Catalytic Enantioselective α-Arylation of Carbonyl Enolates and Related Compounds

Abstract

Optically active α-arylation carbonyl units are widely present in a wide variety of drugs, bioactive natural products, and valuable pharmacologically active molecules. Catalytic enantioselective α-arylation of carbonyl enolates or the related precursors with various arylating agents constitutes a powerful tactic for constructing such privileged scaffolds, which is of great interest and has gained considerable progress. This review summarizes the advances based on two major strategies with diverse arylating agents, discusses in detail the reaction mechanism, limitations, and advantages of each method and their applications, and expounds the synthetic opportunities still open for further exploration.

Metal Free, Direct and Selective Deoxygenation of α‐Hydroxy Carbonyl Compounds: Access to α,α‐Diaryl Carbonyl Compounds

“…2‐(4‐Methoxyphenyl)‐1,2‐diphenylethanone (2g) . [14a] Following the general procedure and purification by flash chromatography ( n ‐hexane/EtOAc, 9:1), the title compound 2g was obtained as a white solid (145 mg, 76 %) from 1g (200 mg, 0.63 mmol). R f = 0.42 ( n ‐hexane/EtOAc, 9:1); Mp 86–87 °C; 1 H NMR (CDCl 3 , 500 MHz): δ = 3.75 (s, 3H; OCH 3 ), 5.98 (s, 1H; ‐CH), 6.84 (dd, J = 6.5, 1.5 Hz, 2H; ArH), 7.18 (dd, J = 6.5, 1.5 Hz, 2H; ArH), 7.22–7.26 (m, 3H; ArH), 7.30 (t, J = 7.5 Hz, 2H; ArH), 7.38 (t, J = 7.5 Hz, 2H; ArH), 7.48 (t, J = 7.0 Hz, 1H; ArH), 7.99 ppm (dd, J = 8.5, 1.0 Hz, 2H; ArH); 13 C NMR (CDCl 3 , 125.76 MHz): δ = 55.2, 58.6, 114.1, 127.0, 128.58, 128.67, 128.93, 129.03, 130.2, 131.1, 133.0, 136.8, 139.5, 158.6, 198.5 ppm; IR (neat): ν̃ = 3027, 2962, 2896, 2839, 1685 (CO), 1597, 1511, 1445, 1255, 1169 cm –1 .…”

“…2‐(Naphthalen‐1‐yl)‐1,2‐diphenylethanone (2j) . [14a] Following the general procedure and purification by flash chromatography ( n ‐hexane/EtOAc, 9:1), the title compound 2j was obtained as a white solid (160 mg, 84 %) from 1j (200 mg, 0.59 mmol). R f = 0.57 ( n ‐hexane/EtOAc, 9:1); Mp 110–111 °C; 1 H NMR (CDCl 3 , 500 MHz): δ = 6.73 (s, 1H; ‐CH), 7.20–7.38 (m, 9H; ArH), 7.45–7.49 (m, 3H; ArH), 7.77 (d, J = 8.0 Hz, 1H; ArH), 7.86–7.87 (m, 1H; ArH), 7.96–7.98 (m, 2H; ArH), 7.99–8.01 ppm (m, 1H; ArH); 13 C NMR (CDCl 3 , 125.76 MHz): δ = 55.9, 123.2, 125.4, 125.8, 126.7, 127.1, 127.3, 128.1, 128.7, 128.79, 128.9, 129.1, 129.6, 131.3, 133.1, 134.2, 135.0, 136.6, 138.1, 198.3 ppm; IR (neat): ν̃ = 3060, 3035, 1682 (CO), 1597, 1449, 1291, 1210, 1177 cm –1 .…”

“…There is an added advantage to this strategy. The deoxygenation of –OH group in α‐hydroxy‐α,α‐diaryl carbonyl compounds can furnish α,α‐diaryl carbonyl compounds, which are an important class themselves . 1,2,2‐Triarylethanones, for example, are very important precursors for the synthesis of dibenzo[ a,c ]phenanthridine, analogues of biologically active benzo[ c ]phenanthridine alkaloids .…”

“…In addition, 1,2,2‐triarylethanones are also useful synthons for tamoxifen, the most widely used drug for the treatment of breast cancer . The synthetic methodology that result in α,α‐diaryl carbonyl compounds are mostly metal assisted …”

Computational Analysis of Enantioselective Pd-Catalyzed α-Arylation of Ketones

“… 17 − 33 However, in spite of these achievements, this research area still suffers many limitations. 34 In this regard, the computational study of this reaction could greatly improve our understanding of its general mechanism by evaluation of the energetics of each possible pathway A–C ( Figure 1 b). Visualization and analysis of the diastereomeric transition structures (TSs) leading to different enantiomeric products could help in understanding the interactions responsible for the observed selectivity.…”