Volume 91 Issue 16 | p. 36 | Concentrates
Issue Date: April 22, 2013

Carbonyl Anion Reaction Builds Chiral Hindered Amino Acid Derivatives

Important motif in pharmaceuticals falls to rare type of chemistry
Department: Science & Technology
News Channels: Organic SCENE, JACS In C&EN
Keywords: organic synthesis, amino acids, chiral, asymmetric synthesis, pharmaceuticals, peptide

Despite their importance in pharmaceuticals, many sterically hindered amino acids remain tough to build, particularly with high chiral purity. A team at Boehringer Ingelheim Pharmaceuticals has now surmounted this challenge with carbonyl anion chemistry (J. Am. Chem. Soc., DOI: 10.1021/ja402647m). Jonathan T. Reeves and colleagues explored carbamoyllithium species. These anions that were first generated in 1967 but have rarely been used in asymmetric reactions. When they combined these species with N-sulfinyl imines, which are well-known chiral-directing groups, they obtained α-amino amides, the essential subunit of peptides. The method worked with bulky substrates to produce chiral, highly hindered amino acid derivatives (shown). The team also performed the reaction twice in succession to obtain a dipeptide. “In terms of substrate scope and enantiomeric purity, it will be difficult, if not impossible, for asymmetric catalysis to compete with this method for preparing hindered and rare amino acids,” says Jeffrey W. Bode of ETH Zurich, an expert in peptide synthesis.

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