. The thereapeutic importance of antitumor and antiviral agents requires a continued effort to develop new methodology to define significantly improved efficient synthetic strategies to better understand structure - biological activity relationships. Choosing classes of compounds known for this type of biological acitivity as targets, this project develops new chemical principles that may evolve into unprecedented strategies for creating such molecular architectures. Four general types of chemical reactions under investigation to improve selectivity and atom economy serve as the new core technology to realize these goals - asymmetric allylic alkylation, cycloadditions to form odd membered rings, unprecedented C-C bond forming reactions by simple additions, and the ability to spontaneously self-assemble dinuclear metal complexes for asymmetric catalysis. Indoline alkaloids represented by rather diverse structures such as communesins, gliocladins/leptosins, and diazonamides as well as iboga type alkaloids represented by vindoline and kopimaline A are greatly simplified by examining new classes of nucleophiles for palladium and molybdenum catalyzed asymmetric allylic alkylation. Examination of the prospect of an unprecedented [6+3] asymmetric cycloaddition provides access to a novel oxindole alkaloid that addresses multidrug resistance. Macrocyclic lactones constitute a highly diverse array of structural types possessing potent and diverse activities as anti-cancer and antiviral agents. The very potent laulimalide and the amphidinolides, whose structures need confirmation, represent structural types that probe new directions for ruthenium catalyzed C-C bond formation. Peluroside A, a highly active inducer of apoptosis, and the salicylate macrolactones represented by apicularin A stimulate multiple new applications of asymmetric catalysis using dinuclear metal complexes. The densely functionalized pholactomycins which show diverse activity represented by leustroducsin B, a potent cytokine inducer, may simplify to a highly convergent strategy where its stereochemistry largely derives from both the dinuclear metal complexes and the asymmetric allylic alkylation reaction.

Public Health Relevance

. Inventing new drugs for the treatment of cancer and viruses requires a better understanding of mechanisms and the relation of structure to function. This proposal helps to address this key challenge by developing the underlying initial technology within classes of compounds having demonstrably antitumor or antiviral activities.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM033049-37
Application #
8318840
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
1987-04-01
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
37
Fiscal Year
2012
Total Cost
$420,177
Indirect Cost
$151,752
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; 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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