4430
J . Org. Chem. 2001, 66, 4430-4432
two protecting groups. We now report that the tert-butyl
ester can be cleaved in preference to the N-Boc protecting
group by the CeCl3‚7H2O-NaI system in acetonitrile,
representing a reversal of the usual selectivity under
acidic conditions.
Fukuzawa has demonstrated that the CeCl3‚7H2O-
NaI system promotes the carbon-carbon bond formation
between R-halogeno ketones and carbonyl compounds
under anhydrous conditions.7 We have extended this
work and have reported a variety of useful selective
deprotections in high yield utilizing CeCl3 in the presence
of NaI, without the necessity of anhydrous conditions.8,9
The efficiency of the CeCl3‚7H2O-NaI system in depro-
tection reactions of carbonyl and hydroxyl groups10
prompted us to study as to whether this combination
would be effective in promoting other useful organic
transformations.11
Selective Dep r otection of N-Boc-P r otected
ter t-Bu tyl Ester Am in o Acid s by th e
CeCl3‚7H2O-Na I System in Aceton itr ile
Enrico Marcantoni,* Massimo Massaccesi,† and
Elisabetta Torregiani
Dipartimento di Scienze Chimiche, via S. Agostino 1,
I-62032 Camerino (MC), Italy
Giuseppe Bartoli,* Marcella Bosco, and Letizia Sambri
Dipartimento di Chimica Organica “A. Mangini”, v.le
Risorgimento 4, I-40136 Bologna, Italy
enricom@camserv.unicam.it
Received J anuary 3, 2001
In tr od u ction
Resu lts a n d Discu ssion
The utilization of natural and unnatural R-amino acids
in the chemical, physical, and biological sciences contin-
ues to grow.1a In addition to their key biological roles as
components of peptides, proteins, and other natural
products, R-amino acids are utilized in the pharmaceuti-
cal, agrochemical, and related industries. Recently, mul-
tifunctional R-amino acids have also been utilized in
organic synthesis as chiral auxiliaries, reagents, and
catalysts for asymmetric synthesis.1b For these reasons,
the task of differentiating the carboxyl and amino groups
becomes particularly important in the synthetic use of
R-amino acids. Since the amino group is commonly
protected2 by Boc (tert-butoxycarbonyl), while the acid
group is frequently protected as an ester,3 such as tert-
butyl ester,4 selective deprotection of both groups has
imposed a challenge. Several methods have been reported
for the selective deprotection of Boc groups in the
presence of tert-butyl esters.5 In contrast, to the best of
our knowledge, only one previous example for the selec-
tive deprotection of the tert-butyl esters in the presence
of N-Boc groups under nonaqueous conditions has been
reported to date.6 In this regard, the realization of such
an idea would broaden the synthetic usefulness of these
We began an investigation in which a series of simple
tert-butyl esters were treated with a suspension of CeCl3‚
7H2O and NaI in refluxing acetonitrile.12 Usual workup
furnished the pure carboxylic acid. We believe that tert-
butyl ester cleavage was effected by CeCl3‚7H2O-NaI
(Scheme 1) through the selective coordination of cerium
with tert-butyl ester oxygen atoms to form a complex (2)
which then undergoes water hydrolysis to carboxylic acid
(3), liberating the tert-butyl carbocation. The latter is
trapped by nucleophilic attack of iodide ion to afford tert-
butyl iodide 4 as identified by GC-MS. In general, 1.5
equiv of CeCl3‚7H2O and 1.3 equiv of NaI were found to
give the best results (Table 1).
Unfortunately attempts to extend this procedure to the
selective deprotection of tert-butyl esters in the presence
of N-Boc protecting groups met with failure. In fact, the
treatment of N-Boc-(S)-R-alanine tert-butyl ester deriva-
tive 5a with CeCl3‚7H2O in the presence of NaI in
(6) Wu, Y. Limburg, D. C.; Wilkinson, D. E.; Vaal, M. J .; Hamilton,
G. S. Tetrahedron Lett. 2000, 41, 2847-2849.
(7) (a) Fukuzawa, S.; Tsuruto, T.; Fujinami, T.; Sakai, S. J . Chem.
Soc., Perkin Trans. 1 1987, 1473-1477. (b) Fukuzawa, S.; Fujinami,
T.; Sakai, S. J . Chem. Soc., Chem. Commun. 1985, 777-778.
(8) (a) Alessandrini, S.; Bartoli, G.; Bellucci, M. C.; Dalpozzo, R.;
Malavolta, M.; Marcantoni, E.; Sambri, L. J . Org. Chem. 1999, 64,
1986-1993. (b) Bartoli, G.; Bosco, M.; Cingolani, S.; Marcantoni, E.;
Sambri, L. J . Org. Chem. 1998, 63, 3624-3630. (c) Bartoli, G.;
Marcantoni, E.; Sambri, L.; Tamburini, M. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2046-2048. (d) Bartoli, G.; Marcantoni, E.; Petrini,
M. Angew. Chem., Int. Ed. Engl. 1993, 32, 1061-1062.
* To whom correspondence should be addressed. Tel: +39 0737
402255. Fax: +39 0737 637345.
† Present address: Dipartimento di chimica Organica “A. Mangini”,
v.le risorgimento 4, I40136 Bologna.
(1) (a) Wagner, I.; Musso, H. Angew. Chem., Int. Ed. Engl. 1983,
22, 816-828. (b) Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835-
875.
(2) Subhas Bose, D.; Lakshminayoma, V. Synthesis 1999, 66-68,
and references therein.
(9) (a) Bartoli, G.; Bosco, M.; Marcantoni, E.; Nobili, F.; Sambri, L.
J . Org. Chem. 1997, 62, 4183-4184. (b) Bartoli, G.; Bellucci, M. C.;
Bosco, M.; Cappa, A.; Marcantoni, E.; Torregiani, E. J . Org. Chem.
1999, 64, 5696-5699. (c) Bartoli, G.; Bosco, M.; Marcantoni, E.; Sambri.
L.; Torregiani, E. Synlett, 1998, 209-211.
(10) (a) Bartoli, G.; Bellucci, M. C.; Bosco, M.; Marcantoni, E.;
Massaccesi, M.; Petrini, M.; Sambri, L. J . Org. Chem. 2000, 65, 4553-
4559. (b) Recently two Indian’s groups have efficiently utilized same
our methodology for cleavage trityl ethers and toluene sulfonates
respectively: Yadav, J . S.; Subba Reddy, B. V. Synlett, 2000, 1275-
1276, and Sudhakar Reddy, G. Hari Mohan, Iyengar, D. S. Synth.
Commun. 2000, 30, 3829-3832.
(11) (a) Bartoli, G.; Bellucci, M. C.; Marcantoni, E.; Petrini, M.;
Sambri, L.; Torregiani, E. Org. Lett. 2000, 2, 1791-1793. (b) Bartoli,
G.; Bellucci, M. C.; Bosco, M.; Marcantoni, E.; Sambri, L.; Torregiani,
E. Eur. J . Org. Chem. 1999, 617-620.
(12) Bartoli, G.; Bellucci, M. C.; Marcantoni, E.; Sambri, L.; Torre-
giani, E. Abstracts of Papers, 20th National Meeting of the Italian
Chemical Society, Rimini; Italian Chemical Society: Rome, 2000; OR-
PO113.
(3) (a) Kocienski, P. Protecting Groups; Thieme Verlag: Stuttgart,
1994. (b) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley & Sons: New York, 1991.
(4) (a) Strazzolini, P.; Scuccato, M.; Giumanini, A. G. Tetrahedron
2000, 56, 3625-3633. (b) Wright, S. W.; Hageman, D. L.; Wright, A.
S.; McClure, L. D. Tetrahedron Lett. 1997, 38, 7345-7348. (c) Stanton,
M. G.; Gagne`, M. R. J . Org. Chem. 1997, 62, 8240-8242. (d) Nagasawa,
K.; Ohashi, K.; Yamashita, A.; Ito, K. Chem. Lett. 1994, 209-212. (e)
Bodanszky, M.; Bodanszky, A. The pratice of Peptide Synthesis, 2nd
ed.; Springer-Verlag: Berlin, 1994.
(5) (a) Lin, L. S.; Lanza, T. J r.; de Laszlo, S. E.; Truong, Q.;
Kamenecka, T.; Hagmann, W. K. Tetrahedron Lett. 2000, 41, 7013-
7016. (b) Hruby, V.; Tamaki, M.; Han, G. Abstracts of Papers, 219th
National Meeting of the American Chemical Society, San Francisco,
CA.; American Chemical Society: Washington, DC, 2000; ORG140. (c)
Gibson, F. S.; Bergmeier, S. C.; Rapoport, H. J . Org. Chem. 1994, 59,
3216-3218.
10.1021/jo010010y CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/19/2001