utility of the AOC reagent.4 One drawback associated with the
AOC derivatives is the competitive decarboxylative N-allylation,
caused by the high nucleophilicity of the deprotected free amine
toward a Pd-π-allyl complex.5 The use of metal hydrides6 in
combination with the Pd catalysis has been reported to lessen
the degree of the N-allylation by producing the metal carbamate
and propene. An excess amount of nucleophilic amines7 and
other nucleophiles8 has also been reported to facilitate the
deprotection. The presence of an excessive amount of these
additives often leads to difficulties during the isolation of the
deprotected product. The problem becomes particularly serious
during the synthesis of biologically relevant polar oligomers,
such as peptides and nucleotides.
Catalytic Removal of N-Allyloxycarbonyl
Groups Using the
[CpRu(IV)(π-C3H5)(2-quinolinecarboxylato)]PF6
Complex. A New Efficient Deprotecting Method
in Peptide Synthesis
Shinji Tanaka, Hajime Saburi, Takanori Murase,
Masahiro Yoshimura, and Masato Kitamura*
Research Center for Materials Science and
Department of Chemistry, Nagoya UniVersity, Japan
ReceiVed March 1, 2006
We recently reported a new catalyst, [CpRu(IV)(π-C3H5)(2-
quinolinecarboxylato)]PF6 (3), for the efficient chemoselective
cleavage and formation of allyl ethers.9 First, we have applied
the catalytic system to the removal of the AOC group from an
AOC-protected 2-phenylethan-1-ol (1a to 2a). The reaction
completed within 30 min in methanol at 30 °C with a substrate/
catalyst (S/C) ratio of 500, and a turnover number (TON) of
106 was achieved by continuous removal of the low-boiling-
point coproduct, allyl methyl ether, from the reaction mixture
([1a] ) 500 mM, [3] ) 0.5 µM, 9 days, 70 °C). As shown in
Scheme 1, the π-allyl complex first reacts with methanol solvent
to form a cationic Ru(II) species 4 through reductive elimination
of allyl methyl ether. The nucleophilicity of the Ru atom of the
complex 4 is enhanced by the simultaneous coordination of
monoanionic η5Cp ligand and the highly donative sp2N atom
of the quinoline moiety, while the H atom of COOH acts as an
acceptor of the O atom of AOC-protected alcohol 1a.10 The
donor-acceptor functionality11 dramatically accelerates the
A variety of amines including even sterically less de-
manding and highly nucleophilic secondary amines have
been efficiently deprotected without decarboxylative N-
allylation from the corresponding N-allyloxycarbonyl (N-
AOC) compounds by using a catalytic amount of [CpRu-
(IV)(π-C3H5)(2-quinolinecarboxylato)]PF6 in the presence of
1 molar amount of trifluoromethanesulfonic acid, the general
utility of which has been demonstrated by the efficient
synthesis of a collagen protein unit tripeptide, Pro-Pro-Gly.
(2) (a) ProtectiVe Groups in Organic Synthesis, 3rd ed.; Greene, T. W.,
Wuts, P. G. M., Eds.; John Wiley & Sons: New York, 1999. (b) Schelhaas,
M.; Waldmann, H. Angew. Chem., Int. Ed. Engl. 1996, 35, 2056-2083.
(3) (a) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965,
6, 4387-4388. (b) Trost, B. M.; Fullerton, T. J. J. Am. Chem. Soc. 1973,
95, 292-294. For recent review, see: Tsuji, J. J. Synth. Org. Chem. Jpn.
1999, 57, 1036-1057.
Among the many sophisticated protecting groups for primary
and secondary amines, carbamates (e.g., N-AOC, -Z, -BOC, and
-Fmoc) are widely used in organic synthesis, particularly for
the synthesis of natural and unnatural peptides and nucleotides.1
The popularity of these protecting groups arises from their
efficient coupling, using the corresponding chloride or anhydride
derivatives, and their neutralization or suppression of basicity
or nucleophilicity of the reactive amino functionality. Thus, the
structurally simple N-AOC derivatives can satisfy a key requisite
for multistep synthesis by conferring high stability under a wide
range of different conditions (e.g., pH, temperature) for both
nucleophilic or electrophilic molecules.2 Furthermore, the
development of Tsuji-Trost chemistry3 has facilitated the
straightforward removal of the protecting group, increasing the
(4) For review: (a) Guibe´, F. Tetrahedron 1998, 54, 2967-3042. Origin
and selected examples: (b) Stevens, C. M.; Watanabe, R. J. Am. Chem.
Soc. 1950, 72, 725-727. (c) Corey, E. J.; Suggs, J. W. J. Org. Chem. 1973,
38, 3223-3224. (d) Ho, T.-L. Synth. Commun. 1978, 8, 15-17. (e)
Szumigala, R. H., Jr.; Onofiok, E.; Karady, S.; Armstrong, J. D.; Miller, R.
A. Tetrahedron Lett. 2005, 46, 4403-4405.
(5) Minami, I.; Ohashi, Y.; Shimizu, I.; Tsuji, J. Tetrahedron Lett. 1985,
26, 2449-2452.
(6) Stannane: (a) Four, P.; Guibe´, F. Tetrahedron Lett. 1982, 23, 1825-
1828. Silane: (b) Dessolin, M.; Guillerez, M.-G.; Thieriet, M.; Guibe´, F.;
Loffet, A. Tetrahedron Lett. 1995, 36, 5741-5744. Borane: (c) Beugelmans,
R.; Neuville, L.; Bois-Choussy, M.; Chastanet, J.; Zhu, J. Tetrahedron Lett.
1995, 36, 3129-3132.
(7) Schmidt, U.; Riedl, B. J. Chem. Soc., Chem. Commun. 1992, 1186-
1187.
(8) Potassium carbonate: (a) Vutukuri, D. R.; Bharathi, P.; Yu, Z.;
Rajasekaran, K.; Tran, M.-H.; Thayumanavan, S. J. Org. Chem. 2003, 68,
1146-1149. Sulfinic acid: (b) Honda, M.; Morita, H.; Nagakura, I. J. Org.
Chem. 1997, 62, 8932-8936. Dimedone: (c) Kunz, H.; Unverzagt, C.
Angew. Chem., Int. Ed. Engl. 1984, 23, 436-437. 2-Ethylhexenoic acid:
(d) Jeffrey, P. D.; McCombie, S. W. J. Org. Chem. 1982, 47, 587-590.
(9) Tanaka, S.; Saburi, H.; Kitamura, M. AdV. Synth. Catal. 2006, 348,
375-378.
* To whom correspondence should be addressed. Tel: +81-52-789-2957.
Fax: +81-52-789-2261.
(1) (a) Pseudo-peptides in Drug DiscoVery; Nielsen, P. E., Ed.; John
Wiley & Sons: New York, 2004. (b) Cheng, R. P.; Gellman, S. H.;
DeGrado, W. F. Chem. ReV. 2001, 101, 3219-3232. (c) Seebach, D.; Beck,
A. K.; Bierbaum, D. J. Chem. BiodiVersity 2004, 1, 1111-1239.
10.1021/jo060445r CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/13/2006
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J. Org. Chem. 2006, 71, 4682-4684