Table 4 DKR of racemic Ibuprofenal in phosphate buffer (pH = 7.5)
and phosphate buffer/organic solvents with EtOH-mediated NADH
recycling. Reaction conditions: 0.5 mM 2-(4-iso-butylphenyl)propanal,
0.01 mg ml21 HLADH, 0.01 mM NADH, 0.5 M EtOH
Notes and references
1 H. Pellissier, Tetrahedron, 2003, 59, 8291–8327; F. F. Huerta, A. B. E.
Minidis and J.-E. Ba¨ckvall, Chem. Soc. Rev., 2001, 30, 321–331.
2 O. Pamies and J.-E. Ba¨ckvall, Trends Biotechnol., 2003, 22, 130–135;
O. Pamies and J.-E. Ba¨ckvall, Chem. Rev., 2003, 103, 3247–3262.
3 B. Martin-Matute, M. Edin and J.-E. Ba¨ckvall, Chem.–Eur. J., 2006, 12,
6053–6061.
4 W. Kroutil, H. Mang, K. Edegger and K. Faber, Curr. Opin. Chem.
Biol., 2004, 8, 120–126; W. Kroutil, H. Mang, K. Edegger and K. Faber,
Adv. Synth. Catal., 2004, 346, 125–142.
5 A. Ji, M. Wolberg, W. Hummel, C. Wandrey and M. Mu¨ller, Chem.
Commun., 2001, 57–58; M. Wolberg, A. Ji, W. Hummel and M. Mu¨ller,
Synthesis, 2001, 937–942.
6 D. Giacomini, G. Cainelli, P. Galletti, G. Gucciardo and A. Quintavalla,
Procedimento per la sintesi di alcoli 2-arilpropilici chirali, Pat. Pending,
RM2006S000686, University of Bologna, 21 December 2006.
7 X. Li and B. List, Chem. Commun., 2007, 1739–1741; J.-H. Xie,
Z.-T. Zhou, W.-L. Kong and Q.-L. Zhou, J. Am. Chem. Soc., 2007, 129,
1868–1869.
Co-solvent
Entry (%)
Alcohol (S)-Alcohol (R)-Alcohol Reaction
(%)
yield (%)
(%)
time/h
1
2
3
4
5
6
—
—
48.8
69.3
36.6
45.6
—
97
—
.99
—
—
3
—
5
24
5
THF (10)
THF (10)
CH3CN (10) 81.4
CH3CN (10) 93.0
not detected 24
—
not detected 24
5
8 G. Cainelli, P. C. Engel, P. Galletti, D. Giacomini, A. Gualandi and
F. Paradisi, Org. Biomol. Chem., 2005, 3, 4316–4320.
.99
9 G. Cainelli, P. Galletti, D. Giacomini, A. Gualandi and A. Quintavalla,
Helv. Chim. Acta, 2003, 86, 3548–3559; G. Cainelli, V. De Matteis,
P. Galletti, D. Giacomini and P. Orioli, Chem. Commun., 2000,
2351–2352.
10 J. Grunwald, B. Wirz, M. P. Scollar and A. M. Klibanov, J. Am. Chem.
Soc., 1986, 108, 6732–6134.
11 R. Berardi, G. Cainelli, P. Galletti, D. Giacomini, A. Gualandi,
L. Muccioli and C. Zannoni, J. Am. Chem. Soc., 2005, 127,
10699–10706; C. Botuha, M. Haddad and M. Larcheveque,
Tetrahedron: Asymmetry, 1998, 9, 1929–1931.
12 C. C. Gruber, I. Lavandera, K. Faber and W. Kroutila, Adv. Synth.
Catal., 2006, 348, 1789–1805.
13 In this work, Ibuprofenal (2-(4-iso-butylphenyl)propanal) was prepared
in a two-step procedure starting from the commercially available
racemic Ibuprofen by preliminary esterification followed by DIBAH
reduction (ESI{). However, for large scale preparations, Ibuprofenal can
be conveniently prepared through the hydroformylation of 4-iso-
butylstyrene, as reported by: J. J. Kim and H. Alper, Chem.
Commun., 2005, 3059–3061; D. Neibecker and R. Re´au, J. Org.
Chem., 1989, 54, 5208–5210.
pharmaceutical industry was preliminarily tested on racemic
Ibuprofenal.13
The DKR enzymatic reaction worked well in buffered aqueous
solution. In the presence of an organic co-solvent (CH3CN or
THF), the yields were excellent and enantiomeric ratios always in
favour of (S)-Ibuprofenol (Table 4).14 The oxidation of (S)-
Ibuprofenol to (S)-Ibuprofen has already been reported in the
literature,15 and here we can claim to have established a
chemoenzymatic process to obtain (S)-Ibuprofen via an efficient
DKR of the parent aldehyde.
Work is in progress on the optimization of the reaction
parameters (pH, solvent and temperature) for
a more
efficient scale-up and application to other relevant Profen
derivatives.
14 Absolute configurations were established in comparison with
(S)-Ibuprofenol, obtained by the reduction of commercially available
(S)-Ibuprofen with BH3?SMe2.
15 A. Basak, A. Nag, G. Bhattacharya, S. Mandal and S. Nag,
Tetrahedron: Asymmetry, 2000, 11, 2403–2408.
Financial support for this work came from MIUR and the
University of Bologna. The authors would like to thank Mrs Elena
Benedetto for technical assistance and Dr Michael Sharkey for his
English revision.
4040 | Chem. Commun., 2007, 4038–4040
This journal is ß The Royal Society of Chemistry 2007