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. In the first domain, a new strategy to effect cyclizations, in general, and macrocyclizations, in particular, asymmetrically may provide a unique opportunity to approach a variety of significant targets. The concept involves a new dinuclear catalyst design for an asymmetric aldol addition that involves no preactivation of either partner (i.e., no stoichiometric formation of an enol or enolate) and that could also provide an unusual ability to perform macrocyclizations at high concentration. This development leads to the use of hydroxyacetone as a lynchpin to form macrocycles aymmetrically and a synthesis of the antitumor amphidinolides. In the second domain, the development of a new annulation to form heterocycles leads to a novel convergent and practical approach to the potent antitumor agents, the bryostatins, and potential analogues. The asymmetric aldol reaction also will play an important role. This domain embodies an atom economic cross-coupling of two different alkynes. This new concept for C-C bond formation performed intramolecularly sets the stage for macrocyclizations that can lead to the cochleamycins, new structural class of antitumor antibiotics. The third domain embodies a new class of cycloaddition reactions to create odd membered rings. Exploring a new class of acceptors in conjunction with a novel class of reactive intermediates creates a conceptual framework to the anthelmintic and antinematodal mold metabolites paraherquamide and marcfortine. An unusual (6+3) cycloaddition may create strategies for the structurally unusual farnesyl transferase inhibitor CP-263,114 and simple analogues. A new bifunctional conjunctive reagent combined with a ring expansion provides a novel approach to the antitumor agent penostatin 1. A (4+3) cycloaddition combines with two other concepts being developed in these laboratories, asymmetric allylic alkylation and metal catalyzed enyne cycloisomerizations, to create a powerful strategy to the neurotrophic agents, the erinacines. The fourth domain transitions to ruthenium catalysis for (5+2) cycloadditions. This new concept sets the stage for solutions to a long standing problem, the ion channel blockers, the grayanotoxins. as well as the more recently discovered rameswaralide, a potent antiinflamatory.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM013598-39
Application #
6747840
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1987-06-01
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
39
Fiscal Year
2004
Total Cost
$524,128
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; 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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