A Straightforward Protocol for the Synthesis of Functionalized Tryptophan Peptides via Stille Coupling, Azidation and Photoinduced Nitrene Insertion

Abstract

All air-or moisture-sensitive reactions were carried out in dried glassware (> 100 °C) under an atmosphere of argon. THF was distilled over Na/benzophenone prior to use. Dichloromethane (DCM), MeCN and DMF (anhydrous) were purchased from Sigma-Aldrich. EtOAc and petroleum ether (PE) were distilled prior to use. Reactions were monitored by analytical TLC, which was performed on silica gel on TLC PET-foils by Sigma-Aldrich. Visualization was accomplished with UV-light (254 nm), KMnO 4 solution or an iodine chamber. Rotary evaporation was conducted at 40 °C. The products were purified by flash chromatography on silica gel columns (Macherey-Nagel 60, 0.063-0.2 mm) or by automated flash chromatography (Grace Reveleris®, Teledyne Isco RediSep R f silica cartridges). Mixtures of EtOAc and PE were generally used as eluents. Melting points were determined with a melting point apparatus IA 9100 by Electrothermal and are uncorrected. 1 H, 13 C, 119 Sn and 19 F NMR spectra were recorded with a Bruker AV II 400 [400 MHz (1 H), 100 MHz (13 C), 149 MHz (119 Sn), 376 MHz (19 F)] or a Bruker AV 500 [500 MHz, (1 H), 125 MHz (13 C)] spectrometer in CDCl 3 (+0.01% Si(CH 3) 4) unless otherwise specified. NMR spectra were evaluated using iNMR (Version 5.4.4). Chemical shifts are reported in ppm relative to Si(CH 3) 4 and CHCl 3 was used as the internal standard [δ(1 H) = 7.26 ppm, δ(13 C) = 77.0 ppm]. Multiplicities are reported as bs (broad signal), s (singlet), d (doublet), t (triplet), q (quartet) and m (multiplet). High resolution mass spectra were recorded with a Finnigan MAT 95 spectrometer using the CI technique. Optical rotations were measured with a Perkin-Elmer polarimeter (model 341) in a thermostated (20 °C ± 1 °C) cuvette. The radiation source used was a sodium vapor lamp (λ = 589 nm). The concentrations are given in g/100 ml. Diastereomeric ratios were determined by HPLC using an instrument from Merck-Hitachi (model LaChrom D-7000). The chiral stationary phase used was Repropsil 100 Chiral-NR 8 µm (250 × 4.6 mm) from Trentec. The evaluation was conducted using Multi-HSM-Manager (Merck). Photochemical experiments were conducted with a UV-LED [UV-LED SMART by Opsytec Dr. Gröbel GmbH (max. irradiance >25 W/cm 2 , λ = 365 nm, beam profile: standard, distance from reaction mixture: ca. 5 cm)]. 2. Experimental Section General procedures (GP) 2.1. General procedure 1: Stille cross coupling An oven dried Schlenk tube was charged with LiCl (2.0 equiv) and heated with a heat gun under vacuum (< 0.1 mbar). After cooling to room temperature CuI (2.0 equiv), (substituted) o-iodoaniline (1.0 equiv) and Pd(PPh 3) 4 (5 mol%) were added and the flask was evacuated and refilled with Ar three times. DMF (10 mL/mmol), which was previously degassed by bubbling with Ar, and the organotin compound (1.2 equiv) was added and the mixture was heated to 80 °C for 18 h. After reaching full conversion (TLC) the mixture was diluted with EtOAc and 1 M KF-solution (5 mL/mmol) was added. Upon vigorous shaking (in the Schlenk tube) a colorless precipitate...