Robert Williams

rmwUniversity Distinguished Professor
Office: C310 and Chemistry Research Building 311
Phone: 970-491-6747 & 970-495-2569
Education: Ph.D., Massachutsetts Institute of Technology

Research interests currently focus on the study of significant problems in the general area of biological chemistry, particularly those concerning the biosynthesis of natural products, multiple drug-resistant bacterial infectious diseases and cancer. These studies demand the intimate interplay of synthetic organic chemistry, physical organic chemistry, microbiology, and molecular biology. The study of medically significant natural products and mechanism-based synthetic substances is a key element of the approach utilized. New synthetic organic methodology is frequently developed in our group as a result of the needs to synthesize biomechanistically intriguing natural products, analogs of natural products, and mechanistically inspired probe molecules. We developed a versatile asymmetric synthesis of alpha-amino acids based on various C-C couplings to the glycinates 1 (now commercially available from Aldrich). These versatile templates have been manipulated to function as electrophiles, nucleophiles, Wittig reagents, and [1,3]-dipoles. The functionalized lactones can be reductively or oxidatively cleaved to the either zwitterionic or N-t-BOC-protected amino acids in high optical purity. New methodology has been developed to convert these templates into an array of biologically active peptide isosteres. Current applications include approaches to complex amino acid-containing or derived natural products quinine, nakadomarin A, cyindrospermopsin, palau’amine amongst others. Other areas of active investigation include the total synthesis, biosynthesis and mechanism of action studies on the clinically significant antitumor antibiotic FR-900482 and mitomycin C. We are also examining the synthesis and biological chemistry of the clinically important family of tetrahydroisoquinoline antitumor agents including ecteinascidin 743, bioxalomycin, saframycin and congeners. In these areas, we are concerned with elucidating the detailed chemical mechanism of interaction of these drugs with DNA and the impact these agents have on the cell biology of tumor cells. Our laboratory is also investigating the synthesis and biosynthesis of a family of biogenetically related complex indole alkaloids including stephacidin B, paraherquamide F and asperparaline A. In particular, we have focused on the hypothesis that the common, core bicyclo[2.2.2] ring system of this family arises via an enzyme-mediated intramolecular Diels-Alder cycloaddition. Here, the total synthesis of isotopically labeled biosynthetic intermediates is employed to map the detailed conversion of amino acids and isoprenoids into the final natural products. In addition, our laboratory is investigating the biosynthesis of the potent antitumor drug taxol through the synthesis and isotopic labeling of biosynthetic intermediates. Many of these projects are highly collaborative and we have active collaborations established with numerous laboratories throughout the world. Examples of biomedically intriguing and significant natural products recently synthesized in our laboratory include: TMC-95A, spirotryprostatin B, FR900482, paraherquamide A, capreomycin IB, VM55599, tetrazomine and cylindropsermopsin.