Peptide/laccase cocatalyzed asymmetric α-oxyamination of aldehydes

Article abstract of DOI:10.1021/ol2012956

An asymmetric α-oxyamination could be successfully performed by a peptide catalyst and laccase. The combination of peptide catalysis and enzymatic air oxidation promoted the reaction smoothly in water without employing a metal reagent. The oxyaminated compounds could be obtained as both aldehyde and carboxylic acid products depending on the reaction conditions.

Full text of DOI:10.1021/ol2012956

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3498–3501
Peptide/Laccase Cocatalyzed Asymmetric
r-Oxyamination of Aldehydes
Kengo Akagawa and Kazuaki Kudo*
Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku,
Tokyo 153-8505, Japan
kkudo@iis.u-tokyo.ac.jp
Received May 13, 2011
ABSTRACT
An asymmetric R-oxyamination could be successfully performed by a peptide catalyst and laccase. The combination of peptide catalysis and
enzymatic air oxidation promoted the reaction smoothly in water without employing a metal reagent. The oxyaminated compounds could be
obtained as both aldehyde and carboxylic acid products depending on the reaction conditions.
Recent advancements in the field of organocatalysis
have offered a variety of useful synthetic methods.1 In
addition to being used alone, organocatalysts have been
combined with metal reagents.2 There are examples
for organocatalyzed CÀC and CÀheteroatom bond for-
mations using metals as oxidizing agents.3 Among them,
Sibi’s asymmetric R-oxyamination of aldehydes using
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and a cat-
alytic amount of an iron salt is noteworthy in terms of
enabling oxidation with molecular oxygen as a terminal
oxidant.4,5 Such air oxidation is an atom-efficient and
clean reaction, only generating water as waste.6
On the other hand, because metal reagents are some-
times environmentally harmful, it is highly desirable to
replace them with greener alternatives. Concerning this, an
oxidative enzyme, laccase (EC 1.10.3.2), has been recognized
as a promising candidate, which is inexpensive, stable, and
widely applicable for various reactions.7 For example,
(1) For selected reviews, see: (a) Dalko, P. I.; Moisan, L. Angew.
€
Chem., Int. Ed. 2004, 43, 5138. (b) Erkkila, A.; Majander, I.; Pihko,
P. M. Chem. Rev. 2007, 107, 5416. (c) Mukherjee, S.; Yang, J. W.;
Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. (d) Pellissier, H.
Tetrahedron 2007, 63, 9267. (e) Dondoni, A.; Massi, A. Angew. Chem.,
Int. Ed. 2008, 47, 4638. (f) Melchiorre, P.; Marigo, M.; Carlone, A.;
Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138. (g) Bertelsen, S.;
Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178.
(2) For reviews, see: (a) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38,
2745. (b) Zhou, J. Chem.;Asian J. 2010, 5, 422. (c) Rueping, M.;
Koenigs, R. M.; Atodiresei, I. Chem.;Eur. J. 2010, 16, 9350. (d) Zhong,
C.; Shi, X. Eur. J. Org. Chem. 2010, 2999.
(3) MacMillan et al. have developed the new class of reactions
proceeding through SOMO activation with imidazolidinone catalysts
and metal oxidizing reagents. For selected examples, see: (a) Beeson,
T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C.
Science 2007, 316, 582. (b) Kim, H.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2008, 130, 398. (c) Amatore, M.; Beeson, T. D.; Brown, S. P.;
MacMillan, D. W. C. Angew. Chem., Int. Ed. 2009, 48, 5121. (d) Wilson,
J. E.; Casarez, A. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131,
11332. (e) Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010,
132, 5027. (f) Jui, N. T.; Lee, E. C. Y.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2010, 132, 10015. For other examples, see:(g) Jang, D. O.;
Kim, S. Y. J. Am. Chem. Soc. 2008, 130, 16152. (h) Nicewicz, D. A.;
MacMillan, D. W. C. Science 2008, 322, 77. (i) Nicolaou, K. C.;
(4) (a) Sibi, M. P.; Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 4124.
(b) Van Humbeck, J. F.; Simonovich, S. P.; Knowles, R. R.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2010, 132, 10012.
(5) Maruoka et al. reported the R-oxyamination with TEMPO using
a peroxide instead of a metal reagent. (a) Kano, T.; Mii, H.; Maruoka,
K. Angew. Chem., Int. Ed. 2010, 49, 6638. For other examples of the
R-oxyamination with TEMPO, see:(b) Koike, T.; Akita, M. Chem. Lett.
2009, 38, 166. (c) Bui, N.-N.; Ho, X.-H.; Mho, S.-i.; Jang, H.-Y. Eur. J.
Org. Chem. 2009, 5309. (d) Pouliot, M.; Renaud, P.; Schenk, K.; Studer,
A.; Volger, T. Angew. Chem., Int. Ed. 2009, 48, 6037. (e) Inokuchi, T.;
Nakagawa, K.; Torii, S. Tetrahedron Lett. 1995, 36, 3223.
(6) Wertz, S.; Studer, A. Adv. Synth. Catal. 2011, 353, 69 and
references therein.
€
Reingruber, R.; Sarlah, D.; Brase, S. J. Am. Chem. Soc. 2009, 131,
2086. (j) Xie, J.; Huang, Z.-Z. Chem. Commun. 2010, 46, 1947.
r
10.1021/ol2012956
Published on Web 06/07/2011
2011 American Chemical Society

Rutjes et al. demonstrated that laccase can be used as a
catalyst for the oxidative removal of the p-methoxyphenyl
protective group on amines under aerobic conditions, in
place of the conventional stoichiometric reaction with ceric
ammonium nitrate.8 If an air oxidation mediated by lac-
case can be combined with an organocatalytic reaction,
this will provide a new green chemical transformation.
In the absence of an amine catalyst, the aldehyde was
simply converted to carboxylic acid 3 in acetate buffer
(entry 1). This type of TEMPO-mediated air oxidation of
aldehydes by laccase has been reported,14,15 and such a
reaction is supposed to be brought about by the oxoam-
monium ion which is generated by means of laccase-
catalyzed one-electron oxidation of TEMPO.16 When the
catalytic amount of pyrrolidine was added to the reaction,
R-oxyaminated carboxylic acid 5 was formed along with
carboxylic acid 3 (entry 2). The product 5 was considered
to be generated by the further oxidation of R-oxyaminated
aldehyde 4. While acidic conditions are optimal in many
laccase-catalyzed reactions,7 in the present case, the
R-oxyamination occurred smoothly in neutral water as
well asin acetate buffer (entry 3). The reaction rate was low
in the presence of THF or DMF (entries 4 and 5). The
Figure 1. Resin-supported peptide catalyst.
To realize such a reaction in a single flask, the organo-
catalyst should be active in water, since water is generally a
suitable solvent for enzymatic reactions.9 Meanwhile, our
group has developed resin-supported peptide catalyst 1
(Figure 1)10 for asymmetric organocatalytic reactions in
aqueous media.11 For example, this catalyst is quite effec-
tive for the chiral-amine-catalyzed asymmetric R-oxyami-
nation of aldehydes in the presence of either Fe(II) or Cu(I)
cocatalyst.12,13 Because of the high efficiency of the peptide
catalyst in water and the versatile applicability of the
laccase oxidation, we envisaged that the peptide-catalyzed
R-oxyamination could proceed through the laccase-
mediated air oxidation without using a metal reagent.
Herein, we report the novel system for the asymmetric
R-oxyamination of aldehydescatalyzed by resin-supported
peptide 1 and laccase in water.
(7) For reviews, see: (a) Witayakran, S.; Ragauskas, A. J. Adv. Synth.
Catal. 2009, 351, 1187. (b) Hollmann, F.; Arends, I. W. C. E.; Buehler,
K. ChemCatChem 2010, 2, 762.
(8) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.;
€
Schoemaker, H. E.; Schurmann, M.; van Delft, F. L.; Rutjes, F. P. J. T.
Adv. Synth. Catal. 2007, 349, 1332.
€
(9) Groger et al. reported the sequential reaction using an organo-
catalyst and alcohol dehydrogenase for the synthesis of chiral 1,3-diols.
€
Baer, K.; Krauβer, M.; Burda, E.; Hummel, W.; Berkessel, A.; Groger,
H. Angew. Chem., Int. Ed. 2009, 48, 9355.
(10) The peptide possesses a polyleucine chain synthesized with
N-carboxyanhydride monomer, and the number of -(Leu)n- means
weight-average degree of polymerization.
(11) (a) Akagawa, K.; Akabane, H.; Sakamoto, S.; Kudo, K. Org.
Lett. 2008, 10, 2035. (b) Akagawa, K.; Akabane, H.; Sakamoto, S.;
Kudo, K. Tetrahedron: Asymmetry 2009, 20, 461. (c) Akagawa, K.;
Yamashita, T.; Sakamoto, S.; Kudo, K. Tetrahedron Lett. 2009, 50,
5602. (d) Akagawa, K.; Kudo, K. Adv. Synth. Catal. 2011, 353, 843.
(12) (a) Akagawa, K.; Fujiwara, T.; Sakamoto, S.; Kudo, K. Org.
Lett. 2010, 12, 1804. (b) Akagawa, K.; Fujiwara, T.; Sakamoto, S.;
Kudo, K. Chem. Commun. 2010, 46, 8040.
Initially, oxidation of 3-phenylpropanal with TEMPO/
laccase under various conditions was examined (Table 1).
(13) For recent selected examples of peptide-based asymmetric cat-
alysts, see: (a) Fowler, B. S.; Mikochik, P. J.; Miller, S. J. J. Am. Chem.
Soc.2010, 132, 2870. (b) Wiesner, M.; Upert, G.; Angelici, G.; Wennemers,
H. J. Am. Chem. Soc. 2010, 132, 6. (c) Gustafson, J. L.; Lim, D.; Miller, S. J.
Science 2010, 328, 1251. (d) Cowen, B. J.; Saunders, L. B.; Miller, S. J.
J. Am. Chem. Soc. 2009, 131, 6105. (e) Wu, F.-C.; Da, C.-S.; Du, Z. X.;
Guo, Q.-P.; Li, W.-P.; Yi, L.; Jia, Y.-N.; Ma, X. J. Org. Chem. 2009, 74,
4812. (f) Fiori, K. W.; Puchlopek, A. L. A.; Miller, S. J. Nat. Chem. 2009, 1,
Table 1. R-Oxyamination of 3-Phenylpropanal with Amine
Catalyst and Laccase
€
630. (g) Muller, C. E.; Wanka, L.; Jewell, K.; Schreiner, P. R. Angew.
Chem., Int. Ed. 2008, 47, 6180. (h) Lewis, C. A.; Gustafson, J. L.; Chiu, A.;
Balsells, J.; Pollard, D.; Murry, J.; Reamer, R. A.; Hansen, K. B.; Miller,
S. J. J. Am. Chem. Soc. 2008, 130, 16358. (i) Wiesner, M.; Revell, J. D.;
Tonazzi, S.; Wennemers, H. J. Am. Chem. Soc. 2008, 130, 5610. (j) D’Elia,
V.; Zwicknagl, H.; Reiser, O. J. Org. Chem. 2008, 73, 3262. (k) Peris, G.;
Jakobsche, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 8710.
(14) This system has been used for oxidizing alcohols to aldehydes.
(a) Fabbrini, M.; Galli, C.; Gentili, P.; Macchitella, D. Tetrahedron Lett.
2001, 42, 7551. (b) d’Acunzo, F.; Baiocco, P.; Fabbrini, M.; Galli, C.;
Gentili, P. Eur. J. Org. Chem. 2002, 4195. (c) Arends, I. W. C. E.; Li, Y.-
X.; Ausan, R.; Sheldon, R. A. Tetrahedron 2006, 62, 6659. (d) Tromp,
ꢀ
_
S. A.; Matijosyte, I.; Sheldon, R. A.; Arends, I. W. C. E.; Mul, G.;
Kreutzer, M. T.; Moulijn, J. A.; de Vries, S. ChemCatChem 2010, 2, 827.
ꢀ
_
(e) Tropm, S. A.; Matijosyte, I.; Sheldon, R. A.; Arends, I. W. C. E.;
Mul, G.; Kreutzer, M. T.; Moulijn, J. A.; de Vries, S. ChemCatChem
2010, 2, 827.
(15) For examples for overoxidation of aldehydes to carboxylicacids,
see: (a) Marzorati, M.; Danieli, B.; Haltrich, D.; Riva, S. Green Chem.
2005, 7, 310. (b) Baratto, L.; Candido, A.; Marzorati, M.; Sagui, F.;
Riva, S.; Danieli, B. J. Mol. Catal. B: Enzym. 2006, 39, 3. (c) Monti, D.;
ꢀ
Candido, A.; Silva, M. M. C.; Kren, V.; Riva, S.; Danieli, B. Adv. Synth.
Catal. 2005, 347, 1168. (d) Viikari, L.; Niku-Paavola, M.-L.; Buchert, J.;
Forssell, P.; Teleman, A.; Kruus, K. WO Patent 99/23240, 1999. (e)
Jetten, J. M.; van den Dool, R. T. M.; van Hartingsveldt, W.; Besemer, A. C.
WO Patent 00/50463, 2000.
(16) (a) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem.
1987, 52, 2559. (b) de Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H.
Synthesis 1996, 1153.
a Determined after being reduced to the corresponding alcohol by a
boraneÀTHF complex (BH3•THF). b n.d. = Not determined. c Isolated
yield of 5 was 46%.
Org. Lett., Vol. 13, No. 13, 2011
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reaction in water/1,4-dioxane afforded the oxyaminated
products as a mixture of aldehyde 4 and carboxylic acid 5
(entry 6). When resin-supported peptide catalyst 1, which
has been previously reported by us for the enantioselective
R-oxyamination of aldehydes, was employed instead of
pyrrolidine, oxyaminated carboxylic acid 5 was obtained
in a highly enantioselective manner (entry 7). Simple pro-
line was not effective for the R-oxyamination reaction
(entry 8). Imidazolidinone catalyst 6 was able to promote
the oxyamination; however, the enantioselectivity was
only moderate (entry 9). In all the cases, the oxyamination
reaction competed with the oxidation of the starting
aldehyde to carboxylic acid 3. Use of 1.5 mol equiv of
aldehyde 2 afforded the desired product 5 in an acceptable
yield based on the amount of TEMPO (Scheme 1).
Table 2. R-Oxyamination of 4-Arylbutanals
Scheme 1. Reaction of 3-Phenylpropanal to Chiral R-Oxyami-
nated Carboxylic Acid
a Determined after being reduced to the corresponding alcohol by
NaBH4 for aldehyde 9 or by BH3•THF for carboxylic acid 10. b Reaction
was performed in acetate buffer (pH 4.4). c Amount of TEMPO was 1.5
equiv. Tween 80 was added, after 2 h had passed.
conditions. When the reaction was conducted with Tween
80, oxyaminated carboxylic acid 10 was obtained with
good enantioselectivity in 5 to 8 h (Table 4, entries 1À4 and
6). The presence of Tween 80 accelerated the oxidation of
R-oxyaminated aldehydes to carboxylic acids as expected
from the results in Table 2. It is worth noting that the yield
of oxyaminated carboxylic acid 10 was not significantly
decreased by the potential competitive reaction of 7 to 8
Further optimization of the reaction conditions was
carried out using 4-arylbutanals, and somewhat different
results were obtained (Table 2). When 4-phenylbutanal
was used as a substrate, pyrrolidine did not promote the
oxyamination (entry 1). The reaction with imidazolidinone
6 afforded oxyaminated carboxylic acid 10; however,
the yield and enantioselectivity were low (entry 2). On
the contrary, use of peptide catalyst 1 exclusively gave
oxyaminated aldehyde 9 with good yield and enantioselec-
tivity (entry 3). It should be mentioned that further oxida-
tion to the corresponding carboxylic acid did not occur. In
the case of 4-(4-methoxyphenyl)butanal, the oxyaminated
aldehyde was also obtained as a main product with peptide
catalyst 1 (entry 5), while imidazolidinone 6 showed low
catalytic efficiency (entry 4). Although the isolated yield
of 9 was moderate in water (entry 5), it could be improved
in acetate buffer (entry 6). We speculate the reason for
the different product distributions for 3-phenylpropanal
and 4-arylbutanals is the differences in hydrophobicity
of the oxyaminated aldehydes. For the oxidation of
4-(4-methoxyphenyl)butanal, addition of a nonionic sur-
factant, Tween 80, resulted in changing the main product
from aldehyde 9 to carboxylic acid 10 (entry 7).
Table 3. R-Oxyamination of Aldehydes with Peptide and
Laccase
The asymmetric R-oxyamination of aldehydes with
peptide 1 and laccase was performed in both the absence
and presence of Tween 80 (Tables 3 and 4). In acetate
buffer without a surfactant, the oxyamination proceeded
smoothly and completed within 1 h to afford aldehyde
product 9 with good to moderate yields (Table 3). Com-
pared to the cases with a longer reaction time (Table 2,
entries 3 and 5), enantioselectivities were slightly higher.
This indicates that aldehyde 9 racemizes under the reaction
a Determined after being reduced to the corresponding alcohol by
NaBH4.
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Org. Lett., Vol. 13, No. 13, 2011

Table 4. Direct Conversion of Aldehydes to R-Oxyaminated
Carboxylic Acids
Scheme 2. R-Oxyamination with Oxoammonium Ion
The R-oxyamination of the aldehydes is most likely to
proceed through the reaction of the oxoammonium ion
generated by the laccase oxidation of TEMPO and the
enamine formed between the peptide catalyst and the
aldehyde.5a In fact, when the preformed oxoammonium
ion was used as an oxidizing agent, the enantioselectively
R-oxyaminated product was obtained (Scheme 2).
Another plausible pathway for the oxyamination is the
oxidation of the enamine by laccase and subsequent
coupling with TEMPO. Because there is a report showing
that an enamine is easier to be oxidized than TEMPO,5b
such a mechanism cannot be excluded.
In conclusion, an efficient asymmetric R-oxyamination
of aldehydes was realized by combining the oxidative
enzyme, laccase, and the peptide catalyst in water. It is
synthetically advantageous that both the oxyaminated
aldehydes and carboxylic acids could be obtained depend-
ing on the reaction conditions. The present study demon-
strates the usefulness of enzymes instead of metal reagents
as a cocatalyst for organocatalytic oxidation, and this
might contribute to the field of green chemistry. Further
expansion of the system employing enzymes and organo-
catalysts is currently underway in our laboratory.
a Unless otherwise noted, determined after being reduced to the
corresponding alcohol by BH3•THF. b Reaction was performed with
5 mol % of peptide 1 and 1.0 equiv of TEMPO. c Determined after being
reduced to the corresponding alcohol by LiAlH4.
even in the presence of Tween 80 from the beginning of the
reaction. This type of tandem conversion has not been
reported and is useful to obtain the chiral R-oxyaminated
carboxylic acids directly from aldehydes while avoiding the
possible racemization of R-substituted aldehyde 9. The
catalytic system using peptide 1 and laccase was so efficient
that the amount of catalysts could be reduced to 5 mol %
with only a slight decrease in the yield and enantioselec-
tivity (entry 5). The active site of laccase contains four
copper atoms, and the weight of copper accounts for
less than 1% of the whole enzyme. Therefore, the
amount of the metal species employed in the reaction is
quite low.17
Acknowledgment. This work was partially supported
by a Grant-in-Aid for Young Scientists (B) (23750171 for
K.A.) from Japan Society for the Promotion of Science.
(17) In entry 5 of Table 4, 0.05 mg (<0.002 mol %) of laccase was
used for 0.05 mmol of the aldehyde. In other cases, 0.5 mg of laccase was
used for the same amount of aldehydes. For experimental details, see
Supporting Information.
Supporting Information Available. Experimental proce-
dure and spectroscopic data for products. This material is
available free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 13, 2011
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