Enantioselective Synthesis of a Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 5 (mGluR5) Receptor via Dynamic Kinetic Resolution of α‐Amino Ketones

Abstract

Thec oncise synthesis of ap harmaceutical candidate is described. Thec hiral core of the molecule is assembled using an aza-benzoin condensation and ad ynamic kinetic resolution (DKR)a st he key reactions.T his enables superb control of the regio-, diastereo-a nd enantioselectivity of the synthesis.B othb iocatalystsa nd transition metal catalysts are remarkably effective in the keyasymmetric reductions tep.S imilar approaches could be considered in the synthesis of other 1,2-amino alcohols where traditional approaches based on functionalization of alkenes,e poxides or aziridines may suffer from selectivity issues.Glutamate is the major excitatory neurotransmitter in the mammalian brain, playing an importantr ole in aw ide variety of physiological process. [1] Glutamatergic neurotransmission is predominantly mediated througha ctivation of cell surface receptors including ligand-gated ion channels (ionotropic receptors) and metabotropic glutamate Gp rotein coupled receptors (mGluRs). [2] Withint his family,t he mGluR5 receptor is expressed broadly throughout the central nervous system( CNS) and hasa ttracted interest for an umber of therapeutic indications with implications in different behavioral andc ognitive processes. [3] During the course of ap rogram directedt ot he discoveryo f mGluR5 modulators,o xazolidinone 1 was identified as ap otential candidate for pre-clinical development ( Figure 1). [4] Thei nitial routet o1 relied on the osmium-catalyzed aminohydroxylation of trans alkene 3 (Figure 2) to set both the absolute andr elativec onfiguration of the chiral centers on the target molecule. [5] This reaction occurred with modest regioselectivity (3:1)a nd 90% ee,n egatively impacting the overall yield and throughput of the synthesis.H erein, we report as tereoselective synthesis of 1 avoiding the use of the toxic osmium catalyst and precluding the formationof undesiredr egioisomers (Scheme 1). Theser esults may prove useful towards the asymmetric synthesiso ft he popular 1,2-aminoa lcohol motif where approaches based on the functionalization of alkenes,e poxides or aziridineso ften are challenged with selectivity issues.Tw om ajor strategic challenges to accomplish as elective synthesis of 1 were recognized. Thef irst was to identify ah ighly enantioselective method to set the vicinals tereocenters with the desired relative stereochemistry.T he second was to devise an approach that wouldn ot form regioisomers,t hus preventing undesired yield losses. To address the enantioselectivity challenge,w ew ere drawn to explore the asymmetric Figure1.mGluR5 modulator 1.

Recent Developments in the Stereoselective Synthesis of Nitrogen‐Containing Heterocycles using N‐Acylimines as Reactive Substrates

“…Chiral oxazolidin‐2‐one 96 is a metabotropic glutamate G protein coupled receptor modulator (mGluR5) particularly useful in treating cognitive process diseases. Reaction of α‐amido sulfone 90 with aldehyde 91 is carried out in the presence of thiazolium salt 92 leading to racemic 2‐amino ketone derivative 93 (Scheme ) . The latter compound is efficiently converted into optically active amino alcohol 95 by a dynamic kinetic resolution with the Ikariya catalyst 94 under hydrogen transfer conditions using HCO 2 H. The same enantioselective process can also be achieved by enzymatic reduction using various ketoreductases and yeast strains evidencing similar performances but showing a low catalyst turnover.…”

Recent Progress and Applications of Transition-Metal-Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines through Dynamic Kinetic Resolution

“…Because the mGluR5 receptor has attracted interest for a few therapeutic indications, in 2016 González-Bobes and co-workers reported the enantioselective preparation of a pharmaceutical candidate mGluR5 modulator via the ATH of an -amino ketone derivative (Scheme 21). 34 The key reactions to access the chiral core of the targeted molecule involved an aza-benzoin condensation and a transfer hydrogenation through a DKR process. The ATH was performed at room temperature in THF using 1.5 mol% of (S,S)-Ts-DENEB [(S,S)-CAT12] with HCO 2 H/DABCO (3:5) as the hydrogen donor for 24 h to provide the corresponding anti--amino alcohol intermediate in 80% yield with >200:1 dr and 98.5% ee.…”

An Overview on the N-Heterocyclic Carbene-Catalyzed Aza-Benzoin Condensation Reaction

“…The molecule depicted in Figure 4 has been identified as a potential candidate for the pre-clinical development of mGluR5 modulators [43]. …”

“…The molecule depicted in Figure 4 has been identified as a potential candidate for the pre-clinical development of mGluR5 modulators [43]. Synthetic approach, through the aza-benzoin reaction, for the preparation of mGluR5 modulator.…”