Asymmetric reductive acylation of aromatic ketoximes by enzyme-metal cocatalysis

Article abstract of DOI:10.1021/jo800270n

(Chemical Equation Presented) We have developed an efficient procedure for the asymmetric synthesis of chiral amides from ketoximes. This one-pot procedure employs two different types of catalysts, Pd nanocatalyst and lipase, for three consecutive transfo

Full text of DOI:10.1021/jo800270n

SCHEME 1. Asymmetric Reductive Acylation of Ketoximes
to Amides
Asymmetric Reductive Acylation of Aromatic
Ketoximes by Enzyme-Metal Cocatalysis
Kiwon Han, Jaiwook Park,* and Mahn-Joo Kim*
Department of Chemistry, Pohang UniVersity of Science and
Technology, San-31 Hyojadong, Pohang 790-784, Korea
mjkim@postech.ac.kr
ReceiVed February 2, 2008
oxidation of alcohols,7 the hydrogenolysis of epoxides,8 and the
dynamic kinetic resolution (DKR) of primary amines.9 The Pd
nanocatalyst, readily prepared as palladium nanoparticles en-
trapped in aluminum oxyhydroxide (Pd/AlO(OH)), displayed
high activity and excellent stability even at 100 °C. These superb
properties encouraged us to further explore its utility as a
component of catalyst for the asymmetric conversion of
ketoximes to chiral amides, in which it acts as a dual catalyst
for both hydrogenation and racemization (Scheme 1). Previously,
we used Pd/C as such a dual catalyst, which required a long
reaction time (5 days) for moderate yields.10
First, we explored the reactions of 1a as a standard substrate
to optimize the reaction conditions. In addition to the Pd
nanocatalyst, thermostable Candida antarctica lipase B (CALB;
trade name, Novozym-435) was chosen as the catalyst for the
enantioselective acylation of amine intermediate with ethyl
methoxyacetate. The acyl donor was chosen because it is more
reactive than other acyl donors such as ethyl acetate and thus
requires much smaller amounts of enzyme.11 The reactions were
carried out with 1 mol% of Pd/AlO(OH), 30 mg/mmol of
Novozym-435, 1.7 equiv of ethyl methoxyacetate in toluene at
70 °C with a variation in hydrogen pressure from 0.05 to 1 bar
for 48 h.
The data from Table 1 indicate that the reaction under 1 atm
of hydrogen afforded unsatisfactory results (71% yield and 87%
ee) with the formation of a significant amount of ethylbenzene
5 as a byproduct (entry 1). This byproduct has been known to
come from a nonproductive pathway including the condensation,
hydrogenation, and deamination of amines.5b Interestingly, the
addition of molecular sieves substantially improved the enan-
tiopurity of product to a satisfactory level with a slight increase
in yield (entry 2). On the other hand, the yield was markedly
enhanced by decreasing the hydrogen pressure. The best results
(90% yield and 98% ee) thus were obtained in the presence of
We have developed an efficient procedure for the asymmetric
synthesis of chiral amides from ketoximes. This one-pot
procedure employs two different types of catalysts, Pd
nanocatalyst and lipase, for three consecutive transformations
including hydrogenation, racemization, and acylation. Eight
ketoximes have been efficiently transformed to the corre-
sponding amides in good yields (83-92%) and high enan-
tiomeric excesses (93-98%).
Optically active amines and their simple derivatives are an
important class of chiral molecules which are useful as chiral
building blocks, auxiliaries, or resolving agents in asymmetric
synthesis.1 A number of methods are currently available for their
asymmetric syntheses.2 For example, asymmetric reductive
amination of ketones provides a useful route to them, particularly
R-chiral amines.3 We herein wish to report an alternative using
Pd nanocatalyst and lipase in combination for the synthesis of
R-chiral amides.4,5 In this one-pot procedure, ketoximes are
converted to optically active amides through three coupled
reactions (hydrogenation, racemization, and enantioselective
acylation) (Scheme 1).
Recently, we have developed a practical Pd nanocatalyst for
use in several reactions including the reduction of olefins,6 the
(1) Breuer, M.; Dietrich, K.; Habicher, T.; Hauer, B.; Kessaeler, M.; Stu¨rmer;
Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788–824.
(2) Tararov, V. I.; Bo¨rner, A. Synlett 2005, 203–211.
(3) (a) Nugent, T. C.; Ghosh, A. K.; Wakchaure, V. N.; Mohanty, R. R.
AdV. Synth. Catal. 2006, 348, 1289–1299. (b) Nugent, T. C.; El-Shazly, M.;
Wakchaure, V. N. J. Org. Chem. 2008, 73, 1297–1305.
(6) Kwon, M. S.; Kim, N.; Park, C. M.; Lee, J. S.; Kang, K. Y.; Park, J.
Org. Lett. 2005, 7, 1077–1079.
(7) Kwon, M. S.; Kim, N.; Seo, S. H.; Park, I. S.; Cheedrala, R. K.; Park, J.
Angew. Chem., Int. Ed. 2005, 44, 6913–6915.
(4) Reviews for chemoenzymatic DKR: (a) Kim, M.-J.; Ahn, Y.; Park, J.
Curr. Opin. Biotechnol. 2002, 13, 578–587. (b) Pamies, O.; Ba¨ckvall, J.-E. Chem.
ReV. 2003, 103, 3247–3262. (c) Kim, M.-J.; Park, J.; Ahn, Y. In Biocatalysis in
the Pharmaceutical and Biotechnology Industries; Patel, R. N., Ed.; CRC Press:
Boca Raton, FL, 2007; pp 249-272.
(8) Kwon, M. S.; Park, I. S.; Jang, J. S.; Lee, J. S.; Park, J. Org. Lett. 2007,
9, 3417–3419.
(9) Kim, M.-J.; Kim, W.-H.; Han, K.; Choi, Y. K.; Park, J. Org. Lett. 2007,
9, 1157–1159.
(5) For chemoenzymatic DKRs of amines, see: (a) Reetz, M. T.; Schimossek,
K. Chimia 1996, 50, 668–669. (b) Parvulescu, A.; Vos, D. D.; Jacobs, P. Chem.
Commun. 2005, 5307–5309. (c) Paetzold, J.; Ba¨ckvall, J. E. J. Am. Chem. Soc.
2005, 127, 17620–17621.
(10) Choi, Y. K.; Kim, M. -J.; Ahn, Y. Org. Lett. 2001, 3, 4099–4101.
(11) For molecular modeling study of N-acylation of amine with methoxy-
acetate, see: Cammenberg, M.; Hult, K.; Kim, S. ChemBioChem 2006, 7, 1745–
1749.
4302 J. Org. Chem. 2008, 73, 4302–4304
10.1021/jo800270n CCC: $40.75 2008 American Chemical Society
Published on Web 05/03/2008

TABLE 1. Asymmetric Reductive Acylation of 1aa
TABLE 2. Asymmetric Reductive Acylation of Ketoximes (1a-h)a
MS 4A
(wt %)
H2
(bar)
convb
(%)
3ab
(%)
2ab
(%)
4b
(%)
5b
(%)
eec
(%)
entry
1
2
3
4
5
6
1
1
0.5
0.2
0.1
0.05
>98
>98
>98
>98
>98
60
71
73
80
88
90
42
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
9
29
27
20
12
10
1
87
95
94
98
98
92
250
250
250
250
250
a All of the reactions were performed in a 75 mL Schlenk flask.
b
Measured by H NMR. c Measured by HPLC with a chiral column.
1
molecular sieves with 0.1 bar of molecular hydrogen (entry 5).
Further decrease in hydrogen pressure resulted in slow conver-
sion with a poor yield (entry 6).
The reactions of additional ketoximes 1b-h12 were carried
out under the optimized conditions: a substrate (0.3 mmol), Pd/
AlO(OH) (1 mol % of Pd), Novozym-435 (30 mg/mmol), ethyl
methoxyacetate (1.7 equiv), 4Å molecular sieve (330 mg/mmol),
toluene (3 mL), 0.1 bar of hydrogen, 70 °C, 48 h. 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 enantiopurities of
products were determined by HPLC using a chiral column.
The data from Table 2 indicate that all the substrates were
successfully transformed into the corresponding amides with
good yields (83-92%) and high enantiopurities (93-98%). It
is noteworthy that the nature of substituent on benzene ring of
substrate affected the yield more or less. Among acyclic
substrates, 1c was transformed with the highest yield and 1d
with the lowest yield (entries 1-4). This observation suggests
that substrates with a strongly electron-attracting substituent
should be less prone to the side reactions. Among cyclic
substrates, 1h was transformed with the highest yield (entries
6-8). At present, a clear rationale is not available for the highest
yield. It might be a result of reduced hindrance by the presence
of oxygen in the aliphatic ring.
a All of the reactions were performed in a 75 mL Schlenk flask.
b Isolated yield. c Measured by HPLC with (R,R) Whelk-O1 column.
d Measured by HPLC with a Chiralcel-OD column.
The amide products can be readily reduced to the corre-
sponding secondary amines which should be useful as chiral
building blocks, ligands, or auxiliaries for asymmetric synthe-
sis.13 As a representative example, amide 3a was reduced with
LiAlH4 to obtain secondary amine 6 quantitatively without loss
in enantiopurity (Scheme 2). This conversion thus illustrates
an atom-economical use of the amide products without deacy-
lation. In summary, we have demonstrated that achiral ketoximes
are efficiently converted by the cooperation of two different
types of catalysts, Pd nanocatalyst and lipase, to chiral amides
in good yields.
SCHEME 2. Reduction of Chiral Amide to Secondary
Amine
were added to 50 mL round-bottom flask. After the mixture was
stirred at 50 °C for 20 min to give a black suspension, water (3
mL) was added for gelation. The black solid was filtered, washed
with acetone, and dried in a 120 °C oven for 5 h and in vacuo at
room temperature for 1 day to give Pd/AlO(OH) as dark gray
powder (1.16 g, 0.9 wt % of Pd).
General Procedure for Asymmetric Reductive Acylation of
Ketoximes. A suspension containing 1a (41 mg, 0.30 mmol), Pd
nanocatalyst (36 mg, 1.0 mol% Pd), Novozym-435 (9 mg, 30 mg/
mmol), 4 Å molecular sieves (100 mg, 330 mg/mmol), and ethyl
methoxyacetate (70 mg, 1.7 equiv) in dry and degassed toluene (3
mL, 0.10 M) was stirred at 70 °C under 0.1 bar of hydrogen pressure
Experimental Section
Preparation of Pd/AlO(OH). Pd(OAc)2 (22 mg, 0.1 mmol), (s-
BuO)3Al (4 g, 16.2 mmol), THF (1 mL), and 2-butanol (1 mL)
(12) Ketoximes were prepared from corresponding ketones 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.
(13) (a) Kozma, D. In Optical Resolutions Via Diastereomeric Salt Formation;
Kozma, D., Ed.; CRC Press: Boca Raton, 2002; p 690. (b) Whitesell, J. K. Chem.
ReV. 1989, 89, 1581–1590. (c) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers,
Racemates, and Resolution; John Wiley & Sons: New York, 1981.
J. Org. Chem. Vol. 73, No. 11, 2008 4303

in a 75 mL Schlenk flask. After 48 h, the reaction mixture was
cooled to room temperature and filtered through a glass filter (pore
size: 20-30 µm). The filtrate was concentrated and analyzed by
1H NMR spectroscopy, indicating that all of the substrate was
consumed. The mixture was subjected to flash chromatography
(silica gel, n-hexane/ethyl acetate ) 1/1) to provide 3a (51 mg,
0.26 mmol, 88%, 98% ee).
removed by filtration followed by washing with methylene chloride
(10 mL), and the filtrate was dried with Na2SO4 and concentrated
to obtain 6 (colorless liquid, (45 mg, 97%, 98% ee)). The % ee
was determined by HPLC after converting to the corresponding
amide by treatment with a few drops of acetic anhydride. 1H NMR
(300 MHz, CDCl3, ppm): δ 7.33-7.21 (m, 5H), 3.80-3.73 (m,
1H), 3.48-3.42 (m, 2H), 3.33 (s, 3H), 2.67-2.59 (m, 2H), 1.37
(d, J ) 6.57 Hz, 3H). 13C NMR (75 MHz, CDCl3, ppm): δ 145.6,
128.4, 126.9, 126.6, 58.7, 58.4, 47.3, 24.4; HPLC ((R,R) Whelk-
O1, n-hexane/2-propanol ) 80/20, flow rate ) 0.5 mL/min, UV
2-Methoxy-N-((R)-1-phenylethyl)acetamide (3a). 1H NMR
(300 MHz, CDCl3, ppm): δ 7.37-7.25 (m, 5H), 6.76 (s, 1H),
5.23-5.13 (m, 1H), 3.89 (dd, J1 ) 19.65 Hz, J2 ) 14.97 Hz, 2H),
3.39 (s, 3H), 1.51 (d, J ) 6.93 Hz, 3H). 13C NMR (75 MHz, CDCl3,
ppm): δ 168.6, 143.0, 128.7, 127.4, 126.1, 72.0, 59.1, 48.0, 21.9.
HPLC ((R,R) Whelk-O1, n-hexane/2-propanol ) 80/20, flow rate
) 2.0 mL/min, UV 217 nm): (S)-3a ) 4.97 min, (R)-3a ) 11.86
min; mp 59-60 °C. [R]25D +84.7 (c ) 0.5, CHCl3). Anal. (VarioEL
III CHN) Calcdfor C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found:
C, 68.31; H, 7.82; N, 7.24.
Synthesis of (R)-N-(2-Methoxyethyl)-1-phenylethylamine
(6). A suspension containing 3a (50 mg, 0.259 mmol, 98% ee) and
LiAlH4 (79 mg, 2.07 mmol) in distilled THF (1.5 mL, 0.2 M) was
refluxed in a 10 mL round-bottom flask equipped with a condenser.
After confirming that the reaction was completed with TLC, the
reaction mixture was cooled to 0 °C in ice bath, and water (75 µL,
4.14 mmol) and 1 N NaOH solution (75 µL) were added to the
reaction mixture for quenching of LiAlH4. The precipitate was
217 nm): (S)-6 ) 16.87 min, (R)-6 ) 18.02 min. [R]25 +36.2 (c
D
) 1.06, MeOH). HRMS (EI): C11H17NO calcd 179.1310 (M+), obsd
179.1310.
Acknowledgment. This work was supported by the Ministry
of Science and Technology through KOSEF (R01-2006-000-
10696-0) and by the Ministry of Education and Human
Resources through KRF (BK21 program).
Supporting Information Available: Characteristic data of
3b-h, 1H and 13C NMR spectra, and HPLC chromatograms of
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO800270N
4304 J. Org. Chem. Vol. 73, No. 11, 2008