Synthetic approaches to a chiral 4-amino-3-hydroxy piperidine with pharmaceutical relevance (original) (raw)

Table of Contents I. General Experimental S1 II. Experimental and Spectral data S2 III. Microbial Assays S17 IV. Chromatograms S19 V. Copies of 1 H NMR and 13 C NMR Spectra S22 I. General Experimental All reaction were carried out under a nitrogen atmosphere with dry solvents and under anhydrous conditions unless otherwise noted. Reagents and solvents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25mm E. Merck silica gel plates (60F-254) using UV light as visualization agent and ethanolic solution of phosphomolybdic acid and cerium sulfate, and heat as developing agents. E. Merck silica gel (60, particle size, 0.040-0.063 mm) was used for flash column chromatography. NMR were recorded on a Bruker DRX-500 and calibrated using Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2012 S2 undeuterated solvent as an internal reference. Infrared (IR) spectra were recorded on a Perkin-Elmer 1600 series FT-IR spectrometer. High-resolution mass spectra (HRMS) were recorded on a Thermo Orbi-trap Discovery instrument. II. Experimental and Spectral data Preparation of sodium salt 7: Crude (3R,4R)-ethyl 1-benzyl-3-hydroxypiperidine-4carboxylate 5 (1.0 equiv, 9.27 g, 35.21 mmol; prepared from 9.2 g of ketoester 4) was placed in a 250 mL round bottom flask, followed by ethanol (97 mL). To the resulting dark solution, sodiumtrimethylsilanolate (1.65 equiv, 6.50 g, 57.94 mmol,) was added in one portion. The reaction was maintained at ambient temperature under nitrogen for 12 hours. The resulting solids were collected by filtration using a Buchner funnel. The crude product was rinsed with two 10 mL portion of ethanol followed to 10 mL of MTBE. The resulting material was dried under vacuum for 4 hours to yield 7 (7.79 g, 30.28 mmol, 86%) as an off-white solid.