82 Journal of Natural Products, 2007, Vol. 70, No. 1
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(2) Examples utilizing the Pictet-Spengler reaction. (a) Czerwinski, K.
M.; Cook, J. M. In AdVances in Heterocyclic Natural Products
Synthesis; Pearson, W., Ed.; JAI Press: Greenwich, CT, 1996; Vol.
3, pp 217-277. (b) Ashley, E. R.; Cruz, E. G.; Stoltz, B. M. J. Am.
Chem. Soc. 2003, 125, 15000-15001. (c) Niesen, T. E.; Meldal, M.
J. Org. Chem. 2004, 69, 3765-3773. (d) Bunin, B. A.; Dener, J.
M.; Kelly, D. E.; Paras, N. A.; Tario, J. D.; Tushup, S. P. J. Comb.
Chem. 2004, 6, 487-496.
(3) (a) Ungemach, F.; DiPierro, M.; Weber, R.; Cook, J. M. J. Org.
Chem. 1981, 46, 164-168. (b) Czarnocki, Z.; Suh, D.; MacLean, D.
B.; Hultin, P. G.; Szarek, W. A. Can. J. Chem. 1992, 70, 1555-
1561. (c) Reddy, M. S.; Cook, J. M. Tetrahedron Lett. 1994, 35,
5413-5416. (d) Waldmann, H.; Schmidt, G.; Henke, H.; Burkard,
M. Angew. Chem., Int. Ed. Engl. 1995, 34, 2402-2403. (e) Yamada,
H.; Kawate, T.; Matsumizu, M.; Nishida, A.; Yamaguchi, K.;
Nakagawa, M. J. Org. Chem. 1998, 63, 6348-6354. (f) Gremmen,
C.; Willemse, B.; Wanner, M. J.; Koomen, G-J. Org. Lett. 2000, 2,
1955-1958. (g) Taylor, M. S; Jacobsen, E. N. J. Am. Chem. Soc.
2004, 126, 10558-10559. (h) Seayad, J; Seayad, A. M.; List, B. J.
Am. Chem. Soc. 2006, 128, 1086-1087.
(4) (a) Sandrin, J.; Soerens, D.; Mokry, P.; Cook, J. M. Heterocycles
1977, 6, 1133-1139. (b) Soerens, D.; Sandrin, J.; Ungemach, F.;
Mokry, P.; Wu, G. S.; Yamanaka, E.; Hutchins, L.; DiPierro, M.;
Cook, J. M. J. Org. Chem. 1979, 44, 535-545. (c) Cain, M.; Campos,
O.; Guzman, F.; Cook, J. M. J. Am. Chem. Soc. 1983, 105, 907-
913.
(5) (a) Bi, Y.; Zhang, L. H.; Hamaker, L. K.; Cook, J. M. J. Am. Chem.
Soc. 1994, 116, 9027-9041. (b) Yu, P.; Wang, T.; Li, J.; Cook, J.
M. J. Org. Chem. 2000, 65, 3173-3191. (c) Wang, T.; Cook, J. M.
Org. Lett. 2000, 2, 2057-2059. (d) Liu, X.; Deschamps, J. R.; Cook,
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however, the difference in rates in the epimerization process can
be understood via analysis of the conformations of the diastereo-
mers. The cis-compounds 3b and 5b, which exist in a boat-like
conformation in which the σ*-orbital of the C(1)-N(2) bond is
approximately parallel with the π-system of the indole ring,
epimerized much faster than the half-chair Na-CH3 cases. In
agreement with this orbital overlap, the 7-methoxy-substituted cis-
isomersepimerizedmuchfasterthantheNa-H(parent)compounds.6b,c,8
These findings support the boat-like transition states proposed
earlier8 and provide support for the existence of the carbocationic
intermediate. This conformational evidence, when combined with
previous results,6 supports the epimerization mechanism mediated
by this carbocationic intermediate.6 This study may provide a means
for the future design of asymmetric Pictet-Spengler reactions.
Experimental Section13
General Procedure for the Preparation of Both the trans- and
cis-Diastereoisomers. The optically active Nb-benzyl-D-tryptophan ethyl
ester (16.2 mmol) and methyl 4-oxobutanoate (1.15 equiv) were
dissolved in C6H6 (100 mL) in a round-bottom flask that was equipped
with a Dean-Stark trap and a reflux condenser. The reaction mixture
was degassed and heated to reflux under argon until all of the tryptophan
ethyl ester was consumed (TLC). The solvent was removed under
reduced pressure, and the crude residue was purified by careful column
chromatography (silica gel, gradient elution, EtOAc/hexane ) 20:1,
15:1, 10:1, 8:1) to provide the pure trans-diastereomer and pure cis-
isomer, respectively.
(6) (a) Zhang, L. H.; Gupta, A. K.; Cook, J. M. J. Org. Chem. 1989, 54,
4708-4712. (b) Cox, E. D.; Li, J.; Hamaker, L. K.; Yu, P.; Cook, J.
M. Chem. Commun. 1996, 2477-2478. (c) Cox, E. D.; Hamaker, L.
K.; Li, J.; Yu, P.; Czerwinski, K. M.; Deng, L.; Bennett, D. W.;
Cook, J. M.; Watson, W. H.; Krawiec, M. J. Org. Chem. 1997, 62,
44-61.
(7) Gaskell, A. J.; Joule, J. A. Tetrahedron 1967, 23, 4053-4063.
(8) (a) Liu, X., Ph.D. Thesis, University of Wisconsin-Milwaukee, 2002.
(b) Han, D.; Liu, X.; Cook, J. M. 227th American Chemical Society
National Meeting, Anaheim, CA, March 28-April 1, 2004, ORGN-
485.
General Procedure for the Kinetic Epimerization Experiments.
The TFA (1.5 equiv) was added to the diastereoisomer, which had been
dissolved in dry CH2Cl2 (0.375 mol/mL), and the mixture was stirred
at rt under argon. At each data point (as indicated in Table 1), a small
amount of reaction solution was diluted with EtOAc. The organic layer
was stirred with a cold dilute aqueous solution of NaHCO3 and dried
(Na2SO4). The solvent was removed under reduced pressure and the
residue was dissolved in CD2Cl2 or CDCl3 to determine the ratio of
1
the two diastereoisomers by H NMR spectroscopy.
(9) (a) Shimizu, M.; Ishikawa, M.; Komoda, Y.; Nakajima, T.; Yamagu-
chi, K.; Yoneda, N. Chem. Pharm. Bull. 1984, 32, 463-474. (b)
Shimizu, M.; Ishikawa, M.; Komoda, Y.; Nakajima, T.; Yamaguchi,
K.; Sakai, S. Chem. Pharm. Bull. 1984, 32, 1313-1325. (c) Zhang,
L.H.; Cook, J. M. Heterocycles 1988, 27, 1357-1363. (d) Zhang,
L. H. Ph.D. Thesis, University of Wisconsin-Milwaukee, 1990. (e)
Li, J. Ph.D. Thesis, University of Wisconsin-Milwaukee, 1999.
(10) Bailey, P. D.; Hollinshead, S. P.; Mclay, N. R.; Morgan, K.; Palmer,
S. J.; Prince, S. N.; Reynolds, C. D.; Wood. S. D. J. Chem. Soc.,
Perkin Trans. 1 1993, 431-439.
Acknowledgment. The authors thank the NIMH (MH-46851) and
NSF (instrumentation grant NSF-9512622) for support of this work.
Moreover, the authors acknowledge NIDA and ONR for support of
the X-ray crystallography.
Supporting Information Available: X-ray crystallographic data,
NOE spectra (Figures 2, 3, and 8), proton NMR spectra (Figure 1),
and 13C NMR spectra of 2a, 2b, 3a, and 3b (Figures 4-7) as well as
the characterization of 2a, 2b, 3a, 3b, 4a, 4b, 5a, and 5b are available
(11) Williamson, R. T.; Marquez, B. L.; Gerwick, W. H.; Ko¨ver, K. E.
Magn. Reson. Chem. 2000, 38, 265-273.
(12) (a) Johnson, F. Chem. ReV. 1968, 68, 375-413. (b) Casy, A. F;
Beckett, A. H.; Iorio, M. A. Tetrahedron 1966, 22, 2751-2760. (c)
Beckett, A. H.; Casy, A. F.; Iorio, M. A. Tetrahedron 1966, 22,
2745-2750.
(13) Please see the Supporting Information for materials and general
instrumentation.
References and Notes
(1) (a) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030-
2036. (b) Tatsui, G. Yakugaku Zasshi 1928, 48, 453-459. (c) Whaley,
W. M.; Govindachari, T. R. In Organic Reactions; Adams, R., Ed.;
John Wiley and Sons: New York, 1951; Vol. VI, pp 151-190. (d)
Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 1797-1842.
NP060391G