Kinetic resolution of propargylic alcohols via stereoselective acylation catalyzed by lipase PS-30

Article abstract of DOI:10.1016/j.molcatb.2013.08.009

By using lipase PS-30 as catalyst, the kinetic resolution of a series of racemic propargylic alcohols has been achieved via stereoselective acylation. The value of kinetic enantiomeric ratio (E) reached up to 139. Substituent effect is briefly discussed.

Full text of DOI:10.1016/j.molcatb.2013.08.009

Journal of Molecular Catalysis B: Enzymatic 97 (2013) 184–188
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Journal of Molecular Catalysis B: Enzymatic
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Letter
Kinetic resolution of propargylic alcohols via stereoselective acylation catalyzed by lipase PS-30
a r t i c l e i n f o
a b s t r a c t
Keywords:
Propargylic alcohols
Lipase PS-30
Kinetic resolution
Stereoselective acylation
Kinetic enantiomeric ratio (E)
By using lipase PS-30 as catalyst, the kinetic resolution of a series of racemic propargylic alcohols has
been achieved via stereoselective acylation. The value of kinetic enantiomeric ratio (E) reached up to 139.
Substituent effect is briefly discussed.
© 2013 Elsevier B.V. All rights reserved.
1. Introduction
spectra were obtained on a Bruker AM-300 (282 M Hz) spectrom-
eter using CFCl3 as an external standard; downfield shifts being
Chiral propargylic alcohols are among the most versatile syn-
thetic materials [1,2] as they bear a hydroxyl group and an
propargylic group on one chiral carbon. A series of bio-active com-
pounds such as eicosanoids [3–5], macrolides [6] and enediyne
antibiotics [7] were enantio-selectively prepared with optically
active propargylic alcohols as important intermediates. Catalytic
enantioselective formation of these chiral propargylic alcohols
[8–16]5 or TMS acetylenes[17–22] included kinetic resolution (KR)
or dynamic kinetic resolution(DKR) promoted with ruthenium
complex, chiral Brønsted acids, or bio-catalyst.
In KR, propargylic alcohol racemates are treated by an acylat-
ing reagent in the presence of catalyst to stereoselectively obtain
an acylated enantiomer and an unreacted enantiomer [23–26].
Alternatively, acylated propargylic alcohol racemates are stere-
oselectively hydrolyzed in buffer solution with the promotion of
a lipase or an esterase to achieve the corresponding hydrolyzed
enantiomer and an unreacted enantiomer [24,27–30]. A pair of
enantiomers can be obtained simultaneously and the theoretical
yield of this method is 50%.
designated as positive, all chemical shifts (ı) were expressed in ppm
and coupling constants (J) are in Hz. Mass spectra were recorded
on a Finnigan-MAT-8430 instrument using EI ionization at 70 eV.
High-Resolution mass spectral (ESI) analyses were performed on
a Finnigan MAT 8430 spectrometer. IR spectra were recorded on
a Nicolet 380 spectrometer. Optical rotations were measured by
WZZ-2 polarimeter. Melting points were measured on a WRS-2A
melting point apparatus. Enantiomeric excess values were per-
formed by a Breeze LC system (Waters Corporation) on a Chiralcel
OJ-H, OD-H or AD-H column using isopropanol–hexanes as mobile
phase.
2.3. General experimental procedure for the kinetic resolution of
racemic propargylic alcohols
General procedure for KR of propargylic alcohols: In a 5 mL
bake-dried vial charged with lipase PS-30 (50 mg, corresponding
to 1 mmol of the racemic propargylic alcohols) and 2 grains of
4A molecular sieves was flushed with nitrogen for several times,
the racemic cyanohydrins dissolved in dry toluene (2 mL) and
vinyl acetate (130 mg, 1.5 mmol) dissolved in dry toluene (4 mL)
were added. The mixture was stirred at 25 ◦C and analyzed by TLC
[petroleum ether/ethyl acetate (20:1–3:1)] until consumption of
the starting material was about 50%. The mixture was then filtered
and the solid washed with dry DCM (5 mL). The solvent was evap-
orated in vacuo and the residue was purified on silica gel using
petroleum ether/ethyl acetate as the eluent.
Following our previous investigation in the kinetic resolution
of cyanohydrins [31,32] and allylic alcohols [33] catalyzed by the
lipase, we are now investigating the stereoselective preparation of
propargylic alcohols catalyzed by enzyme.
2. Materials and methods
2.1. Materials
Lipase PS-30 was purchased from Sigma–AldrichTM. All the
other lipases were purchased from Amano. All the solvents used
in the reaction were purified by re-distillation. Vinyl acetate was
purified by re-distillation. Other reagents were used as purchased
from commercial suppliers without further purification.
3. Results and discussion
Racemic propargylic alcohols were treated with allyl acetate
in the presence of lipase PS-30 (Sigma–Aldrich) in toluene to
afford the (S)-propargylic alcohol acetate and the unreacted (R)-
propargylic alcohol (Scheme 1). After consumption of the starting
material reached to about 50%, the reaction was stopped and
worked up for enantiomeric excess (ee) value evaluation. From
2.2. General methods
1H and 13C NMR spectra were recorded on a Bruker AV-400
(400 MHz) spectrometer with Me4Si as internal standard. 19F NMR
1381-1177/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molcatb.2013.08.009

Letter / Journal of Molecular Catalysis B: Enzymatic 97 (2013) 184–188
185
Table 1
Stereoselective acetylation of propargylic alcohols 1a-n with vinyl acetate catalyzed by lipase PS-30.
O
lipase PS-30
vinyl acetate
O
OH
OH
R'= H or Me
+
R
R
R
Toluene, r.t.
R'
R'
R'
rac 1a-n
2a-n
3a-n
.
e
Entry
Alcohol
eeP(2)a (%)
eeS(3)b (%)
Ec
Cd (%)
CHPLC (%)
Reaction time (h)
OH
1
89.6
83.8
48.6
45
47
43
45
48.3
51.8
44.5
53.3
24
72
24
24
2a
OH
2
3
4
88.2
94.1
86.1
94.8
75.4
98.4
58.5
73.9
64.4
Br
Br
2b
2c
OH
OH
F
2d
OH
5
87.4
23.8
19.0
29
21.4
72
O2N
2e
OH
6
90.1
65.5
37.4
39
42.1
24
MeO
2f
OH
7
8
34.4
73.8
79.6
82.4
4.6
38
44
69.8
52.8
24
18
Me
2g
16.6
OH
S
2h

186
Letter / Journal of Molecular Catalysis B: Enzymatic 97 (2013) 184–188
Table 1 (Continued)
e
Entry
Alcohol
eeP(2)a (%)
eeS(3)b (%)
Ec
Cd (%)
CHPLC (%)
Reaction time (h)
OH
9
51.4
99.6
17.2
41
52.8
43.5
34.4
48
2i
OH
10
11
96.1
96.8
74.1
48.8
95.0
41
43
24
24
2j
OH
OH
OH
103.0
2k
12
13
94.2
77.2
80.8
44
45
24
2l
96.1
68.1
139.2
44
41.2
24
OMe
2m
OH
14
2.8
2.7
1.0
27.9
49
120
CH
3
a
ee(P) stands for enantiomeric excess of propargylic alcohol acetate of the fast reacting enantiomer of the propargylic alcohol. Analysis was performed on Chiralcel OJ-H
or OD-H column with hexane/i-PrOH in varying ratios to afford ee values.
b
ee(S) stands for enantiomeric excess of the slow reacting enantiomer of the propargylic alcohol, which was obtained after the propargylic alcohol was converted into the
corresponding acetate then subjected to chiral HPLC analysis on Chiralcel OD-H column with hexane/i-PrOH in varying ratios.
c
E = ln[(1 − CHPLC)(1 − eeS)]/ln[(1 − CHPLC)(1 + eeS)], as defined in Ref. [9].
d
Determined by isolated yield of 2.
e
CHPLC = eeS/(eeP + eeS), as defined in Ref. [9].
the ee values, the values of kinetic enantiomeric ratio (E), which
is defined in Refs. [34,35], were calculated.
For discussion of the data shown in Table 1, we take 2a (entry 1,
E = 48.6) as the parent compound for comparison with the others.
We can see the phenomena as follows:
Table 1 summarizes our results. Some substrates shown in
Table 1 (compounds shown in entries 5–7 and 10–11) are in the
first time subjected to KR. The E values of seven substrates (entries
2, 3, 4, 10, 11, 12 and 13) are close to or larger than 50. Accord-
ing to Schneider et al. [27], value of E > 50 would be sufficient for
the production of the desired alcohol acetates in good yield and
enantiomeric purity.
(1) Compound 2b–2d (entries 2–4, E = 58.3–64.4), which bear a
substituent of moderate size on meta or para position of the
phenyl group, gave higher E values, while compound 2e, 2f and
2i (entry 5, 6 and 9, E = 19.0, 37.4, 17.2, respectively), which bear
a substituent of larger size on para position, gave significantly
lower E values. This fact implies that the size of substituent
(i.e. the size of R group) has influence on the interaction of the
substrate with the enzyme.
(2) When the size of substituents on the phenyl group was small
enough, such as F and Br (whose atomic radius is only 42 and
94 pm, respectively, while that of H is 53 pm) [36], the steric
hindrance would not be the key factor for the combination of
the substrates and the enzyme and the electronic-withdrawing
O
lipase PS-30
vinyl acetate
O
OH
OH
R'= H or Me
+
R
R
R
Toluene, r.t.
R'
R'
R'
Scheme 1.

Letter / Journal of Molecular Catalysis B: Enzymatic 97 (2013) 184–188
187
Table 2
Configuration assignment of 2a, 2f, 3g, 3i, 3j and 3l by comparison with the reported [␣]D data.
Compound
Measured values
Reported values
Ref
[␣]D
ee (%)
[␣]D
ee (%)
2a
2f
3g
3i
3j
3l
+2.8(c 0.52, CHCl3)
+17.9(c 0.52, CHCl3)
+11.8(c 0.42, CHCl3)
+6.4(c 0.61, CHCl3)
+4.7(c 0.44, CHCl3)
+2.6(c 0.39 CHCl3)
89.7
90.0
79.6
51.3
74.1
77.2
+3.4(c 1.07, CHCl3)
−6.6(c 1.02, CHCl3)
+27.7(c 0.74, CHCl3)
+38.2(c 1.07, CHCl3)
+11.1(c 2.05, CHCl3)
+6.8(c 2.35, CHCl3)
99(S)
5e
5e
5e
5d
5f
24(R)
94 (R)
94(R)
>95(R)
>95(R)
5f
NMR and HRMS of the new compounds and HPLC chromatograms
for the ee value determination.
OH
OH
M
L
L
M
Acknowledgements
This work is financially supported by a grant of The National
Natural Science Foundation of China (NSFC, Grant No. 21272305),
The Natural Science Foundation of Shanghai Municipality (Grant
No. 12ZR1400200) and The Fundamental Research Funds for the
Central Universities.
unfavored enentiomer
favored enantiomer
L= large size group; in this paper, L=aryl group
Appendix A. Supplementary data
M= middle size groip; in this paper, M= alkynyl group
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.molcatb.2013.
08.009.
Fig. 1. A schematic presentation of the Kazlauskas’ rule.
effect would make some positive contribution to the E values
(entries 2–4, E = 58.3–64.4, while in entry 1, E = 48.6).
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Xiyin Zhua
a Key Lab of Eco-Textile, The Ministry of Education,
Donghua University, 2999 Renmin Road North,
Songjiang District, Shanghai 201620, China
∗ Corresponding author at: Key Lab of Eco-Textile,
The Ministry of Education, Donghua University,
2999 Renmin Road North, Songjiang District,
Shanghai 201620, China. Tel.: +86 21 67792594.
E-mail address: prchen@dhu.edu.cn (P. Chen)
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Peiran Chena,b,∗
a Key Lab of Eco-Textile, The Ministry of Education,
Donghua University, 2999 Renmin Road North,
Songjiang District, Shanghai 201620, China
21 May 2013
Available online 28 August 2013