Utility of the Ammonia‐Free Birch Reduction of Electron‐Deficient Pyrroles: Total Synthesis of the 20S Proteasome Inhibitor, clasto ‐Lactacystin β‐Lactone

A new synthesis of the 20S proteasome inhibitor clasto ‐lactacystin β‐lactone is described. Our route to this important natural product involves the partial reduction of an electron deficient pyrrole as a key step. By judicious choice of enolate counterion, we were able to exert complete control over the stereoselectivity of the reduction/aldol reaction. Early attempts to complete the synthesis by using a C‐4 methyl substituted pyrrole are described in full, together with our attempts to promote regioselective elimination of a tertiary alcohol. The lessons learnt from this first approach led us to develop another, and ultimately successful, route that introduced the C‐4 methyl group at a late stage in the synthesis. Our successful route is then described and this contains several highly stereoselective steps including a cis ‐dihydroxylation and an enolate methylation. The final synthesis proceeds in just 13 steps and in 15 % overall yield making it an extremely efficient route to this valuable compound.