Efficient deprotection of N-benzyloxycarbonyl group from amino acids by hydroxyapatite-bound Pd catalyst in the presence of molecular hydrogen

Article abstract of DOI:10.1016/S0040-4039(03)01181-X

Hydroxyapatite-bound Pd catalyst was found to be highly effective for the deprotection of N-benzyloxycarbonyl group from amino acids in the presence of molecular hydrogen. The catalyst was also applicable to the hydrogenolysis of a sterically encumbered core-Z-protected poly(amido amine) dendrimer, affording the dendritic amino compound in 99% yield.

Full text of DOI:10.1016/S0040-4039(03)01181-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4981–4984
Efficient deprotection of N-benzyloxycarbonyl group from amino
acids by hydroxyapatite-bound Pd catalyst in the presence of
molecular hydrogen
Makoto Murata, Takayoshi Hara, Kohsuke Mori, Masahiko Ooe, Tomoo Mizugaki, Kohki Ebitani
and Kiyotomi Kaneda*
Department of Chemical Science and Engineering, Graduate School of Engineering Science, Osaka University,
1
–3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan
Received 4 April 2003; revised 8 May 2003; accepted 9 May 2003
Abstract—Hydroxyapatite-bound Pd catalyst was found to be highly effective for the deprotection of N-benzyloxycarbonyl group
from amino acids in the presence of molecular hydrogen. The catalyst was also applicable to the hydrogenolysis of a sterically
encumbered core-Z-protected poly(amido amine) dendrimer, affording the dendritic amino compound in 99% yield. © 2003
Elsevier Science Ltd. All rights reserved.
Benzyloxycarbonyl (Z) group is a widely utilized amine
protecting group in peptide chemistry, in which its
catalyst system as a simple and strong protocol for the
removal of the Z group from bulky compounds.
1
removal is achieved with molecular hydrogen in the
2
presence of Pd/C catalyst. However, a large amount of
Calcium hydroxyapatite (HAP), Ca (PO ) (OH) , was
10
4 6
2
the Pd/C is often used for the deprotection from steri-
synthesized according to procedures described in litera-
3
6
cally hindered compounds. An alternate method for
ture. HAP (2.0 g) was stirred in a PdCl (PhCN)
2
2
−
4
the removal of the Z group involves the use of homoge-
(2.67×10 M) solution in acetone (150 mL) at 25°C for
3 h. The obtained slurry was filtered, washed with
acetone, and dried under vacuum to yield the PdHAP
as a pale yellow powder (2.01 g; Pd content: 0.02 mmol
g ). Using elemental analysis, XPS, EDAX, IR, and
Pd-K edge XAFS, the local structure of Pd in the
4
neous acids, such as trifluoroacetic acid/thioanisole;
however, this method can potentially damage other
acid-labile groups, and moreover, often shows low
selectivity for multifunctional molecules. In view of the
current interest in environmentally benign organic syn-
thetic methodologies, much attention has been paid to
the development of highly efficient heterogeneous cata-
lysts for removal of the Z group with functional group
tolerance.
−
1
powder was characterized as monomeric PdCl species
2
that are grafted on the surface of HAP by chemisorp-
Table 1. Hydrogenolysis of Z-
L
-alanine by various hetero-
a
geneous Pd catalysts
We have previously reported that a hydroxyapatite-
bound Pd complex (PdHAP) can act as an efficient
heterogeneous catalyst for the oxidation of alcohols in
5
the presence of molecular oxygen. Subsequently, our
ongoing studies of the PdHAP and its applications in
practical organic synthesis have revealed the enhanced
deprotection of Z groups in the presence of molecular
hydrogen. Herein, we describe the use of this PdHAP
Entry
Pd catalyst
Isolated yield (%)
1
2
3
4
5
PdHAP (0.2 wt% Pd)
5% Pd/C
0.5% Pd/C
0.5% Pd/SiO2
0.5% Pd/Al O
92
68
67
64
60
Keywords: hydrogenolysis; benzyloxycarbonyl; heterogeneous palla-
2
3
dium catalyst; hydroxyapatite; dendrimer.
a
*
Corresponding author. Tel.:/fax: +81-6-6850-6260; e-mail: kaneda@
Reaction conditions: Z-L-alanine 1 mmol, catalyst 0.004 mmol of Pd,
cheng.es.osaka-u.ac.jp
MeOH 5 mL, 40°C, 1.5 h, H2 atmosphere.
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01181-X

4
982
M. Murata et al. / Tetrahedron Letters 44 (2003) 4981–4984
5
tion. Under the deprotection conditions, the PdCl2
species were readily transformed into Pd nanoclusters
methanol solution (4 mL) of Z-protected compound (1
mmol), and the combined reaction mixture was vigor-
ously stirred at 40°C. Upon completion of the reaction,
the spent catalyst and solid product were filtered, then
washed with water to dissolve the product. The
aqueous filtrate was evaporated under reduced pressure
to afford an analytically pure amino acid, as confirmed
with a mean diameter of 30 A having a narrow size
,
distribution, as confirmed by TEM analysis.
A general procedure for the deprotection of Z-pro-
tected amino acids catalyzed by the PdHAP in the
presence of molecular hydrogen is described as follow.
The PdHAP (0.2 g, 0.004 mmol Pd) in methanol (1 mL)
was stirred at 40°C for 0.5 h under hydrogen atmo-
sphere. To this heterogeneous mixture was added a
1
by H NMR.
Catalytic activities of heterogeneous Pd catalysts for the
deprotection of Z-L-alanine with molecular hydrogen in
a
Table 2. Hydrogenolysis of various Z-protected amino acids catalyzed by PdHAP

M. Murata et al. / Tetrahedron Letters 44 (2003) 4981–4984
4983
methanol were initially studied. As summarized in
Table 1, the PdHAP exhibited the highest activity
among the conventional Pd catalysts such as Pd/C,
Pd/SiO , and Pd/Al O , affording deprotected alanine
The PdHAP catalyst system was also shown to be
effective in the removal of Z group from sterically
hindered compounds. For the deprotection of a core-Z-
protected poly(amido amine) dendrimer functionalized
2
2
3
8,9
with n-hexyl groups, the PdHAP afforded the den-
dritic amino compound in 99% yield (Scheme 1). In
contrast, 5% Pd/C catalyst did not exhibit any measur-
able activities. The prominent catalysis of the PdHAP
might be due to the highly dispersed Pd nanoclusters
with a narrow particle size distribution on the non-
in 92% yield (entries 1–5). In the case of the PdHAP,
the optical rotation of the product was comparable to
1
4
that of authentic -alanine [h] =+2.3 (c 6, water).
L
D
As shown in Table 2, excellent yields of the correspond-
ing amino acids were obtained from the hydrogenolysis
of various Z-protected compounds. For example,
deprotection of Z-proline using the PdHAP in
methanol readily afforded proline in 99% yield within 1
h. Among the solvents tested, DMF was also shown to
be a favorable solvent for the deprotection of Z-proline,
whereas the use of DMA, THF, ethanol, and toluene
solvents resulted in poor yields of proline (entries 3–7).
5
porous hydroxyapatite surfaces.
In summary, the PdHAP was found to be an effective
catalyst for the deprotection of N-benzyloxycarbonyl
compounds with molecular hydrogen. This heteroge-
neous PdHAP catalyst system has the following advan-
tages: (1) high catalytic activity and substrate tolerance,
(
2) simple work-up procedures and reusable catalyst,
and (3) applicability to sterically hindered substrate. We
expect that the PdHAP catalyst can be widely utilized
for organic functional group transformations, including
oligo- and macromolecular syntheses.
Next, our studies involved the hydrogenolysis of Z
groups in the presence of tert-butyl groups, which were
7
potentially decomposed at elevated temperature. Nota-
bly, the PdHAP showed high catalytic activity under
mild conditions to afford the corresponding tert-butyl-
protected products in high yields (entries 12 and 13).
The PdHAP catalyst was also applied to the removal of
benzyl group from Z-glu(OBnz)-OH to give glutamic
acid in a high yield (entry 15).
Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research from Ministry of Education, Culture,
Sports, Science, and Technology of Japan (14750626).
We are grateful to the Department of Chemical Science
and Engineering, Graduate School of Engineering Sci-
ence, Osaka University, for Lend–Lease Laboratory
System. We also thank Dr. T. Akita (AIST) for TEM
measurements.
Upon completion of the reaction, the spent PdHAP was
separated from the reaction mixture by simple filtration
and reused without any loss of its activity; for example,
proline was afforded in 99% yield in an experiment
using recycled catalyst (entry 2).
Scheme 1. Reaction conditions: Z-protected dendrimer 0.6 mmol, Pd catalyst 0.002 mmol of Pd, MeOH 5 mL, 40°C, 24 h, H2
atmosphere.

4
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M. Murata et al. / Tetrahedron Letters 44 (2003) 4981–4984
8. (a) Aoi, K.; Motoda, A.; Ohno, M.; Tsutsumiuchi,
References
. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley and Sons, Inc: New
York, 1999.
. (a) Bodanszky, M.; Bodanszky, A. The Practice of Peptide
Synthesis; Springer: Berlin, 1984; p. 153; For recent exam-
ples of the hydrogenolysis using Pd/C catalyst, see: (b)
Jost, M.; Greie, J.-C.; Stemmer, N.; Wilking, S. D.;
Altendorf, K.; Sewald, N. Angew. Chem., Int. Ed. 2002, 41,
K.; Okada, M.; Imae, T. Polym. J. 1999, 30, 1071; (b)
Aoi, K.; Ito, K.; Okada, M. Macromolecules 1997, 30,
8072.
1
2
9. Core-Z-protected poly(amido amine) dendrimer 1 was syn-
8
thesized by the divergent method according to literature.
Characterizations of 1 and the amino product 2 were as
follows. 1: IR (KBr) 3080 (wNꢀH), 2958, 2928, 2856 (wCꢀH),
1
1
654 (wCꢁO, amide), 1560 (lNꢀH, amide). H NMR (400
MHz, DMSO, TMS, 40°C) l 7.42 (br, NH), 7.34 (br,
4
267; (c) Chibale, K.; Chipeleme, A.; Warren, S. Tetra-
NH), 7.08–6.92 (m, aromatic CH of Z), 5.08 (s, CH of Z),
2
hedron Lett. 2002, 43, 1587; (d) Li, J.; Jeong, S.; Esser, L.;
Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 4765; (e)
Liras, S.; Lynch, C. L.; Fryer, A. M.; Vu, B. T.; Martin, S.
F. J. Am. Chem. Soc. 2001, 123, 5918; (f) Nakamura, H.;
Fujiwara, M.; Yamamoto, Y. Bull. Chem. Soc. Jpn. 2000,
3
.20 (br, NHCH CH N), 3.17 (m, CH (CH ) CH ), 2.68
2 2 2 2 4 3
(
br, NCH CH CONH), 2.55 (m, NHCH CH N), 2.31 (br,
2 2 2 2
NCH CH CONH), 1.48 (m, CH (CH ) CH ), 1.28 (m,
2
2
2
2 3
3
13
(
CH ) CH ), 0.88 (m, (CH ) CH ). C NMR (400 MHz,
2 3 3 2 5 3
DMSO, TMS, 40°C) l 172.3 (CONH), 156.6 (CONH of
Z), 136.7 (quaternary aromatic carbon of Z), 128.3–127.8
7
3, 231.
3
. Bodanszky, M.; Ondetti, M. A.; Levine, S. D.; Williams,
N. J. J. Am. Chem. Soc. 1967, 89, 6753.
(
aromatic carbon), 66.4 (CH of Z), 52.6 (NHCH CH N),
2 2 2
5
1.3 (NCH CH CONH), 39.5 (CH (CH ) CH ), 37.7
2 2 2 2 3 3
4
. For typical examples of the deprotection with homoge-
neous acids, see: trifluoroacetic acid/thioanisole: (a)
Asayama, S.; Maruyama, A.; Akaike, T. Bioconjugate
Chem. 1999, 10, 246; p-TsOH; (b) VanNieuwenhze, M. S.;
Mauldin, S. C.; Zia-Ebrahimi, M.; Winger, B. E.; Horn-
back, W. J.; Saha, S. L.; Aikins, J. A.; Blaszczak, L. C. J.
Am. Chem. Soc. 2002, 124, 3656; HBr/AcOH; (c) Becerril,
J.; Burguete, M. I.; Escuder, B.; Luis, S. V.; Miravet, J. F.;
Querol, M. Chem. Commun. 2002, 738.
. Mori, K.; Yamaguchi, K.; Hara, T.; Mizugaki, T.; Ebitani,
K.; Kaneda, K. J. Am. Chem. Soc. 2002, 124, 11572.
. Sugiyama, S.; Minami, T.; Hayashi, H.; Tanaka, M.;
Shigemoto, N.; Moffat, J. B. J. Chem. Soc., Faraday
Trans. 1996, 92, 293.
(
NHCH CH N), 34.4 (NCH CH CONH), 31.7 (CH -
2 2 2 2 2
(
CH ) CH ), 29.6 (CH (CH ) CH ), 26.7 (CH CH CH ),
2 3 3 2 2 2 3 2 2 3
2
2.6 (CH CH ), 14.0 ((CH ) CH ). 2: IR (KBr) 3080
2
3
2 5
3
(
w
), 2929, 2857 (wCꢀH), 1647 (w
amide), 1559 (lNꢀH
,
NꢀH
CꢁO,
1
amide). H NMR (400 MHz, DMSO, TMS, 40°C) l
.81–7.73 (br, NH), 3.16 (br, NHCH CH N), 3.01 (m,
7
2
2
CH (CH ) CH ), 2.65 (br, NCH CH CONH), 2.44 (m,
2
2 4
3
2
2
NHCH CH N), 2.18 (br, NCH CH CONH), 1.38 (m,
2
2
2
2
5
CH
CH
2
(CH
2
)
3
CH ), 1.24 (m, (CH ) CH ), 0.86 (m, (CH ) -
3 2 3 3 2 5
13
). C NMR (400 MHz, DMSO, TMS, 40°C) l 170.9
CH N), 49.6 (NCH CH CONH),
), 36.8 (NHCH CH N), 33.2 (NCH
CH CONH), 30.8 (CH (CH ) CH ), 29.0 (CH (CH ) -
3
6
(CONH), 52.0 (NHCH
39.3 (CH (CH CH
2
2
2
2
)
2
-
2
2
3
3
2
2
2
2
2 3
3
2
2 2
7. Felix, A. M.; Heimer, E. P.; Lambros, T. J.; Tzougraki,
CH ), 26.0 (CH CH CH ), 21.9 (CH CH ), 13.7 ((CH ) -
3
2
2
3
2
3
2 5
C.; Meienhofer, J. J. Org. Chem. 1978, 43, 4194.
CH3).