Synthesis of β-Silyl-α-amino Acid Derivatives by Cu-Catalyzed Regio- and Enantioselective Silylamination of α,β-Unsaturated Esters

Abstract

A copper-catalyzed silylamination of α,β-unsaturated esters with silylboranes and hydroxylamines has been developed to afford the corresponding β-silyl-α-amino acid derivatives, which are of great interest in medicinal and pharmaceutical chemistry. Additionally, by using a suitable chiral bisphosphine ligand, the asymmetric induction is possible, delivering the optically active β-silyl-α-amino acids with synthetically acceptable diastereomeric ratios (55:45−82:18 dr) and high enantiomeric ratios (81:19−99:1 er).

Synthesis of α-Aminophosphonates by Umpolung-Enabled Cu-Catalyzed Regioselective Hydroamination

“…After our preliminary survey, the silylborane, pinB-SiMe 2 Ph, was found to work as the efficient silyl nucleophile in Cu(OPiv) 2 /TMS-dppbz catalysis to produce the corresponding β-silyl-α-aminophosphonate 7aa in 52% yield with 12/88 dr (Scheme 5). Similar to our previous work, 5,8 the anti diastereomer might be mainly formed probably because of intramolecular P�O to Si coordination of the phosphorus α-cuprate intermediate corresponding to 5 in Scheme 4a. The crotonate-and cinnamate-type substrates also participated in the reaction, and the corresponding silylaminated products 7ba and 7ka were obtained with similar efficiency and diastereoselectivity.…”

“…The reaction time was 18 h. It was purified by silica gel column chromatography with hexane/ethyl acetate (1/1, v/v): 79 mg (65%, 0.25 mmol scale); colorless oil; 1 H NMR (CDCl 3 , 400 MHz) δ 7.33−7.17 (m, 15H), 4.31 (d,J = 11.8 Hz,1H),4.27 (d,J = 11.8 Hz,1H),4H), 3.91 (dd, J = 13.5, 3.9 Hz, 2H), 3.86 (d,J = 13.5 Hz,2H),1H),1H),3.20 (ddd,J = 16.0,8.4,5.1 Hz,1H), 2.04−1.96 (m, 2H), 1.31 (t, J = 6.9 Hz, 3H), 1.29 (t, J = 7.0 Hz, 3H); 13 C{ 1 H} NMR (CDCl 3 , 100 MHz) δ 139. 8,138.5,129.2,128.21,128.19,127.6,127.4,127.0,72.7,67.3 (d,J = 12.5 Hz),61.5 (d,J = 6.9 Hz),61.1 (d,J = 7.4 Hz), 54.9 (d, J = 2.4 Hz), 52.1 (d,J = 135.1 Hz), 28.0 (d, J = 6.6 Hz), 16.62 (d,J = 5.4 Hz),16.58 (d,J = 5.4 Hz); 31 P{ 1 H} NMR (CDCl 3 , 162 MHz) δ 28.47; HRMS (APCI) m/z (M + H) + calcd for C 28 H 37 NO 4 P 482.2455NO 4 P 482. , found 482.2443.…”

“…The reaction time was 18 h. It was purified by silica gel column chromatography with hexane/ethyl acetate (1/1, v/v): 83 mg (73%, 0.25 mmol scale); yellow oil; 1 H NMR (CDCl 3 , 400 MHz) δ 7.29 −7.26 (m, 2H), 7.20−7.16 (m, 3H), 4.15−4.03 (m, 4H), 3.35−3.30 (m, 4H), 2.89−2.77 (m, 3H), 2.68−2.55 (m, 4H), 1.92−1.63 (m, 4H), 1.45 (s, 9H), 1.31 (t, J = 7.0 Hz, 3H), 1.29 (t, J = 7.0 Hz, 3H); 13 C{ 1 H} NMR (CDCl 3 , 100 MHz) δ 154. 8,142.1,128.39,128.36,125.8,79.6,61.94 (d,J = 7.2 Hz),61.90 (d,J = 137.6 Hz),61.2 (d,J = 7.0 Hz),49.8 (d,J = 3.4 Hz),44.5,35.5,28.9 (d,J = 12.1 Hz),28.4,26.0 (d,J = 5.6 Hz),16.7 (d,J = 5.6 Hz) 7.27 (m,2H),3H),4H),2H),2H),2.77 (ddd,J = 16.7,9.9,4.4 Hz,1H), 2.68−2.54 (m, 6H), 1.92−1.63 (m, 4H), 1.33 (t, J = 7.0 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H); 13 C{ 1 H} NMR (CDCl 3 , 100 MHz) δ 142. 1,128.39,128.35,125.8,63.4 (d,J = 138.0 Hz),61.9 (d,J = 7.3 Hz),61.2 (d,J = 7.5 Hz),52.7 (d,J = 3.8 Hz),35.4,28.92 (d,J = 12.2 Hz),28.86,…”

“…By using a suitable ancillary chiral bisphosphine ligand, the asymmetric induction can also form the enantioenriched αaminophosphonate. Additionally, the use of a silylborane instead of the hydrosilane enables the regioselective silylamination 8 reaction. Detailed optimization studies and the substrate scope are described herein.…”

Cu-Catalyzed Enantioselective Hydrogermylation: Asymmetric Synthesis of Unnatural β-Germyl α-Amino Acids

“…From the synthetic point of view, catalytic enantioselective hydrofunctionalization of dehydroalanine derivatives represents one of the most straightforward and atom-economic methods toward β-heteroatom unnatural α-amino acids (Scheme a). Although transition metal-catalyzed hydrosilylation processes have been well established, − to our surprise, catalytic enantioselective hydrosilylation of dehydroalanines is rare. − To our knowledge, only one case via an Rh-catalyzed asymmetric intramolecular hydrosilylation of dehydroalanines has been reported toward cyclic chiral β-silyl α-amino acids (Scheme b), while the method for the catalytic asymmetric synthesis of enantioenriched β-germyl α-amino acids remains unknown to date. Herein, we report the demonstration of a novel copper-catalyzed enantioselective hydrogermylation of dehydroalanines with dihydrogermanes and trihydrogermanes that gives access to a wide range of β-germyl α-amino acid derivatives in decent yields with good to excellent enantioselectivities (Scheme c).…”