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 #
2R01GM033049-38
Application #
8494200
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
2013-09-01
Budget End
2014-08-31
Support Year
38
Fiscal Year
2013
Total Cost
$381,442
Indirect Cost
$131,442
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Trost, Barry M; Saget, Tanguy; Hung, Chao-I Joey (2017) Efficient Access to Chiral Trisubstituted Aziridines via Catalytic Enantioselective Aza-Darzens Reactions. Angew Chem Int Ed Engl 56:2440-2444
Trost, Barry M; Gnanamani, Elumalai; Hung, Chao-I Joey (2017) Controlling Regioselectivity in the Enantioselective N-Alkylation of Indole Analogues Catalyzed by Dinuclear Zinc-ProPhenol. Angew Chem Int Ed Engl 56:10451-10456
Trost, Barry M; Chan, Walter H; Malhotra, Sushant (2017) Development of the Regiodivergent Asymmetric Prenylation of 3-Substituted Oxindoles. Chemistry 23:4405-4414
Trost, Barry M; Tracy, Jacob S (2017) Carbon-Nitrogen Bond Formation via the Vanadium Oxo Catalyzed Sigmatropic Functionalization of Allenols. Org Lett 19:2630-2633
Trost, Barry M; Kalnmals, Christopher A (2017) Stereoselective Synthesis of Exocyclic Tetrasubstituted Vinyl Halides via Ru-Catalyzed Halotropic Cycloisomerization of 1,6-Haloenynes. Org Lett 19:2346-2349
Trost, Barry M; Li, Xiaoxun (2017) Pd-catalyzed asymmetric allylic alkylations via C-H activation of N-allyl imines with glycinates. Chem Sci 8:6815-6821
Trost, Barry M; Cregg, James J; Quach, Nicolas (2017) Isomerization of N-Allyl Amides To Form Geometrically Defined Di-, Tri-, and Tetrasubstituted Enamides. J Am Chem Soc :
Trost, Barry M; Sharif, Ehesan U; Cregg, James J (2017) Ru-catalyzed sequence for the synthesis of cyclic amido-ethers. Chem Sci 8:770-774
Trost, Barry M; Stivala, Craig E; Fandrick, Daniel R et al. (2016) Total Synthesis of (-)-Lasonolide A. J Am Chem Soc 138:11690-701
Trost, Barry M; Debien, Laurent (2016) Re-Orienting Coupling of Organocuprates with Propargyl Electrophiles from SN2' to SN2 with Stereocontrol. Chem Sci 7:4985-4989

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