The therapeutic importance of antitumor antiviral agents requires a continued effort to develop new methodology to define better synthetic strategies. Choosing classes of compounds known for this type of biological activity as targets, this project develops new chemical principles that may evolve into unprecedented strategies for creating such molecular architectures. Asymmetric allylic akylation involving palladium and epoxides or related cyclic carbonates may provide a simple strategy to form a building block directed toward mitomycin - type structures. Inducing asymmetry at a prochiral nucleophile represents one of the most challenging tasks ever for chiral recognition in a catalytic asymmetric event. Preliminary successes stimulates its exploration. The breadth of applications is huge - ranging from alkaloids like the clinically important vinca alkaloids to macrocycles like peloruside A. A novel version combines asymmetric induction of a pronucleophile with a new class of pro-electrophiles, allenes, to create an extremely short synthesis of unusual amide types such as spirotyprostatin. A series of tandem stereospecific processes initiated by the asymmetric allylic alkylation invoking cyclic diketones creates a conceptually unprecedented approach to novel terpenes like terpestacin. New Ru catalyzed reactions being invented will be tested and explored in the synthesis of diverse polyketides like the laulimalides and pelorusides. A totally new concept for simple polyfunctional ring construction by atom economic additions is visualized via Ru catalyzed cycloisomerization or water addition to suitable diynes. Numerous targets emerge with the most exciting. In a number of projects, totally unprecedented selectivities in hdyrosilylation helps simplify the synthetic design including the mitomycin mimic and ptsloruside A. A direct asymmetric aldol protocol provides access to numerous structural types represented by leustroducsin, peloruside A, and apicularen A. By expediting access to very diverse arrays of structural types, the best opportunities to discover new therapeutic agents arise.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM033049-32
Application #
7283628
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Schwab, John M
Project Start
1987-04-01
Project End
2009-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
32
Fiscal Year
2007
Total Cost
$341,519
Indirect Cost
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; Huang, Zhongxing; Murhade, Ganesh M (2018) Catalytic palladium-oxyallyl cycloaddition. Science 362:564-568
Trost, Barry M; Ryan, Michael C (2017) Indenylmetal Catalysis in Organic Synthesis. Angew Chem Int Ed Engl 56:2862-2879
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; 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; 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; 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; 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; 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; 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; 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

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