L ‐Phenylalanine Cyclohexylamide: A simple and convenient auxiliary for the synthesis of optically pure α,α‐disubstituted (R)‐ and (S)‐amino acids

This work describes L‐phenylalanine cyclohexylamide (5c) as a simple, cheap, and powerful chiral auxiliary for the synthesis of a series of optically pure α,α‐disubstituted (R)‐ and (S)‐amino acids of type 1, such as (R)‐ and (S)‐2‐methyl‐phenylalanine (1a), (R)‐ and (S)‐2‐methyl‐2‐phenylglycine (1b), and (R)‐ and (S)‐2‐methylvaline (1c; Scheme 3). These amino acids were efficiently transformed into the suitably protected and activated amino acid building blocks (R)‐ and (S)‐12b and (R)‐ and (S)‐12c (Scheme 4) which are ready for incorporation into peptides by solution or solid‐phase techniques. Based on the crystal structures of 6b, 6c, and 7a belonging to the diastereoisomeric peptides series 6 and 7, the absolute configurations of each member of the series were determined. β‐Turn geometries of type II′ and I were observed for 6b and 7a, respectively, whereas 6c crystallized in an extended conformation. The impacts of side‐chain variation on conformation and crystal packing of these triamides are discussed.