Lipase/palladium-catalyzed asymmetric transformations of ketoximes to optically active amines.

Article abstract of DOI:10.1021/ol0168622

[reaction: see text] Prochiral ketoximes were asymmetrically transformed to optically active amines in the acetylated forms by coupled lipase/palladium catalysis in the presence of an acyl donor under 1 atm of hydrogen.

Full text of DOI:10.1021/ol0168622

ORGANIC
LETTERS
2
001
Vol. 3, No. 25
099-4101
Lipase/Palladium-Catalyzed Asymmetric
Transformations of Ketoximes to
Optically Active Amines
4
Yoon Kyung Choi, Mi Jung Kim, Yangsoo Ahn, and Mahn-Joo Kim*
National Research Laboratory of Chirotechnology, Department of Chemistry,
DiVision of Molecular and Life Sciences, Pohang UniVersity of Science and
Technology, San 31 Hyojadong, Pohang, Kyungbuk 790-784, Korea
mjkim@postech.ac.kr
Received October 5, 2001
ABSTRACT
Prochiral ketoximes were asymmetrically transformed to optically active amines in the acetylated forms by coupled lipase/palladium catalysis
in the presence of an acyl donor under 1 atm of hydrogen.
Optically active amines are an important class of organic
compounds that can be widely used as useful chiral building
blocks in asymmetric synthesis and medicinal chemistry.
Some of the procedures currently available for the synthesis
of optically active amines include the asymmetric catalytic
resolution (DKR) of racemic amines using readily available
catalysts. A German group recently reported the DKR of
1-phenethylamine using lipase/palladium as the catalysts.7
The procedure, however, required a long reaction time and
provided a modest yield. We herein wish to report a better
procedure employing ketoxime as the substrate with pal-
ladium and lipase as the catalysts.
1
2
3
hydrogenation of imines, oximes, or their derivatives, the
4
asymmetric borane reduction of oximes, the asymmetric
5
hydrosilylation of imines or oximes, and the asymmetric
On the basis of our experiences in the studies of the lipase/
ruthenium-catalyzed asymmetric transformations of ketones
6
hydrogenation of enamides. Most of them require relatively
8,9
expensive chiral catalysts such as metals with chiral ligand
or chiral reagents. A useful alternative is the dynamic kinetic
to the esters of chiral alcohols, we envisaged that optically
active amines could be synthesized from readily available
ketoximes by using two catalysts, one for reduction and
racemization and one for resolution. We chose palladium as
the reduction/racemization catalyst and lipase as the resolu-
tion catalyst (Scheme 1). The preliminary studies indicated
that the palladium-catalyzed racemization of (S)-1-phenethyl-
amine took place more efficiently in the presence of tertiary
(1) (a) Das, A. J.; Peng, S.-M.; Bhattacharya, S. J. Chem. Soc., Dalton
Trans. 2000, 181. (b) Inoue, T.; Sato, D.; Komura, K.; Itsuno, S. Tetrahedron
Lett. 1999, 40, 5379. (c) Mao, J.; Baker, D. C. Org. Lett. 1999, 1, 841. (d)
Kainz, S.; Brinkmann, A.; Leitner, W.; Pfaltz, A. J. Am. Chem. Soc. 1999,
1
21, 6421.
(2) Krsik, P.; Alper, H. Tetrahedron: Asymmetry 1992, 3, 1283.
3) Sakio, Y.; Yoneyoshi, Y.; Suzukamo, G. Tetrahedron Lett. 1988,
(
2
6
9, 223.
(4) (a) Itsuno, S.; Matsumoto, T.; Sato, D.; Inoue, T. J. Org. Chem. 2000,
(7) Reetz, M. T.; Schimossek, K. Chimia 1996, 50, 668.
(8) Jung, H. M.; Koh, J. H.; Kim, M.-J.; Park, J. Org. Lett. 2000, 2, 409
and 2487.
5, 5879. (b) Sailes, H. E.; Watts, J. P.; Whiting, A. J. Chem. Soc., Perkin
Trans. 1 2000, 3362. (c) Masui, M.; Shiori, T. Tetrahedron Lett. 1998, 39,
195.
5) (a) Brunner, H.; Becker, R. Angew. Chem., Int. Ed. 1984, 23, 222.
b) Blackwall, J. M.; Sonmor, E. R.; Scoccitti, T.; Piers, W. E. Org. Lett.
000, 2, 3921. (c) Hansen, M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 713.
d) Takei, I.; Nishibayashi, Y.; Arikawa, Y.; Uemura, S.; Hidai, M.
Organometallics 1999, 18, 2271.
6) (a) Burk, M. J.; Wang, Y. M.; Lee, J. R. J. Am. Chem. Soc. 1996,
18, 5142. (b) Zhu, G.; Zhang, X. J. Org. Chem. 1998, 63, 9590.
5
(9) For the dynamic kinetic resolutions by lipase/ruthenium catalysis,
see: (a) Persson, B. A.; Larsson, A. L. E.; Ray, M. L.; B a¨ ckvall, J.-E. J.
Am. Chem. Soc. 1999, 121, 1645. (b) Koh, J. H.; Jung, H. M.; Kim, M.-J.;
Park, J. Tetrahedron Lett. 1999, 40, 6281. (c) Huerta, F. F.; Laxmi, Y. R.
S.; B a¨ ckvall, J.-E. Org. Lett. 2000, 2, 1037. (d) Lee, D.; Huh, E. A.; Kim,
M.-J.; Jung, H. M.; Koh, J. H.; Park, J. W. Org. Lett. 2000, 2, 2377. (e)
Kim, M.-J.; Choi, Y. K.; Choi, M. Y.; Kim, M. J.; Park, J. J. Org. Chem.
2001, 66, 4736.
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0.1021/ol0168622 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/16/2001

Scheme 1. Enzyme/Metal-Catalyzed Transformations of
Table 1. Asymmetric Transformation of Ketoximes to
Optically Active Amines
Ketones and Ketoximes
amines. In the absence of the bases, the reductive elimination
of the amino group was more dominant. It was found that
diisopropylethylamine was the most effective among the
bases tested with enzyme.10
The reactions of ketoximes were explored with eight
11
different ketoximes (1a-h), Candida antarctica lipase B
CALB, immobilized on polyacrylamide; trade name Novo-
zym-435) as the resolution catalyst, and palladium on carbon
Pd/C) as the reduction/racemization catalyst. Typically the
reactions were performed with substrate (50 mg, 0.3-0.4
mmol), Novozym-435 (2 mass equiv), Pd/C (0.66 mass
equiv), ethyl acetate (2 equiv), and diisopropylethylamine
a
On the basis of 1H NMR analysis. b Isolated yields. c Enantiomeric
(
excess on the basis of the HPLC analyses using a chiral column. Analytical
conditions: Whelk-O1, n-hexane/2-propanol ) 80/20, flow rate ) 2.0 mL/
min, UV 217 nm (3a-d); Chiralcel OD, n-hexane/2-propanol ) 93/7 (3e),
(
8
5/15 (3f), 90/10 (3g,h), flow rate ) 1 (3a-f), 0.5 mL/min (3g,h), UV
217 nm.
insignificant. The isolated yields of the acetylated products
ranged from 70 to 89%: the highest in the reaction of 1h
and the lowest in that of 1g. The volatile deaminated
byproducts constituting the rest were removed readily during
the workup. The optical purities were high (94-99% ee).
The R-configuration was confirmed for four products (3a,b,d,e)
by comparing their optical rotations with the literature data.13
These results from Table 1 indicate that both acyclic and
cyclic oximes are similarly good substrates toward the
bicatalytic reductive acetylation. It is noteworthy that among
(
3 equiv) in toluene (3-4 mL) at 60 °C under hydrogen gas
12
(1 atm) for 5 days (eq 1). After the reaction was complete,
the catalysts were filtered off. The filtrate was concentrated
and then subjected to column chromatography to fractionate
the desired products. The optical purities were determined
by HPLC using a chiral column. The results are summarized
in Table 1.
(
12) Experimental detail: A representative procedure is described for
the reaction of 1a. Substrate (50 mg, 0.37 mmol), Novozym-435 (100 mg),
ethyl acetate (65 mg, 0.74 mmol), and diisopropylethylamine (143 mg, 1.11
mmol) were added to the suspension of Pd/C (5%, 33 mg, activated as
described in the literature ) in toluene (3.7 mL) in a Schlenk flask. The
flask was charged with dry hydrogen and heated at 60 °C for 5 days. The
7
In all cases, substrates were consumed almost completely
and the amounts of the remaining amine intermediates were
reaction mixture was cooled to room temperature, and the catalysts were
filtered off. The resulting filtrate was concentrated and analyzed by H NMR
spectroscopy. The residue was then subjected to a flash column chroma-
1
tography (silica gel, ethyl acetate/n-hexane ) 1/1) to obtain 3a (48 mg,
6a
(
10) In the racemization, the use of DBN (1,5-diazabicyclo[4.3.0]non-
0.29 mmol, 80%): mp 97-100 °C (lit. mp 98-100 °C).
25
5
-ene) or DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) as the base gave the
better results. However, the enzymatic acylation reaction did not proceed
smoothly in the presence of the strong organic bases.
(13) The optical rotations ([R] D , c ) 0.1, CHCl3) of the products (the
literature data6a are given in parentheses): 3a, +141° (-140°, c ) 0.96,
CHCl3, (S)-isomer), 3b, +146° (+144°, c ) 1.03, CHCl3); 3c, +126°
(-73.6°, c ) 0.21, CHCl3); 3d, +145° (+51.2°, c ) 0.11, CHCl3); 3e,
+123° (+135°, c ) 0.12, CHCl3); 3f, +72.4°; 3g, +83.6°; 3h, +79.2°. It
is noted that our optical rotation of 3c has an opposite sign from that of the
literature value, indicating that the latter was reported incorrectly.
(11) Ketoximes were prepared according to the general methods. See:
(
a) Lachman, A. Organic Syntheses; Wiley: New York, 1943; Collect. Vol.
II, p 70. (b) Larock, R. C. ComprehensiVe Organic Transformation; VCH
Publishers: New York, 1989; p 426.
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Org. Lett., Vol. 3, No. 25, 2001

those examined the bicyclic substrate 1h was the best and
its deoxa analogue 1g the poorest, indicating that the latter
is more prone to reductive deamination.14
products by reductive elimination of the amino group should
1
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be more effectively reduced. Further studies to overcome
17
this limitation and broaden the scope are in progress.
In summary, this work has demonstrated for the first time
that prochiral ketoximes are asymmetrically converted to
optically active amines by lipase-palladium bi-catalysis.
The procedure uses readily available substrates, catalysts,
and reagents. It provides good yields and high optical
purities. However, there is still some room for further
improvements in yields. Particularly, the formation of side
Acknowledgment. We thank the Korean Ministry of
Science and Technology for the support of this work by the
NRL program and the Korean Ministry of Education for the
support of our graduate program by the BK 21 program.
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OL0168622
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14) In this case, the steric crowdness in the cyclohexane ring increases
(16) The reductive elimination of amino group is particularly significant
when the concentration of amine is high. That is why amines are not good
substrates for lipase/ruthenium-catalzyed DKR. The side reaction can be
reduced by increasing the amount of enzymes at the cost of ee.
(17) Simple imines are expected to be asymmetrically transformed to
optically amines by the lipase/ruthenium bi-catalysis. However, simple
imines have some disadvantages over ketoximes. They are more difficult
to make and less stable.
going from oxime to amine, and thus the reductive deamination is slightly
more favored.
(15) For the enantioselective synthesis of other chiral compounds such
as allylic alcohols by the lipase/palladium bi-catalysis, see: (a) Allen, J.
V.; Williams, J. M. J. Tetrahedron Lett. 1996, 37, 1859. (b) Choi, Y.-K.;
Suh, J. H.; Lee, D.; Lim, I.; Jung, J. Y.; Kim, M.-J. J. Org. Chem. 1999,
6
4, 8423.
Org. Lett., Vol. 3, No. 25, 2001
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