Reaction Steps
To a suspension of (E)-(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid [2(ii-a)] (10 g, 26.1 mmol) in degassed ethanol (90 ml) is added a solution of diiodo(p-cymene)ruthenium(II) dimer (0.156 g, 0.16 mmol) and (αS,αS)-2,2′-bis(α-N,N-dimethylaminophenylmethyl)-(R,R)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphine]ferrocene (=Mandyphos SL-M004-2) (0.348 g, 0.33 mmol) in degassed ethanol (30 ml) portion wise over the entire reaction time of 5 days. The solution is degassed using vacuum and a pressure of 5.5 bar hydrogen is applied. The mixture is heated to 60° C. and stirred at this temperature for 5 days. The vessel is then purged with nitrogen. The solvent is removed in vacuo. The resulting solid is dissolved in isopropyl acetate (34 ml) and heated to reflux. An heptane fraction (68 ml) is added and the mixture is cooled to room temperature. The solid is collected by filtration and washed with an heptane-isopropyl acetate 2:1 mixture (20 ml). The solid is dried overnight at 50° C. under 1-50 mbar vacuum to afford the title compound [Ratio 2(i-a): 2(i-b) 6:94, as determined by HPLC analysis] as a grey solid. δH (500 MHz; DMSO) 1.06 (3H, d, J 7.0, 1-CH3), 1.32 (9H, s, (CH3)3), 1.42 (1H, m, 3-HA), 1.78 (1H, m, 3-HB), 2.39 (1H, m, 2-H), 2.73 (2H, d, J 7.0, 5-H), 3.73 (1H, m, 4-H), 6.75 (1H, d, J 9.5, NH), 7.29 (2H, d, J 8.0, Ar-ortho-H(Ph)), 7.35 (1H, t, J 7.0, Ar-(Ph)-para-H), 7.46 (2H, t, J 7.5, Ar-(Ph)-meta-H), 7.57 (2H, d, J 8.0, Ar-meta-H(Ph), 7.64 (2H, d, J 7.5, Ar-(Ph)-ortho-H), 12.01 (1H, s, CO2H); δC (500 MHz, DMSO) 16.2 (1-CH3), 28.2 [(CH3)3], 35.7 (2-C), 37.9 (3-C), 40.7 (5-C), 49.2 (4-C), 77.4 [(C(CH3)3], 126.3, 126.5, 127.2, 128.9, 129.7 (Ar—CH), 137.8 (Ar-ipso-C(Ph)), 138.4 (Ar-para-C(Ph)), 140.1 (Ar-(Ph)-ipso-C), 155.3 (NCO), 177.6 (CO2H); m/z (+ESI) 406 ([MNa]+, 4%), 384 ([MH]+, 44), 328 (100), 284 (22); Found: [MH]+, 384.21696. C23H30NO4 requires MH 384.21693.
