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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
Author(s) -
Obrecht Daniel,
Abrecht Christine,
Altorfer Michael,
Bohdal Udo,
Grieder Alfred,
Kleber Martina,
Pfyffer Patrick,
Müller Klaus
Publication year - 1996
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19960790508
Subject(s) - chemistry , succinimide , stereochemistry , side chain , amino acid , alkylation , turn (biochemistry) , nuclear magnetic resonance spectroscopy , diastereomer , serine , catalysis , organic chemistry , polymer , biochemistry , enzyme
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(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 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.