A highly efficient azide-based protecting group for amines and alcohols

Article abstract of DOI:10.1021/ol0707160

The azide-based carbamate or carbonate protecting group (Azoc) shown above can be removed in less than 2 min under neutral condition using trimethyl or tributyl phosphine as well as polymer-bound triphenyl phosphine. It was shown to be orthogonal to Fmoc

Full text of DOI:10.1021/ol0707160

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
winssinger@isis.u-strasbg.fr
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

Scheme 2. Peptide Synthesis Using Azoc (Inset: LC-MS of Compound 8)
substitution can be carried out on the purified or crude
in our hands using Me3P and required acid or base to catalyze
the elimination of the 4-aminobenzyloxycarbonyl moiety.
material obtained in the first steps in a variety of solvents
including DMF, DMSO, or different mixtures with H2O
including MeCN-H2O. This two-step process affords the
desired azidomethyl carbamate 1 in 70% isolated yield. To
our gratification, it was found that the deprotection of this
compound was complete within 2 min using Me3P or Bu3P
and quantitative in both cases as judged by LC-MS and
NMR. The use of polymer-bound triphenyl phosphine was
equally efficient albeit slower (30 min). The deprotection
presumably proceeds through the formation of the imino-
phosphorane which rapidly decomposes to afford the phos-
phine oxide, CO2, and methyleneamine. The methyleneamine
furthur decomposes or polymerizes to uncharacterized mate-
rial. Although this protecting group is conceptually related
to the previously reported 4-azidobenzyloxy-carbonyl group,5
the deprotection of this latter group was found to be sluggish
We then turned our attention to the utility of this protecting
group for peptide synthesis. As shown in Scheme 2, Azoc-
protected amino acids 3 were obtained from primary amino
methyl esters 2a or secondary amino methyl ester 2b using
the same general procedure as those for benzyl amine. Thus
reaction with the chloromethyl chloroformate in CH2Cl2 for
15 min at -20 °C followed by azide displacement in
MeCN-H2O (1:1) for 8-36 h at 23 °C afforded the product
in moderate to good yield (76% for Ala, 64% for Gly, 34%
for Leu, 65% for Phe, and 82% for Pro). Hydrolysis of the
methyl ester using LiOH in MeOH-H2O (1:1) afforded the
Azoc-protected amino acids 3 in good yields (88-95%)
without detectable isomerization (see Supporting Informa-
tion). It should be noted that prolonged exposure (>30 min)
of 3 to LiOH led to partial Azoc hydrolysis. With these five
amino acids at hand, we investigated the orthogonality of
Azoc with Fmoc and Mtt. To this end, we prepared a
(5) Griffin, R. J.; Evers, E.; Davison, R.; Gibson, A. E.; Layton, D.;
Irwin, W. J. J. Chem. Soc., Perkin Trans. 1 1996, 1205-1211.
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Org. Lett., Vol. 9, No. 11, 2007

branched hexapeptide which would require such compat-
ibilities. Thus resin 4 was substituted on the ꢀ-nitrogen of
lysine with Azoc-protected Ala, and the Azoc group was
removed in the presence of Fmoc. Deprotection of the Azoc
using Bu3P (1 M) in 9:1 THF-H2O for 5 min resulted in
quantitative conversion, and two more coupling cycles were
used to introduce Azoc-protected Leu and Phe thus affording
resin 5. Next, the Fmoc group was removed (20% piperidine
in DMF) in the presence of Azoc and HO-Lys(Mtt)-Fmoc
was introduced affording resin 6. A further cycle of Azoc
deprotection and coupling yielded resin 7 from which the
Mtt group was removed (2.5% TFA for 5 min), and the
resulting amine was acylated with acetic anhydride. Cleavage
of the final product from the resin with concomitant Azoc
deprotection afforded hexapeptide 8 free of a truncated
sequence or scramble sequences stemming from incompatible
protecting groups as judged by LC-MS and MALDI analysis
of the crude cleavage product.
ethanolamine gave the suitably protected lactol 11. Activation
of the anomeric position via formation of the trichloro-
acetimidate6 followed by glycosylation (TMSOTf for 20 min
at 23 °C) with isopropanol as a model glycosyl acceptor
afforded the product 12 in 61% yield as the â-anomer
exclusively. Treatment of this compound with trimethyl
phosphine afforded compound 13 cleanly without any acetyl
migration. To explore the suitability of the Azoc protecting
group for alcohol protection, benzyl-protected thiomanoside
14 (Scheme 4) bearing a free hydroxyl group at the C6
Scheme 4. Azoc Protection and Deprotection of Glycoside 14
We then turned our attention to the use of Azoc for
carbohydrate synthesis. As shown in Scheme 3, 2-amino
position was protected with Azoc using the same general
procedure as that for amines to obtain 15 in 65% yield. As
for the carbamates previously investigated, this product was
found to be cleanly deprotected with either Me3P and Bu3P
in less than 2 min or polymer-bound Ph3P in 5 min thus
affording 14 in excellent yield.
Scheme 3. Azoc Protection and Deprotection of Amino
Glucose
In conclusion, the Azoc group adds to the repertoire of
protecting groups for the nitrogen and hydroxyl groups
offering very fast and mild deprotection conditions using
phosphines, with the benefits of carbamate-based protecting
groups. The rapidity and efficiency of deprotection rival those
of Fmoc and Boc.
Acknowledgment. The French Ministry of Research and
Education is gratefully acknowledged for a fellowship.
Supporting Information Available: Experimental details
and analytical data for compounds 1, 3, 8, 10, 12, 13, and
15. This material is available free of charge via the Internet
at http://pubs.acs.org.
glucose was persilylated and the amino group was protected
with Azoc to obtain, after workup, the Azoc-protected
aminoglucose tetrol. Peracetylation of this crude product
afforded compound 10 in 56% yield for four steps as a
mixture of anomers. Selective anomeric deprotection using
OL0707160
(6) Schmidt, R. R.; Jung, K.-H. In Carbohydrates in Chemistry and
Biology; Ernst, B., Hart, G. W., Sinay¨, P., Eds.; Wiley-VCH: Weinheim,
Germany, 2000; Vol. 1, pp 5-59.
Org. Lett., Vol. 9, No. 11, 2007
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