large scale which can be problematic using known procedures.
This approach might also be more suitable for the synthesis of
2,4-methanoproline analogues. Futher elaboration of this
methodology is currently under investigation for the preparation
of analogues containing the azabicyclic skeleton in order to
evaluate the assumed anti-feedant properties of the analogues.
This work was supported by the Belgian IWT (Instituut ter
bevordering van het Wetenschappelijk en Technologisch On-
derzoek in Vlaanderen) (Institute for the Promotion of Innova-
tion by Science and Technology in Flanders).
Scheme 3 Reagents and conditions: i, conc. HBr–H2O, D 7 h, 55%.
Notes and references
1 E. A. Bell, M. Y. Qureshi, R. Y. Pryce, D. H. Janzen, P. Lemke and J.
Clardy, J. Am. Chem. Soc., 1980, 102, 1409.
2 G. T. Montelione, P. Hughes, J. Clardy and H. A. Scheraga, J. Am.
Chem. Soc., 1986, 108, 6765; S. Talluri, G. T. Montelione, G. van
Duyne, L. Piela, J. Clardy and H. A. Scheraga, J. Am. Chem. Soc., 1987,
109, 4473; C. Mapelli, H. Van Halbeek and C. H. Stammer,
Biopolymers, 1990, 29, 407.
3 M. C. Pirrung, Tetrahedron Lett., 1980, 21, 4577; P. Hughes, M. Martin
and J. Clardy, Tetrahedron Lett., 1980, 21, 4579; P. Hughes and J.
Clardy, J. Org. Chem., 1988, 53, 4793.
Scheme 4 Reagents and conditions: i, 0.5 N NaOH, D 24 h, 100%; ii, conc.
HBr–H2O, D 1 h; iii, conc. HBr–H2O, D 6 h, 73%.
4 Y. Gaoni, Org. Prep. Proced. Int., 1995, 27, 185.
5 Y. Tamura, H. Ishibashi, M. Hirai, Y. Kita and M. Ikeda, J. Org. Chem.,
1975, 40, 2702; F. M. Schell, P. M. Cook, S. W. Hawkinson, R. E.
Cassady and W. E. Thiessen, J. Org. Chem., 1979, 44, 1380; C. S.
Esslinger, H. P. Koch, M. P. Kavanaugh, D. P. Philips, A. R.
Chamberlin, C. M. Thompson and R. J. Bridges, Bioorg. Med. Chem.
Lett., 1998, 8, 3101; D. W. Piotrowsky, Synthesis, 1999, 1091; Y.-S.
Kwak and J. D. Winkler, J. Am. Chem. Soc., 2001, 123, 7429; B. Vogler,
R. Bayer, M. Meller, W. Kraus and F. M. Schell, J. Org. Chem., 1989,
54, 4165; F. Toda, H. Miyamoto, K. Takeda, R. Matsugawa and N.
Maruyama, J. Org. Chem., 1993, 58, 6208.
6 G. R. Krow, Y. B. Lee, W. S. Lester, H. Christian, D. A. Shaw and J.
Yaun, J. Org. Chem., 1998, 63, 8558; G. R. Krow, Y. B. Lee, W. S.
Lester. N. Liu, J. Yuan, J. Duo, S. B. Herzon, Y. Nguyen and D.
Zacharias, J. Org. Chem., 2001, 66, 1805; G. R. Krow, W. S. Lester, N.
Liu, J. Yuan, A. Hiller, J. Duo, S. B. Herzon, Y. Nguyen and K. Cannon,
J. Org. Chem., 2001, 66, 1811.
The ether functionality was subsequently converted to the
3-bromomethylcyclobutanyl amino acid 8.11 Interrupting the
reaction after one hour of reflux showed that the ether function
was almost completely converted to the alcohol 10 and benzyl
bromide. An additional period of reflux of six hours was needed
yielding 8 in 73%.
In order to build the azabicyclic ring system, the amino acid
8 was refluxed in a sodium hydroxide solution and was
quantitatively converted to 2,4-methanoproline (Scheme 5).
After recrystallisation this amino acid could be obtained in 91%
yield.
In conclusion, the synthesis of 2,4-methanoproline was
performed in 5 steps in an overall yield of 10%. The advantage
of this procedure lays in the possibility to perform it on quite a
7 C. Lescop, L. Mevellec and F. Huet, J. Org. Chem., 2001, 66, 4187.
8 C. V. Stevens and N. De Kimpe, J. Org. Chem., 1996, 61, 2174.
9 V. Kaiwar, C. B. Reese, E. J. Gray and S. Neidle, J. Chem. Soc., Perkin
Trans. 1, 1995, 2281.
10 Hydantoin 7: dH (270 MHz, CDCl3) 2.19–2.25 (m, 2H), 2.59–2.75 (m,
3H), 3.46 (d, J = 4.0 Hz, 2H), 4.56 (s, 2H), 6.61 (s, br, 1H), 7.28–7.40
(m, 5H), 8.92 (s, br, 1H); dC (68 MHz; CDCl3) 27.14, 34.86, 59.41,
72.06, 73.13, 127.74, 127.85, 128.52, 137.99, 156.48, 177.95.
11 Amino acid 8: dH (270 MHz, D2O) 2.0 (CH3CN, ref.), 2.18–2.27 (m,
2H), 2.67–2.76 (m, 2H), 2.94 (sept, 1H), 3.53 (d, J = 10.3 Hz, 2H);
dC (68 MHz; D2O) 2.0 (CH3CN, ref), 29.94, 35.26, 38.46, 52.60,
173.70.
Scheme 5 Reagents and conditions: i, 3 equiv. NaOH, D 1.5 h.
CHEM. COMMUN., 2002, 250–251
251