Total synthesis of platensimycin and platencin and design and synthesis of SARS coronavirus chymotrypsin-like protease inhibitors
Platensimycin and Platencin are two novel and closely related antibacterial natural products. Both compounds can inhibit bacterial cellular lipid biosynthesis and exhibited potent inhibitory activity against a broad range of antibiotic-resistant strains. We have accomplished an enantioselective total synthesis of platensimycin as it is described in Chapter 1. This chiral pool-based synthesis starts from the commercially available natural product (+)-carvone, which determines the stereochemistry of the final product. An asymmetric Horner-Wadsworth-Emmons reaction successfully set up the critical trisubstituted E -olefin. The key step was an innovative intramolecular Diels-Alder reaction, which provided the complex oxatetracyclic core together with four stereocenters, including two quaternary chiral centers present in the molecule, in a single step operation. Chapter 2 described our formal total synthesis of platencin. This concise synthesis utilized only nine steps starting from a commercially available material with 11% overall yield, featuring a Michael cyclization to produce a symmetric diketone key intermediate and a radical cyclization to provide the complex core structure. ^ My thesis work also involved the design and synthesis of severe acute respiratory syndrome (SARS) coronavirus (CoV) chymotrypsin-like protease (3CLpro) inhibitors. SARS is a fatal respiratory illness and there exists no effective therapy. SARS-CoV 3CLpro plays an important role in the life cycle of SARS-CoV and is an attractive target for anti-SARS drug development. Two sets of inhibitors were developed based on the lead compound AG7088. These inhibitors exhibited potent antiviral activity against SARS-CoV, in infected cells, in the micromolar range. Two crystal structures of inhibitors bound to SARS-CoV 3CLpro were successfully determined. All the synthesized inhibitors share the same lactam P1-ligand that was stereoselectively synthesized by utilizing 1,3-asymmetric induction by a dianionic alkylation protocol. The modified P2-ligands were installed using asymmetric alkylation of a lactone precursor, which possessed the required P3-ligand.^
Arun K. Ghosh, Purdue University.