Practical Multigram Approach to Conformationally Constrained α-Proline-Based Building Blocks With γ-Spiro Conjunction

Unusual amino acids have arisen as an indispensable instrument at the disposal of modern medicinal chemistry. While extensively exploited as building blocks in the search for new pharmaceuticals, their application goes far beyond. They are currently involved in exploring the structure and conformational mobility of peptides, modification and amplification of peptidomimetics’ activity, and others. Herein, we report an effective synthetic approach to non-planar, conformationally restricted, sp3-enriched spirocyclic -prolines. The protocol employs readily available nitrile-based starting materials and conventional experimental procedures. The synthetic sequence is concise and includes three principal stages (one of them is a 4-step telescopic process). The reactions proceed on a multigram scale affording the target prolines in overall good yields. The possibility of chiral separation of synthesized racemic spiro prolines to both pure enantiomers was shown. The building blocks synthesized in the study are expected to have practical uses in the field of medicinal chemistry.