Enzymatic kinetic resolution of a functionalized 4-hydroxy-cyclopentenone: Synthesis of the key intermediates in the total synthesis of isoprostanes

Article abstract of DOI:10.1016/j.tetasy.2005.03.028

The enzymatic kinetic resolution of racemic alcohol 4-hydroxy- cyclopentenone 1 was investigated using four different lipases for enantioselective transacetylation, as well as for enantioselective hydrolysis, leading to the pure (R)- and (S)-enantiomers 2 and 3.

Full text of DOI:10.1016/j.tetasy.2005.03.028

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1893–1895
Enzymatic kinetic resolution of a functionalized
-hydroxy-cyclopentenone: synthesis of the key intermediates
in the total synthesis of isoprostanes
4
Edith Pinot, Alexandre Guy, Ann-Laure Guyon, Jean-Claude Rossi and Thierry Durand*
UMR CNRS 5074, Facult e´ de Pharmacie, Lab. de Chimie, Universit e´ Montpellier I, 15 Av. Ch. Flahault,
BP 14491, F-34093 Montpellier, France
Received 15 March 2005; accepted 28 March 2005
Available online 10 May 2005
Abstract—The enzymatic kinetic resolution of racemic alcohol 4-hydroxy-cyclopentenone 1 was investigated using four different
lipases for enantioselective transacetylation, as well as for enantioselective hydrolysis, leading to the pure (R)- and (S)-enantiomers
2
ꢀ
and 3.
2005 Elsevier Ltd. All rights reserved.
1
. Introduction
interested by accessing the two pure 4-hydroxy-cyclo-
pentenones 2 and 3 which are important building blocks
for the total synthesis of isoprostanes and analogues
Lipases are extensively used for the synthesis of enantio-
merically pure compounds via resolution of racemic
mixtures. These enzymes possess broad substrate spec-
3
(Scheme 1).
1
ificity, generally high regio- and enantioselectivity and in
many cases perform under mild conditions. Recently,
Rodriguez and Spur used an enzymatic kinetic resolu-
2. Results and discussion
2
tion for the synthesis of the E type I phytoprostanes.
2.1. Preparation of 4-hydroxy-cyclopentenone 1
As a consequence, and in connection with our program
directed towards the synthesis of isoprostanes, we were
The preparation of racemic 4-hydroxy-cyclopente-
none 1, depicted in Scheme 2, was achieved with the
O
O
CO2Me
CO2H
O
OMe
CO2Me
OMe
HO
(R)-2
HO
2t
15-E -IsoP
MeO
OH
O
O
HO
CO2Me
OMe
MeO
CO2H
rac-1
(
S)-3
HO
HO
1
1-epi-15-E2t-IsoP
MeO
OH
Scheme 1.
*
0
Corresponding author. Tel.: +33 4 67 54 86 23; fax: +33 4 67 54 86 25; e-mail: thierry.durand@univ-montp1.fr
957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.03.028

1894
E. Pinot et al. / Tetrahedron: Asymmetry 16 (2005) 1893–1895
a, b
reactions were achieved in multi-gram scale, up to 50
gram and afforded at least 20 g of rac-1.
CO H
CO Me
2
OHC
2
O
O
4
2.2. Enzymatic kinetic resolution of 4-hydroxy-cyclo-
pentenone rac-1
c
d
(
MeO) HC
CO Me
2
2
O
5
O
Our first attempt was to screen a range of lipases for
enantioselective transacetylation of the racemic alcohol
1 (Table 1). We have used four well-known different
lipases with the best results being obtained with the
Candida antarctica lipase B (CAL-B). All the enzymes
investigated preferentially converted the (R)-enantiomer
e, f
MeO
MeO) HC
OMe
CO Me
2
OH
(
CO Me
2
2
O
6
OMe
7
O
MeO
5
g
of rac-1, in agreement with the literature.
CO Me
2
Using CAL-B, we were also interested in finding the best
conditions and investigated the effect of the solvent (hex-
ane), time of reaction and finally the amount of CAL-B
(Table 1). The results are shown in Table 1, and the
highest conversion obtained, was by using 0.2 equiv of
CAL-B, in hexane at room temperature for 20 h. Under
these conditions, we obtained 45.4% of acetate (R)-8 and
HO
OMe
rac-1
MeO
Scheme 2. Reagents and conditions: (a) MeOH, H
followed by H , Pd–C 10%, 80%; (b) POCl , DMF, 92%; (c)
HC(OMe) , APTS, TsOH, 73%; (d) Br , MeOH, Na CO ; (e) citric
acid, Na HPO , dioxane; (f) Na HPO ; (g) chloral hydrate, Et N,
EtOAc, reflux.
2 4
SO , reflux,
2
3
3
2
2
3
2
4
2
4
3
4
8.5% of alcohol (S)-3.
It is worth noting that during the resolution process, the
reaction was monitored by HPLC using a chiral station-
ary phase (Chiralcel OD column). This process enables
us to control the degree of conversion. Typical chro-
matograms are shown in Figure 1.
commercially available trans-3-(2-furyl)acrylic acid as
4
starting material, using the Fre ¨ı manis procedure.
The first step was a Pd-catalyzed reduction under hydro-
gen atmosphere, followed by a Vilsmeyer reaction for
the introduction of the formyl group at C5, which was
protected in the presence of methyl orthoformate. Elec-
2.3. Enzymatic hydrolysis
trophilic addition with MeOH/Br under basic condi-
2
We also used the CAL-B for the enzymatic hydrolysis of
(R)-acetate 8 to reach the enantiomerically pure (R)-
alcohol 2 (Scheme 3). In a typical experiment for the
enzymatic hydrolysis, the (R)-acetate 8 was dissolved
in acetonitrile, at which point the phosphate buffer
(0.1 M, pH = 7) was added and the mixture was stirred
at room temperature in the presence of the enzyme
(0.8 mass equivalent). The progress of the reaction
tions to the furan 5, afforded bis-acetal 6, which
underwent an Ôaldol-typeÕ cyclization under acidic
hydrolysis and basic treatment leading to the 3-hydr-
oxy-cyclopentenone 7. Finally, migration of the hydroxy
group and double bond with chloral under basic condi-
tions led to the racemic 4-hydroxy-cyclopentenone 1 in
2
8% yield after five steps. It is worth noting that all these
Table 1. Enzyme-catalyzed transesterification of rac-1 with vinyl acetate
O
O
O
CO2Me
CO2Me
CO2Me
Lipase
OAc
+
O
O
O
AcO
HO
HO
O
O
(R)-8
O
rac-1
(S)-3
Enzyme
% of Enzyme w/w (equiv)
Solvent
Time (h)
Conversion (%) (R)-8
Conversion (%) (S)-3
PPL
1
—
—
168
72
72
72
72
72
48
40
48
48
20
10
—
Amano F-AP15
Amano F-AP15
Amano PS
Amano PS
CAL-B
1
—
—
1
Hexane
—
—
1
45.4
43.7
40.2
45.4
36.7
41.9
43
45
1
Hexane
—
—
36.8
38.9
45
1
CAL-B
CAL-B
1
1
Hexane
Hexane
Hexane
Hexane
45.3
43
CAL-B
CAL-B
CAL-B
1
0.5
0.2
43
48.5
45.4
PPL: porcine pancreatic lipase; CAL-B: Candida antarctica lipase B.

E. Pinot et al. / Tetrahedron: Asymmetry 16 (2005) 1893–1895
1895
2
D
0
ꢁ2
Table 2. ½aꢀ (c 1 · 10 , MeOH) for alcohols 2 and 3 and acetates 8
(a)
and 9
(
(
R)-2
R)-8
+0.21
ꢁ0.05
ꢁ0.21
(S)-3
(S)-9
(
R)-8
(S)-9
+0.05
(R)-2
(S)-3
6
ing Mosher esters (Fig. 2). We also confirmed these ee
by H NMR experiments (data not shown).
1
1
5 h.
(b)
2
0 h.
(c)
0
21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46
19
Figure 2. F NMR spectra of alcohols (S)-3 and (R)-2.
Figure 1. (a) Chromatogram of a racemic mixture of acetates 8, 9 and
alcohols 2, 3. (b) and (c) Chromatograms of the kinetic resolution of
rac-1 by CAL-B after 15 h (b) and 20 h (c). Column: Chiralcel OD,
3. Conclusion
25 cm · 4.6 mm. Mobile phase: 97/3 hexane/i-PrOH. Flow rate:
0.7 mL/min. Detection : 210 nm.
In conclusion, we have developed an efficient asymmet-
ric synthesis of the two enantiomerically pure hydroxy-
cyclopentenones (R)-2 and (S)-3. The extension of this
methodology towards the synthesis of new isoprostanes
will be reported in due course.
monitored by TLC and the enantiomerically pure (R)-
alcohol 2 obtained in 98% yield.
O
O
CO2Me
OMe
CO Me
Acknowledgments
2
a
OMe
We wish to thank the Minist e` re de lÕEducation Natio-
nale, de lÕEnseignement Sup e´ rieur et de la Recherche
for financial support to E.P.
AcO
HO
MeO
R)-8
MeO
(R)-2
(
3
Scheme 3. Reagents and conditions: (a) CAL-B, CH CN, phosphate
buffer (0.1 M) pH = 7.
References
1
. Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in
Organic Synthesis—Regio- and Stereoselective Biotransfor-
mations; Wiley-VCH: Weinheim, 1999.
2.4. Comparison of the specific rotations of 2 and 3, and 8
and 9
2
. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2003, 44,
7411–7415.
Acetate 9 was obtained from alcohol 3 with (Ac) O in
2
Et O in the presence of DMAP in 74% yield.
2
3. For a general review, see: Chem. Phys. Lipids 2004, 128,
–193.
4
1
. (a) Loza, E.; Lola, D.; Freimanis, J.; Turovskis, I.; Gavars,
M.; Liepipa, A. Latvijas PSR ZA vestis, Chem. Ser. 1985, 4,
The physicochemical properties of the enantiomerically
pure alcohol (R)-2 and acetate (R)-8 were identical to
those of (S)-3 and (S)-9, respectively, except for the sign
of the specific rotation, as shown in Table 2.
465–472; (b) Loza, E.; Lola, D.; Freimanis, J.; Leipina, A.
Latv. Kim. Z. 1998, 1, 76–82.
5
. Babiak, K. A.; Ng, J. S.; Dygos, J. H.; Weyker, C. L.;
Wang, Y.-F.; Wong, C.-H. J. Org. Chem. 1990, 55, 3377–
2
.5. Determination of the ee
3
2
381; For a general review, see: Tetrahedron: Asymmetry
004, 15, 2727–3009.
The ee of alcohol (S)-3 (94%) and (R)-2 (94%) was deter-
mined by F NMR spectra analysis of the correspond-
6. Dale, A. J.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969,
34, 2543–2549.
1
9