Unique oxidation reaction of amides with pyridine-N-oxide catalyzed by ruthenium porphyrin: Direct oxidative conversion of N-acyl-L-proline to N-acyl-L-glutamate

Article abstract of DOI:10.1021/ja045603f

Oxidations of alkanes, alkenes, and aromatic rings with pyridine N-oxides are efficiently catalyzed by ruthenium porphyrins under mild conditions. We show here that the oxidation of N-acyl cyclic amines with Ru^IVtetraarylporphyrin dichloride-2,6-substituted pyridine N-oxides directly gives N-acyl amino acids in modest to good yield via oxidative C-N bond cleavage. N-Acylpyrrolidines and N-acylpiperidines were converted to N-acyl-γ-aminobutyric acids and N-acyl-δ-aminovaleric acids, respectively. This type of reaction is a novel one in which the C-N bond is cleaved selectively at the less substituted carbon. Notably, the proline residue in proline-containing peptides was selectively converted to glutamate. A large intramolecular kinetic isotope effect (k_H/k_D = 9.8) was observed in the oxidation of N-benzoyl[2,2,-d₂]pyrrolidine, indicating that the reaction should involve an α-hydrogen atom abstraction process as the rate-determining step. N-Acylcarbaldehyde, the putative intermediate ring-opened form of α-hydroxylated N-acyl cyclic amine, was readily oxidized with the oxidizing system to afford the corresponding N-acylamino acid in good yield. Further, lactams (1-methyl-2-pyrrolidone and 1-methyl- 2-piperidone) were also oxidized to give the corresponding imides (1-methylsuccinimide and 1-methylpiperidine-2,6-dione). Copyright

Full text of DOI:10.1021/ja045603f

Published on Web 12/29/2004
Unique Oxidation Reaction of Amides with Pyridine-N-oxide Catalyzed by
Ruthenium Porphyrin: Direct Oxidative Conversion of N-Acyl-L-proline to
N-Acyl-L-glutamate
Rina Ito, Naoki Umezawa, and Tsunehiko Higuchi*
Graduate School of Pharmaceutical Sciences, Nagoya City UniVersity, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Japan
Received July 22, 2004; E-mail: higuchi@phar.nagoya-cu.ac.jp
Table 1. Oxidation of N-Acyl Cyclic Amines by Ru Porphyrin/
Cytochrome P450 plays a central role in drug metabolism. The
exceptionally potent reactivity of P450 enables oxidative modifica-
tion of unactivated alkanes and aromatic compounds. Consequently,
the development of small-molecule catalysts with similar activity
has been the subject of extensive research efforts, and various
metalloporphyrins have been reported that oxidize alkanes and
alkenes similarly to P450.1 However, very few examples of amide
oxidation have been reported, and all of them involve oxidative
conversion to imides with highly active oxidants (e.g., RuO4,2 Co-
(II),3 Mn(II, III),4 Fe(II) salts,5 photooxidation,6 and anodic oxida-
tion7). We have shown that the oxidation of alkanes, alkenes, and
arenes is efficiently catalyzed by ruthenium porphyrins with pyridine
N-oxides as oxidants.8 In the presence of HCl or HBr, this catalytic
system efficiently oxidizes even unactivated alkanes to alcohols
and/or ketones in high yields with extremely high turnover numbers
(up to 105 times).8f,g We have also reported the first examples of
catalytic hydroxylation of unactivated alkanes by stable Ru(TMP)-
Cl2 even in the absence of HCl or HBr.8g We now report that this
highly reactive Ru porphyrin/pyridine N-oxide system shows unique
reactivity for the oxidation of various amides, including the direct
oxidative conversion of N-acyl-L-proline to N-acyl-L-glutamate.
2,6-Dichloropyridine N-Oxide Systema
a Reaction conditions: substrate (0.16 M), Ru(TMP)Cl2 (0.6 mol %),
and 2,6-dichloropyridine N-oxide (0.40 M) were stirred in benzene at 40
°C under Ar overnight, unless otherwise noted. Yields are based on the
substrate used. b 0.32 M 2,6-dichloropyridine N-oxide was used.
Table 2. Oxidation of L-Proline Derivatives
Oxidation of various N-acyl cyclic amines was performed with
the 2,6-dichloropyridine N-oxide-RuIV(TMP)Cl2 system. This
system worked quite well; N-acyl cyclic amines were oxidized to
N-acyl amino acids as main products in modest to good yields
(Table 1). Replacement of the catalyst or the oxidant with Ru-
(TPP)Cl2 or 2,6-lutidine N-oxide caused a drop in yield (see
Supporting Information). The oxidation of N-acyl cyclic amines
under conventional conditions is known to afford lactams such as
1d.2-5 In contrast, our system mainly gave ring-opened products
(1b and 1c) via C-N bond cleavage. Compound 1b was supposed
to be further oxidized at the alpha position of the amide to afford
1c by ring closure. Compounds 2a and 3a were also oxidized to
ring-opened products. Compound 3c may be a precursor of 3b, as
discussed later. The oxidation of 4a and Boc-protected 5a proceeded
efficiently to give 4b and 5b via selective C-N bond cleavage at
the less-substituted carbon. This selectivity probably arises because
attack of an active species would be restricted to axial hydrogen at
the 6-position under the influence of both Coulombic repulsion
between oxo-Ru species and carbonyl oxygen, and steric hindrance
of the N-acyl group (see Supporting Information). The turnover
number reached 5000 in the oxidation of 4a.
a Reaction conditions were the same as described in Table 1.
We next applied this catalytic system to the oxidation of
N-acylproline. If the selectivity between secondary and tertiary
carbons is a general phenomenon in this system, prolines could be
converted directly to glutamates. N-Benzoyl-L-proline (N-Bz-L-Pro)
6a was indeed efficiently oxidized to N-Bz-L-Glu 6b (Table 2, entry
1). The configuration of the product 6b was confirmed to be retained
by checking the optical rotation of 6b methyl ester ([R]D ) -25°).
Next, we extended this reaction to L-Pro-containing peptides (entries
2 and 3). N-Bz-L-Pro-L-Ala-OEt 7a and N-Bz-L-Pro-L-Val-OEt 8a
9
834
J. AM. CHEM. SOC. 2005, 127, 834-835
10.1021/ja045603f CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Oxidation of Lactamsa
were converted to N-Bz-L-Glu-L-Ala-OEt 7b and N-Bz-L-Glu-L-
Val-OEt 8b, respectively. The proline residue in the peptides was
selectively converted to glutamate; this type of reaction could be a
useful method in peptide chemistry. Many researchers have reported
on the conversion of L-Pro to L-Glu, but all reported methods require
two steps.9 As a representative example, N-acyl-L-Pro esters were
oxidized by RuO4 to afford the 2-pyrrolidones, followed by
hydrolysis with aqueous HCl. In contrast, our system can directly
convert N-acyl cyclic amines to N-acyl amino acids under mild
conditions.
Oxidative N-dealkylations catalyzed by heme enzyme or met-
alloporphyrin model compounds are known to involve the genera-
tion of a carbinolamine. Although the mechanism of this reaction
is still controversial, the electron-transfer pathway has received more
support than the hydrogen atom-transfer route.10
To obtain insight into the mechanism of our reaction, the kinetic
isotope effect was measured using N-benzoyl[2,2-d2]pyrrolidine 1e.
The effect of the acyl functionality on H and D was confirmed to
be the same; the rotation of the N-C(O) bond was observed by 1H
NMR spectroscopy at room temperature (see Supporting Informa-
tion). The intramolecular kinetic isotope effect in the oxidation of
1e with this system was evaluated from the product ratio of 1f-h
vs 1b-d as A/B. The kH/kD value was found to be 9.8 ( 0.2 (see
Supporting Information), strongly suggesting that the rate-determin-
ing step is hydrogen abstraction and not one-electron oxidation.
a Reaction conditions were the same as described in Table 1, except that
the reaction time was 2 d. b Isolated yield. c Ring-opened products were
also formed. d This yield was estimated from the NMR spectra.
In summary, we present the first direct conversion of N-acyl
cyclic amines to N-acyl amino acids via oxidative C-N bond
cleavage with pyridine N-oxides catalyzed by ruthenium porphyrin.
Our system should be useful to prepare biologically active
compounds such as γ- and δ-amino acids. The occurrence of this
novel reaction with metalloporphyrin suggests that P450 or per-
oxidases might also catalyze a similar type of oxidation. Further
investigation is in progress.
Acknowledgment. This research was supported in part by a
Grant-in-Aid for University and Society Collaboration (No. 12793009)
from the Ministry of Education, Science, Sports and Culture, Japan.
Supporting Information Available: Experimental details and
further information concerning the catalytic system and the oxidation
of aldehydes. This material is available free of charge via the Internet
at http://pubs.acs.org.
When hydrogen abstraction occurs, aldehydes are supposed to
be formed as precursors of the carboxylate. We confirmed that
various aldehydes were oxidized and converted to carboxylic acids
in good yields with this catalytic system (see Supporting Informa-
tion).
On the basis of the above observations, we propose the following
reaction mechanism. The cleavage of the C-N bond occurs via
the equilibrium of the hydroxylated amide b and the ring-opened
aldehyde d, which is critical for the unique reactivity of this catalytic
system. Some hydroxylated amide is oxidized to give the imide
form f, but this is not the main pathway. The detection of b and d
at the initial stage of the reaction by 1H NMR supports the validity
of this mechanism (see Supporting Information).
References
(1) (a) Meunier, B.; Robert, A.; Pratviel, G.; Bernadou, J. In The Porphyrin
Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic
Press: San Diego, 2000; Vol. 4, pp 119-187. (b) Groves, J. T.; Shalyaev,
K.; Lee, J. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M.,
Guilard, R., Eds.; Academic Press: San Diego, 2000; Vol. 4, pp 17-40.
(2) (a) Berkowitz, L. M.; Rylander, P. N. J. Am. Chem. Soc., 1958, 80, 6682-
6684. (b) Yoshifuji, S.; Arakawa, Y.; Nitta, Y. Chem. Pharm. Bull. 1987,
35, 357-363. (c) Yoshifuji, S.; Tanaka, K.; Kawai, T.; Nitta, Y. Chem.
Pharm. Bull. 1985, 33, 5515-5521.
(3) (a) Lock, M. V.; Sagar, B. F. J. Chem. Soc. B 1966, 690-696. (b) Sagar,
B. F. J. Chem. Soc, B 1967, 428-439.
(4) Doumaux, A. R.; McKeon, J. E.; Trecker, D. J. J. Am. Chem. Soc. 1969,
91, 3992-3993.
(5) Murata, S.; Miura, M.; Nomura, M. J. Chem. Soc., Perkin Trans. 1 1987,
1259-1262
(6) (a) Sigwart, C.; Spence, J. T. J. Am. Chem. Soc. 1969, 91, 3991-3992.
(b) Gramain, J.; Remuson, R.; Troin, Y. J. Chem. Soc., Chem. Commun.
1976, 194-195.
(7) Masui, M.; Hara, S.; Ozaki, S. Chem. Pharm. Bull. 1986, 34, 975-979.
(8) (a) Higuchi, T.; Ohtake, H.; Hirobe, M. Tetrahedron Lett. 1989, 30, 6545-
6548. (b) Higuchi, T.; Ohtake, H.; Hirobe, M. Tetrahedron Lett. 1991,
32, 7435-7438. (c) Ohtake, H., Higuchi, T.; Hirobe, M. Tetrahedron Lett.
1992, 33, 2521-2524. (d) Ohtake, H.; Higuchi, T.; Hirobe, M. J. Am.
Chem. Soc. 1992, 114, 10660-10662. (e) Ohtake, H.; Higuchi, T.; Hirobe,
M. Heterocycles 1995, 40, 867-903. (f) Shingaki, T.; Miura, K.; Higuchi,
T.; Hirobe, M.; Nagano, T. Chem. Commun. 1997, 861-862. (g) Higuchi,
T.; Satake, C.; Hirobe, M. J. Am. Chem. Soc. 1995, 117, 8879-8880.
(9) (a) Yoshifuji, S.; Tanaka, K.; Nitta, Y. Chem. Pharm. Bull. 1985, 33,
1749-1751. (b) Tanaka, K.; Yoshifuji, S.; Nitta, Y. Chem. Pharm. Bull.
1987, 35, 364-369. (c) Konas, D. W.; Coward, J. K. J. Org. Chem. 2001,
66, 8831-8842. (d) Hudlicky, M. J. Fluorine Chem. 1993, 60, 193-210.
(e) Hart, B. P.; Coward, J. K. Tetrahedron Lett. 1993, 34, 4917-4920.
(f) Yoshifuji, S.; Kaname, M. Chem. Pharm. Bull. 1995, 43, 1617-1620.
(10) Guengerich, F. P. Chem. Res. Toxicol. 2001, 14, 611-650.
The oxidation reactions of lactams are also consistent with the
above scheme. In the case of 9a, the cyclic form is more stable
than the ring-opened form of hydroxylated amide, and 9a was
efficiently converted to the imide 9b, whereas in the case of 11a,
the ring-opened form is more stable, and 11a was mainly converted
to the ring-opened product 11b (Table 3).
JA045603F
9
J. AM. CHEM. SOC. VOL. 127, NO. 3, 2005 835