Synthesis and Structural Analysis of a New Class of Azaspiro[3.3]heptanes as Building Blocks for Medicinal Chemistry (original) (raw)

All non-aqueous reactions were carried out using oven-dried (90 °C) or heat gun dried glassware under a positive pressure of dry argon unless otherwise noted. CH 2 Cl 2 , THF, Et 2 O, CH 3 CN, and toluene were purified by distillation and dried by passage over activated alumina under an argon atmosphere (H 2 O content < 30 ppm, Karl-Fischer titration). Triethylamine was distilled from KOH under an atmosphere of dry nitrogen. All other commercially available reagents were used without further purification. Except if indicated otherwise, reactions were magnetically stirred and monitored by thin layer chromatography using Merck Silica Gel 60 F254 plates and visualized by fluorescence quenching under UV light. In addition, TLC plates were stained using ceric ammonium molybdate, potassium permanganate, ninhydrin or Dragendorff's stain. Chromatographic purification of products (flash chromatography) was performed on Brunschwig silica 32-63, 60 Å using a forced flow of eluent at 0.3-0.5 bar. Concentration under reduced pressure was performed by rotary evaporation at 40 °C at the appropriate pressure. Purified compounds were further dried under high vacuum. Yields refer to chromatographically purified and spectroscopically pure compounds, unless otherwise stated. Melting points: measured on a Büchi SMP-20 or Büchi B-540 apparatus. All melting points were measured in open capillaries and are uncorrected. NMR spectra: NMR spectra were recorded on a Varian Mercury 300 spectrometer operating at 300 MHz and 75 MHz for 1 H and 13 C acquisitions, respectively, or on Bruker DRX400 (or AV400) spectrometers operating at 400 MHz (1 H) and 101 MHz (13 C). Chemical shifts (δ) are reported in ppm with the solvent resonance as the internal standard relative to chloroform (δ 7.26) or water (δ 4.79) for 1 H, and chloroform (δ 77.0) for 13 C. All 13 C spectra were measured with complete proton decoupling. Data are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad signal; coupling constants in Hz. IR spectra: recorded on a Perkin Elmer Spectrum RX-I FT-IR (as thin film), PerkinElmer Spectrum BX FT-IR (neat) or Varian 800 FT-IR (neat) spectrometer. Absorptions are given in wavenumbers (cm-1). Mass spectra: recorded by the MS service at ETH Zürich. EI-MS (m/z): VG-TRIBRID spectrometer. ESI-MS (m/z): Varian IonSpec spectrometer. MALDI-MS (m/z): IonSpec Ultima Fourier Transform Mass Spectrometer. Chemical names: generated with ChemBioDraw Ultra 11.0 (CambridgeSoft) and modified where appropriate. S3 EXPERIMENTAL PROCEDURES tert-Butyl 3-(2-oxoethylidene)azetidine-1-carboxylate (2). To a solution of tert-butyl 3-oxoazetidine-1carboxylate (680 mg, 3.97 mmol, 1.0 equiv) in CH 2 Cl 2 (14.6 ml) was added at RT (formylmethylene)triphenylphosphorane (1370 mg, 4.37 mmol, 1.1 equiv), and the reaction mixture was stirred at 40 °C for 5 h, when it was concentrated in vacuo. The residue was purified by FC (SiO 2 ; hexanes : EtOAc 2:1) to afford the pure title compound. Yield: 735 mg (3.73 mmol, 94%). Colorless oil.