Kinetic resolution of cyanohydrins via enantioselective acylation catalyzed by lipase PS-30

Article abstract of DOI:10.1016/j.tetlet.2008.08.090

By using lipase PS-30 as catalyst, the kinetic resolution of a series of racemic cyanohydrins has been achieved via enantioselective acylation. The values of kinetic enantiomeric ratio (E) reached up to 314. Substituent effect is also briefly discussed.

Full text of DOI:10.1016/j.tetlet.2008.08.090

Tetrahedron Letters 49 (2008) 6440–6441
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Tetrahedron Letters
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Kinetic resolution of cyanohydrins via enantioselective acylation catalyzed
by lipase PS-30
*
Qing Xu, Xiaohong Geng, Peiran Chen
Laboratory of Organic Fluorine Chemistry, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 Renmin Road North,
Songjiang District, Shanghai 201620, China
a r t i c l e i n f o
a b s t r a c t
Article history:
By using lipase PS-30 as catalyst, the kinetic resolution of a series of racemic cyanohydrins has been
achieved via enantioselective acylation. The values of kinetic enantiomeric ratio (E) reached up to 314.
Substituent effect is also briefly discussed.
Received 27 June 2008
Revised 23 August 2008
Accepted 26 August 2008
Available online 29 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Cyanohydrin
Lipase PS-30
Kinetic resolution
Enantioselective acylation
Kinetic enantiomeric ratio (E)
Enantiomerically pure (or enriched) cyanohydrins are versatile
synthetic intermediates as they bear a hydroxyl group and a cyano
group on one chiral carbon. They therefore provide a wide space
for transformation into a large number of chiral molecules, which
are important in the synthesis of biologically active molecules.
Asymmetric formation of cyanohydrins has been an extensively
investigated topic and several excellent reviews have appeared.1
The methods for their formation can roughly be divided into three
major categories: (1) hydrocyanation of aldehydes or ketones
catalyzed by chemical catalyst, (2) hydrocyanation of aldehydes
or ketones catalyzed by biological catalyst, and (3) enantioselective
acylation or hydrolytic deacylation of racemic cyanohydrins or
racemic cyanohydrin esters catalyzed by esterase or lipase,
namely, simple kinetic resolution (KR) and dynamic kinetic resolu-
tion (DKR).
In the KR, a cyanohydrin racemate is treated by an acylating
reagent in the presence of a lipase or an esterase to enantioselec-
tively obtain an acylated enantiomer and an unreacted enantio-
mer,2 or alternatively, an acylated racemic cyanohydrin racemate
is enantioselectively hydrolyzed in the presence of a lipase or an
esterase to give a hydrolyzed enantiomer and an unreacted enan-
tiomer.2b,3 The theoretical yield of this method is 50% and, in the
ideal cases, both of the two enantiomers can be obtained simulta-
neously in high ee values.
As a continuation of our previous investigation of asymmetric
synthesis of cyanohydrin catalyzed by plant originated catalysts,4
we are now undertaking a study on the stereoselective formation
of cyanohydrins by alternative methods. Here we report our KR
results.
Cyanohydrin racemate was treated with vinyl acetate in the
presence of lipase PS-30 (Amano) in diethyl ether to afford the
(S)-cyanohydrin acetates and the unreacted (R)-cyanohydrin
(Scheme 1). After the reaction proceeded by about 50%, the reac-
tion was stopped and worked up for enantiomeric excess (ee) value
analysis. The kinetic enantiomeric ratio (E) was calculated based on
the measured ee values according to the equation defined in Ref. 5.
Table 1 summarizes the results. As can be seen from the data in
Table 1, the ee values can be altered by adjusting the conversion
through changing the reaction time to obtain the desired product
with high ee value and reasonable yield. Among the observed ten
substrates, seven (entries 1, 2, 3, 5, 6, 9, and 10) gave satisfactory
E values, which are close to or higher than 100. According to
Schneider et al.,3a values of E >50 are sufficient for the production
O
OH
OH
O
lipase PS-30 / Vinyl acetate
+
R
CN
, 15 oC
Et2O
R
CN
R
CN
1a-j
2a-j
3a-j
* Corresponding author. Tel.: +86 21 67792612.
E-mail address: prchen@dhu.edu.cn (P. Chen).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.090

Q. Xu et al. / Tetrahedron Letters 49 (2008) 6440–6441
6441
Table 1
negative substituent (fluorine) (entries 4 and 6) decrease the E val-
ues remarkably probably due to their weaker interaction with the
enzyme. However, fluorine substituted on meta position of the
phenyl group (entry 5) appears to be of not much influence. 4-F-
(entry 6) substitution in the benzene ring requires considerably
longer reaction time (50 h) to achieve about 50% conversion. Dif-
fering from the aromatic cyanohydrins in Table 1, compounds 2i
and 2j (entries 9 and 10) are aliphatic cyanohydrins with phenyl
group substituted on the b or Y carbon atom, which also gave high
E values.
Configuration assignment of the KR products was made by com-
paring the observed optical rotation with those reported in the lit-
eratures2i,4a,6–8,2c (for details, see Table 2 in Supplementary data).
As a result, the acetates have an S configuration, while the unre-
acted cyanohydrins have an R configuration.
Stereoselective acetylation of cyanohydrins 1a–j with vinyl acetate in diethyl ether at
15 oC catalyzed by lipase PS-30
O
OH
OH
O
lipase PS-30 / Vinyl acetate
+
R
CN
, 15 oC
Et2O
R
CN
R
CN
1a-j
2a-j
eeA (3)b
3a-j
Entry
1
R
eeE (2)a
(%)
Ec
Cc
Reaction
time (h)
(%)
(%)
98.3
71.1
48.6
249
191
42
24
2a
In conclusion, we have achieved the kinetic resolution of ten
racemic cyanohydrins via enantioselective acylation by using li-
pase PS-30 as the catalyst. Majority of the substrates gave E values
close to or higher than 100.
2
3
4
5
98.3
98.7
94.3
98.6
33
32
25
33
23.5
H3C
2b
Acknowledgments
47.1
31.3
47.8
244
46
29
25
27
H3CO
We are grateful to The National Natural Science Foundation of
China (Grant No. 20602007) and The State Key Laboratory of Bio-
organic Chemistry and Natural Products Chemistry, SIOC, CAS, for
financial support.
2c
F
Supplementary data
2d
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.08.090.
F
F
228
References and notes
2e
2f
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6
7
92.8
87.2
93.6
36.5
94
21
50
30
50
25
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2g
8
9
72.8
94.1
98.4
82.3
82.6
80.7
17
85
54
47
45
24
20
24
2h
2i
10
314
2j
a
eeE stands for enantiomeric excess of cyanohydrin acetate of the fast reacted
enantiomer of the cyanohydrin. Analysis was performed on Chiralcel OJ-H or OD-H
column with hexane/iPrOH in varying ratios to afford ee values.
b
eeA stands for enantiomeric excess of the slow reacted enantiomer of the cya-
nohydrin, which was obtained after the cyanohydrin was converted into the cor-
responding acetate (but into its propionate for 3g and 3h for HPLC baseline
separation) then subjected to chiral HPLC analysis on Chiralcel OD-H column with
hexane/iPrOH in varying ratios.
c
E = ln[1 À C(1 + eeE)]/ln[1 À C(1 À eeE)], where C = eeE/(eeE + eeA) as defined in
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of the desired cyanohydrin acetates in good chemical yield and
enantiomeric purity. Data in Table 1 show that the bulky aryl
group (entries 7 and 8) and the aryl group bearing a strong electro-