The overall objectives for the 17-20 years of this research program are: (A) to achieve the total synthesis of breynin A, a glycoside closely related to the phyllanthostatin antitumor agents; (B) to complete syntheses of the antitumor antibiotics trienomycin A, B, and C; (C) to construct the cytotoxic sponge metabolite calyculin A; and (D) to develop an efficient route to the macrolactins, potent inhibitors of several pathogenic viruses including the human immunosuppressive virus (HIV). In addition to the proposed target work, we plan: (E) to embark upon a synthetic methods program employing substrate-derived dioxiranes for diastereoselective intramolecular epoxidation of keto olefins, as well as highly chemoselective remote oxidation of steroids and other substrates; and (F) to explore the utility of iodine monobromide for the Bartlett iodocarbonate cyclizations and related transformations. A central theme of these efforts is the development of novel synthetic strategies which are not single-target oriented, but instead will permit construction of entire classes of natural products. We believe that this philosophy of """"""""unified synthetic strategies will be further developed in this proposal. Beyond the specific synthetic objectives, a general, long-range aim of this program is the identification of molecular architecture responsible for the biological properties of these and related systems. Thus, as we develop an approach to each target structure, we will also prepare model compounds designed to permit the elucidation of structure-activity relationships. The design of new and possibly more effective agents should then be feasible.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA019033-19
Application #
2086741
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1976-06-30
Project End
1996-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
19
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Nguyen, Minh H; Imanishi, Masashi; Kurogi, Taichi et al. (2018) Synthetic Access to the Mandelalide Family of Macrolides: Development of an Anion Relay Chemistry Strategy. J Org Chem 83:4287-4306
Ai, Yanran; Kozytska, Mariya V; Zou, Yike et al. (2018) Total Synthesis of the Marine Phosphomacrolide, (-)-Enigmazole A, Exploiting Multicomponent Type I Anion Relay Chemistry (ARC) in Conjunction with a Late-Stage Petasis-Ferrier Union/Rearrangement. J Org Chem 83:6110-6126
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
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
Montgomery, Thomas D; Smith 3rd, Amos B (2017) ?-Silyl Amides: Effective Bifunctional Lynchpins for Type I Anion Relay Chemistry. Org Lett 19:6216-6219
Liu, Qi; Deng, Yifan; Smith 3rd, Amos B (2017) Total Synthesis of (-)-Nahuoic Acid Ci (Bii). J Am Chem Soc 139:13668-13671
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
Nazari, Mohamad; Serrill, Jeffrey D; Wan, Xuemei et al. (2017) New Mandelalides Expand a Macrolide Series of Mitochondrial Inhibitors. J Med Chem 60:7850-7862
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
Adams, Gregory L; Smith 3rd, Amos B (2016) The Chemistry of the Akuammiline Alkaloids. Alkaloids Chem Biol 76:171-257

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