Compound 71
((8R,9S,10S,Z)-9-(2',3'-dimethyl-[1,1'-biphenyl]-4-yl)-6-((1-methyl-1H-imidazol-2-yl)sulfonyl)-1,6-diazabicyclo[6.2.0]dec-3-en-10-yl)methanol
From: Substrate-selective inhibitors that reprogram the activity of insulin-degrading enzyme
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Compound data: 1H NMR
Compound data: 13C NMR
Compound data: COSY
Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.
A solution of bromoaryl intermediate 70 (58 mg, 0.124 mmol) in THF (15 mL), was added 3 mL of K3PO4 solution (0.5 M), followed by 2,3-dimethyl phenylboronic acid (50 mg, 0.333 mmol, 2.5 equiv.), and the heterogeneous mixture was purged by vigorously bubbling with argon gas for 1 hour. The solution was treated with X-Phos-Pd G3 catalyst (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)] palladium (II) methanesulfonate, 21 mg, 0.025 mmol, 0.2 equiv.). After vigorous stirring for 48 hr at 50 °C under an argon atmosphere, the solution was added EtOAc (50 mL), followed by 1 g Na2SO4 and 1 g MgSO4, and the organic layer was decanted. The aqueous slurry was washed 3 times with EtOAc (25 mL). The combined organic fractions were dried again over MgSO4 and evaporated to a residue under vacuum, followed by purification by column chromatography (0 → 2% MeOH in CH2Cl2) and evaporation of the collected fractions gave 37.2 mg of title compound 71 (61%, 0.0755 mmol), an amorphous solid. High resolution mass, calculated for C27H32N4O3S [M+H]+ = 493.2268, found 493.2263, Δ = -1.01 ppm. 1H NMR (400 MHz, DMSO-d6) δ 7.55 – 7.48 (m, 2H), 7.44 (d, J = 1.1 Hz, 1H), 7.35 – 7.29 (m, 2H), 7.18 (dd, J = 7.6, 1.7 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.01 (dd, J = 7.2, 1.5 Hz, 2H), 6.99 (d, J = 1.1 Hz, 1H), 6.04 – 5.89 (m, 2H), 5.03 (t, J = 9.6 Hz, 1H), 4.43 (ddd, J = 10.8, 6.7, 3.5 Hz, 1H), 4.34 (dd, J = 15.0, 4.9 Hz, 1H), 4.23 – 4.08 (m, 2H), 4.06 – 3.97 (m, 2H), 3.97 – 3.84 (m, 3H), 3.82 (s, 3H), 3.74 (t, J = 10.0 Hz, 1H), 2.29 (s, 3H), 2.10 (s, 3H). 13C NMR (101 MHz, DMSO) δ 158.37 (q, J = 35.8 Hz*), 141.61, 141.57, 141.05, 136.89, 133.71, 133.36, 129.46, 129.37, 128.88, 127.70, 127.63, 127.42, 127.31, 126.34, 125.35, 115.87 (q, J = 292.7 Hz*), 72.96, 69.59, 59.27, 49.26, 48.20, 43.35, 40.49, 39.52, 34.34, 20.29, 16.70. * TFA salt.
