enantioselectivities for the major anti diastereomer. Besides
cyclohexanone (entries 1–4, and 12–14) other donors like
hydroxyacetone (entries 5–9), tetrahydro-4H-pyran-4-one
(entries 10–11) and acetone (entries 15–17) were used in these
reactions. In particular, the reaction with water miscible
acetone yielded the product 1e in good yields but not in
synthetically useful enantioselectivities, a result which parallels
previous literature reports.19 Using isatin as the acceptor
system (entries 12–14) allowed the formation in very high
yields and good enantioselectivity of the oxindole 1d having
a structural moiety of high interest in medicinal chemistry.20
The contrasting diastereoselectivity observed when cyclo-
hexanone and hydroxyacetone were used as donors can be
rationalised with the models shown in Scheme 1. Following
the generally accepted mechanistic picture,14,21 cyclohexanone
condenses with chitosan primary amine to give E-enamine A,
whereas hydroxyacetone results predominantly in Z-enamine
B stabilised by an intramolecular hydrogen bond. These
enamines then react with the incoming aldehyde, likely activated
by a hydrogen-bond with the 4-hydroxy group in intermediates C
and D, affording as the major products the corresponding anti-
and syn-aldol adducts, respectively. However, the possibility
of additional hydrogen-bond interactions between substrates
and other hydroxyl moieties (of the same or adjacent saccharide
units) cannot be ruled out.
efficiency and stereoselectivity (Table 3). The use of powdered
chitosan from a commercial source (entries 2, 6, 8, 13 in
Table 2) led to results to some extent comparable to those
with the aerogel and hydrogel but the formation of a slurry in
the reaction medium prevented the easy recycle and recovery
of the catalyst as a solid-like heterogeneous phase.
In summary, we have developed the first direct asymmetric
aldol reaction that can be performed in the presence of water
using as a heterogeneous organocatalyst chitosan, a renewable
feedstock material. The simple and environmentally friendly
experimental procedure and the recycling of the catalytic
system highlight good assets of this catalytic protocol.
Further studies focusing on a wider scope of these catalyzed
asymmetric transformations are currently in progress.
We acknowledge financial support from ‘Stereoselezione in
Sintesi Organica Metodologie e Applicazioni’ 2007.
Notes and references
1 F. Cozzi, Adv. Synth. Catal., 2006, 348, 1367.
2 R. A. A. Muzzarelli, Chitin, Pergamon Press, Oxford, 1977;
G. A. F. Roberts, Chitin Chemistry, Macmillan, London, 1992.
3 (a) M. N. V. Ravi Kumar, React. Funct. Polym., 2000, 46, 1;
(b) K. Kurita, H. Ikeda, Y. Yoshida, M. Shimojoh and M. Harata,
Biomacromolecules, 2002, 3, 1.
4 (a) J. J. E. Hardy, S. Hubert, D. J. Macquerrie and A. J. Wilson,
Green Chem., 2004, 6, 53; (b) V. Calo, A. Nacci, A. Monopoli,
L. Fornaro, L. Sabbatini, N. Cioffi and N. Ditaranto, Organo-
metallics, 2004, 23, 5154.
5 (a) F. Quignard, A. Choplin and A. Domard, Langmuir, 2000, 16,
9106; (b) P. Buisson and F. Quignard, Aust. J. Chem., 2002, 55, 73.
6 W. Sun, C.-G. Xia and H.-W. Wang, New J. Chem., 2002, 26, 755.
7 A. V. Kucherov, N. V. Kramareva, E. D. Finashima, A. E. Koklin
and L. M. Kustova, J. Mol. Catal. A: Chem., 2003, 198, 377.
8 M. Chtchigrovsky, A. Primo, P. Gonzalez, K. Molvinger, M. Robitzer,
F. Quignard and F. Taran, Angew. Chem., Int. Ed., 2009, 48, 5916.
9 H. Zhang, W. Zhao, J. Zou, Y. Liu, R. Li and Y. Cui, Chirality,
2009, 21, 492.
The efficacy of chitosan aerogel in terms of its reusability as
an organocatalyst in the aldol reaction between cyclohexanone
and p-nitrobenzaldehyde was finally tested. After completion
of the reaction and decantation of the organic/aqueous layer
the aerogel did not seem macroscopically affected and could be
reused for at least 3 more additional runs displaying the same
10 For a comprehensive review see: D. J. Macquarrie and J. J. E.
Hardy, Ind. Eng. Chem. Res., 2005, 44, 8499.
11 K. R. Reddy, K. Rajgopal, C. U. Maheswari and M. L. Kantam,
New J. Chem., 2006, 30, 1549.
12 R. Valentin, K. Molvinger, F. Quignard and D. Brunel,
New J. Chem., 2003, 27, 1690.
13 F. Quignard, R. Valentin and F. Di Renzo, New J. Chem., 2008,
32, 1300.
14 (a) S. Mukherjee, J. W. Yang, S. Hoffmann and B. List, Chem.
Rev., 2007, 107, 5471; (b) P. Melchiorre, M. Marigo, A. Carlone
and G. Bartoli, Angew. Chem., Int. Ed., 2008, 47, 6138;
(c) S. Bertelsen and K. A. Jørgensen, Chem. Soc. Rev., 2009, 38,
2178; (d) D. W. C. MacMillan, Nature, 2008, 455, 304.
15 (a) A. Cordova, W. Zou, I. Ibrahem, E. Reyes, M. Engqvist and
W.-W. Liao, Chem. Commun., 2005, 3586; (b) A. Cordova,
W. Zou, P. Dziedzic, I. Ibrahem, E. Reyes and Y. Xu, Chem.–Eur.
J., 2006, 12, 5383; (c) L.-W. Xu, J. Luo and Y. Lu, Chem.
Commun., 2009, 1807 and references therein.
Scheme 1 Proposed reaction pathway.
Table 3 Recyclability of chitosan aerogel catalysta
16 Modern Aldol Reactions, ed. R. Mahrwald, Wiley-VCH,
Weinheim, 2004, vol. 1 and 2.
Cycle
Yieldb (%)
anti/sync
eed (%)
17 (a) E. A. C. Davie, S. M. Mennen, Y. Miller and S. J. Xu, Chem. Rev.,
2007, 107, 5759; (b) A. P. Brogan, T. J. Dickerson and K. D. Janda,
Angew. Chem., Int. Ed., 2006, 45, 100; (c) Y. Hayashi, Angew. Chem.,
Int. Ed., 2006, 45, 8103; (d) J. Paradowska, M. Stodulski and
J. Mlynarski, Angew. Chem., Int. Ed., 2009, 48, 4288.
1
2
3
4
85
80
82
87
70/30
67/33
69/31
65/35
84
82
80
83
a
Conditions: chitosan aerogel 13.5 mg (corresponding to 22 mol%
free amino units with respect to aldehyde), p-nitrobenzaldehyde
(0.30 mmol), cyclohexanone (6.0 mmol), H2O (1.5 mL), 48 h. Then
after phase separation, the beads were washed with H2O and reused.
18 N. Mase, N. Noshiro, A. Moyuka and K. Takabe, Adv. Synth.
Catal., 2009, 351, 2791.
19 N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F. Tanaka
and C. F. Barbas III, J. Am. Chem. Soc., 2006, 128, 734.
20 M. Raj, N. Veerasamy and V. K. Singh, Tetrahedron Lett., 2010,
51, 2157.
21 S. S. V. Ramasastry, H. Zhang, F. Tanaka and C. F. Barbas III,
J. Am. Chem. Soc., 2007, 129, 288.
b
c
Isolated yield after chromatography on silica gel. Determined by
d
1H NMR spectroscopy on the crude mixture. Determined by chiral
stationary phase HPLC. Refers to the major anti diastereomer.
ꢁc
This journal is The Royal Society of Chemistry 2010
6290 | Chem. Commun., 2010, 46, 6288–6290