A new and efficient chemoenzymatic access to both enantiomers of 4-hydroxycyclopent-2-en-1-one

Article abstract of DOI:10.1016/S0957-4166(02)00168-4

A chemoenzymatic synthesis of both enantiomers of pharmacologically interesting 4-hydroxycyclopent-2-en-1-one in three steps starting from 3-methoxycyclopent-2-en-1-one is described. Manganese(III) acetate-mediated acetoxylation followed by enzyme-mediate

Full text of DOI:10.1016/S0957-4166(02)00168-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 667–670
A new and efficient chemoenzymatic access to both enantiomers
of 4-hydroxycyclopent-2-en-1-one
Ayhan S. Demir* and Ozge Sesenoglu
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Received 21 March 2002; accepted 8 April 2002
Abstract—A chemoenzymatic synthesis of both enantiomers of pharmacologically interesting 4-hydroxycyclopent-2-en-1-one in
three steps starting from 3-methoxycyclopent-2-en-1-one is described. Manganese(III) acetate-mediated acetoxylation followed by
enzyme-mediated hydrolysis of a-acetoxy enone affords acetoxy enone 3 and hydroxy enone 4 with high enantiomeric excesses and
in good yields. The reduction of the acetoxy and hydroxy enones furnished both enantiomers of 4-hydroxycyclopent-2-en-1-one
in high enantiomeric excess. © 2002 Published by Elsevier Science Ltd.
1. Introduction
in enantiomerically pure form, and we describe herein
an efficient chemoenzymatic route to the three step
synthesis of both enantiomers of 1 starting from 3-
methoxycyclopent-2-en-1-one 2, which is a representa-
tive example for the simple enantioselective synthesis of
cyclic 4-hydroxy enones (Scheme 1).
The enantiomers of 4-hydroxycyclopent-2-en-1-one (S)-
and (R)-1 have been the key starting materials for a
variety of applications, most notably in one of the most
popular routes to prostaglandins,1 and the synthesis of
natural products such as pentenomycin antibiotics2 and
ophiobolins,3 as well as marine natural products such
as clavulones,4 antimicrobial diterpene, halimedatrial,5
and antimicrobial and antileukemic didemnenones.6
Several chemical and enzymatic methods have been
described for the synthesis of both enantiomers of 1.7
We were interested to develop a chemoenzymatic proce-
dure for the preparation of both isomers of 1.
2. Results and discussion
Commercially available cyclopentane-1,3-dione was
converted to the 3-methoxycyclopent-2-en-1-one
2
using a procedure reported in the literature.9 As an
initial reaction (Scheme 2), oxidation of the enone 2
with manganese(III) acetate in cyclohexane was per-
formed to obtain the desired 5-acetoxy enone, ( )-3, in
83% yield after purification by column chromatogra-
phy.10 The use of benzene as a solvent also furnished
the acetoxy enone in 79% yield, however, with some
side products.11 Direct synthesis of acyloxy enone ( )-3
under mild conditions from enone 2 using mangane-
se(III) acetate is an attractive alternative to the other
(multistep) procedures for the a%-oxidation. Lipase
enzymes are used extensively for the synthesis of enan-
tiomerically pure compounds via resolution of racemic
mixtures. The high stereoselectivity in organic media
and their low cost make them very useful catalysts for
enantioselective resolution.
In our ongoing work we have published several papers
about the Mn(OAc)3-mediated direct acetoxylation and
acyloxylation of enones and aromatic ketones followed
by the enzymatic- and fungus-mediated resolution of
acyloxy enones to obtain enantiomerically pure a-
hydroxy ketones.8 The great importance of the enan-
tiomeric 4-hydroxycyclopent-2-en-1-ones 1 led us to
explore a chemoenzymatic method for obtaining them
O
O
*
n
n
MeO
HO
Scheme 1.
Based on the preliminary information available to us
from our previous work with biocatalyst-mediated reac-
tions,8 we screened a series of enzymes for the enan-
* Corresponding author. E-mail: asdemir@metu.edu.tr
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00168-4

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A. S. Demir, O. Sesenoglu / Tetrahedron: Asymmetry 13 (2002) 667–670
MS with a chiral column using acetoxy enone ( )-3 and
O
O
O
K2CO3,
MeOH
Mn(OAc)3,
cyclohexane
hydroxy enone ( )-4 (synthesized from acetoxy enone
( )-3 with K2CO3/MeOH)12 as references. When
approximately 50% conversion was attained, the crude
product was separated by flash column chromatogra-
phy to afford acetoxy enone (S)-3 and hydroxy enone
(R)-4. Best results were obtained on using PLE and
Amano PS. Absolute configuration determination of the
products (R)-4 and (S)-3 was based on the absolute
configuration of the known final product 1.7a Acetoxy
enones obtained after bioconversion and acetylation
reactions can be epimerized using DBU in hexane/
THF13 to afford the racemic acetoxy enone 3 in 85–90%
yields after purification by column chromatography.
Recycling of the ester makes this method quite efficient
for the enantioselective synthesis of the desired hydroxy
enones. The enantiomers of the enones (S)-3 and (R)-4
with multi functional groups are quite interesting start-
ing materials for many biologically active compounds.
O
OH
O
MeO
MeO
MeO
(_+)-3
-4
(_+)
2
DBU,
hexane, THF
enzyme,
DMSO/buffer (pH=7)
O
O
O
OH
+
O
MeO
MeO
(S)-3
(R)-4
LAH, ether
OH
LAH, ether
OH
O
O
(S)-1
(R)-1
Scheme 2.
Since the reduction and hydrolysis of a%-acetoxy or
a%-hydroxy-a,b-unsaturated enone 3 and 4 provide
access to g-hydroxy-a,b-unsaturated enones,16 the reac-
tion of 3 and 4 with LiAlH4 followed by acid-catalyzed
hydrolysis and elimination furnished the desired
hydroxy enone 1 in 71–83% yields after separation of
the crude product by column chromatography. The
absolute configuration of the product was assessed by
comparison of its specific rotation value with data from
the literature.7a The HPLC analysis of the products
with racemic reference compounds7d using a chiral
column and comparison of specific rotations showed
that no isomerization occurred during this reaction
(Chiralcel OA column, UV detection at 210 nm, eluent:
hexane/2-propanol=9:1, flow 0.50 mL min−1 20°C,
Rt(S)=38.3 min, Rt(R)=43.5 min, 98% e.e.).17
tioselective hydrolysis of acetoxy enone ( )-3. Ester
hydrolysis of ( )-3 was investigated using three readily
available enzymes PLE (Pig Liver esterase), Amano PS,
and PPL (Porcine Pancreatic lipase). Surprisingly, all
enzymes affected hydrolysis, with PLE and Amano PS
exhibiting high enantioselectivity, while PPL exhibits no
selectivity. Careful monitoring of the reactions with
TLC and LC–MS (Chiralpak AD column, UV detec-
tion at 254 nm, eluent: hexane/2-propanol=9:1, flow
0.80 mL min−1 20°C, and Chiralcel OD column, UV
detection at 254 nm, eluent: hexane/2-propanol=95:5,
flow 0.75 mL min−1 20°C, using racemic compounds as
references) furnished the acetoxy enone (S)-3 (96–97%
e.e.) and hydroxy enone (R)-4 (96–>98% e.e.) (Table 1).
In a typical experiment, for enzymatic hydrolysis, the
racemic acetoxy enone 3 was dissolved in DMSO then
phosphate buffer was added and the mixture was
stirred at room temperature in the presence of enzyme.
The reaction was monitored by TLC analysis and LC–
The results show that manganese(III) acetate-mediated
acetoxylation of enone followed by enzyme-mediated
hydrolysis of the acetoxy group provides hydroxy
enone (R)-4 and acetoxy enone (S)-3 with high enan-
tiomeric excesses (97–98%) and in good chemical yields.
Table 1. Enzymatic hydrolysis of 5-acetoxy-3-methoxycyclopent-2-en-1-one 3
No.
Enzyme
Reaction time (h)
Conversion ca (%)
Acetate
Yieldc (%)
Alcohold
Yieldc (%)
Ef
E.e.b (%)
E.e.e (%)
1
2
3
PLE
Amano PS
PPL
22
24
36
50
50
–
96
97
–
37
43
37
96
\98
–
42
45
41
196
277
–
a c=e.e.s/(e.e.s+e.e.p).
b Determined by HPLC using chiral column (Chiralpak AD column, UV detection at 254 nm, eluent:hexane/2-propanol=9:1, flow 0.80 mL min−1
20°C, using racemic compounds as references).
c Isolated yield after flash column chromatography.
d Racemization-free acetylation of alcohol (R)-4 was carried out with acetic anhydride/Cu(OTf)3 according to a procedure reported in the
literature and (R)-3 was obtained in 84% yield.14 Likewise, racemization-free hydrolysis of chiral acetoxy enone was carried out with
Sc(OTf)3/MeOH–H2O15 and the reaction furnished (S)-4 in 91% yield. The e.e. of the alcohol was also determined by HPLC via its acetate
derivatives.
e Determined by HPLC using chiral column (Chiralcel OD column, UV detection at 254 nm, eluent:hexane/2-propanol=95:5, flow 0.75 mL min−1
20°C, using racemic compounds as references).
f Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294.

A. S. Demir, O. Sesenoglu / Tetrahedron: Asymmetry 13 (2002) 667–670
669
The undesired acetoxy enone can be epimerized in good
yield and reused. In these conversion reactions,
enzymes favor the (R)-enantiomers. The reduction of
the acetoxy and hydroxy enone followed by acid
hydrolysis furnished both enantiomers of 4-hydroxy-
cyclopent-2-en-1-one 1 in high enantiomeric excess.
This method gives a simple new entry to the synthesis
of cyclic 4-hydroxy enones, which are important pre-
cursors for pharmacologically interesting compounds.
(R)-4: semisolid, 58.4 mg, [h]2D0=+17 (c=0.5, CHCl3)
[(S)-4 [h]2D0=−18 (c=0.5, CHCl3)]; Rt(R)=46.8 min
[Rt(S)=45.1 min], >98% e.e.; 1H NMR (400 MHz,
CDCl3) l 2.52 (dd, J=3.2, 17.7 Hz, 1H), 2.89 (dd,
J=7.1, 17.7 Hz, 1H), 3.81 (s, 3H), 4.26 (dd, J=3.2, 7.1
Hz, 1H), 5.24 (s, 1H); 13C NMR (100 MHz, CDCl3) l
37.5, 59.1, 71.7, 101.9, 189.0, 206.0. Anal. calcd for
C6H8O3 (128.13): C, 56.24; H, 6.29; found: C, 56.21; H,
5.98%.
3.3. General procedure for reductions
3. Experimental
To a suspension of LiAlH4 (33.4 mg, 0.9 mmol) in
anhydrous Et2O (30 mL) was added acetoxy enone
(S)-3 (50.3 mg, 0.3 mmol) or hydroxy enone (S)-4 (37.6
mg, 0.3 mmol) at rt over 15 min. The mixture was
refluxed for 30 min, cooled to rt and quenched with
water and 10% H2SO4. Organic phase was washed with
sat. NaHCO3 solution, brine, and dried over MgSO4.
After evaporation of the solvent flash column chro-
matography (EtOAc) was performed to obtain 4-
hydroxy-cyclopent-2-en-1-one 1 in 71–83% yield.
3.1. General methods
NMR spectra were recorded on a Bruker DPX 400.
Column chromatography was conducted on silica gel
60 (mesh size 40–63 mm). Optical rotations were mea-
sured with a Bellingham–Stanley P20 polarimeter or
Autopol IV automatic polarimeter. Enantiomeric
excesses were determined by HPLC analysis using a
Thermo Quest (TSP) GC–LC–MS equipped with an
appropriate optically active column, as described in the
corresponding footnotes of Table 1.
(R)-1: viscous oil, 24.5 mg, [h]2D0=+78 (c=1.2, CHCl3),
[(S)-1 [h]2D0=−76 (c=1.2, CHCl3)];7a Rt(S)=38.3 min
1
[Rt(R)=43.5 min, 97–98% e.e.]; H NMR (400 MHz,
CDCl3) l 2.25 (dd, J=2.3, 18.5 Hz, 1H), 2.74 (dd,
J=6.1, 18.5 Hz, 1H), 3.9 (m, 1H), 5.05 (br.s, 1H), 6.18
(d, J=5.7 Hz, 1H), 7.58 (dd, J=2.3, 5.7 Hz, 1H); 13C
NMR (100 MHz, CDCl3) l 44.2, 70.2, 134.9, 163.9,
207.3
3.1.1. ( )-5-Acetoxy-3-methoxycyclopent-2-en-1-one 3. A
solution of 3-methoxycyclopent-2-en-1-one 29 (2.5 g,
22.3 mmol), Mn(OAc)3 (17.2 g, 66.9 mmol) and cyclo-
hexane or benzene (200 mL) were heated under reflux
for 45–54 h. After cooling, the reaction mixture was
first filtered then washed with sat. NaHCO3 solution.
Dried over MgSO4, concentrated and purified by flash
column chromatography (2:1 EtOAc:hexane) to yield
79–83% of racemic 5-acetoxy-3-methoxycyclopent-2-en-
1-one (3.1 g) 3.
Acknowledgements
The financial support of the Scientific and Technical
Research Council of Turkey (TUBITAK), the Turkish
State Planning Organization (for GC–LC–MS) and
Middle East Technical University (AFP 2001) is grate-
fully acknowledged.
3.2. General procedure for enzyme-catalyzed hydrolysis
To a stirred solution of ( )-5-acetoxy-3-methoxycyclo-
pent-2-en-1-one 3 (180 mg, 1.1 mmol) in DMSO (2 mL)
and phosphate buffer (pH 7.0, 60 mL) enzyme (PLE
200 mL, Amano PS and PPL 6 mg) was added in one
portion and the reaction mixture was stirred at rt.
Conversion was monitored by TLC and LC–MS up to
50%. After filtration, the filtrate was extracted with
dichloromethane, dried over MgSO4, concentrated and
purified by flash column chromatography (2:1
EtOAc:hexane) to obtain (S)-5-acetoxy-3-methoxy-
cyclopent-2-en-1-one 3 and (R)-5-hydroxy-3-methoxy-
cyclopent-2-en-1-one 4 in 37–43% and 42–45% yields,
respectively.
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