Synthesis, Conformational Properties, and Synthetic Applications of Novel Optically Pure α,α‐Disubstituted (R)‐ and (S)‐Glycines (‘α‐Chimeras’) Combining Side Chains of Asp, Glu, Leu, Phe, Ser, and Val

A series of novel open‐chain and cyclic conformationally constrained α,α‐disubstituted (R)‐ and (S)‐glycine derivatives (‘α‐chimeras’) combining side chains of Asp, Glu, Leu, Phe, Ser, and Val have been efficiently synthesized by using α‐alkylation of racemic 4‐monosubstituted 2‐phenyl‐1,3‐oxazol‐5(4H)‐ones of type 5, resolution after reaction with (S)‐phenylalanine cyclohexylamide (8) as chiral auxiliary, a novel azlactone/dihydrooxazole interconversion reaction to synthesize optically pure α‐substituted (R)‐ and (S)‐serine derivatives coupled with succinimide‐ring formation of aspartic‐acid derivatives. Based on X‐ray structures of (R,S)‐9b, (R,S)‐11c, (R,S)‐18, and (S,S)‐30, the absolute configuration of these novel amino‐acid building blocks could be unambiguously determined and their preferred conformations in the crystalline state be assessed. The high preference of the open‐chain derivatives (R,S)‐1, (S,S)‐3, and (R,S)‐11c for β‐turn type‐I conformations, as well as of the succinimide derivatives (R,S)‐2, (S,S)‐19, (S,S)‐24, (S,S,S)‐26, and (R,S)‐29 for β‐turn type‐II conformations and of (S,S)‐4, (R,S)‐18, (R,S)‐23, and (S,S)‐30 for β‐turn type‐II′ conformations could be confirmed in solution by using CD and NMR spectroscopy. Finally, the spiro derivatives (R,S)‐29 and (S,S)‐30 incorporating the ‘α‐chimera’ of Asp/Glu constitute doubly constrained peptide building blocks combining the properties of α‐substituted prolines and aspartimides.