Paul E. Wiedeman

Synthesis of N-arylated oxazolidinones via a palladium catalyzed cross coupling reaction. Application to the synthesis of the antibacterial agent Dup-721

Abstract A method for the intermolecular coupling of aryl bromides and oxazolidinones is described. Application to intermediates useful for the preparation of a known class of antibacterial agent and the synthesis of the known antibacterial oxazolidinone Dup-721 are described.

Identification of halosalicylamide derivatives as a novel class of allosteric inhibitors of HCV NS5B polymerase

Halosalicylamide derivatives were identified from high-throughput screening as potent inhibitors of HCV NS5B polymerase. The subsequent structure and activity relationship revealed the absolute requirement of the salicylamide moiety for optimum activity. Methylation of either the hydroxyl group or the amide group of the salicylamide moiety abolished the activity while the substitutions on both phenyl rings are acceptable. The halosalicylamide derivatives were shown to be non-competitive with respect to elongation nucleotide and demonstrated broad genotype activity against genotype 1-3 HCV NS5B polymerases. Inhibitor competition studies indicated an additive binding mode to the initiation pocket that is occupied by the thiadiazine class of compounds and an additive binding mode to the elongation pocket that is occupied by diketoacids, but a mutually exclusive binding mode with respect to the allosteric thumb pocket that is occupied by the benzimidazole class of inhibitors. Therefore, halosalicylamides represent a novel class of allosteric inhibitors of HCV NS5B polymerase.

A relay approach to (+)-pleuromutilin. III. direct degradation of the natural product to the key diketone intermediate and its chemospecific functionalization

Abstract Pleuromutilin or tiamulin can be degraded to the important bicyclic relay compound (−)- 1 in only four steps. Various methods for achieving chemoselective functionalization of 1 are set in focus.

A relay to (+)-pleuromutilin. I. De novo synthesis of a levorotatory tricyclic lactone subunit

Abstract Construction of the optically active lactone (−)−13, required for a proposed total synthesis of (+)-pleuromutilin, has been successfully achieved.