Practical Syntheses of N-Substituted 3-Hydroxyazetidines and 4-Hydroxypiperidines by Hydroxylation with Sphingomonas sp. HXN-200

Abstract

[reaction: see text] Hydroxylation of N-substituted azetidines 11 and 12 and piperidines 15-19 with Sphingomonas sp. HXN-200 gave 91-98% of the corresponding 3-hydroxyazetidines 13 and 14 and 4-hydroxypiperidines 20-24, respectively, with high activity and excellent regioselectivity. High yields and high product concentrations (2 g/L) were achieved with frozen/thawed cells as biocatalyst. For the first time, rehydrated lyophilized cells were successfully used for the biohydroxylation.

A Cascade Aza‐Cope/Aza‐Prins Cyclization Leading to Piperidine Derivatives

“…The residue was purified by column chromatography (petroleum ether/EtOAc, 9:1) to deliver homoallylamine 16 (0.467 g, 82 % yield) as a yellow oil. 1 [24] To a solution of 1,4-bis(bromomethyl)-2,5-dimethylbenzene (18, 1.0 g, 3.73 mmol) in CCl 4 (30 mL) were added NBS (1.33 g, 7.46 mmol) and (BzO) 2 (180 mg, 0.745 mmol, 20 mol-%). The mixture was heated at reflux for 24 h and then treated with water (20 mL).…”

“…), K 2 CO 3 (276.4 mg, 2.0 mmol, 2.0 equiv. ), Pd(OAc) 2 (1.1 mg, 0.005 mmol, 0.5 mol-%), and ligand 26 (2.8 mg, 0.005 mmol, 0.5 mol-%). The reaction mixture was stirred at room temperature for 15 min and then filtered through a small pad of Celite, which was rinsed with CH 2 Cl 2 (2 ϫ 15 mL).…”

“…[1] The 4-hydroxypiperidine core is present in precursors ( Figure 1) for the preparation of ebastine (I) and betotastine besilate (allergic rhinitis drugs), nadifloxacin (an antibacterial), linazolast (II, antiallergy/antiasthmatic), lamifiban (antiplatelet therapy), [2] and 4-hydroxypipecolic acid (III, antidiabetic and antioxidative). Piperidine-based cocaine has the potential to inhibit the reuptake of DA (dopamine) and 5-HT (serotonin) [3] and is an in vivo ligand for muscarinic acetylcholine receptors.…”

3‐Hydroxyazetidine Carboxylic Acids: Non‐Proteinogenic Amino Acids for Medicinal Chemists

“…[25] Despite the interest in hydroxyprolines, [26] the sole reported preparation of 3-hydroxy-Aze 5 is by biohydroxylation of Aze with proline hydroxylases; [27] other azetidine substrates have been biohydroxylated to 3-hydroxyazetidines. [28] There is no previous report of the chemical synthesis of a 3-hydroxyazetidine-2-carboxylic acid with free NH and OH groups in the structure. In the pursuit of a synthesis of 3-epi-hydroxymugineic acid 7, an N-alkylated derivative was generated (Figure 2 A).…”

A Practical and Facile Synthesis of Azetidine Derivatives for Oral Carbapenem, L-084

“…A practical method for the scale-up production of derivatives of azetidinols bearing a less bulky substituent has not been developed yet. 31,[36][37][38][39][40] a less bulky N-benzyl derivative, 41,42) only the O-protected compound 14 has been obtained by cyclization of 13 in low yield (Entry 1 in Table 1). In order to provide an industryoriented reaction of azetidine ring-closure, we focused on Nbenzyl-3-chloro-2-hydroxypropylamine (15) as a precursor of the azetidine derivative 16, because 15 was prepared from benzylamine which was less expensive than benzhydrylamine.…”