Copper(I) catalyzed exo-selective [CN+C+CC] 1,3-dipolar cycloadditions, and, Studies towards the total synthesis of kaitocephalin

A novel exo-selective [CN+C+CC] 1,3-dipolar cycloaddition catalyzed by Cu(I)-phosphine ligand complex has been developed for ring formation using a chiral glycyl sultam exerting powerful stereochemical control with an aldehyde and an activated olefin. It is the best exo-selective condition so far reported that is suitable for use with a variety of aliphatic aldehydes. This method has great potential in natural product synthesis for the construction of tri- or tetra-substituted pyrrolidine rings bearing an alpha-aliphatic chain.;A new synthetic route to kaitocephalin, a glutamate receptor antagonist, has been designed featuring a disubstituted pyrrolidine as the key intermediate. An auxiliary-controlled [CN+C+CC] 1,3-dipolar cycloaddition followed by removal of auxiliary and sulfone was employed to synthesize 2,5-disubstituted pyrrolidines. The key intermediate disubstituted pyrrolidine was prepared in 10 steps and 4% overall yield. Acylation at C4 introduced the C1-C3 moiety and afforded an important precursor to kaitocephalin bearing a complete carbon skeleton in 8% unoptimized yield.