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.

Keywords: Amino acids; carbenes; cyclopropanation; rhodium; spiro compounds.

Figure 1

Glutamate receptor ligands.

Scheme 1

Proposed synthetic plan for the preparation of compound of type Ib.

Scheme 2

Synthesis of 3-azetidinone derivative 16.

Scheme 3

Synthetic routes to prepare target cyclopropyl derivatives 20. Reagents and conditions: a) (EtO)₂POCH₂COOEt, NaH, THF, 0 °C, −78 °C, rt, 2 h 30 min, 68%; b) i. methyltriphenylphosphonium bromide, n-BuLi, THF, −78 °C to rt, 2 h 30 min, 23%; ii. Tebbe reagent 0.5 M in toluene, Pyr, THF, −40 °C to rt, 36%; iii. Petasis reagent, toluene, 70–90 °C in the dark, 2 h, 58%; iv. trimethylsilylsulfoxonium iodide, DBU, MeCN, 60 °C, 6 h; v. Et₂Zn, CH₂I₂, DCM, 0 °C to rt, 5 days; vi. ethyl diazoacetate, Rh₂(OAc)₄ 10 mol %, DCM, 40 °C, 48 h, 60%. vii. TEA^.3HF, TEA, THF, 50 °C, 24 h, 92%; viii. TEA^.3HF, TEA, THF, 50 °C, 24 h, 92% then DIBAL, DCM, −78 °C to rt, 12 h, 27%.

Figure 2

Mechanism for the attack of the carbene intermediate to the olefin moiety 18.

Figure 3

Representation of the lowest energy conformation of each diastereoisomers.

Scheme 4

Synthesis of glutamate “frozen” analogues 4-carboxy-1-(ethoxycarbonyl)-5-azaspiro[2.3]hexane.