Fig. 2
Scheme 2
using the MEDKR process. However, an improvement in the
efficiency of the racemisation reaction is necessary in order to
explore the full potential of the concept. Paetzold and Ba¨ckvall
reported a very high product yield (90% isolated yield) and purity
(98% ee) of acetamide from the DKR of amine 2 with a
tetramethoxy-analogue of the Shvo catalyst.14 This remains the
benchmark process for DKR of amines, but has the disadvantage
that the racemisation catalyst is not, as yet, commercially available.
as the acyl donor in this work as their boiling points are closer to
that of toluene, the main organic solvent used. These esters limited
the enzyme distortion by keeping the log P value of the combined
reaction medium above 2.0, while maintaining the optimum water
activity required for the reaction.11,12
Continuous DKR reactions were performed in the MEDKR
apparatus (Fig. 1) which consists of three vessels: (A) a 60 mL
closed stainless steel hydrogenation vessel for the racemisation; (B)
an 83 mL closed stainless steel cross-flow cell for the kinetic
resolution; (C) a 50 mL partially opened glass vessel connected to a
gas bubbler used as a pressure equaliser. The HPLC pump was
located between vessel C and A, the fluid circulation was from
vessel A to B (passing through a cooling unit) and to vessel C
before the cycle was repeated. The apparatus was degassed with
argon during the initial 15–30 minutes before increasing the
temperature of the racemisation reactor vessel A to 100 uC. The
conditions for the MEDKR reaction are shown in Scheme 2.13
The kinetic resolution of amine 2 without catalyst 3 advanced to
38% conversion at 99% ee after 48 hours.
Notes and references
1 J. F. Jenck, F. Agterberg and M. J. Droescher, Green Chem., 2004, 6,
544–556.
2 J. M. Lee, Y. Na, H. Han and S. Chang, Chem. Soc. Rev., 2004, 33,
302–312.
3 S. Caddick and K. Jenkins, Chem. Soc. Rev., 1996, 25, 447–456;
F. F. Huerta, A. B. Minidis and J. E. Ba¨ckvall, Chem. Soc. Rev., 2001,
30, 321–331; M. J. Kim, Y. Ahn and J. Park, Curr. Opin. Biotechnol.,
2002, 13, 578–587; M. T. El Gihani and J. M. J. Williams, Curr. Opin.
Chem. Biol., 1999, 3, 11–15.
4 A. B. Persson, A. L. Larsson, M. L. Ray and J. E. Ba¨ckvall, J. Am.
Chem. Soc., 1999, 121, 1645–1650; O. Pa`mies and J. E. Ba¨ckvall, Chem.
Rev., 2003, 103, 3247–3261; M. J. Kim, Bull. Korean Chem. Soc., 2005,
26, 515–522; E. J. Gibbins, J. L. Irwin, A. G. Livingston, J. C. Muir,
D. A. Patterson, C. Roengpithya and P. C. Taylor, Synlett, 2005, 19,
2993–2995.
5 E. J. Ebbers, G. J. A. Ariaans, J. P. M. Houbiers, A. Bruggink and
B. Zwanenburg, Tetrahedron, 1997, 53, 9417–9476; C. Roengpithya,
D. A. Patterson, E. J. Gibbins, P. C. Taylor and A. G. Livingston, Ind.
Eng. Chem. Res., 2006, 45, 7101–7109.
6 S. I. Murahashi, N. Yoshimura, T. Tsumiyama and T. Kojima, J. Am.
Chem. Soc., 1983, 105, 5002–5011.
The MEDKR reaction proceeded to 91% conversion at 99% ee
after 72 hours in the membrane reactor, as illustrated in Fig. 2,
with the remaining 9% of material corresponding to known amine
and imine dimer by-products of the reaction.7 Very similar results
were obtained when the reaction was repeated on two further
occasions. A conversion of over 50% proves that the racemisation
was effective and the high ee shows that the kinetic resolution was
effective in the 30 uC reactor chamber as planned. Therefore, we
have proved the principle that a tandem catalytic process can be
run in membrane separated chambers.
7 M. T. Reetz and K. Schimossek, Chimia, 1996, 50, 668–669.
8 O. Pa`mies, A. H. Ell, J. S. M. Samec, N. Hermanns and J. E. Ba¨ckvall,
Tetrahedron Lett., 2002, 43, 4699–4702.
A considerable amount of work remains to render this a useful
process. Isolated yields were poor and after 72 hours the mass
balance was only 55%. Clearly, much of the material has been lost
from solution. To probe the origins of this problem, on one
occasion we held back addition of the catalyst 3 until the 72 hour
mark, well after the kinetic resolution was complete. Under these
conditions, while the quantity of amine (S)-2 that remained after
the kinetic resolution was racemised by catalyst 3, very little new
acetamide (R)-1 was formed. This suggests that, after prolonged
exposure to the conditions, either the kinetic resolution fails or the
amine is subject to competing reactions.
9 Y. Shvo, D. Czarkie and Y. Rahamim, J. Am. Chem. Soc., 1986, 108,
7400–7402.
10 P. L. A. Overbeeke, J. Ottosson, K. Hult, J. A. Jongejan and J. A. Duine,
Biocatal. Biotransform., 1999, 17, 61–79.
11 K. Faber, Biotransformations in Organic Chemistry, Springer-Verlag,
Berlin, 5th edn, 2004.
12 The log P of a given solvent between octanol and water is commonly
used to provide a measure of the compatibility of an organic solvent
with enzyme activity.
13 Concentrations were determined using an Agilent 6850 Series gas
chromatograph (GC) fitted with a flame ionisation detector (FID) and
Agilent 7683 autoinjector. Separation was achieved on an HP-Chiral
20B capillary column (30 m 6 250 mm 6 0.25 mm nominal, J&W
Scientific, USA).
Overall, this work has proved that a tandem catalytic reaction
such as the DKR reaction can be operated as a continuous process
14 J. Paetzold and J. E. Ba¨ckvall, J. Am. Chem. Soc., 2005, 127,
17620–17621.
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 3462–3463 | 3463