Enabling the optimal design of molecular structure for biologic function requires the invention of new methodologies that are chemo-, regio-, diastereo-, and enantio-selective to allow access to the designed molecular target in a time-efficient manner regardless of its structural complexity. Another aspect of importance is to design such methodologies that also are atom economic - ie to maximize the use of valuable raw materials and to minimize the generation of waste. Furthermore, the development of methods that form multiple bonds in a single pot wherein molecular complexity is rapidly assembled offers the opportunity to reduce step count. Multi-bond forming reactions introduce more structural complexity in a single step and thereby shortens step count. Metal catalyzed cycloadditions has the advantage of using the metal and its attendant ligands to control selectivity, notably diastereo- and enantioselectivity. This latter ability of metal complexes to control selectivity provides incredible opportunity uniquely in allylic alkylations because the exact same catalysts are applicable to formation of a wide diversity of bond types - C-H, C-O, C-N, C-F, C-S, C-P, and C-C, etc., and a wide diversity of mechanisms for enantiodiscrimination. The targets have biological activity mainly as anti-cancer and anti-viral agents. Citrinadin A exhibits cytotoxicity against murine leukemia L1210 and human epidermoid carcinoma KB cells. A facile synthesis will confirm stereochemistry and, importantly, supply larger quantities for further biological evaluation. Welwistatin (N-methylwelwitindolinone C isothiocyanate) is a potent MDR reversing agent reducing the IC50 by 90 fold for many anticancer agents. The serine protease inhibitors, the aeruginosins, have potential as antiviral agents. The cyclotryptamine alkaloids exhibit a broad range of biological properties including antitumor, antiviral, antifungal, and analgesic triggering the question of how structural changes may beget selectivity. The hexacyclic ascidian perophoramidines induce apoptosis by PARP cleavage and the more complicated communesins are microfilament disrupters. The aspidosperma type indole alkaloid, kopimaline A reverses multidry resistance in vincristine-resistant KB cells and has not been synthesized previously.

Public Health Relevance

Synthesis of complex potential pharmaceutical candidates made easy is the goal of this research. Designing safe and efficacious pharmaceuticals with minimum side effect profiles requires proper design of molecular structure. Inventing novel synthetic methodologies based upon chemo-, regio-, diastereo-, and enantioselective catalytic processes will enable new concepts in synthetic strategies that will enable drug design.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM033049-39
Application #
8721425
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
Project End
Budget Start
Budget End
Support Year
39
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304
Trost, Barry M; Miege, Frédéric (2014) Development of ProPhenol ligands for the diastereo- and enantioselective synthesis of ?-hydroxy-?-amino esters. J Am Chem Soc 136:3016-9
Trost, Barry M; Masters, James T; Lumb, Jean-Philip et al. (2014) Asymmetric synthesis of chiral cycloalkenone derivatives via palladium catalysis. Chem Sci 5:1354-1360
Trost, Barry M; Stivala, Craig E; Hull, Kami L et al. (2014) A concise synthesis of (-)-lasonolide A. J Am Chem Soc 136:88-91
Trost, Barry M; Malhotra, Sushant (2014) Asymmetric stereodivergent strategy towards aminocyclitols. Chemistry 20:8288-92
Trost, Barry M; Bringley, Dustin A; Zhang, Ting et al. (2013) Rapid access to spirocyclic oxindole alkaloids: application of the asymmetric palladium-catalyzed [3 + 2] trimethylenemethane cycloaddition. J Am Chem Soc 135:16720-35
Trost, Barry M; Osipov, Maksim (2013) Palladium-catalyzed asymmetric construction of vicinal all-carbon quaternary stereocenters and its application to the synthesis of cyclotryptamine alkaloids. Angew Chem Int Ed Engl 52:9176-81
Trost, Barry M; Bringley, Dustin A (2013) Enantioselective synthesis of 2,2-disubstituted tetrahydrofurans: palladium-catalyzed [3+2] cycloadditions of trimethylenemethane with ketones. Angew Chem Int Ed Engl 52:4466-9
Trost, Barry M; Masters, James T; Burns, Aaron C (2013) Palladium-catalyzed asymmetric allylic alkylation of 3-aryloxindoles with allylidene dipivalate: a useful enol pivalate product. Angew Chem Int Ed Engl 52:2260-4
Trost, Barry M; Michaelis, David J; Truica, Mihai I (2013) Dinuclear zinc-ProPhenol-catalyzed enantioselective *-hydroxyacetate aldol reaction with activated ester equivalents. Org Lett 15:4516-9
Trost, Barry M; Bringley, Dustin A; O'Keefe, B Michael (2013) Highly substituted enantioenriched cyclopentane derivatives by palladium-catalyzed [3 + 2] trimethylenemethane cycloadditions with disubstituted nitroalkenes. Org Lett 15:5630-3

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