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The Skaggs Institute for Chemical Biology
Scientific Report 1998-1999


Organic and Organometallic Chemistry and Catalysis


M.G. Finn, J. Guo, S. Maddock, M. Dintzner, C. Averbuj

Transition metals are found at the sites of action in many chemical and biological processes. We seek to uncover and use the unique patterns of reactivity of transition metals in a multidisciplinary approach for the development of new reagents, catalysts, and synthetic processes.

Polymer-Supported Chiral Lewis Acid Catalysts

Our long-range goal is the development of true combinatorial methods for the synthesis and rapid screening of chiral catalysts for a variety of organic transformations. We start with the assembly and analysis of multidentate chiral ligands covalently bound to polystyrene resins and other support materials and use electron-deficient metal complexes of these ligands as chiral Lewis acid catalysts. An important theme is the relationship between the properties of the polymeric support and the chemistry of the attached catalyst species.

For example, electron-deficient early transition-metal complexes often aggregate in the solution phase. We are testing the abilities of various solid supports to control the interaction of attached Lewis acidic species, thereby shifting such equilibria toward specific aggregates or to monomeric species. We recently developed several tools necessary for this enterprise, including a family of thermally cleavable linkage units, which enable us to control the identity and concentration of active ligand sites on a polymer, and a method for the rapid analysis of enantiomeric excess on an extremely small scale (Fig. 1). Combinatorial methods for discovery of new reactions and asymmetric catalytic processes will also be aided by a collaborative project with G. Siuzdak, The Scripps Research Institute, on new mass spectrometry assays.

Catalytic Antibodies: Selection and Metal-Based Reactivity

In collaboration with R. Lerner and C. Barbas, the Skaggs Institute, we are enlarging the scope of enantioselective reactions that can be performed by catalytic antibody systems. The strong association of ß-diketones with the active sites of aldolase antibodies enables us to import nonbiological reactivity engines into chiral binding pockets on the back of diketone carriers. We are attempting this step with several catalytically active metal complexes and are using the phage display technique to evolve antibodies specifically adapted for the role of catalyst "host." New selection methods are also being used for the discovery of catalytic function.

Metal-Mediated Diradical Cycloaromatization Reactions

Several years ago we pioneered the use of the organometallic rearrangement of terminal acetylenes to vinylidenes in the enediyne cycloaromatization process. This strategy converts a high-energy Bergman-type process into a lower-energy Myers-style cycloaromatization, with the production of a metal-centered radical and a carbon σ-radical (Fig. 2). We recently returned to this process to expand its scope and explore its catalytic variations. Water-soluble versions are of interest for their potential ability to cleave polynucleotide or protein structures.

Publications

Boring, E., Sabat, M., Finn, M.G., Grimes, R.N. Alkene and alkyne insertion reactions with tantalum metallacarborane complexes: The Et2C2B4H4 carborane ligand as spectator and participant. Organometallics 17:3865, 1998.

Brody, M.S., Finn, M.G. Palladium-catalyzed coupling of functionalized bromoarenes to a polystyrene-bound aryl tributylstannane. Tetrahedron Lett. 40:415, 1999.

Curtis, M.A., Finn, M.G., Grimes, R.N. A hydridotantalum(V)-carborane analogue of Schwartz's reagent: Synthesis and reactivity. J. Organomet. Chem. 550:469, 1998.

Dopico, P.G., Finn, M.G. Synthesis and cycloaromatization kinetics of aromatic allene enynes. Tetrahedron 55:29, 1999.

Finn, M.G., Lerner, R.A., Barbas, C.F. Cofactor induced refinement of catalytic antibody activity: A metal-specific allosteric effect. J. Am. Chem. Soc. 120:2963, 1998.

Guo, J., Wu, J., Siuzdak, G., Finn, M.G. Measurement of enantiomeric excess by kinetic resolution and mass spectrometry. Angew. Chem. Int. Ed. 38:1755, 1999.

McCleland, B.W., Nugent, W.A., Finn, M.G. Mechanistic studies of the zirconium-triisopropanolamine catalyzed enantioselective addition of azide to cyclohexene oxide. J. Org. Chem. 63:6656, 1998.

Nugent, W.A., Licini, G., Bonchio, M., Borolini, O., Finn, M.G., McCleland, B.W. Homogeneous catalysis as a tool for organic synthesis. Pure Appl. Chem. 70:1041, 1998.

 

 







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