Stereocontrolled synthesis of 5-azaspiro[2.3]hexane derivatives as conformationally “frozen” analogues of L-glutamic acid

• Main Authors: Beatrice Bechi, David Amantini, Cristina Tintori, Maurizio Botta, Romano di Fabio
• Format: Article
• Language: English
• Published: Beilstein-Institut 2014-05-01
• Series: Beilstein Journal of Organic Chemistry
• Subjects: Amino acids; carbenes; cyclopropanation; rhodium; spiro compounds
• Online Access: https://doi.org/10.3762/bjoc.10.110

Several strategies aimed to “freeze” natural amino acids into more constrained analogues have been developed with the aim of enhancing in vitro potency/selectivity and, more in general, drugability properties. The case of L-glutamic acid (L-Glu, 1) is of particular importance since it is the primary excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays a critical role in a wide range of disorders like schizophrenia, depression, neurodegenerative diseases such as Parkinson’s and Alzheimer’s and in the identification of new potent and selective ligands of ionotropic and metabotropic glutamate receptors (GluRs). To this aim, bicycle compound Ib was designed and synthesised from D-serine as novel [2.3]-spiro analogue of L-Glu. This frozen amino acid derivative was designed to further limit the rotation around the C3–C4 bond present in the azetidine derivative Ia by incorporating an appropriate spiro moiety. The cyclopropyl moiety was introduced by a diastereoselective rhodium catalyzed cyclopropanation reaction.