LETTER
DKR of Aliphatic Cyanohydrins
2383
Table 1 The Use of Cyanide Salts as Bases in the DKR Using 380 U/mmol of Candida antarctica Lipase Ba
Substrate
Enzyme
NaCNb,c
99 (76)
KCNb,c
78 (58)
86 (29)
–
Zn(CN)2b,c
47 (82)
32 (92)
79 (62)
60 (68)
NaOAcb,c
54 (74)
31 (89)
68 (27)
51 (56)
Amberliteb,d
70 (74)
1
1
1
1
a
a
b
b
Novozyme 435
CAL-B on Celite
Novozyme 435
CAL-B on Celite
100 (42)
100 (49)e
97 (46)e
46 (90)
73 (28)
93 (29)
68 (52)
a
b
c
d
e
Reaction time: 6 d.
Conversion into 3a and 3b [% and ee (%)].
1
0
Equiv.
.3 Equiv.
Reaction time: 2 d.
Zn(CN) , NaOAc and Amberlite gave the highest ee for 3 products were lower than what could be expected, most
2
when they were used in combination with the Celite R- likely due to a small degree of base-catalysed chemical
6
33 immobilised enzyme (Table 1). NaCN and KCN gave acylation.
the best results in combination with Novozyme 435. Prob-
ably Celite R-633 has a higher affinity to water and binds
it, while the methacrylate polymer carrier of CAL-B in
Acknowledgment
Novozyme 435 more readily releases the water bound to We thank Peter Halling (Strathclyde) and Liisa Kanerva (Turku) for
6
b
stimulating discussions and many suggestions. L.V. thanks ACTS/
NWO for financial support. U.H. thanks the Royal Netherlands
Academy of Arts and Sciences (KNAW) for a fellowship. The au-
thors gratefully acknowledge Roche Diagnostics Penzberg (Dr. W.
Tischer) and Novo Nordisk (Dr. Deussen) for the generous gift of
CAL-B.
the carrier into the reaction media. Since NaCN and
KCN will neutralise any acetic acid formed by hydrolysis
of the acylating agent, it is less critical for the reaction to
use Celite R-633 as the carrier for CAL-B. The formed
HCN will add to the aldehyde to form 2, and the metal
acetate, which acts as a mild base.
On the other hand when NaOAc and Amberlite are used,
it is more important to use a carrier that does not release
any water into the reaction mixture. Amberlite will
neutralise the acid but at the same time form a new mole-
cule of water. NaOAc will form a buffer with the acetic
acid but the capacity of this buffer might be exceeded.
References
(
1) (a) Gregory, R. J. H. Chem. Rev. 1999, 99, 3649. (b) North,
M. Tetrahedron: Asymmetry 2003, 14, 147. (c) Brunel, J.
M.; Holmes, I. P. Angew. Chem. Int. Ed. 2004, 43, 2752.
2) Hanefeld, U. Org. Biomol. Chem. 2003, 1, 2405.
(
(
3) (a) Kanerva, L. T.; Rahiala, K.; Sundholm, O. Biocatalysis
1
994, 10, 169. (b) Paizs, C.; Toşa, M.; Majdik, C.; Tähtinen,
P.; Irimie, F. D.; Kanerva, L. T. Tetrahedron: Asymmetry
003, 14, 619. (c) Paizs, C.; Tähtinen, P.; Lundell, K.;
As expected, Zn(CN) seems to follow the trend of
NaOAc and Amberlite, rather than that of the two other
2
2
cyanide salts. This shows that the Zn(CN) is a weaker
2
Poppe, L.; Irimie, F. D.; Kanerva, L. T. Tetrahedron:
Asymmetry 2003, 14, 1895. (d) Paizs, C.; Tähtinen, P.; Toşa,
M.; Majdik, C.; Irimie, F. D.; Kanerva, L. T. Tetrahedron
base than KCN or NaCN and therefore less efficient in the
neutralisation of the acid.
2004, 60, 10533.
In order to probe whether a higher ee could be obtained
with an aldehyde containing a longer chain than 1b, we
also tested 1c and 1d as substrates for the reaction, but
neither the reaction rate nor the enantioselectivity of the
reaction changed significantly.1
(
(
(
4) (a) Effenberger, F.; Förster, S.; Wajant, H. Curr. Opin.
Biotechnol. 2000, 11, 532. (b) Griengl, H.; Schwab, H.;
Fechter, M. Trends Biotechnol. 2000, 18, 252.
(c) Sukumaran, J.; Hanefeld, U. Chem. Soc. Rev. 2005, 34,
530.
1
5) (a) Inagaki, M.; Hiratake, J.; Nishioka, T.; Oda, J. J. Am.
Chem. Soc. 1991, 113, 9360. (b) Inagaki, M.; Hiratake, J.;
Nishioka, T.; Oda, J. J. Org. Chem. 1992, 57, 5643.
(c) Inagaki, M.; Hatanaka, A.; Mimura, M.; Hiratake, J.;
Nishioka, T.; Oda, J. Bull. Chem. Soc. Jpn. 1992, 65, 111.
6) (a) Veum, L.; Hanefeld, U. Tetrahedron: Asymmetry 2004,
1
2
When the reaction was scaled up using Novozyme 435
in combination with NaCN, 3a and 3b were isolated with
1
3
14
a yield of 92% and 74%, and an ee of 78% and 50%,
respectively. This is a significant improvement of the first
DKR of aliphatic cyanohydrins.
1
5, 3707. (b) Veum, L.; Kanerva, L. T.; Halling, P. J.;
Maschmeyer, T.; Hanefeld, U. Adv. Synth. Catal. 2005, 347,
015.
–
In conclusion, by exchanging the Amberlite OH , which
is commonly used as a base in the DKR of cyanohydrins
against NaCN, a true DKR of the aliphatic cyanohydrins
could be developed. In addition, by using NaCN, the reac-
tion also became less sensitive towards water that is
present in the reaction mixture. However, the ee of the
1
(7) (a) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2004, 126,
8106. (b) Chang, C. W.; Yang, C. T.; Hwang, C. D.; Uang,
B. J. Chem. Commun. 2002, 54. (c) Belokon, Y. N.; Carta,
P.; North, M. Lett. Org. Chem. 2004, 1, 81.
Synlett 2005, No. 15, 2382–2384 © Thieme Stuttgart · New York