194
R. Melgar-Fern a´ ndez et al. / Bioorg. Med. Chem. Lett. 14 (2004) 191–194
336033; e-mail: deposit@ccdc.cam.ac.uk). Deposition
number: CCDC 206055.
0 ꢀ
5. Physical properties: (2S,2 S)-7, mp 109–110 C;
1
2
D
2
0
0 ꢀ
3
OH). (2R,2 S)-7, mp 74–75 C;
½
½
½
½
ꢁꢁ =+10.3 (c1, CH
0
0 ꢀ
3
OH). (2R,2 R)-8, mp 109–110 C;
ꢁꢁ =+10.3 (c1, CH
D
2
0
0 ꢀ
3
OH). (2S,2 R)-8, mp 74–75 C;
ꢁꢁ =À10.8 (c1, CH
D
2
0
ꢁꢁ =À10.8 (c1, CH
3
OH).
D
1
6. 4-(2-methoxyethyl)phenol (3). 1H NMR (CDCl
3
,
3
00 MHz) d: 2.85 (t, J=7.1 Hz, 2H), 3.42 (s, 3H), 3.64 (t,
J=7.5 Hz, 2H), 6.75 (d, J=11 Hz, 2H), 7.05 (d, J=11
Figure 7. (c) Contraction responses induced by increasing concentra-
tions of calcium ions.
13
Hz, 2H). C NMR (CDCl
7
ethyl)-phenoxymethyl]-oxirane (4). Z=1.519 (25 C).
3
, 75.4 MHz) d: 35.27, 58.65,
0
4.17, 115.53, 130.05, 130.45, 154.55. 2-[4-(2 -methoxy-
ꢀ
1
H
NMR (CDCl , 400 MHz) d: 2.82 (t, J=7.1 Hz, 2H), 2.74,
3
0
of calcium access to cells. In particular, (2S,2 S)-7 and
0
2
J=6.9 Hz, 2H), 3.92, 4.18 (dd, J=11.2 Hz, 2H), 6.85 (d,
.89 (dd, J=5.1, 2H), 3.32 (m, 1H), 3.34 (s, 3H), 3.56 (t,
(2S,2 R)-8, presenting the (S) configuration at C(2),
seem to be most effective to mimic the desired biological
effect of eutomeric (S)-metoprolol.
1
3
J=8.8 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H). C NMR
(CDCl , 100.5 MHz) d: 35.31, 40.74, 50.21, 58.66, 68.80,
3.82, 114.57, 129.83, 131.64, 156.99. General experi-
3
7
0
mental procedure for the preparation of (2S,2 S)-7,
0 0 0
(
2R,2 S)-7, (2R,2 R)-8, and (2S,2 R)-8. In a 50-mL round-
bottom flask was placed 8.9 g (0.1 mol) of (S)-6 and 8.9
Acknowledgements
mL of water. The resulting solution was treated with 2.7 g
(
We are indebted to IXON, S. A., Me
support, and to Mr. Julio Sanchez Martı
cal assistance.
´
xico, for financial
0.013 mol) of (Æ)-4 and the reaction mixture was stirred
´
´
nez for techni-
at ambient temperature for 24 h. 5 mL of water was added
and the resulting precipitate was filtered, washed with
water, and air-dried to afford 1.9 g of crude product,
which was recrystallized from 10 mL of ethyl acetate to
0
References and notes
give 1.65 g (43% yield) of (2S,2 S)-7. The mother liquor
was heated at reduced pressure to recover excess (S)-6 (bp
ꢀ
1
2
. Brody, T.; Larner, J.; Minneman, K. Human Pharmacol-
ogy, 3rd ed.; Mosby: St. Louis, 1998.
35–40 C/4 mmHg) and the residue was dissolved in 10
mL of hot water. Upon cooling, a precipitate formed, that
was rinsed with cold water and air-dried to furnish 1.3 g
of crude product, which was recrystallized from 10 mL of
. Mexican Ministry of Health. Principales Causas de Mor-
talidad General en los Estados Unidos Mexicanos;
INEGI: 1999. http://www.ssa.gob.mx, July 26, 2001.
. Teerlink, J.; Massie, B. Am. J. Cardiol. 1999, 84, 94.
. Johnson, G.; Forssman, O. Cardiovascular Information, ꢀ-
Blocker and Cardiac Arrhythmias; AB Ha
Sweden, 1981.
. Mostafavi, S.; Foster, R. T. Int. J. Pharm. 2000, 202, 97.
. Sheldon, R. A. Chirotechnology; Marcel Dekker: New
York, 1993.
0
ethyl acetate to give 0.95 g (25% yield) of (2R,2 S)-7.
0
1
3
4
(2S,2 S)-7: H NMR (CDCl , 400 MHz) d: 0.90 (t, J=7.6
3
Hz, 3H), 1.41, 1.49 (ddq, J=7.3, 13.9 Hz, 2H), 2.54 (m,
J=5.4, 12 Hz, 2H), 2.67, 2.93 (dd, J=12 Hz, 2H), 2.80 (t,
J=6.9 Hz, 2H), 3.33 (s, 3H), 3.38, 3.64 (dd, J=5, 11 Hz,
2H), 3.54 (t, J=7.3 Hz, 2H), 3.92 (dd, 2H), 4.06 (m, J=4
Hz, 1H), 6.82 (d, J=8.8 Hz, 2H), 7.10 (d, J=8.8 Hz, 2H).
¨ ¨
ssle: Molndal,
5
6
1
3
3
C NMR (CDCl , 100.5 MHz) d: 10.44, 24.12, 35.27,
7
8
9
. Young, J. W. and Barberich, T. J. European Patent 0 677,
49.26, 58.63, 60.70, 63.02, 69.18, 70.55, 73.83, 114.53,
129.85, 131.45, 157.15. EM; m/z (%), 298 (M+1, 12), 266
291, A2, 1995
À1
. Iseki, K.; Oishi, S.; Sasai, H.; Shibasaki, M. Bioorg. Med.
Chem. Lett. 1997, 7, 1273.
. Juaristi, E. Introduction to Stereochemistry and Con-
formational Analysis; J. Wiley: New York, 1991.
(100), 102 (65.7), 72 (23.7). IR nmax (KBr), cm : 3349,
2917, 1616, 1514, 1244, 1100, 1044, 822. (2R,2 S)-7: H
0
1
NMR (CDCl , 400 MHz) d: 0.91 (t, J=7.3 Hz, 3H), 1.40,
3
1.48 (ddc, J=6.9, 17.2 Hz, 2H), 2.54 (m, J=6.9, 9.9 Hz,
2H), 2.80 (t, J=6.9 Hz, 4H), 3.33 (s, 3H), 3.37, 3.64 (dd,
J=7.4, 11 Hz, 2H), 3.54 (t, J=6.9 Hz, 2H), 3.92 (d,
J=5.1 Hz, 2H), 4.05 (m, J=5.8, 11 Hz, 1H), 6.81 (d,
1
1
1
1
1
0. Eliel, E.; Wilen, H. Stereochemistry of Organic Com-
pounds; J. Wiley: New York, 1994.
1. Gurjar, M. K.; Shreerang, V. J.; Sastry, B. S.; Rama-Rao,
A. V. Synthetic Commun. 1990, 20, 3489.
1
3
J=8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H). C NMR
2. Luch, J. R. Analytical Profiles of Drug Substances; Florey:
New York, 1983; Vol. 12, p 325.
3. Smith, B. L., Mueller, W. H. and Strutz, H. European
Patent 0, 449, 602, A1, 1991
4. The coordinates can be obtained, on request from the
Director, Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK (Fax: +44-1223-
(CDCl , 100.5 MHz) d: 10.44, 24.21, 35.27, 49.17, 58.65,
3
60.60, 63.06, 69.07, 70.58, 73.83, 114.49, 129.82, 131.48,
À1
157.08. IR nmax (KBr), cm : 3355, 2917, 1611, 1516,
1244, 1100, 825.
17. Murray, K.; Reilly, C.; Koshakji, R.; Roden, D.; Line-
berry, M.; Word, A.; Siddoway, I.; Barbey, J.; Woosley,
R. J. Clin. Invest. 1990, 85, 836.