Catalytic Asymmetric Reductive Acyl Cross-Coupling: Synthesis of Enantioenriched Acyclic α,α-Disubstituted Ketones

Abstract

Unless otherwise stated, reactions were performed under a nitrogen atmosphere using freshly dried solvents. Tetrahydrofuran (THF), methylene chloride (CH 2 Cl 2), and acetonitrile (MeCN), were dried by passing through activated alumina columns. Anhydrous dimethylacetamide (DMA) was purchased from Aldrich and stored under inert atmosphere. Manganese powder (-325 mesh, 99.3%) was purchased from Alfa Aesar. Unless otherwise stated, chemicals and reagents were used as received. All reactions were monitored by thin-layer chromatography using EMD/Merck silica gel 60 F254 pre-coated plates (0.25 mm) and were visualized by UV, panisaldehyde, or KMnO 4 staining. Flash column chromatography was performed as described by Still et al. 1 using silica gel (partical size 0.032-0.063) purchased from Silicycle. Optical rotations were measured on a Jasco P-2000 polarimeter using a 100 mm path-length cell at 589 nm. 1 H and 13 C NMR spectra were recorded on a Varian 400 MR (at 400 MHz and 101 MHz, respectively) or a Varian Inova 500 (at 500 MHz and 126 MHz, respectively), and are reported relative to internal CHCl 3 (1 H, ! = 7.26) or acetone (1 H, ! = 2.05), and CDCl 3 (13 C, ! = 77.0) or acetone (13 C, ! = 29.8). Data for 1 H NMR spectra are reported as follows: chemical shift (! ppm) (multiplicity, coupling constant (Hz), integration). Multiplicity and qualifier abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, app = apparent. IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm-1). HRMS were acquired using an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI) or mixed (MM) ionization mode, or obtained from the Caltech Mass Spectral Facility in fast-atom bombardment mode (FAB). Analytical SFC was performed with a Mettler SFC supercritical CO 2 analytical chromatography system with Chiralcel AD-H, OD-H, ASH , OB-H, and OJ-H columns (4.6 mm x 25 cm) with visualization at 210 nm. Analytical achiral GC was performed with an Agilent 6850 GC utilizing an Agilent DB-WAX (30.0 m x 0.25 mm) column (1.0 mL/min He carrier gas flow).

Nickel-Catalyzed Reductive Couplings

“…Reisman first discovered that under Ni-catalyzed reductive conditions, acylation of racemic benzylic chlorides with acid chlorides generated the ketones in high ees using a chiral box ligand (Scheme 27) [79]. With the Ni-catalyzed reductive coupling strategy, the same group also developed asymmetric vinylation of benzylic chlorides with vinyl bromides (Scheme 27).…”

Enantioconvergent Fukuyama Cross‐Coupling of Racemic Benzylic Organozinc Reagents

“…[12] However,t hese strategies are not effective for the synthesis of enantioenriched adisubstituted ketones because of the stringent requirement for site-selective enolization and the potential racemization of the newly formed stereogenic center under the reaction conditions.T ransition-metal-catalyzed acyl cross-couplings can circumvent the difficulties described above,h owever, only one example of such atransformation has been described recently. [13] Herein, we report ap alladium-catalyzed crosscoupling of thioesters with racemic benzylic organozinc reagents as an approach for the construction of acyclic adisubstituted ketones with high yields and enantioselectivities.…”

Nickel‐Catalyzed Synthesis of Ketones from Alkyl Halides and Acid Chlorides: Preparation of Ethyl 4‐Oxododecanoate

“…15 Purity was assessed at 98 wt% by quantitative 1 H NMR using dimethyl fumarate as an internal standard. 16 The yield of a second duplicate run was 20.0 g (84%). less reactive alkyltin, 4 alkylzinc, 5,6 dialkylzinc, 7 or alkylboron 8 reagents have been developed.…”

“…In addition, by substituting a chiral bis(oxazoline) ligand for bipyridine, Reisman was able to realize the enantioconvergent coupling of a secondary benzyl chloride to form enantioenriched α-aryl ketones. 16 Finally, although several mechanisms had been proposed in the literature for these reactions by ourselves and others, recent investigations have led to a revised mechanism. We proposed a connection between the cross-electrophile coupling of aryl halides with alkyl halides based upon mechanistic studies of isolated acylnickel intermediates 17 and subsequent work by Gong 12 suggested that the mechanism is nearly identical to the one we proposed for the coupling of aryl halides with alkyl halides.…”

“…All the eluted solution is collected. After the solvent is removed by rotary evaporation (50 °C, 50 mmHg), ethyl 4-oxododecanoate (19.90 g, 84%) is collected as a pale yellow oil (Notes 14,15,and 16).…”