An Ir-catalyzed enantioselective hydrogenation of 2-alkyl-pyridines has been developed using ligand MeO-BoQPhos. High levels of enantioselectivities up to 93:7 er were obtained. The resulting enantioenriched piperidines can be readily converted into biologically interesting molecules such as the fused tricyclic structures 5, 6, and 7 in 99:1 er, providing a novel, concise synthetic route to this family of chiral piperidine-containing compounds.
(2R,3S)-3-(tert-butyl)-2-(pyridin-2-yl)-2H-benzo[d][1,3] oxaphosphole 3- oxide
(2R,3S)-3-(tert-butyl)-2-(pyridin-2-yl)-2H-benzo[d][1,3] oxaphosphole 3- oxide: white solid,
mp 164.0-166.0 °C; [α]D 20 = + 87.4 (c 0.05, EtOH);
1 H NMR (500 MHz, CDCl3): δ 8.61 (d, J = 5.0 Hz, 1H), 7.67 (qd, J = 7.0, 1.4 Hz, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.21 (m, 1H), 7.12 (m, 2H), 5.74 (d, J = 1.8 Hz, 1H), 1.37 (d, J = 5.0 Hz, 9H);
13C NMR (125 MHz, CDCl3): δ 163.9 (d, JC−P = 17.5 Hz), 154.3 (d, JC−P = 4.0 Hz), 149.3 (d, JC−P = 1.5 Hz),136.7 (d, JC−P = 1.8 Hz), 135.1 (d, JC−P = 1.9 Hz), 130.0 (d, JC−P = 6.1 Hz), 122.9 (d, JC−P = 2.0 Hz), 122.5 (d, JC−P = 9.0 Hz), 121.4 (d, JC−P = 2.6 Hz), 113.8 (d, JC−P = 90.9 Hz), 113.7 (d, JC−P = 5.6 Hz), 77.7 (d, JC−P = 53.9 Hz), 33.9 (d, JC−P = 71.7 Hz), 24.1;
31P NMR (202 MHz, CDCl3): δ 60.5;
HRMS (ESI) [M+H]+ m/z calcd for [C16H19NO2P]+ is 288.1075, found 288.1148.
Synthesis of Enantioenriched 2-Alkyl Piperidine Derivatives through Asymmetric Reduction of Pyridinium Salts
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, United States
Org. Lett., Article ASAP
DOI: 10.1021/acs.orglett.6b02401
*E-mail: bo.qu@boehringer-ingelheim.com.
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