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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM029028-30
Application #
8627173
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
1991-09-01
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
30
Fiscal Year
2014
Total Cost
$302,247
Indirect Cost
$106,247
Name
University of Pennsylvania
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Farrell, Mark; Melillo, Bruno; Smith 3rd, Amos B (2016) Type II Anion Relay Chemistry: Exploiting Bifunctional Weinreb Amide Linchpins for the One-Pot Synthesis of Differentiated 1,3-Diketones, Pyrans, and Spiroketals. Angew Chem Int Ed Engl 55:232-5
Martinez-Solorio, Dionicio; Melillo, Bruno; Sanchez, Luis et al. (2016) Design, Synthesis, and Validation of an Effective, Reusable Silicon-Based Transfer Agent for Room-Temperature Pd-Catalyzed Cross-Coupling Reactions of Aryl and Heteroaryl Chlorides with Readily Available Aryl Lithium Reagents. J Am Chem Soc 138:1836-9
Nguyen, Minh H; Imanishi, Masashi; Kurogi, Taichi et al. (2016) Total Synthesis of (-)-Mandelalide A Exploiting Anion Relay Chemistry (ARC): Identification of a Type II ARC/CuCN Cross-Coupling Protocol. J Am Chem Soc 138:3675-8
Sokolsky, Alexander; Cattoen, Martin; Smith 3rd, Amos B (2015) Synthesis of a C(1)-C(23) fragment for spirastrellolide E: development of a mechanistic rationale for spiroketalization. Org Lett 17:1898-901
Li, Bo; Williams, Brett D; Smith 3rd, Amos B (2015) A mild, diastereoselective construction of cyclic and spirocyclic ketals employing a tandem photoisomerization/cyclization tactic. Org Lett 17:3-5
Melillo, Bruno; Chen, Ming Z; Forestieri, Roberto et al. (2015) An Effective Bifunctional Aldehyde Linchpin for Type II Anion Relay Chemistry: Development and Application to the Synthesis of a C16-C29 Fragment of Rhizopodin. Org Lett 17:6242-5
Han, Heeoon; Smith 3rd, Amos B (2015) Total Synthesis of (-)-Secu'amamine A Exploiting Type II Anion Relay Chemistry. Org Lett 17:4232-5
Zou, Yike; Melvin, Jason E; Gonzales, Stephen S et al. (2015) Total Synthesis of (-)-Nodulisporic Acid D. J Am Chem Soc 137:7095-8
Sokolsky, Alexander; Wang, Xiaozhao; Smith 3rd, Amos B (2015) Spirastrellolide E: Synthesis of an advanced C(1)-C(24) southern hemisphere. Tetrahedron Lett 56:3160-3164
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

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