Synthesis, conformational properties, and synthetic applications of novel optically pure alpha,alpha-disubstituted (R)- and (S)-glycines ('alpha-chimeras') combining side chains of Asp, Glu, Leu, Phe, Ser, and Val

• Published in: Helvetica chimica acta Vol. 79; no. 5; pp. 1315 - 1337
• Main Authors: Obrecht, D, Abrecht, C, Altorfer, M, Bohdal, U, Grieder, A, Kleber, M, Pfyffer, P, Muller, K
• Format: Journal Article
• Language: English
• Published: BASEL NEW SWISS CHEMICAL SOC 07.08.1996
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; BETA-TURNS; AMINO-ACIDS; SECONDARY STRUCTURE; EXTENDED STRUCTURES; L-ALA-OME; LINEAR PEPTIDES; DISUBSTITUTED GLYCINES; TRIPEPTIDE MODELS; SOLID-STATE; METHYL-ESTER
• ISSN: 0018-019X
• DOI: 10.1002/hlca.19960790508

A series of novel open-chain and cyclic conformationally constrained alpha,alpha-disubstituted (R)- and (S)-glycine derivatives ('alpha-chimeras') combining side chains of Asp, Glu, Leu, Phe, Ser, and Val have been efficiently synthesized by using alpha-alkylation of racemic 4-monosubstituted 2-phenyl-1,3-oxazol-5(4-H)-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 alpha-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 beta-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 beta-turn type-II conformations and of (S,S)-4, (R,S)-18, (R,S)-23, and (S,S)-30 for beta-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 'alpha-chimera' of Asp/Glu constitute doubly constrained peptide building blocks combining the properties of alpha-substituted prolines and aspartimides.