Asymmetric synthesis of chiral cycloalkenone derivatives via palladium catalysis

Palladium-catalyzed oxidative desymmetrization enables the efficient synthesis of both enantioenriched cycloalkenone building blocks and diverse epoxyquinoid natural products.


Asymmetric Synthesis of Chiral Cycloalkenone Derivatives via Palladium Catalysis
Barry M. Trost,* James T. Masters, Jean-Philip Lumb, and Dahlia Fateen Department of Chemistry,Stanford University,Stanford, Supporting Information oven-or flame-dried glassware with magnetic stirring under a nitrogen or argon atmosphere. Airand moisture-sensitive liquids and solutions were transferred via oven-dried, stainless steel syringe or cannula and were introduced into the reaction vessel through rubber septa. Reactions performed below room temperature (23 °C) were cooled with ice/water baths (0 °C) or dry ice/isopropanol baths (− 78 °C). Anhydrous PhMe, PhH, CH 2 Cl 2 and THF were obtained from a Seca solvent purification system by Glass Contour. Hexamethyldisilazane (HMDS) and 1,2dichloroethane (DCE) were distilled from CaH 2 under nitrogen. For use in Pd-AA reactionsexcept the oxidations of meso diesters, as noted below-anhydrous and deoxygenated THF was obtained from a Na/benzophenone ketyl still under argon. Unless otherwise indicated, yields are of isolated products. pH 7 buffer was prepared by dissolving K 2 HPO 4 (99 g) and KH 2 PO 4 (77 g) in DI water (1 L). Meso dibenzoates 13 and 15 were prepared by benzoylation of the corresponding diols. 1 Pd 2 dba 3 ·CHCl 3 , 2 ligand L1, 3 and IBX (2-iodoxybenzoic acid) 4 were prepared by literature procedures. (η 3 -C 3 H 5 ) 2 Pd 2 Cl 2 was prepared by the literature procedure 5 and then crystallized from CH 2 Cl 2 / hexanes.
Analytical and preparative thin-layer chromatography was performed using pre-coated 250 µm layer thickness silica gel 60 F 254 plates (EMD Chemicals Inc.). Visualization was performed by ultraviolet light fluorescence quenching and/or by staining with aqueous potassium permanganate, aqueous ceric ammonium molybdate, or ethanolic para-anisaldehyde solutions followed by heating. Flash column chromatography was performed using 40-63 µm silica gel (Silicycle silica gel) using compressed air. The eluent employed for flash chromatography is reported using volume/volume ratios. Proton nuclear magnetic resonance ( 1 H NMR) spectra were acquired using a Varian Inova 600 MHz, Varian Inova 500 MHz, Varian Inova 300 MHz, or Varian Mercury 400 MHz spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) and are calibrated to the residual solvent peak (CHCl 3, 7.26 ppm). Coupling constants (J) are reported in Hz. Multiplicities are reported using the following abbreviations: app = apparent, s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet (range of multiplet is given).
Carbon nuclear magnetic resonance ( 13 C NMR) spectra were recorded using a Varian Inova 150 MHz, Varian Inova 125 MHz, Varian Inova 75 MHz, or a Varian Mercury 100 MHz spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) and are calibrated to the residual solvent peak (CHCl 3, 77.16 ppm).
Infrared spectroscopic data were recorded on a Thermo Scientific Nicolet IR100 FT-IR spectrometer, using thin films of the sample on NaCl plates. The absorbance frequencies are recorded in wavenumbers (cm -1 ). Chiral HPLC analysis was performed using an Agilent Representative procedure for oxidative desymmetrization: Synthesis of 17.

38:
Based on the procedure of Kitahara and co-worker. 18  Preparation of Mukaiyama reagent 40: The synthesis of N,N-dichloro-tert-butylamine (SI-5) was adapted from the literature procedure for tert-butyl hypochlorite. 20 To a 250 mL Erlenmeyer flask equipped with a stir bar was added commercial, household bleach (ca. 5-10% NaOCl, 100 mL). The flask was cooled to 0 °C, and the fume hood lights were turned off. AcOH (4.9 mL, 86 mmol, 2.2 equivalents) was added dropwise, followed by tert-butylamine (SI-4, 4.1 mL, 39 mmol, 1 equivalent, added cautiously). The reaction mixture was stirred for 5 min, and then it was poured into a separatory funnel containing CH 2 Cl 2 (100 mL). At this point, the fume hood lights were turned on. The aqueous phase was discarded, and the organic phase was washed with saturated aqueous NaHCO 3 (50 mL) then water (50 mL), dried over MgSO 4 , filtered, and concentrated to provide the volatile SI-5 (2.23 g, 15.7 mmol, 40%) as a light yellow oil. SI-5 was used immediately in the next step, which was adapted from the literature. 21 SI-5 (2.23 g, 15.7 mmol, 1.2 equivalents) was dissolved in PhH (13 mL), and S-phenyl thioacetate (SI-6, 1.77 mL, 13.1 mmol, 1 equivalent) was added. The flask was heated to 80 °C and then sealed with a plastic cap. After 1 h 15 min, TLC (5:1 hexanes:Et 2 O) indicated complete consumption of SI-6.
The flask was cooled to room temperature and concentrated. Volatile material was removed azeotropically with PhH (2 x 20 mL). The residue was dissolved in CH 2 Cl 2 , filtered through a large pipet column of sand, and concentrated to deliver crude 40 ( -78 °C, the reaction mixture was poured into a mixture of pH 7 buffer (10 mL) and Et 2 O (10 mL). The phases were separated, and the aqueous phase was extracted with Et 2 O (2 x 10 mL).