title: Stereocontrolled synthesis of 5-azaspiro[2.3]hexane derivatives as conformationally "frozen" analogues of L-glutamic acid.
abstract: 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.
authors.affiliation: Università degli Studi di Siena, Dipartimento Farmaco Chimico Tecnologico, Via A. Moro 2, 53100, Siena, Italy ; Present address: Manchester Institute of Biotechnology, School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bechi
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135, Verona, Italy ; Present address: Galapagos SASU, 102 avenue Gaston Roussel, 93230 Romainville, France.
authors.forename: David
authors.initials: D
authors.lastname: Amantini
authors.affiliation: Università degli Studi di Siena, Dipartimento Farmaco Chimico Tecnologico, Via A. Moro 2, 53100, Siena, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tintori
authors.affiliation: Università degli Studi di Siena, Dipartimento Farmaco Chimico Tecnologico, Via A. Moro 2, 53100, Siena, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135, Verona, Italy ; Present address: Drug Design and Discovery, Aptuit S.r.l., Via A. Fleming 4, 37135 Verona, Italy.
authors.forename: Romano di
authors.initials: Rd
authors.lastname: Fabio
keywords: Amino acids; carbenes; cyclopropanation; rhodium; spiro compounds