ORGANIC
LETTERS
2007
Vol. 9, No. 11
2223-2225
A Highly Efficient Azide-Based
Protecting Group for Amines and
Alcohols
Srinivasu Pothukanuri and Nicolas Winssinger*
Institut de Science et Inge´nierie Supramole´culaires, UniVersite´ Louis Pasteur - CNRS,
8 alle´e Gaspard Monge, 67000 Strasbourg, France
Received March 27, 2007
ABSTRACT
The azide-based carbamate or carbonate protecting group (Azoc) shown above can be removed in less than 2 min under neutral conditions
using trimethyl or tributyl phosphine as well as polymer-bound triphenyl phosphine. It was shown to be orthogonal to Fmoc and Mtt for
peptide synthesis and to afford
â-glycoside with a 2-aminoglucosyl donor by virtue of the neighboring group participation.
The choice of protecting groups remains one of the crucial
factors in the successful synthesis and manipulation of
complex molecules. In peptide synthesis, the most frequently
used strategies for the R-nitrogen are Boc and Fmoc.
Carbohydrate syntheses involving 2-amino sugars have
required a wider arsenal of protecting groups due to the more
stringent demands of glycosylation chemistry; however,
phthalamates and Cbz or Troc groups have recurrently been
used to direct a â-glycosylation. In both cases, peptide1 and
oligosaccharide2 synthesis, azides3 have successfully been
used to mask the amino group; however, this strategy has
limitations. For instance, it cannot be used to mask secondary
nitrogens such as in the case of proline and may lead to
diketopiperazine formation in peptide synthesis. In the case
of glycosylations, azide is a nonparticipating group in the
reaction and thus leads predominantly to R-glycosylation.
On the basis of the success of carbamate-type protecting
groups (Boc, Fmoc, Alloc, Troc, etc.), we reasoned that an
azidomethyl carbamate (Azoc) may provide rapid deprotec-
tion under azide-reduction conditions while preserving the
advantages of carbamate protecting groups. As shown in
Scheme 1, such Azoc-protected compounds are readily
Scheme 1. Azoc Protection and Deprotection
prepared using commercially available chloromethyl chlo-
roformate to obtain the chloromethyl carbamate followed by
an azide displacement of the chloride.4 The first reaction is
carried out in dichloromethane (the use of DMF leads to the
formation of the Vilsmeier-Haack reagent) affording a
product which is stable to workup and purification. The azide
(1) Zaloom, J.; Calandra, M.; Roberts, D. C. J. Org. Chem. 1985, 50,
2601-2603. Tornoe, C. W.; Davis, P.; Porreca, F.; Meldal, M. J. Pept.
Sci. 2000, 6, 594-602. Lundquist, J. T. I. V.; Pelletier, J. C. Org. Lett.
2001, 3, 781-783.
(2) Vasella, A.; Witzig, C.; Chiara, J. L.; Martin-Lomas, M. HelV. Chim.
Acta 1991, 74, 2073-2077. Alper, P. B.; Hung, S.-C.; Wong, C.-H.
Tetrahedron Lett. 1996, 37, 6029-6032.
(3) For a general review, see: Brase, S.; Gil, C.; Knepper, K.;
Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188-5240.
(4) Loren, J. C.; Krasinski, A.; Fokin, V. V.; Sharpless, K. B. Synlett
2005, 2847-2850.
10.1021/ol0707160 CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/05/2007