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 #
5R01GM058133-10
Application #
7788113
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Hagan, Ann A
Project Start
1998-08-01
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
10
Fiscal Year
2010
Total Cost
$336,110
Indirect Cost
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
Chen, Liang-An; Ashley, Melissa A; Leighton, James L (2017) Evolution of an Efficient and Scalable Nine-Step (Longest Linear Sequence) Synthesis of Zincophorin Methyl Ester. J Am Chem Soc 139:4568-4573
Tekle-Smith, Makeda A; Williamson, Kevin S; Hughes, Isaac F et al. (2017) Direct, Mild, and General n-Bu4NBr-Catalyzed Aldehyde Allylsilylation with Allyl Chlorides. Org Lett 19:6024-6027
Ho, Stephen; Sackett, Dan L; Leighton, James L (2015) A ""methyl extension"" strategy for polyketide natural product linker site validation and its application to dictyostatin. J Am Chem Soc 137:14047-50
Foley, Corinne N; Leighton, James L (2015) A Highly Stereoselective, Efficient, and Scalable Synthesis of the C(1)-C(9) Fragment of the Epothilones. Org Lett 17:5858-61
Foley, Corinne N; Leighton, James L (2014) Beyond the Roche ester: a new approach to polypropionate stereotriad synthesis. Org Lett 16:1180-3
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
Suen, Linda M; Steigerwald, Michael L; Leighton, James L (2013) A new and more powerfully activating diamine for practical and scalable enantioselective aldehyde crotylsilylation reactions. Chem Sci 4:2413-2417
Ho, Stephen; Bucher, Cyril; Leighton, James L (2013) A highly step-economical synthesis of dictyostatin. Angew Chem Int Ed Engl 52:6757-61
Reznik, Samuel K; Leighton, James L (2013) Toward a more step-economical and scalable synthesis of spongistatin 1 to facilitate cancer drug development efforts. Chem Sci 4:1497-1501
Harrison, Tyler J; Rabbat, Philippe M A; Leighton, James L (2012) An ""aprotic"" Tamao oxidation/syn-selective tautomerization reaction for the efficient synthesis of the C1-C9 fragment of fludelone. Org Lett 14:4890-3

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