Compounds possessing antitumor activity vary greatly in their structures. Development of methodology and strategy to approach diverse classes of such compounds is required to permit systematic structural variation to develop structure-activity relationships and new candidates for biological evaluation as clinical candidates. For example, a major area of interest is the development of modified nucleosides and carbonucliosides as antitumor and antiviral agents. Use of transition metal mediated couplings offer a novel strategy to such compounds in a potentially greatly more efficient process. The potential of compounds of this class in AIDS research makes this phase of the program particularly timely. The power of transition metal catalyzed reactions for complex synthesis is highlighted by the approach to 2 beta-hydroxyjatrophone which examines three new reactions; a metal catalyzed [3+2] cycloaddition, beta-furanone synthesis, and macrocyclization. The macrocyclization also provides and entry to the cytotoxic agent shikodomedin. In addition, this synthesis examines a novel strategy for diastereoselectivity invoking an antiaromatic intermediate generated through transition metal catalysis. The taxanes, which possess members of potent clinically interesting antitumor activity, may be approached by a new strategy involving a macrocyclization and a transannular cyclization to form this difficultly accessible ring system. A totally new approach to cyclizations invoking the concept of catalytic intramolecular carbametallation may provide an effective entry to a clinically proven class of antitumor agents the podophyllotoxins, and a promising class of clinical antitumor agents, the phyllanthosided. The antileukemic agent, rocaglamide, may be accessible in an incredibly short sequence invoking a cycloaddition to substituted cyclopentryl rings. A new coupling of acetylenes with vinyl epoxides is proposed as an approach for the powerful and unusual antitumor agents represented by neocarzinostatin. The laxity of geometric limitations of metal catalyzed cyclizations will be exemplified by a strategy toward the clinically important antitumor agents belonging to the pyrrolizidine family. Understanding tumor promotion also is important to understanding the beginnings of tumor production. A strategy to one family of tumor promoters represented by teleocidin explores the concept of chemical chameleons. In most cases, the strategy also considers the problem of absolute stereochemistry.

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National Institute of General Medical Sciences (NIGMS)
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Medicinal Chemistry Study Section (MCHA)
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Stanford University
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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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