Exploring biological phenomena at a molecular level provides the basis of understanding from which new therapeutic agents derive. The ability to construct a defined molecular architecture requires highly selective reactions and reagents to permit the development of effective synthetic strategies. Cyclic compounds have biological activities across a broad spectrum. Furthermore, constraining conformations of mobile molecules by forming rings also frequently enhances biological potency. Thus, a concerted effort to apply new chemical principles being developed in these laboratories to the formation of rings becomes an important objective. Two new methods for accessing pyrans by simple one operation cycloaddition - like strategy relying on palladium and / or ruthenium catalysis may lead to biologically active targets containing such subunits illustrated by dactyolide and the bryostatins. Unprecedented cycloadditions of norcarane type substrates will be a major focus that may lead to a structural motif so common to a great number of bioactive molecules ranging from ion channel blockers like grayanotoxin to anti-inflammatories like ramaswaralide. Cascade reactions involving creation of three rings in one step can provide rapid entry to complex targets like guanacastepene. The reactivity and selectivity of palladium complexes of chemically reactive intermediates to form odd membered rings including five, seven and even nine members can lead to strategies to families of compounds possessing powerful antihelmintic and antinematodol mold metabolites ranging to squalene synthase and Ras farnesyl transfer inhibitors. A new concept for the synthesis of macrocyclic compounds at high concentrations will be examined in the context of the antitumor amphidinolide and the immunosuppressive ushikulide families. These new synthetic methods apply to many structural types beyond those illustrated and constitutes a significant to gain access to complex molecular targets more easily.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Schwab, John M
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Stanford University
Schools of Arts and Sciences
United States
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Trost, Barry M; Yang, Hanbiao; Dong, Guangbin (2011) Total syntheses of bryostatins: synthesis of two ring-expanded bryostatin analogues and the development of a new-generation strategy to access the C7-C27 fragment. Chemistry 17:9789-805
Trost, Barry M; Silverman, Steven M; Stambuli, James P (2011) Development of an asymmetric trimethylenemethane cycloaddition reaction: application in the enantioselective synthesis of highly substituted carbocycles. J Am Chem Soc 133:19483-97
Trost, Barry M; Gutierrez, Alicia C; Ferreira, Eric M (2010) Differential reactivities of enyne substrates in ruthenium- and palladium-catalyzed cycloisomerizations. J Am Chem Soc 132:9206-18
Trost, Barry M; O'Boyle, Brendan M; Hund, Daniel (2010) Investigation of a domino Heck reaction for the rapid synthesis of bicyclic natural products. Chemistry 16:9772-6
Trost, Barry M; Brindle, Cheyenne S (2010) The direct catalytic asymmetric aldol reaction. Chem Soc Rev 39:1600-32
Trost, Barry M; Dong, Guangbin (2010) Total synthesis of bryostatin 16 using a Pd-catalyzed diyne coupling as macrocyclization method and synthesis of C20-epi-bryostatin 7 as a potent anticancer agent. J Am Chem Soc 132:16403-16
Trost, Barry M; Hitce, Julien (2009) Direct asymmetric Michael addition to nitroalkenes: vinylogous nucleophilicity under dinuclear zinc catalysis. J Am Chem Soc 131:4572-3
Trost, Barry M; Gutierrez, Alicia C; Livingston, Robert C (2009) Tandem ruthenium-catalyzed redox isomerization--O-conjugate addition: an atom-economic synthesis of cyclic ethers. Org Lett 11:2539-42
Trost, Barry M; Xu, Jiayi; Schmidt, Thomas (2009) Palladium-catalyzed decarboxylative asymmetric allylic alkylation of enol carbonates. J Am Chem Soc 131:18343-57
Trost, Barry M; Bertogg, Andreas (2009) Si-based benzylic 1,4-rearrangement/cyclization reaction. Org Lett 11:511-3

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