(2R,3S)-3-(tert-butyl)-2-(pyridin-2-yl)-2H-benzo[d][1,3] oxaphosphole 3- oxide

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

Bo Qu*, Hari P. R. Mangunuru, Xudong Wei, Keith R. Fandrick, Jean-Nicolas Desrosiers, Joshua D. Sieber, Dmitry Kurouski, Nizar Haddad, Lalith P. Samankumara, Heewon Lee, Jolaine Savoie, Shengli Ma, Nelu Grinberg, Max Sarvestani, Nathan K. Yee, Jinhua J. Song, and Chris H. Senanayake

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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(2R, 3S)-3-Hydroxy-2-methyl-1-morpholino-5-phenylpentan-1-one

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 (2R, 3S)-3-Hydroxy-2-methyl-1-morpholino-5-phenylpentan-1-one (4), 97% ee , as white solid, mp 76-78 °C










 (S)-MTPA ester of (-)-4:  

¹⁹F (CDCl₃) δ: -70.88; ¹H (400 MHz, CDCl₃) δ: 1.14 (d, J = 6.9 Hz, 3H), 1.96 (m, 2H), 2.49 (t, J = 8.0 Hz, 2H), 2.91 (quint, J = 6.8 Hz, 1H), 3.32 (m, 2H), 5.42 (m, 1H).

Partial data for the (R)-MTPA ester of (-)-4: ¹⁹F (CDCl₃) δ: -70.81; ¹H (400 MHz, CDCl₃) δ: 1.06 (d, J = 6.9 Hz, 3 H), 2.00 (m, 2 H), 2.61 (m, 2 H), 2.89 (quint, J = 6.9 Hz, 1 H), 3.29 (m, 2H), 5.46 (m, 1 H).



  Syn-4 exhibits the following properties: white solid; mp 76-78 °C; [∝]_D^22.8 = -10.7 (c = 0.25, CHCl₃);  

¹H NMR pdf(400 MHz, CDCl₃) δ: 1.15 (d, J = 7.2 Hz, 3 H), 1.51-1.62 (m, 1 H), 1.92 (dtd, J = 5.4, 9.3, 13.6 Hz, 1 H), 2.52 (dq, J = 2.1, 7.2 Hz, 1 H), 2.68 (ddd, J = 7.1, 9.2, 13.8 Hz, 1 H), 2.88 (ddd, J = 5.2, 9.4, 14.3 Hz, 1 H), 3.43 (br t, J = 4.8 Hz, 2 H), 3.51-3.71 (m, 6 H), 3.93 (ddd, J = 2.1, 3.8, 9.4 Hz, 1 H), 4.39 (s, 1 H), 7.16-7.24 (m, 3 H), 7.26-7.31 (m, 2 H);  

¹³C NMR pdf(100 MHz, CDCl₃) δ: 10.2, 32.5, 35.7, 39.0, 41.9, 46.2, 66.8, 66.9, 70.5, 126.0, 128.5 (2C), 128.7 (2C), 142.2, 176.3; IR (neat) 3428, 2921, 2857, 1616, 1454, 1434, 1224, 1114, 1025 cm^-1;

HRMS (ESI) calcd for C₁₆H₂₃NNaO₃ [M+Na]⁺ 300.1570. Found 300.1572; Anal. calcd for C₁₆H₂₃NO₃: C, 69.29; H, 8.36; N, 5.05. Found: C, 69.15; H, 8.41; N, 5.07.

The diastereomer ratio (syn-4/anti-4) was determined to be >20:1 from the ratio of resonance integrations at 1.13-1.17 ppm (methyl substituent of syn isomer) and 1.17-1.21 ppm (methyl substituent of anti isomer-see Note 11). Both isomers co-elute by TLC analysis.

The anti-4 diastereomer was prepared in low yield (with d.r. ca. 8:1 ) from syn-4 by Mitsunobu reaction and exhibits the following properties: colorless oil; [∝]_D^26.4 = -9.4 (c = 0.54, CHCl₃);

¹H NMR (400 MHz, CDCl₃) δ: 1.20 (d, J = 7.1 Hz, 3 H), 1.70-1.85 (m, 2 H), 2.59-2.73 (m, 2 H), 2.92 (ddd, J = 5.4, 9.4, 13.7 Hz, 1 H), 3.44-3.49 (m, 2 H), 3.56-3.71 (m, 7 H), 3.94 (d, J = 6.4 Hz, 1 H), 7.16-7.23 (m, 3 H), 7.26-7.31 (m, 2 H);

¹³C NMR (100 MHz, CDCl₃) δ: 15.3, 32.3, 37.2, 40.2, 41.8, 46.1, 66.7, 66.9, 73.4, 125.8, 128.4 (2C), 128.5 (2C), 142.2, 175.1;


 IR (neat) 3426, 3026, 2922, 2857, 1614, 1496, 1454, 1435, 1361, 1301, 1268, 1220, 1113, 1069, 1026, 934, 846 cm^-1.

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