J. C. Barrow et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1917±1920
1919
Scheme 2.
Table 1. Comparison of in vitro binding Ki (nM) versus human cloned a1a-, a1b-, and a1d-receptorsa
a1a
a1b
a1d
a1a
a1b
a1d
a1a
a1b
a1d
a1a
a1b
a1d
A
B
C
1.0Æ0.15 1900Æ240 620Æ170 0.40Æ0.15 1300Æ680 320Æ60 0.24Æ0.10 130Æ31 16Æ5.4 1.6Æ0.45 28Æ1.5 7.5Æ3.6
2.4Æ0.45
730Æ380 660Æ400
4.7Æ1.2
660Æ330 0.38Æ0.01 350Æ110 500Æ20 0.46Æ0.18 91Æ20 31Æ6.4 0.90Æ0.21 14Æ1.5 5.4Æ3.3
95Æ20 8.3Æ2.8 130Æ5 170Æ10 2.4Æ0.90 36Æ16 11Æ3.8 4.8Æ0.50 15Æ1.5 9.0Æ3.0
290Æ95
550Æ65 0.60Æ0.35 70Æ19 97Æ5.8 0.44Æ0.09 51Æ10 39Æ20
0.37Æ0.12
210Æ75
D
2.3Æ0.25
120Æ2.5
aValues represent the mean Æ SEM (nM) for displacement of 125I-HEAT from the human cloned receptor subtypes.
2. Chapple, C. R. Eur. Urol. 1996, 29, 129.
3. Khan, A. R.; Parrish, J. C.; Fraser, M. E.; Smith, W. W.;
Bartlett, P. A.; James, M. N. G. Biochemistry 1998, 37, 16839.
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5808. See also Ramesh, N. G.; Kiunder, A. J. H.; Zwanenburg, B.
J. Org. Chem. 1999, 64, 3635.
6. Since completion of this work, a similar enzymatic resolu-
tion was reported: Mulvihill, M. J.; Gage, J. L.; Miller, M. J.
J. Org. Chem. 1998, 63, 3357.
that this particular constraint mimics the bioactive con-
formation of 1. Surprisingly, many of the stereo-
chemical permutations were tolerated indicating some
receptor ¯exibility. The divergent chemical strategy uti-
lized to prepare these compounds allowed for expedient
preparation of all possible isomers from the common
starting material (Æ)8 and uses low-cost, readily available
reagents. This process is quite general and ¯exible, and
should prove useful in other contexts as 4-aryl piperidines
and piparazines are common units in bioactive molecules.
7. Theil, F.; Schick, H.; Lapitskaya, M. A.; Pivnitsky, K. K.
Liebigs Ann. Chem. 1991, 195.
8. Deardor, D. R.; Myles, D. C. Tetrahedron Lett. 1985, 26,
5615.
Acknowledgements
The authors would like to thank Carl Homnick for ee
determination of 12 and 13, Sandor Varga for NMR
assignment of 17 and 18, and Mary Becker for assis-
tance in preparation of this manuscript.
9. Deardor, D. R.; Windham, C. Q.; Craney, C. L. Org.
Synth. 1995, 73, 25.
10. Deardor, D. R.; Linde, R. G.; Martin, A. M.; Shulman,
M. J. J. Org. Chem. 1989, 54, 2759.
11. Compound 7 can be stored for at least 3 months at 0 ꢀC
without signi®cant decomposition.
12. Pancreatin is exceptionally cheap ($36.40/kg Aldrich) and
the reaction does not require aqueous conditions.
13. Saito, S.; Nakajima, H.; Inaba, M.; Moriwake, T. Tetra-
hedron Lett. 1989, 30, 837.
14. The ee was determined after conversion to ketones 12 and
13 by HPLC analysis on a 4.6Â250 mm ChiracelTM AD chiral
column, 10% EtOH/Hexane 1.5 mL/min, detected by UV
absorbance at 200 nM.
References and Notes
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Lagu, B.; Wong, W. C.; Chiu, G.; Tyagrajan, M. R.; Miao, S.
W.; Zhang, F.; Sun, W.; Tian, D.; Shen, Q.; Zhang, J.; Wetzel,
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15. The lower yield of the acetylated product is probably
due to Pd catalyzed decomposition of the allylic acetate