Synthesis of the Pleuromutilin Antibiotic SB-268091: A New Practical and Efficient Synthesis of Quinuclidine-4-thiol

A synthesis of the pleuromutilin antibiotic SB-268091 is described which includes a new and improved route to the quinuclidine-4-thiol ligand. This chemistry has been run on multikilo scale and involved a reductive double debenzylation using sodium in liquid ammonia. Alternative conditions have been developed to prepare quinuclidine-4-thiol which avoid the use of sodium in liquid ammonia. The generality of this process to prepare differentially S-protected quinuclidine-4-thiols is also discussed and exemplified by the preparation of a range of analogues.