Abstract

The principle objective of this research program as set forth in this proposal will be to develop a viable synthetic strategy to the milbemycin-avermectin family of macrolide antibiotics which are known to possess potent activity as broad spectrum antiparasitic agents, in particular anthelmintics. As new synthetic targets we have selected the toxic fungal metabolites known as the talaromycins A and B. Our interest in the talaromycins stem directly from the spiroketal structural unit common to both the avermectins and milbemycins. In addition, we believe we are within reach of a unified synthetic strategy for the lathyrane diterpenes, the simplest member of which is the fungalsidal agent casbene. Representative targets here include bertyadionol and the jolkinols. Each of these projects will require the development of new chemistry and synthetic methodology, which will have utility not only to the above specific targets but to the synthesis of important new pahrmacological agents in general.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM029028-06
Application #
3276477
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1981-04-01
Project End
1988-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
6
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Zou, Yike; Smith 3rd, Amos B (2018) Total synthesis of architecturally complex indole terpenoids: strategic and tactical evolution. J Antibiot (Tokyo) 71:185-204
Zou, Yike; Li, Xiangqin; Yang, Yun et al. (2018) Total Synthesis of (-)-Nodulisporic Acids D, C, and B: Evolution of a Unified Synthetic Strategy. J Am Chem Soc 140:9502-9511
Han, Heeoon; Smith 3rd, Amos B (2017) Anion Relay Chemistry: Development of an Effective Diastereoselective [3+2] Annulation Tactic Exploiting an Aldol/Brook Rearrangement/Cyclization Cascade. Angew Chem Int Ed Engl 56:14102-14106
Deng, Yifan; Liu, Qi; Smith 3rd, Amos B (2017) Oxidative [1,2]-Brook Rearrangements Exploiting Single-Electron Transfer: Photoredox-Catalyzed Alkylations and Arylations. J Am Chem Soc 139:9487-9490
Liu, Qi; Deng, Yifan; Smith 3rd, Amos B (2017) Total Synthesis of (-)-Nahuoic Acid Ci (Bii). J Am Chem Soc 139:13668-13671
Nguyen, Minh H; O'Brien, Kevin T; Smith 3rd, Amos B (2017) Design, Synthesis, and Application of Polymer-Supported Silicon-Transfer Agents for Cross-Coupling Reactions with Organolithium Reagents. J Org Chem 82:11056-11071
Liu, Qi; Chen, Yu; Zhang, Xiao et al. (2017) Type II Anion Relay Chemistry: Conformational Constraints To Achieve Effective [1,5]-Vinyl Brook Rearrangements. J Am Chem Soc 139:8710-8717
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
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

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