This research program (GM-29028), now in the twenty-seventh year, embodies the evolution of our long- standing commitment to: (A) enantioselective total synthesis of architecturally challenging, pharmacologically important natural products, (B) development and application of new, innovative synthetic methods, and (C) delivery of select targets and analogues in sufficient quantities (ca. 1 gram) for detailed biological evaluation. Going forward, the major thrust of 28-31 year program will be to define, at a fundamental level, the exciting potential of Anion Relay Chemistry (ARC). To demonstrate the diverse chemotypes accessible employing the ARC tactic, we will also undertake several target-oriented syntheses. Thus the revised overall Specific Aims for this program now include: (1) Design, synthesize and validate new, structurally novel linchpins to expand the utility of the ARC tactic;(2) Develop a detailed mechanistic understanding of the ARC tactic, with particular focus on the precise timing and stereochemical outcome of [1,n]-Brook rearrangements to maximize ARC efficiency;(3) Devise and explore an alternate route into the ARC reaction manifold;and most significantly, (4) Demonstrate the power of Iterative ARC (I-ARC) tactics (cf. living polymerization) for complex molecule synthesis (vide infra). To showcase the ARC tactic, we will: (5) Complete the total synthesis of (+) spirastrellolide B, an extremely potent marine antitumor macrolide;(6) Construct a small library of curvularin family members;and (7) Achieve effective total syntheses of secu'amamine A and EBC-23, an alkaloid and terpene respectively, representing two additional chemotypes that demonstrate the utility of the step-efficient ARC tactic.

Public Health Relevance

The principal goal of this research program comprises the design and application of new, innovative synthetic methods, in conjunction with the development of effective synthetic strategies to synthesize architecturally complex natural and natural product like compounds possessing significant bio-regulatory properties that serve as lead compounds for the discovery of new medicines.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Lees, Robert G
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University of Pennsylvania
Schools of Arts and Sciences
United States
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Nguyen, Minh H; Smith 3rd, Amos B (2014) Recyclable polystyrene-supported siloxane-transfer agent for palladium-catalyzed cross-coupling reactions. Org Lett 16:2070-3
Nguyen, Minh H; Smith 3rd, Amos B (2013) Polymer-supported siloxane transfer agents for Pd-catalyzed cross-coupling reactions. Org Lett 15:4258-61
Martinez-Solorio, Dionicio; Hoye, Adam T; Nguyen, Minh H et al. (2013) The design, synthesis and validation of recoverable and readily reusable siloxane transfer agents for Pd-catalyzed cross-coupling reactions. Org Lett 15:2454-7
Smith 3rd, Amos B; Hoye, Adam T; Martinez-Solorio, Dionicio et al. (2012) Unification of anion relay chemistry with the Takeda and Hiyama cross-coupling reactions: identification of an effective silicon-based transfer agent. J Am Chem Soc 134:4533-6
Smith 3rd, Amos B; Tong, Rongbiao; Kim, Won-Suk et al. (2011) Anion relay chemistry: access to the type II ARC reaction manifold through a fundamentally different reaction pathway exploiting 1-oxa-2-silacyclopentanes and related congeners. Angew Chem Int Ed Engl 50:8904-7
Peyrot des Gachons, Catherine; Uchida, Kunitoshi; Bryant, Bruce et al. (2011) Unusual pungency from extra-virgin olive oil is attributable to restricted spatial expression of the receptor of oleocanthal. J Neurosci 31:999-1009
Smith, Amos B; Sugasawa, Keizo; Atasoylu, Onur et al. (2011) Design and synthesis of (+)-discodermolide-paclitaxel hybrids leading to enhanced biological activity. J Med Chem 54:6319-27
Smith 3rd, Amos B; Han, Heeoon; Kim, Won-Suk (2011) Diversity-oriented synthesis of 2,4,6-trisubstituted piperidines via type II anion relay chemistry. Org Lett 13:3328-31
Smith 3rd, Amos B; Dong, Shuzhi; Fox, Richard J et al. (2011) (+)-Sorangicin A: evolution of a viable synthetic strategy. Tetrahedron 67:9809-9828
Smith 3rd, Amos B; Kutsumura, Noriki; Potuzak, Justin (2011) A Formal Total Synthesis of (-)-Brevisamide. Tetrahedron Lett 52:2117-2119

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