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)
Institute
National Institute of General Medical Sciences (NIGMS)
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
1987-04-01
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
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; Koester, Dennis C; Sharif, Ehesan U (2016) Ruthenium-Catalyzed Multicomponent Reactions: Access to α-Silyl-β-Hydroxy Vinylsilanes, Stereodefined 1,3-Dienes, and Cyclohexenes. Chemistry 22:2634-8
Trost, Barry M; Saget, Tanguy; Lerchen, Andreas et al. (2016) Catalytic Asymmetric Mannich Reactions with Fluorinated Aromatic Ketones: Efficient Access to Chiral β-Fluoroamines. Angew Chem Int Ed Engl 55:781-4
Trost, Barry M; Masters, James T; Taft, Benjamin R et al. (2016) Asymmetric synthesis of chiral β-alkynyl carbonyl and sulfonyl derivatives via sequential palladium and copper catalysis. Chem Sci 7:6217-6231
Trost, Barry M; Saget, Tanguy; Hung, Chao-I Joey (2016) Direct Catalytic Asymmetric Mannich Reactions for the Construction of Quaternary Carbon Stereocenters. J Am Chem Soc 138:3659-62
Trost, Barry M; Masters, James T (2016) Transition metal-catalyzed couplings of alkynes to 1,3-enynes: modern methods and synthetic applications. Chem Soc Rev 45:2212-38
Trost, Barry M; Biannic, Berenger (2015) Redox cycloisomerization approach to 1,2-dihydropyridines. Org Lett 17:1433-6
Trost, Barry M; Hung, Chao-I Joey (2015) Broad Spectrum Enolate Equivalent for Catalytic Chemo-, Diastereo-, and Enantioselective Addition to N-Boc Imines. J Am Chem Soc 137:15940-6
Trost, Barry M; Rao, Meera (2015) Development of chiral sulfoxide ligands for asymmetric catalysis. Angew Chem Int Ed Engl 54:5026-43
Trost, Barry M; Biannic, Berenger; Brindle, Cheyenne S et al. (2015) A Highly Convergent Total Synthesis of Leustroducsin B. J Am Chem Soc 137:11594-7
Trost, Barry M; Bartlett, Mark J (2015) ProPhenol-catalyzed asymmetric additions by spontaneously assembled dinuclear main group metal complexes. Acc Chem Res 48:688-701

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