Z. Dong, L. Wang, X. Chen, X. Liu, L. Lin, X. Feng
FULL PAPER
AD-H; 2-propanol/n-hexane, 20:80; flow rate = 1.0 mLmin–1; λ =
26
4m: White solid (33.5 mg, 89% isolated yield, 78%ee). [α]
=
405
1
254 nm): tR = 7.31 (major), 14.03 (minor) min.
+13.1 (c = 0.321, acetonitrile). H NMR (400 MHz, CDCl3): δ =
1.71 (s, 1.1 H), 1.75 (s, 1.8 H), 1.93–2.04 (m, 0.7 H), 2.31 (s, 0.3
H), 2.39–2.49 (m, 1.4 H), 3.02 (s, 0.3 H), 3.32 (d, 0.7 H), 3.90 (dd,
J = 10.7, 19.3 Hz, 0.09 H), 4.21–4.26 (m, 1 H), 4.70 (d, J = 9.96 Hz,
0.1 H), 7.21–7.58 (m, 8.3 H), 7.82 (d, J = 7.86 Hz, 0.4 H), 7.87 (d,
J = 7.86 Hz, 0.3 H), 7.96 (d, J = 7.86 Hz, 0.1 H), 9.63 (s, 0.1 H)
ppm. HPLC (Daicel Chiralcel AD-H; 2-propanol/n-hexane, 20:80;
flow rate = 1.0 mLmin–1; λ = 254 nm): tR = 4.03 (major), 5.68
(minor) min.
21
4h: White solid (30.8 mg, 95% isolated yield, 88%ee). [α]
=
405
1
+20.8 (c = 0.674, acetonitrile). H NMR (400 MHz, CDCl3): δ =
1.66 (s, 1.5 H), 1.72 (s, 1.4 H), 1.99 (dd, J = 11.4, 14.0 Hz, 0.5 H),
2.27 (s, 0.33 H), 2.34–2.54 (m, 1.3 H), 3.17–3.50 (br. m, 0.6 H),
3.75 (m, 0.16 H), 4.11 (m, 1.2 H), 4.21 (dd, J = 2.76, 6.52 Hz, 0.5
H), 4.67 (dd, J = 2.52, 7.36 Hz, 0.1 H), 6.62–6.82 (m, 3 H), 7.07–
7.14 (m, 1 H), 7.21–7.34 (m, 3 H), 7.47–7.58 (m, 1 H), 7.82 (dd, J
= 1.44, 7.76 Hz, 0.33 H), 7.89 (dd, J = 1.4, 7.76 Hz, 0.33 H), 7.92
(dd, J = 1.56, 7.92 Hz, 0.08 H), 9.49 (s, 0.06 H) ppm. HPLC (Daicel
4n: White solid (35.4 mg, 99% isolated yield, 83%ee). [α]2D6 = –9.8
1
Chiralcel AD-H; 2-propanol/n-hexane, 10:90; flow rate
=
(c = 0.614, acetonitrile). H NMR (400 MHz, CDCl3): δ = 1.68 (s,
1.0 mLmin–1; λ = 254 nm): tR = 34.8 (major), 43.7 (minor) min.
1.5 H), 1.72 (s, 1.5 H), 2.04–2.12 (m, 0.5 H), 2.33 (s, 0.03 H), 2.44–
2.54 (m, 1 H), 2.64 (dd, J = 3.12, 14.2 Hz, 0.5 H), 3.20 (s, 0.5 H),
3.29 (s, 0.5 H), 3.43 (dd, J = 2.48, 19.3 Hz, 0.1 H), 3.96 (dd, J =
9.96, 19.3 Hz, 0.1 H), 4.33 (dd, J = 6.88, 11.4 Hz, 0.5 H), 4.44 (dd,
J = 3.04, 7.0 Hz, 0.5 H), 4.84 (d, 0.1 H), 7.25–7.80 (m, 11 H), 7.84
(d, J = 8.32 Hz, 0.65 H), 7.92 (dd, J = 1.56, 7.84 Hz, 0.4 H), 7.96
(d, J = 1.52 Hz, 0.05 H), 9.52 (s, 0.1 H) ppm. HPLC (Daicel Chi-
ralcel AD-H; 2-propanol/n-hexane, 20:80; flow rate = 1.0 mLmin–1;
λ = 254 nm): tR = 7.127 (major), 13.613 (minor) min.
4o: White solid (26.3 mg, 96% isolated yield, 55%ee). [α]2D0 = +39.3
(c = 0.468, acetonitrile). 1H NMR (400 MHz, CDCl3): δ = 0.83–
0.90 (m, 4 H), 0.92–0.98 (m, 2 H), 1.14–1.29 (m, 3 H), 1.29–1.41
(m, 1.5 H), 1.51–1.64 (m, 1.5 H), 1.70–1.85 (m, 4 H), 1.92–2.04 (m,
1 H), 2.10–2.20 (m, 4 H), 2.24–2.36 (m, 1 H), 2.74 (s, 0.5 H), 2.79–
2.86 (m, 1 H), 2.96–3.02 (m, 0.5 H), 3.20–3.26 (m, 1 H), 3.34–3.41
(m, 1 H), 7.19–7.30 (m, 4 H), 7.44–7.51 (m, 2 H), 7.76 (m, 1 H),
7.91 (m, 1 H), 9.61 (s, 1 H) ppm. HPLC (Daicel Chiralcel AD-H;
2-propanol/n-hexane, 10:90, flow rate = 1.0 mLmin–1; λ = 254 nm):
tR = 8.45 (major), 13.14 (minor) min.
4p: White solid (24.1 mg, 88% isolated yield, 57%ee). [α]2D1 = +48.7
(c = 0.496, acetonitrile). 1H NMR (400 MHz, CDCl3): δ = 0.67
(dd, J = 1.76, 6.88 Hz, 1.03 H), 0.77 (dd, J = 1.68, 6.52 Hz, 4 H),
0.86 (m, 2 H), 1.00 (m, 4.54 H), 1.51–1.65 (m, 1.24 H), 1.77–1.83
(m, 1.80 H), 2.05 (m, 0.42 H), 2.15 (dd, J = 7.12, 13.8 Hz, 0.45 H),
2.21 (s, 3 H), 2.57 (m, 1 H), 2.76 (t, J = 10.2, 20.4 Hz, 1 H), 2.95
(d, J = 20.0 Hz, 1 H), 3.05 (dd, J = 5.1, 8.6 Hz, 0.45 H), 3.27–3.36
(m, 1.3 H), 7.20–7.33 (m, 4 H), 7.45–7.54 (m, 2 H), 7.74–7.80 (m,
1 H), 7.91–7.94 (m, 1 H), 9.48 (s, 1 H) ppm. HPLC (Daicel Chi-
ralcel AD-H; 2-propanol/n-hexane, 10:90; flow rate = 1.0 mLmin–1;
λ = 254 nm): tR = 7.73 (major), 13.34 (minor) min.
4i: White solid (30.8 mg, 90% isolated yield, 79%ee). [α]2D5 = +35.1
1
(c = 0.61, acetonitrile). H NMR (400 MHz, CDCl3): δ = 1.72 (s,
1.5 H), 1.77 (s, 1.5 H), 2.06 (d, J = 3.04 Hz, 1.0 H), 2.31 (s, 0.3 H),
2.39 (dd, J = 7.4, 14.4 Hz, 0.5 H), 2.60 (dd, J = 3.04, 14.4 Hz, 0.7
H), 3.07 (s, 0.5 H), 3.20 (d, J = 19.4 Hz, 0.1 H), 3.28 (s, 0.5 H),
4.01 (dd, J = 11.3, 19.0 Hz, 0.1 H), 4.13 (dd, J = 7.2, 14.3 Hz, 0.7
H), 4.56 (dd, J = 3.0, 7.4 Hz, 0.5 H), 4.83 (d, J = 9.7 Hz, 0.1 H),
7.13–7.21 (m, 3.4 H), 7.27–7.38 (m, 2.7 H), 7.42 (m, 0.5 H), 7.47–
7.61 (m, 1.3 H), 7.73 (s, 0.1 H), 7.83 (dd, J = 1.44, 7.8 Hz, 0.3 H),
7.90 (dd, J = 1.6, 7.9 Hz, 0.3 H), 7.99 (dd, J = 1.4, 7.9 Hz, 0.1 H),
9.54 (s, 0.1 H) ppm. HPLC (Daicel Chiralcel AD-H; 2-propanol/n-
hexane, 20:80; flow rate = 1.0 mLmin–1; λ = 254 nm): tR = 5.48
(major), 8.79 (minor) min.
4j: White solid (33.1 mg, 97% isolated yield, 75%ee). [α]42065 = +17.8
1
(c = 0.36, acetonitrile). H NMR (400 MHz, CDCl3): δ = 1.71 (s,
1.03 H), 1.76 (s, 1.51 H), 2.00 (m, 0.82 H), 2.31 (s, 0.28 H), 2.42–
2.51 (m, 1.19 H), 3.06 (s, 0.33 H), 3.21 (s, 0.47 H), 3.86 (dd, J =
10.6, 19.7 Hz, 0.09 H), 4.13 (m, 0.72 H), 4.22 (m, 0.39 H), 4.67 (dd,
J = 1.8, 10.4 Hz, 0.06 H), 7.13–7.38 (m, 6.66 H), 7.50–7.61 (m, 1.04
H), 7.82 (dd, J = 1.44, 8.2 Hz, 0.37 H), 7.88 (dd, J = 1.56, 7.92 Hz,
0.25 H), 7.97 (dd, J = 1.48, 8.0 Hz, 0.09 H), 9.57 (s, 0.07 H) ppm.
HPLC (Daicel Chiralcel AD-H; 2-propanol/n-hexane, 20:80; flow
rate = 1.0 mLmin–1; λ = 254 nm): tR = 4.88 (major), 6.21
(minor) min.
4k: White solid (31.5 mg, 92% isolated yield, 79%ee). [α]2D5 = –8.8
1
(c = 0.274, acetonitrile). H NMR (600 MHz, CDCl3): δ = 1.69 (s,
1.06 H), 1.74 (m, 1.50 H), 1.95 (d, J = 12.2 Hz, 0.51 H), 2.29 (s,
0.33 H), 2.40 (d, J = 7.14 Hz, 0.35 H), 2.45 (m, 0.85 H), 3.09 (s,
0.33 H), 3.26 (d, J = 19.3, 21.1 Hz, 0.53 H), 3.84 (dd, J = 10.4,
19.4 Hz, 0.09 H), 4.14 (dd, J = 6.84, 11.6 Hz, 0.50 H), 4.20 (dd, J
= 3.5, 6.9 Hz, 0.34 H), 4.64 (dd, J = 2.22, 10.4 Hz, 0.09 H), 7.15–
7.35 (m, 6.2 H), 7.49–7.58 (m, 0.96 H), 7.81 (d, J = 7.92 Hz, 0.36
H), 7.87 (dd, J = 0.9, 7.92 Hz, 0.25 H), 7.94 (dd, J = 0.72, 7.92 Hz,
0.09 H), 9.57 (s, 0.08 H) ppm. HPLC (Daicel Chiralcel AD-H; 2-
propanol/n-hexane, 20:80; flow rate = 1.0 mLmin–1; λ = 254 nm):
tR = 5.35 (major), 6.98 (minor) min.
Supporting Information (see footnote on the first page of this arti-
cle): H NMR and 13C NMR spectra and HPLC chromatograms.
1
Acknowledgments
We are appreciative to the National Natural Science Foundation of
China (Nos. 20732003 and 20702033) and the Ministry of Educa-
tion (No. 20070610019) for financial support. We also thank
Sichuan University Analytical & Testing Center for NMR spectro-
scopic analysis.
4l: White solid (29.3 mg, 90% isolated yield, 80%ee). [α]2D6 = +7.3
1
(c = 0.386, acetonitrile). H NMR (400 MHz, CDCl3): δ = 1.69 (s,
1.2 H), 1.72 (s, 1.7 H), 1.95 (dd, J = 11.6, 13.8 Hz, 0.5 H), 2.29 (s,
0.3 H), 2.37 (dd, J = 7.0, 14.2 Hz, 0.4 H), 2.46 (m, 0.9 H), 3.25–
3.30 (dd, J = 2.4, 19.4 Hz, 0.1 H), 3.37 (s, 0.32 H), 3.79 (s, 0.48 H),
3.85 (dd, J = 10.3, 19.4 Hz, 0.1 H), 4.16 (dd, J = 6.8, 11.5 Hz, 0.6
H), 4.21 (dd, J = 3.8, 6.9 Hz, 0.5 H), 4.67 (d, J = 8.6 Hz, 0.1 H),
6.94–7.02 (m, 1.9 H), 7.15–7.34 (m, 4.1 H), 7.47–7.59 (m, 1 H),
7.80 (dd, J = 1.64, 8.52 Hz, 0.5 H), 7.87 (dd, J = 1.52, 7.88 Hz,
0.33 H), 7.95 (dd, J = 1.44, 7.96 Hz, 0.1 H), 9.60 (s, 0.07 H) ppm.
HPLC (Daicel Chiralcel AD-H; 2-propanol/n-hexane, 20:80; flow
rate = 1.0 mLmin–1; λ = 254 nm): tR = 4.98 (major), 9.06
(minor) min.
[1] For example, see: a) R. A. O’Reilly, N. Engl. J. Med. 1976, 295,
354–357; b) L. B. Wingard, R. A. O’Reilly, G. Levy, Clin. Phar-
macol. Ther. 1978, 23, 212–217; c) H. P. Rang, M. M. Dale,
J. M. Ritter, P. Gardner, Pharmacology, 4th ed., Churchill Liv-
ingstone, Philadelphia, 2001.
[2] H. J. Bardsley, A. K. Daly, PCT patent WO 00/43003, 2000.
[3] a) A. S. Demir, C. Tanyeli, V. Gülbeyaz, H. Akgün, Turk. J.
Chem. 1996, 20, 139–145; b) A. Robinson, H.-Y. Li, J. Feaster,
Tetrahedron Lett. 1996, 37, 8321–8324; c) Y. Tsuchiya, Y. Ham-
5196
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5192–5197