Direct coupling of pyrroles with carbonyl compounds: short enantioselective synthesis of (S)-ketorolac.

Synthesis of (S)-Ketorolac Phil S. Baran*, Jeremy M. Richter and David W. Lin SUPPORTING INFORMATION General Procedures. All reactions were carried out under a nitrogen atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. Dry tetrahydrofuran (THF), triethylamine, benzene, and dimethoxyethane were obtained by passing commercially available pre-dried, oxygen-free formulations through activated alumina columns. Yields refer to chromatographically and spectroscopically (H NMR) homogeneous materials, unless otherwise stated. Reagents 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 0.25 mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and either an ethanolic solution of phosphomolybdic acid or p-anisaldehyde in ethanol/aqueous H2SO4/CH3CO2H and heat as developing agents. NMR spectra were recorded on either Bruker DRX 500 or AMX 400 or Varian Inova-400 instruments, and calibrated using residual undeuterated solvent as an internal reference. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, quin = quintuplet, sext = sextet, sep = septet, b = broad. IR spectra were recorded on a Perkin-Elmer Spetrum BX spectrometer. High resolution mass spectra (HRMS) were recorded on an Agilent Mass spectrometer using ESI-TOF (electrospray ionization-time of flight). Melting points (m.p.) are uncorrected and were recorded on a Fisher-Johns 12-144 melting point apparatus. Optical rotations were obtained on a Perkin-Elmer 431 Polarimeter. Pyrrole 2: Yield = 54% bsm; yellow oil; Rf = 0.55 (silica gel, 3:1 hexane:EtOAc); [α]D = –88 (CH2Cl2, c = 10.6); IR (film) νmax 3378, 3029, 2919, 1654, 1602, 1553, 1494, 1452, 1378, 1354, 1286, 1187, 1097, 1034, 896, 806, 790, 702 cm; H NMR (400 MHz, CDCl3) δ 8.02 (bs, 1 H, D2O exchangeable), 7.05 – 7.10 (m, 3 H), 6.72 (s, Me