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.
Highlights
L-Glutamic acid (L-Glu) is the primary excitatory neurotransmitter in the mammalian central nervous system (CNS) playing a critical role in the learning and memory process [1,2,3]
It was envisioned that the synthesis of compound Ib could be accomplished as highlighted in Scheme 1 starting from the known ketone derivative IV [23,24], pursuing two different synthetic strategies: a) cyclopropanation of an α,β-unsaturated ester; b) metal-catalyzed cyclopropanation of the corresponding terminal olefin derivative with a diazoacetate derivative
After having accomplished this key step, intermediate II would be transformed into the target compound Ib by sequential deprotection and oxidation of the primary alcohol to access the targeted bridged amino acid derivative
Summary
L-Glutamic acid (L-Glu) is the primary excitatory neurotransmitter in the mammalian central nervous system (CNS) playing a critical role in the learning and memory process [1,2,3]. Based on this initial set of results, we decided to abandon the synthetic strategy a) and to explore the synthetic feasibility of approach b), namely the cyclopropanation of the corresponding terminal olefin derivative 18. The former reaction, when accomplished in the presence of methyltriphenylphosphonium bromide and BuLi (butyllithium), successfully afforded the olefin derivative 18, albeit in low yield (23%).
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