Organic & Biomolecular Chemistry
Paper
(R)-tert-Butyl 2-[(R)-1-hydroxy-3-phenylpropyl]-5,6-dihydro- 1H NMR (500 MHz, DMSO-d6, 115 °C) δ (ppm) 8.83 (d, J = 4.4 Hz,
pyridine-1(2H)-carboxylate (18). The title compound (18) was 1 H), 8.21 (d, J = 8.4 Hz, 1 H), 8.02 (d, J = 8.4 Hz, 1 H), 7.70 (dt,
synthesized by the general procedure using tert-butyl-4- J = 7.6, 0.91 Hz, 1 H), 7.56–7.51 (m, 2 H), 5.92–5.89 (m, 1 H),
(nonafluorobutylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carb- 5.75–5.72 (m, 1 H), 5.59 (app t, J = 4.5 Hz, 1 H), 5.39 (app s,
oxylate (8) (481 mg, 1.00 mmol, 1.00 equiv.) and hydrocinna- 1 H), 4.74 (app s, 1 H), 3.85–3.84 (m, 1 H), 2.73 (br s, 1 H),
maldehyde (145 µL, 1.10 mmol, 1.10 equiv.); allylboration was 2.01–1.93 (m, 1 H), 1.83–1.80 (m, 1 H), 1.12 (s, 9 H); 13C NMR
performed for 16 h. The product was obtained as a yellow oil (125 MHz, DMSO-d6, 115 °C) δ (ppm) 153.5, 149.0, 147.5,
(222 mg, 70% yield) after flash column chromatography (25% 147.4, 129.1, 127.9, 126.5, 125.7, 125.2, 125.0, 123.1, 119.0,
Et2O/pentane). Spectral data correspond to that reported.9 Rf = 77.9, 69.4, 56.0, 36.9, 27.2, 23.5; IR (Microscope, cm−1) 3405,
0.65 (50% EtOAc/hexane); 1H NMR (400 MHz, CDCl3, 60 °C) 3180, 3041, 2976, 2930, 1687, 1477; HRMS (ESI-ToF) for
δ (ppm) 7.28–7.15 (m, 5 H), 5.96–5.93 (m, 1 H), 5.68–5.66 (m, C20H25N2O3 (M + H)+: calcd 341.1860; found 341.1863; HPLC
1 H), 4.41–4.37 (m, 1 H), 4.16–4.06 (m, 1 H), 3.72–3.68 (m, 1 H), (Chiralcel IC): 50% i-PrOH/hexane, 20 °C, 0.5 mL min−1, λ =
3.02–2.97 (m, 1 H), 2.93–2.88 (m, 1 H), 2.80–2.76 (m, 1 H), 280 nm, Tmajor = 6.1 min, Tminor = 13.2 min; 90% ee; >96% de.
2.21–2.17 (m, 1 H), 1.98–1.85 (m, 2 H), 1.84–1.78 (m, 1 H), 1.48
(S)-Benzyl
2-[(S)-hydroxy(p-tolyl)methyl]-5,6-dihydropyri-
(s, 9 H); HPLC (Chiralcel OD): 10% i-PrOH/hexane, 25 °C, dine-1(2H)-carboxylate (12). The title compound (12) was syn-
0.5 mL min−1, λ = 210 nm, Tmajor = 12.2 min, Tminor = 9.4 min; thesized by the general procedure (modification: use of
90% ee, >96% de.
(−)-TANIAPHOS instead of (+)-TANIAPHOS) using benzyl-4-
(R)-tert-Butyl 2-[(R)-hydroxy(4-pyridyl)methyl]-5,6-dihydro- (nonafluorobutylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carb-
pyridine-1(2H)-carboxylate (19). The title compound (19) was oxylate (9) (515 mg, 1.00 mmol, 1.00 equiv.) and p-tolualde-
synthesized by the general procedure using tert-butyl-4- hyde (130 µL, 1.10 mmol, 1.10 equiv.); allylboration was
(nonafluorobutylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carb- performed for 16 h. The product was obtained as a colorless
oxylate (8) (481 mg, 1.00 mmol, 1.00 equiv.) and 4-pyridine- oil (202 mg, 60% yield) after flash column chromatography
carboxaldehyde (104 µL, 1.10 mmol, 1.10 equiv.); allylboration (50% Et2O/pentane). Rf = 0.41 (20% EtOAc/hexane); [α]D20
was performed for 3 h. The product was obtained as a colorless −109.1 (c 0.32, CHCl3); 1H NMR (500 MHz, CDCl3) δ (ppm)
oil (206 mg, 71% yield) after flash column chromatography 7.38–7.31 (m, 5 H), 7.31–7.12 (m, 4 H), 5.89–5.82 (m, 1 H),
(100% EtOAc). Rf = 0.27 (100% EtOAc); [α]2D0 +131.6 (c 1.07, 5.41–5.38 (m, 1 H), 5.23–5.11 (m, 2 H), 4.70–4.67 (m, 2 H),
CHCl3); 1H NMR (400 MHz, DMSO-d6) rotamers are present: 4.22–3.46 (m, 1 H), 3.03–2.83 (m, 1 H), 2.34 (s, 3 H), 2.23–2.20
δ (ppm) 8.48–8.47 (m, 2 H), 7.25–7.23 (m, 2 H), 5.91–5.88 (m, (m, 1 H), 1.97–1.93 (m, 1 H); 1H NMR (400 MHz, CDCl3, 65 °C)
1 H), 5.71–5.66 (m, 2 H), 4.77 (app t, J = 4.8 Hz, 1 H), 4.52–4.41 δ (ppm) 7.39–7.29 (m, 5 H), 7.23 (app d, J = 7.9 Hz, 2 H), 7.14
(m, 1 H), 3.94–3.68 (m, 1 H), 2.71–2.62 (m, 1 H), 1.94–1.83 (m, (app d, J = 7.9 Hz, 2 H), 5.89–5.84 (m, 1 H), 5.36–5.34 (m, 1 H),
1
2 H), 1.33–1.21 (m, 9 H); H NMR (400 MHz, DMSO-d6, 80 °C) 5.18 (s, 2 H), 4.68–4.66 (m, 2 H), 4.21–4.16 (m, 1 H), 2.98–2.90
δ (ppm) 8.48 (d, J = 5.8 Hz, 2 H), 7.25 (d, J = 5.8 Hz, 2 H), (m, 1 H), 2.35 (s, 3 H), 2.27–2.17 (m, 1 H), 1.97–1.90 (m, 1 H);
5.89–5.88 (m, 1 H), 5.71–5.68 (m, 1 H), 5.45–5.43 (m, 1 H), 4.78 13C NMR (100 MHz, CDCl3, 65 °C) δ (ppm) 156.8, 138.3, 137.8,
(app t, J = 4.8 Hz, 1 H), 4.51 (app s, 1 H), 3.87–3.83 (m, 1 H), 136.9, 129.2, 128.6, 128.1, 128.0, 127.1, 124.9, 76.2, 67.6, 58.7,
2.64–2.57 (m, 1 H), 1.96–1.91 (m, 1 H), 1.83–1.78 (m, 1 H), 1.32 38.0, 24.8, 21.2; IR (Microscope, cm−1) 3438, 3031, 2921, 1697,
(s, 9 H); 13C NMR (100 MHz, DMSO-d6, 80 °C) δ (ppm) 153.6, 1515, 1431, 1391; HRMS (ESI-ToF) for C21H23NNaO3 (M + Na)+:
151.0, 148.6, 126.7, 124.6, 121.8, 78.3, 72.5, 56.3, 37.2, 27.6, calcd 360.1570; found 360.1567; HPLC (Chiralcel IB): 5%
23.7; IR (Microscope, cm−1) 3402, 3189, 2976, 2929, 1691, i-PrOH/hexane, 20 °C, 0.5 mL min−1, λ = 210 nm, Tmajor
1603, 1477, 1455; HRMS (ESI-ToF) for C16H23N2O3 (M + H)+: 15.8 min, Tminor = 18.9 min; 90% ee; >96% de.
calcd 291.1703; found 291.1707; HPLC (Chiralcel IC): 50%
=
i-PrOH/hexane, 20 °C, 0.5 mL min−1, λ = 254 nm, Tmajor
6.3 min, Tminor = 14.2 min; 94% ee; >96% de.
=
Acknowledgements
(R)-tert-Butyl 2-[(R)-hydroxy(4-quinolinyl)methyl]-5,6-di-
hydropyridine-1(2H)-carboxylate (20). The title compound (20)
was synthesized by the general procedure using tert-butyl-4-
(nonafluorobutylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carb-
oxylate (8) (481 mg, 1.00 mmol, 1.00 equiv.) and 4-quinoline-
carboxaldehyde (173 µL, 1.10 mmol, 1.10 equiv.); allylboration
was performed for 3 h. The product was obtained as a colorless
oil (245 mg, 72% yield) after flash column chromatography
(100% EtOAc). Rf = 0.44 (100% EtOAc); [α]2D0 +51.4 (c 1.56,
CHCl3); 1H NMR (500 MHz, DMSO-d6) rotamers are present:
δ (ppm) 8.85–8.82 (m, 1 H), 8.26–8.11 (m, 1 H), 8.04–7.98 (m,
1 H), 7.74–7.71 (m, 1 H), 7.59–7.50 (m, 2 H), 5.98–5.80 (m, 2 H),
5.69–5.60 (m, 2 H), 4.71–4.59 (m, 1 H), 3.99–3.95 (m, 1 H),
3.18–3.12 (m, 1 H), 1.93–1.86 (m, 2 H), 1.30–0.67 (m, 9 H);
This research was supported by the Natural Science and Engin-
eering Research Council (NSERC, Discovery Grant No. 203287-
2012) of Canada and the University of Alberta. The authors
thank Mr Hao Fu for help with chiral HPLC measurements
and Dr Ryan McKay and Mark Miskolzie for help with NMR
spectrometry.
Notes and references
1 (a) M. G. P. Buffat, Tetrahedron, 2004, 60, 1701;
(b) J. P. Michael, Nat. Prod. Rep., 2008, 25, 139;
(c) S. Källström and R. Leino, Biorg. Med. Chem. Lett., 2008,
16, 601.
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