J. T. Kuethe, D. L. Comins / Tetrahedron Letters 44 (2003) 4179–4182
4181
obtained at NCSU instrumentation laboratories, which
were established by grants from the National Science
Foundation (Grants CHE-9509532, CHE-0078253).
References
1. For leading references, see: (a) Corey, E. J. Angew.
Chem., Int. Ed. 2002, 41, 1650–1667; (b) Nicolau, K. C.;
Snyder, S. A.; Montagnon, T.; Vassiligiannakis, G.
Angew. Chem., Int. Ed. 2002, 41, 1668–1698; (c) Tietze, L.
F.; Kettschau, G. In Topics in Current Chemistry; Metz,
P., Ed.; Springer-Verlag: Berlin, 1997; Vol. 189, pp. 1–120
and references cited therein; (d) Waldmann, H. Synthesis
1994, 535–551.
2. For reviews on the Diels–Alder reaction of amino-substi-
tuted dienes, see: (a) Enders, D.; Meyer, O. Liebigs Ann.
1996, 1023–1035; (b) Barluenga, J.; Suarez-Sobrino, A.;
Lopez, L. A. Aldrichim. Acta 1997, 32, 4–15.
3. (a) Overman, L. E.; Clizbe, L. A. J. Am. Chem. Soc.
1976, 98, 2352; (b) Overman, L. E.; Taylor, G. F.; Jessup,
P. J. Tetrahedron Lett. 1976, 17, 3089; (c) Overman, L.
E.; Yaylor, G. F.; Houk, K. N.; Domelsmith, L. S. J.
Am. Chem. Soc. 1978, 100, 3182; (d) Oppolzer, W.;
Bieber, L.; Francotte, E. Tetrahedron Lett. 1979, 20,
4537; (e) Overman, L. E.; Freerks, R. L.; Petty, C. B.;
Clizbe, L. A.; Ono, R. K.; Taylor, G. F.; Jessup, P. J. J.
Am. Chem. Soc. 1981, 103, 2816.
4. (a) Ha, J. D.; Kang, C. H.; Belmore, K. A.; Cha, J. K. J.
Org. Chem. 1998, 63, 3810 and references cited therein;
(b) Aelterman, W.; De Kimpe, N. Tetrahedron 1998, 54,
2563; (c) Brosius, A. D.; Overman, L. E.; Schwink, L. J.
Am. Chem. Soc. 1999, 121, 700; (d) Jiang, J.; DeVita, R.
J.; Doss, G. A.; Goulet, M. T.; Wyvratt, M. J. J. Am.
Chem. Soc. 1999, 121, 593; (e) Barluenga, J.; Fernandez,
M. A.; Aznar, F.; Valdes, C. Tetrahedron Lett. 2002, 43,
8159 and references cited therein.
5. Kuethe, J. T.; Brooks, C. A.; Comins, D. L. Org. Lett.
2003, 5, 321.
6. Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett.
1983, 1211–1214.
7. Comins, D. L.; Stolze, D. A.; Thakker, P.; McArdle, C.
L. Tetrahedron Lett. 1998, 39, 5693.
Scheme 3.
Alder cyclization/aromatization protocol in 66% yield.
Treatment of 23 with sodium periodate in the presence
of osmium tetraoxide gave aldehyde 24 in nearly quan-
titative yield. Oxidation of 24 to amino acid 25 was
accomplished with sodium chlorite/sodium phophate
solution in a 2:1 mixture of t-BuOH:2-methyl-2-butene
to give 25 in 86% yield.
In conclusion, we have developed a tandem Diels–Alder
cyclization/aromatization reaction of 5-vinyl-1-acyl-2-
substituted-2,3-dihydro-4-pyridones as
a means of
stereoselectivity preparing b-amino ketones, alcohols,
and amino acids with a variety of functional arrays.
Although this study used racemic starting materials, the
methodology can lead to enantiopure products by start-
ing with readily available nonracemic dihydropyri-
dones.9 This new synthetic protocol may be useful for
the preparation of stereodefined hydroxy amino-alco-
hols and hydroxy amino acids, functional arrays which
are well recognized as important components for vari-
ous protease inhibitors and other potential pharmaceu-
ticals.10 Application of this chemistry toward the
synthesis of other complex molecules is currently under
investigation and will be reported in due course.11
8. Comins, D. L.; Joseph, S. P.; Chen, X. Tetrahedron Lett.
1995, 36, 9141.
9. (a) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am.
Chem. Soc. 1994, 116, 4719; (b) Comins, D. L.; LaMun-
yon, D. H. Tetrahedron Lett. 1994, 35, 7343; (c) Comins,
D. L.; Guerra-Weltzien, L. Tetrahedron Lett. 1996, 37,
3807.
10. Goodman, M.; Ro, S. In Burger’s Medicinal Chemistry
and Drug Discovery, 5th ed.; Wolff, M., Ed.; Wiley and
Sons: New York, 1995; pp. 803–861.
11. The structure assigned to each new compound is in
accord with its IR and 1H and 13C NMR spectra and
elemental analysis or high-resolution mass spectra.
Selected characterization data:
Acknowledgements
Compound 12: colorless oil; IR (thin film) 3353, 3063,
1
2923, 1714, 1666, 1600, 1530, 1489, 1306, 1206 cm−1; H
NMR (CDCl3, 300 MHz) l 2.18 (m, 1H), 2.39 (m, 1H),
4.76 (m, 1H), 4.99 (q, 1H, J=6.6 Hz), 5.76 (m, 1H), 6.95
(s, 1H), 7.06 (m, 1H), 7.17 (m, 1H), 7.33 (m, 11H), 7.71
(d, 1H, J=7.8 Hz), 8.00 (m, 1H); 13C NMR (CDCl3, 75
We express appreciation to the National Institutes of
Health (Grant GM 34442) for financial support of this
research. NMR and mass spectra and X-ray data were