scale quantities of such compounds to aid in their biological evaluation and development.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM058133-12
Application #
8246454
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
1998-08-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
12
Fiscal Year
2012
Total Cost
$373,579
Indirect Cost
$152,768
Name
Columbia University (N.Y.)
Department
Chemistry
Type
Other Domestic Higher Education
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
Foley, Corinne N; Leighton, James L (2014) Beyond the Roche ester: a new approach to polypropionate stereotriad synthesis. Org Lett 16:1180-3
Ho, Stephen; Bucher, Cyril; Leighton, James L (2013) A highly step-economical synthesis of dictyostatin. Angew Chem Int Ed Engl 52:6757-61
Tanis, Paul S; Infantine, Joshua R; Leighton, James L (2013) Exploiting pseudo C2-symmetry for an efficient synthesis of the F-ring of the spongistatins. Org Lett 15:5464-7
Harrison, Tyler J; Ho, Stephen; Leighton, James L (2011) Toward more "ideal" polyketide natural product synthesis: a step-economical synthesis of zincophorin methyl ester. J Am Chem Soc 133:7308-11
Kim, Hyunwoo; Ho, Stephen; Leighton, James L (2011) A more comprehensive and highly practical solution to enantioselective aldehyde crotylation. J Am Chem Soc 133:6517-20
Spletstoser, Jared T; Zacuto, Michael J; Leighton, James L (2008) Tandem silylformylation-crotylsilylation/Tamao oxidation of internal alkynes: a remarkable example of generating complexity from simplicity. Org Lett 10:5593-6
Park, Peter K; O'Malley, Steven J; Schmidt, Darby R et al. (2006) Total synthesis of dolabelide D. J Am Chem Soc 128:2796-7
Burns, Noah Z; Hackman, Blaine M; Ng, Pui Yee et al. (2006) The enantioselective allylation and crotylation of sterically hindered and functionalized aryl ketones: convenient access to unusual tertiary carbinol structures. Angew Chem Int Ed Engl 45:3811-3
Zacuto, Michael J; Leighton, James L (2005) Divergent synthesis of complex polyketide-like macrolides from a simple polyol fragment. Org Lett 7:5525-7
Bolshakov, Sergei; Leighton, James L (2005) Efficient asymmetric synthesis of (+)-SCH 351448. Org Lett 7:3809-12

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