The principal goals for the 24-27 years update since July 2005 will now include: (A) development of an enantioselective total synthesis of the potent insecticidal agent (+)-nodulisporic acid A, (B) completion of the total synthesis of the challenging macrolide antibiotic (+)-sorangicin A;and (C) development of a viable enantioselective total synthesis of the architecturally complex marine antitumor macrolide spirastrellolide A. As in the past, each of these targets will require the development of as yet unforeseen new synthetic methodology to overcome unforeseen obstacles. This is indeed the excitement and frustration of target oriented total synthesis. In the area of new synthetic methods, we will: (D) develop the new modular indole synthesis comprising a sequential Stille and Buchwald-Hartwig cross-coupling union/cyclization tactic, devised in conjunction with the nodulisporic acid A synthetic venture;(E) expand and showcase the new concept of Anion Relay Chemistry (ARC), a powerful synthetic tactic introduced at the time of our previous renewal application, albeit without """"""""proof of concept"""""""". Towards the latter end,we will explore a wide variety of nucleophiles, silyl linchpins possessing various anion stabilizing groups (ASG), and electrophiles to demonstrate the feasibility and rapid assembly of diverse, stereochemically complex oxygen and nitrogen substituted products in a single flask. Beyond these specific synthetic objectives, a general, long-range goal of this program is the identification of the molecular architecture responsible for biological activity. Thus, as we develop an approach to each target, we will also prepare model compounds designed to permit the elucidation of structure-activity relationships. Our experience with discodermolide gives us great confidence in this area.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM029028-27
Application #
7743757
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Hagan, Ann A
Project Start
1991-09-01
Project End
2012-04-30
Budget Start
2009-12-01
Budget End
2012-04-30
Support Year
27
Fiscal Year
2010
Total Cost
$276,075
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
Liu, Qi; Deng, Yifan; Smith 3rd, Amos B (2017) Total Synthesis of (-)-Nahuoic Acid Ci (Bii). J Am Chem Soc 139:13668-13671
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
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
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
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
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
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
Han, Heeoon; Smith 3rd, Amos B (2015) Total Synthesis of (-)-Secu'amamine A Exploiting Type II Anion Relay Chemistry. Org Lett 17:4232-5
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

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