Candida rugosa lipase-catalyzed enantioselective hydrolysis in organic solvents. Convenient preparation of optically pure 2-hydroxy-2-arylethanephosphonates

Article abstract of DOI:10.1016/S0040-4039(02)00443-4

A convenient enzymatic method is presented for the preparation of optically pure 2-hydroxy-2-arylethanephosphonates. It is proved that 2-butyryloxy-2-arylethanephosphonates can be enantioselectively hydrolyzed in diisopropyl ether equilibrated with water

Full text of DOI:10.1016/S0040-4039(02)00443-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3247–3249
Candida rugosa lipase-catalyzed enantioselective hydrolysis in
organic solvents. Convenient preparation of optically pure
2-hydroxy-2-arylethanephosphonates†
Yonghui Zhang, Zuyi Li and Chengye Yuan*
Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling Lu, Shanghai 200032, China
Received 26 November 2001; revised 18 February 2002; accepted 28 February 2002
Abstract—A convenient enzymatic method is presented for the preparation of optically pure 2-hydroxy-2-arylethanephosphonates.
It is proved that 2-butyryloxy-2-arylethanephosphonates can be enantioselectively hydrolyzed in diisopropyl ether equilibrated
with water to give both isomers in high yield and excellent enantiomeric excess. © 2002 Elsevier Science Ltd. All rights reserved.
Undoubtedly, lipase-catalyzed kinetic resolution of
enantiomers has become an important tool in organic
chemistry to obtain optically pure compounds.1 The
commonly used method for lipase-catalyzed resolution
is hydrolysis of esters in the aqueous phase. Enzymatic
activity in non-aqueous media did not become a major
field of research until Klibanov’s first report on the
special activity of enzymes in organic solvents.2 Nowa-
days, however, one can carry out reactions such as
esterification and transesterification which are difficult
to conduct in the aqueous phase. This methodology can
overcome the limitations of traditional hydrolysis
methodology, such as poor substrate solubilities, time
consuming work-up procedures and the reuse of
enzymes. The selectivity can be modulated by ‘solvent
engineering’.3 Lipase-catalyzed esterification is, how-
ever, especially effective for primary alcohols; sec-
ondary alcohols often required the use of ‘‘activated
esters’’ such as vinyl acetates, 1-ethoxyvinyl acetate
etc.4 More sterically hindered secondary alcohols, and
those bearing electron withdrawing groups, usually do
not react in this manner in many cases. Enzymatic
alcoholysis of esters of secondary alcohols in organic
solvents seems an attractive alternative.5 However, poor
activity is demonstrated in some cases, probably due to
the weak nucleophility of alcohols. Taking into account
the intensive nucleophility of water, the combination of
hydrolysis and the advantages of enzymatic reactions in
organic media, i.e. hydrolysis in organic solvents, seems
an intriguing solution. One possibility is to perform the
hydrolysis reaction in a water-saturated organic sol-
vent.6 The enzyme can be recovered and recycled easily.
Additionally, the partial loss of specificity due to high
concentration of water in aqueous solutions may be
eliminated, and thus the enantioselectivity may be
higher due to the effect of the organic solvent. Herein
we wish to report this approach for the preparation of
optically pure 2-hydroxy-2-arylethanephosphonates.
Hydroxyalkanephosphonates have received much atten-
tion due to their potential biological activities as well as
their ability to mimic their carboxylic counterparts.7
Moreover, they also serve as useful precursors for a
variety of substituted phosphonates.8 There are several
chemical methods for the preparation of optically
enriched
Although Hammerschmidt has exploited lipases for the
2-hydroxy-2-arylethanephosphonates.7d,9
Scheme 1.
* Corresponding author. Fax: +86-21-64166128; e-mail: yuancy@pub.sioc.ac.cn
† Studies on organophosphorus compounds 116.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00443-4

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Y. Zhang et al. / Tetrahedron Letters 43 (2002) 3247–3249
enantioselective hydrolysis of a series of 1-acyloxy-
phosphonates in an organic-buffer biphase system at
pH 7.0 using an autotitrater,10 few enzymatic methods
have been adopted for the resolution of 2-hydroxy-
alkanephosphonates. We have already developed Can-
dida antarctica lipase B-catalyzed acetylation for the
preparation of such compounds (Scheme 1).11
quently, resulted in low conversion, and also necessi-
tated large excess of lipase to perform the
hydrolysis. After several trials, we chose diisopropyl
ether equilibrated with 0.5% 1.2 M MgCl2 solution,
which resulted in greatly diminished lipase aggrega-
tion (Scheme 2).
a
The choice of the acyl component seemed important
for practical purposes since the acetyl group led to
lower reaction rates under our experimental condi-
tions. Butyryloxyarylethanephosphonates can be
hydrolyzed easily. Indeed, C. rugosa lipase-catalyzed
enantioselective hydrolysis of 2-butyryloxy- 2-aryl-
ethanephosphonates showed even higher enantioselec-
tivity than that performed in buffer system. The
work-up procedure is quite simple and the yield is
also satisfactory since no extraction is needed (see
Table 1).
It is a pity that 2-hydroxy-2-arylethanephosphonates
are not ideal substrates for enzymatic acylation sys-
tems. Although several lipases (Candida cylindracea,
Candida rugosa, Geotrium, Mucor miehei, PS-30,
PPL, Lipozyme, IM-60 etc.) were screened for acetyl-
ation, none proved to be fruitful. We deduced that
the ineffectiveness may be ascribed to the bulkiness of
the molecular structure. Alcoholysis of the esters did
not give satisfactory results either. Among the lipases
tested, however, Candida rugosa lipase (CRL)-cata-
lyzed hydrolysis in buffer system proved effective
(E=65). Unfortunately, the yield was low due to loss
in the unavoidable extraction work-up, and the
enzyme could not be recycled. We then turned our
attention to CRL-catalyzed hydrolysis in water satu-
rated solvents. The aggregation of lipase is serious in
water saturated diisopropyl ether and this, conse-
In conclusion, the high enantioselectivity and the sim-
plicity of the experimental procedure make C. rugosa
lipase-catalyzed enantioselective hydrolysis in diiso-
propyl ether quite a convenient procedure for the
preparation of optically pure 2-hydroxyarylethane-
phosphonates.
Scheme 2.
Table 1. C. rugosa lipase-catalyzed enantioselective hydrolysis of 1-butyryloxylarylethylphosphonatesa
Entry
R1
R2
Time (h)
1
2
Ee
Yield (%)b
Ee (%)c
Yield (%)b
Ee (%)d
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
Me
Et
n-Pr
i-Pr
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
30
40
40
48
38
39
44
30
30
28
15
27
33
40
20
35
41
44
43
41
44
41
43
45
41
42
42
41
41
44
45
41
\95
\95
\95
\95
\95
\95
\95
\95
\95
\95
\95
\95
\95
\95
88.7
42
45
44
42
40
42
44
40
42
42
45
44
42
42
40
39
\95
\95
\95
\95
\95
\95
\95
\95
\95
\95
\95
\95
\95
\95
93.8
\100
\100
\100
\100
\100
\100
\100
\100
\100
\100
\100
\100
\100
\100
93
2-ClC6H4
4-FC6H4
4-NO2C6H4
4-EtC6H4
4-BrC6H4
2-BrC6H4
2,4-Cl2C6H3
3-ClC6H4
4-MeOC6H4
2-CF3C6H4
2-Furyl
9
10
11
12
13
14
15
16
2-Naphthyl
\95
\95
\100
a All reactions were performed on 1 mmol scale with 100 mg crude lipase and 4 ml diisopropyl ether, at 30°C.
b Isolated yield after column chromatography.
c Ee value was determined by 31P NMR with quinine as the solvating agent, a single peak was judged as >95% ee; the configuration of the alcohol
was assigned as (S) by comparing the optical rotation value with the literature.7d,9g,h,i
d Determined by 31P NMR with quinine as the solvating agent after chemical conversion into alcohols using K2CO3/MeOH.
e The enantiomeric ratio, E=ln[(1−c)(1−ees)]/ln[(1−c)(1+ees)]=ln[1−c(1+eep)]/ln[1−c(1−eep)]; c=ees/(ees+eep).

Y. Zhang et al. / Tetrahedron Letters 43 (2002) 3247–3249
3249
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