Paul G Williard

email: pgw@brown.edu
Department of Chemistry web page: http://www.chem.brown.edu

• Professor (b. 1950). B.S./M.S., 1972, Bucknell University; Ph.D., 1976, Columbia University;
• NIH Postdoctoral Fellow, 1976-79, Massachusetts Institute of Technology; NIH Research Career Development Award, 1988-92.
• Organic Chemistry and X-Ray Crystallography: Preparative and Synthetic Organic chemistry directed toward the synthesis of physiologically active compounds, development of new asymmetric synthetic methodology, isolation and structure determination of reactive intermediates.

X-Ray Crystal Structure Determination of Intermediates for Organic Synthesis - The crystal structure of the model I'm holding in my hand is depcited on the right.

This is a tetrameric enolate of pinacolone plus t-butoxide held togerther with Li and K and one equivalent of KOH, see JACS 1989 , 111, 7671-2.
Shown below are the crystal structures of the bis-THF solvated dimer of LDA, the unsolvated hexameric Li enolate of pinacolone, and the KHMDS dimer solvated by toluene.

Hence we are involved in a major project to isolate and characterize common anionic reactive intermediates in organic synthesis, i.e. enolate anions and the alkali metal amide bases used to generate these enolates. To date well over one hundred x-ray crystal structures of enolate anions and dialkyl amide bases used for the generation of enolate anions have been isolated and characterized by x-ray diffraction analysis in our labs.

These and additional structural results prvoide a general outline for the sequence of aggregated intermediates of the aldol reaction depicted below. This proposed scheme appears in J. Am. Chem. Soc., 1993, 115, 3380 and a related sequence incorporating mixed aggregated containing halide anions was proposed in a manscript we published in J. Am. Chem. Soc., 1996, 118, 1339.

Total Synthesis of Physiologically Active Compounds

Our synthetic efforts currently are concentrated on the synthesis and structure elucidation of new metabolites in the vitamin D₃ series. This work is done in collaboration with a group of researchers scattered throughout the various hospitals affiliated with the Brown University. Recently we have synthesized 24-oxo-1a,23,25-trihydroxyvitamin D₃ as depicted below. This represents the first total synthesis of this downstream metabolite of vit. D₃. We are currently involved in several additional aspects of vitamin D chemistry which involve preparing novel hybrids of vitamin A and vitamin D. We believe that the close proximity and the similarity of the vitamin D receptors (VDR) and the retinoic acid (vitamin A) receptors (RAR) may lead to some useful activities in the hybrid molecules. The design of the new compounds proposed for synthesis is guided by molecular modeling of the known steric features of the general class of steroid hormone receptors.

Development of Synthetic Methodology

Based upon the wealth of new structural information which we have generated from the crystal structures of the enolate anions and amide bases, we have begun to design and to synthesize new asymmetric ligands and chiral auxiliaries for the use in asymmetric synthesis. We are currently screening these reagents for their ability to produce high enantioselectivity in enolate reactions such as condensation reactions and alkylation reactions.

Recent Selected Publications:

See my entire publication list

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