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2459
olylalanine described by Beecher and Tirrell.15 The de-
sired dehydro compound 9c was obtained in 43% yield.
Next, the reaction was carried out under the same con-
ditions with DBU as base, to afford indazole 9c in 62%
yield. As described recently by Bonauer et al.,16 the role
of the temperature in the Wittig–Horner reaction is very
important. It was the reason why we tried to improve
the result with a lower temperature. Thus, at À42 °C,
we obtained the desired product in 66% yield, and finally
the best conditions were found to be À84°C to furnish
(Z) dehydro 2-azatryptophans 9a–c in 76, 77 and 81%
yields, respectively (Scheme 4 and Table 2).17 The crys-
tallization of indazole 9b allowed us to record X-ray
data and to confirm its structure.18
5. (a) For the main references at this time to obtain 3-
formylindazoles, see: Suvorov, N. N.; Dikopolova, V. V.
SU 553246, 1977; (b) Tsuchiya, T.; Takayama, K.; Kurita,
J. Chem. Pharm. Bull. 1979, 27, 2476–2480; (c) Buchi, G.;
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A.; Edlin, C. D.; Morley, A. D.; Gardner, C. J.; Pedgrift,
B.; Bouchard, H.; Babin, D.; Gauzy, L.; Le Brun, A.;
Majid, T. N.; Reader, J. C.; Payne, L. J.; Khan, N. M.;
Cherry, M. WO 0335065 A2, 2003; (g) McBride, C. M.;
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Ma, S.; Pineda, R.; Vora, J.; Wiesmann, M.; Shafer, C. M.
˜
Next, our efforts focused on the reduction of the double
bonds of dehydro compounds 9a–c. Preliminary reduc-
tion attempts under hydrogen with palladium on acti-
vated carbon in methanol did not afford the desired
products. Only the starting materials were recovered,
most likely because of the slightly solubility of dehydro
2-azatryptophans in methanol. Fortunately, the reaction
of sodium borohydride with indazoles 9a–c in the pres-
ence of Ni(II) chloride hexahydrate2a,15,19 reduced the
double bonds, and simultaneously cleaved the Boc
group to afford the azatryptophan derivatives 10a–c in
moderate yields (Scheme 4 and Table 2).20
Bioorg. Med. Chem. Lett. 2006, 16, 3595–3599.
6. Crestey, F.; Stiebing, S.; Legay, R.; Collot, V.; Rault, S.
Tetrahedron 2007, 63, 419–428.
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L.; Ellis, P. A.; Meade, M. A.; Roberts, B. J.; Fry, D. W.;
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To conclude we found a new means to access dehydro
2-azatryptophans obtained from a Wittig–Horner reac-
tion between various protected 3-formylindazoles and
the ( )-N-(benzyloxycarbonyl)-a-phosphonoglycine tri-
methyl ester 2. This method was easily scaled up for
the synthesis of multi-gram amounts of dehydro amino
acids. These compounds have been reduced to give the
corresponding amino acid derivatives. This methodol-
ogy allowed us to produce valuable new building blocks
with potential applications in medicinal chemistry,
particularly in the development of peptidomimetics.
Further studies concerning the synthesis of new
substituted derivatives are currently in progress.
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L. Gazz. Chim. Ital. 1967, 97, 1304–1316.
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Acknowledgement
14. (a) Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberkr-
echt, A.; Mangold, R.; Meyer, R.; Riedl, B. Synthesis
1992, 487–490; (b) Masquelin, T.; Broger, E.; Mueller, K.;
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manski, W.; Wong, M. K. Y.; Chen, C. K.; Heikes, J. E.;
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Z.; Mueller, R. H. Org. Lett. 2003, 5, 3155–3158; (e)
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We thank Dr. Christophe Philippo for helpful
discussions.
References and notes
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