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

Article abstract of DOI:10.1016/j.tetlet.2011.08.093

By using lipase PS-30 as catalyst, the kinetic resolution of a series of racemic allylic alcohols has been achieved via stereoselective acylation. The value of kinetic enantiomeric ratio (E) reached up to 968. Substituent effect is briefly discussed.

Full text of DOI:10.1016/j.tetlet.2011.08.093

Tetrahedron Letters 52 (2011) 5758–5760
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Kinetic resolution of allylic alcohols via stereoselective acylation catalyzed
by lipase PS-30
Peiran Chen a,b, , Peng Xiang a
⇑
a School of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 Renmin Road North, Songjiang District, Shanghai 201620, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, CAS, Shanghai 200032, 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 allylic alcohols has been
achieved via stereoselective acylation. The value of kinetic enantiomeric ratio (E) reached up to 968. Sub-
stituent effect is briefly discussed.
Received 26 July 2011
Revised 13 August 2011
Accepted 17 August 2011
Available online 23 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Allylic alcohols
Lipase PS-30
Kinetic resolution
Stereoselective acylation
Kinetic enantiomeric ratio (E)
Chiral allylic alcohols are among the most versatile synthetic
materials as they bear a hydroxyl group and an allylic group on
one chiral carbon. Efforts have been made to obtain these com-
pounds. Catalytic enantioselective formation of these chiral build-
ing blocks can roughly be divided into two major categories: (1)
kinetic resolution (KR) with the Sharpless epoxidation,1 (2) asym-
metric alkenylation of carbonyl compounds.2
Following by our previous investigation in the kinetic resolution
of cyanohydrin catalyzed by the lipase,3 we are now studying on
the stereoselective formation of the allylic alcohols.
In KR, an allylic alcohol racemate are treated by an acylating re-
agent in the presence of catalyst to stereoselectively obtain an
acylated enantiomer and an unreacted enantiomer.4 Alternatively,
acylated allylic alcohol racemate are stereoselectively hydrolyzed
in the presence of a lipase or an esterase to give a hydrolyzed enan-
tiomer and an unreacted enantiomer.4b,5 The theoretical yield of
this method is 50% and a pair of enantiomers can be obtained
simultaneously.
Racemic allylic alcohol was treated with allyl acetate in the
presence of lipase PS-30 (Sigma) in toluene to afford the (S)-cyano-
hydrin acetates and the unreacted (R)-cyanohydrins (Scheme 1). To
our best knowledge, lipase PS-30 has not been reported being used
as a catalyst in the previous allylic alcohol KR literatures. After the
consumption of the starting material reached to about 50%, the
reaction was stopped and worked up for the enantiomeric excess
(ee) value evalution. From the ee values, the values of kinetic
enantiomeric ratio (E), which is defined in Ref. 6 were calculated.
Table 1 summarizes our results. Some substrates shown in
Table 1 (entries 5–7, 10, and 11) are in the first time subjected to
KR. The E values of seven substrates (entries 1, 3–6, 10, and 11)
are close to or larger than 100. According to Schneider et al.5a value
of E >50 would be sufficient for the production of the desired allylic
alcohol acetates in good yield and enantiomeric purity. Results in
Table 1 shows that the aryl group containing an electron-with-
drawing substituent (entries 3, 5, and 6) increase the E values
remarkably probably ascribe to their stronger interaction with
the enzyme. On the other side, electron-donating substituent on
the aryl ring (entries 2 and 7) led to the decrease of E values
obviously.
Configuration of some acylated products and the acetic deriva-
tization of the unreacted alcohols which were obtained after the
allylic alcohol was converted into the corresponding acetate (2a7
and 2k2a) were further proved by comparison of the observed opti-
cal rotations of the obtained products with those reported in the
literatures (Table 2).
O
lipase PS-30
O
vinyl acetate
OH
OH
+
R
R
R
Toluene, r.t.
⇑
Corresponding author. Tel.: +86 21 67792594.
E-mail address: prchen@dhu.edu.cn (P. Chen).
Scheme 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.093

P. Chen, P. Xiang / Tetrahedron Letters 52 (2011) 5758–5760
5759
Table 1
Stereoselective acetylation of allelic alcohols 1a–k with vinyl acetate catalyzed by lipase PS-30
O
lipase PS-30
O
vinyl acetate
OH
OH
+
R
R
R
Toluene, r.t.
rac 1a-k
2a-k
3a-k
c
Entry
1
R
eeE(2)a
%
eeA(3)b
63.2
%
Ec
CHPLC (%)
Reaction time (h)
96.1
77.5
97
46
48
24
a
2
3
4
12.2
21.6
16.2
9
34.7
b
O
99.3
97.5
352
93
30
25
48
48
c
Br
Br
d
5
6
97.1
99.7
92.3
38.1
227
968
50
40
50
50
e
O N
2
f
F
S
7
8
9
77.8
/
22.3
/
10
/
35
48
48
48
g
O
Decomposed
50
h
92.3
72.2
54
N
i
10
11
97.1
95.4
93.8
87
241
121
36
50
48
48
j
k
a
EeE stands for enantiomeric excess of allylic alcohol acetate of the fast reacted enantiomer of the allyllic alcohol. Analysis was performed on Chiralcel OJ-H or OD-H
column with hexane/i-PrOH in varying ratios to afford ee values.
b
EeA stands for enantiomeric excess of the slow reacted enantiomer of the allyllic alcohol, which was obtained after the allyllic alcohol was converted into the corre-
sponding acetate then subjected to chiral HPLC analysis on Chiralcel OD-H column with hexane/i-PrOH in varying ratios.
c
E = ln[(1ÀCHPLC)(1ÀeeA)]/ln[(1ÀC)(1+eeA)], where CHPLC = eeA/(eeE + eeA) as defined in Ref. 6.
Table 2
Configuration assignment of 2a and 2k by comparison with the reported [a] data
D
Compound
Measured values
Reported values
Ref.
[a
]
D
ee (%)
[a
]
D
ee (%)
2a
+30.42(c 0.48, CHCl3)
À24.50(c 0.58, CHCl3)
96.06
95.41
À25.6(c 0.99, CHCl3)
+36.7(c 1.31, CHCl3)
99(S)
91(R)
7
2a
2ka
a
In the case of 2k (entry 11), the slow reacting enantiomer was assigned to (S)-configuration by comparison of the observed optical rotation with the reported literature,2a
while the fast reacting one to (R)-configuration due to the Cahn–Ingold–Prolog rule.

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P. Chen, P. Xiang / Tetrahedron Letters 52 (2011) 5758–5760
1992, 75, 170; (d) Chen, Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002,
Configuration of the other products (2b–j) was proposed to
have the same designation as the known ones based on the
Kazlauskas’ rule.
124, 12225; (e) Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 6538; (f) Pu, L.; Yu,
H.-B. Chem. Rev. 2001, 101, 757; (g) Noyori, R.; Kitamura, M. Angew. Chem., Int.
Ed. Engl. 1991, 30, 49.
3. (a) Xu, Q.; Geng, X.; Chen, P. Tetrahedron Lett. 2008, 49, 6440; (b) Xu, Q.; Xie, Y.;
Geng, X.; Chen, P. Tetrahedron 2010, 66, 624.
In conclusion, we have achieved the KR of eleven racemic allylic
alcohols via stereoselective acylation using lipase PS-30 as the
catalyst. 8 Majority of the substrates gave values of E close to or lar-
ger than 100, the best one achieves 968.
4. (a) Bevinakatti, H. S.; Banerji, A. A.; Newadkar, R. J. Org. Chem. 1989, 54, 2453; (b)
Effenberger, F.; Gutterer, B.; Ziegler, T.; Eckhardt, E.; Aichholz, R. Liebigs Ann.
Chem. 1991, 47; (c) Inagaki, M.; Hiratake, J.; Nishioka, T.; Oda, J. J. Org. Chem.
1992, 57, 5643; (d) Hu, B.; Meng, M.; Wang, Z.; Du, W.; Fossey, J. S.; Hu, X.; Deng,
W.-P. J. Am. Chem. Soc. 2010, 132, 17041.
5. (a) van Almsick, A.; Buddrus, J.; Honicke-Schmidt, P.; Laumen, K.; Schneider, M.
P. JCS Chem. Commun. 1989, 1391; (b) Vänttinen, E.; Kanerva, L. T. Tetrahedron:
Asymmetry 1995, 6, 1779; (c) Hanefeld, U.; Li, Y.; Sheldon, R. A.; Maschmeyer, T.
Synlett 2000, 1775; (d) Veum, L.; Kuster, M.; Telalovic, S.; Hanefeld, U.;
Maschmeyer, T. Eur. J. Org. Chem. 2002, 1516.
6. (a) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104,
7294; (b) Kagan, H. B.; Fiaud, J. C. In Topics in Stereochemistry; Eliel, E. L., Wilen, S.
H., Eds.; John Wiley and Sons: New York, NY, 1988; p 249. Vol. 18.
7. Orrenius, C.; Ohrner, N.; Rotticci, D.; Mattson, A.; Hult, K.; Norin, T. Tetrahedron:
Asymmetry 1995, 6, 1217.
Acknowledgements
This work is financially supported by a grant of The Fundamen-
tal Research Funds for the Central Universities (No. 11D10508) and
the Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, CAS.
Supplementary data
8. General KR procedure: A 5 mL bake-dried vial charged with lipase PS-30 (0.025 g,
corresponding to 0.5 mmol of the racemic allyllic alcohols) and two grains of 4 Å
molecular sieves was flushed with nitrogen for several minutes, the racemic
allyllic alcohols (1a–k) dissolved in dried toluene (1 mL) and vinyl acetate
(86 mg, 1 mmol) dissolved in dry toluene (1.5 mL) were added. The mixture was
stirred at room temperature and analyzed by TLC [petroleum ether/ethyl acetate
(20:1–10:1)] until consumption of the starting material was about 50%. The
mixture was then filtered and the solid washed with dry acetone (5 mL) and
ether (5 mL). The solvent was evaporated in vacuo and the residue was purified
on silica gel using petroleum ether/ethyl acetate as the eluent. The unreacted
allylic alcohol was acetylated for determination of ee value by adding 0.3 mL of
an acetylating solution [anhydrous pyridine (5 mL), acetic anhydride (1 mmol),
and DMAP (1% wt/volume)] to 1 mg of the unreacted allelic alcohol. The mixture
was stirred at rt for 4 h, washed with saturated aqueous CuSO4 (3 Â 2 mL) to
remove pyridine. The solution was dried over MgSO4, concentrated in vacuo and
purified by fast column chromatography [petroleum ether/ethyl acetate (20:1)].
Supplementary data (synthetic procedures of the racemic sub-
strates, 1H NMR, 19F NMR spectra, and chiral HPLC chromatogra-
phy) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2011.08.093.
References and notes
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Asymmetry Synthesis; Ojima, I., Ed.; Wiley-VCH: New York, 2000; p 231.
2. For selected examples, see: (a) Cannon, J. S.; Kirsch, S. F.; Overman, L. E. J. Am.
Chem. Soc. 2010, 132, 15185; Tomita, D.; Wada, R.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2005, 127, 4138; (c) Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta