Synthesis of New Azetidine and Oxetane Amino Acid Derivatives through Aza-Michael Addition of NH-Heterocycles with Methyl 2-(Azetidin- or Oxetan-3-Ylidene)Acetates

Abstract

In this paper, a simple and efficient synthetic route for the preparation of new heterocyclic amino acid derivatives containing azetidine and oxetane rings was described. The starting (N-Boc-azetidin-3-ylidene)acetate was obtained from (N-Boc)azetidin-3-one by the DBU-catalysed Horner–Wadsworth–Emmons reaction, followed by aza-Michael addition with NH-heterocycles to yield the target functionalised 3-substituted 3-(acetoxymethyl)azetidines. Methyl 2-(oxetan-3-ylidene)acetate was obtained in a similar manner, which was further treated with various (N-Boc-cycloaminyl)amines to yield the target 3-substituted 3-(acetoxymethyl)oxetane compounds. The synthesis and diversification of novel heterocyclic amino acid derivatives were achieved through the Suzuki–Miyaura cross-coupling from the corresponding brominated pyrazole–azetidine hybrid with boronic acids. The structures of the novel heterocyclic compounds were confirmed via 1H-, 13C-, 15N-, and 19F-NMR spectroscopy, as well as HRMS investigations.

Synthesis and neuroprotective activity of 3‐aryl‐3‐azetidinyl acetic acid methyl ester derivatives

“…tert ‐Butyl 3‐(2‐methoxy‐2‐oxoethylidene)azetidine‐1‐carboxylate ( 2 ), previously reported in Gudelis et al and Yang et al [ 43,45 ] : To a solution of methyl 2‐(dimethoxyphosphoryl)acetate (1.170 g, 6.44 mmol) in dry THF (20 mL), NaH (60% dispersion in mineral oil, 268 mg, 6.72 mmol) was added portionwise at 0°C under argon atmosphere and the resulting mixture was stirred at 0°C for 20 min. Subsequently, N ‐Boc‐3‐azetidinone ( 1 ) (1.000 g, 5.84 mmol), dissolved in dry THF (4 mL), was added and the reaction mixture was stirred at the room temperature for 30 min.…”

“…The synthesis was started with the preparation of the azetidine ring bearing α,β-unsaturated ester 2, which was accomplished by the condensation of N-Boc-3-azetidinone (1) with trimethyl phosphonacetate under the Horner-Wadsworth-Emmons reaction conditions (Scheme 1). [43,45] Subsequent treatment of 2 with arylboronic acids in the presence of rhodium(I)-catalyst [46] proceeded smoothly and provided the desired azetidines 3-9 as products of conjugate addition in 56%-71% yields. The efficiency of rhodium-catalyzed conjugate addition of arylboron species is strongly dependent on the competing side reaction, that is, protodeboronation.…”

“…[40] In our recent work, we have been pursuing the construction of amino acid-like functionalized heterocyclic molecules possessing azetidine core. [41][42][43][44] In this study, we prepared a library of 3-aryl-3-azetidinyl acetic acid methyl ester derivatives, assessed their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity, and determined their neuroprotective effect in salsolinol (SAL)-induced model of PD and glutamate (Glu)-induced model of oxidative damage on neuron-like SH-SY5Y cells. Consequently, cholinesterase inhibition, alongside neuroprotective effect in Gluinduced Xc-antiporter inhibition models could offer a new strategy for disease-modifying AD and PD therapy.…”

Synthesis of Diverse Oxetane Amino Acids via Visible‐Light‐Induced Photocatalytic Decarboxylative Giese‐Type Reaction

“…[ 9‐10 ] Remarkably, the preparation of various 3,3′‐disubstituted oxetane amino acids, which are metabolically more stable and display greater potential in drug discovery, have been also reported (Scheme 1c). [ 11‐13 ] It is noted that, among them, 3‐amino‐oxetane‐3‐carboxylic acid is a promising anti‐Alzheimer's agent which functions as an inhibitor for the glycine binding site of the N ‐methyl‐ D ‐aspartate (NMDA) receptor complex (Scheme 1c). Nonetheless, it is quite clear that the diversity of oxetane amino acids needs to be further expanded and the present protocols typically suffer from multi‐step procedure, low reaction efficiency and harsh reaction conditions such as extremely strong bases and explosive reagents.…”