Palladium‐Catalyzed Construction of Quaternary Stereocenters by Enantioselective Arylation of γ‐Lactams with Aryl Chlorides and Bromides

Abstract

Materials and Methods Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon. Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLC-MS. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, p-anisaldehyde, or KMnO 4 staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40-63 nm) was used for flash chromatography. 1 H NMR spectra were recorded on a Bruker Avance HD 400 MHz or Varian Mercury 300 MHz spectrometers and are reported relative to residual CHCl 3 (δ 7.26 ppm). 13 C NMR spectra were recorded on a Bruker Avance HD 400 MHz spectrometer (100 MHz) and are reported relative to residual CHCl 3 (δ 77.36 ppm). 19 F NMR spectra were recorded on a Varian Mercury 300 MHz spectrometer (282 MHz). Data for 1 H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d = broad doublet, app = apparent. Data for 13 C NMR are reported in terms of chemical shifts (δ ppm). IR spectra were obtained using a Perkin Elmer Spectrum BXII spectrometer or Nicolet 6700 FTIR spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm path-length cell and are reported as: [α] D T (concentration in 10 mg/1 mL, solvent). Analytical SFC was performed with a Mettler SFC supercritical CO 2 analytical chromatography system utilizing Chiralpak (AD-H) or Chiralcel (OD-H) columns (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. High resolution mass spectra (HRMS) were obtained from Agilent 6200 Series TOF with an Agilent G1978A S3 Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). Reagents were purchased from Sigma-Aldrich, Acros Organics, Strem, or Alfa Aesar and used as received unless otherwise stated. List of Abbreviations ee-enantiomeric excess, SFC-supercritical fluid chromatography, TLC-thin-layer chromatography, IPA-isopropanol, MTBE-methyl tert-butyl ether, PE-petroleum ether, DMAP-4-dimethylaminopyridine, EtOAc-ethyl acetate, LiHMDS-lithium bis(trimethylsilyl)amide, NaHMDS-sodium bis(trimethylsilyl)amide, PMPp-methoxy phenyl, pmdba-4,4'-dimethoxydibenzylideneacetone, THF-tetrahydrofuran, DMEDA-1,2-dimethylethylenediamine.

Chiral Ammonium Salt Catalyzed Asymmetric Alkylation of Unactivated Amides

“…In 2002, a nickel-catalyzed asymmetric arylation of γ-lactones using sodium hexamethyldisilazide (NaHMDS) as base was reported by Buchwald group (Scheme 2 , A1). 5 Recently, the Stoltz group also developed palladium-catalyzed asymmetric arylation (Scheme 2 , A1) 6 and acylation 7 of γ-lactams under strong basic conditions. Hou and co-workers reported palladium-catalyzed asymmetric allylic alkylation (Scheme 2 , A2) 8 and cyclopropanation 9 of acyclic alkyl amides using lithium hexamethyldisilazide (LiHMDS) as base.…”

Nickel-Catalyzed Enantioselective C(sp 3 )–H Arylation of Ketones with Aryl Ethers via Selective C Ar –O Cleavage to Construct All-Carbon Quaternary Stereocenters

“…In 1992, Overman and co-workers developed a seminal work on palladium-catalyzed intramolecular asymmetric Heck reaction for the synthesis of chiral spiro-oxindoles with quaternary stereocenters. 15 Subsequently, transition metalcatalyzed asymmetric Heck reaction, [16][17][18] conjugate addition, 19,20 coupling of tertiary carbon radicals 21 and αarylation of carbonyl and nitrile derivatives [22][23][24][25][26][27][28][29][30][31][32] have been well developed for the synthesis of aryl-substituted quaternary stereocenters (Scheme 1a). However, nickel-catalyzed enantioselective α -arylation of carbonyl compounds for the construction of quaternary carbon centers was only reported in limited examples (Scheme 1b).…”

Catalytic Enantioselective α-Arylation of Carbonyl Enolates and Related Compounds

“…Very recently, Stoltz, Morgan, and co-workers accomplished an enantioselective Pd-catalyzed α-arylation of α-substituted γlactams 92 with aryl chlorides or bromides, allowing for the synthesis of enantioenriched α-aryl α-quaternary lactams 93 (Scheme 24). 48 The combination of 2.5 mol % of Pd 2 (pmdba) 3 with 7.5 mol % of ferrocelane-derived ligand 94a was identified as an effective catalyst for the arylation with aryl chlorides 29 and gave rise to the desired lactams bearing α-quaternary stereocenters with excellent enantioselectivities. However, ligand 94b turned out to be optimal in the case of aryl bromides 14.…”