A Chemoenzymatic Approach to Optically Active 5-Hydroxy-3-oxocarboxylates

Article abstract of DOI:10.1055/s-2004-817746

Enzymatic hydrolysis was applied to the preparation of certain chiral 5-hydroxy-3-oxo-carboxylates that are potential precursors for natural product synthesis via the formation of lactone derivatives and tetrahydropyran rings.

Full text of DOI:10.1055/s-2004-817746

LETTER
485
A Chemoenzymatic Approach to Optically Active 5-Hydroxy-3-oxo-
carboxylates
A
C
hemoenzyma
h
tic
A
pproach
e
to Optica
l
n
ly
A
ctive 5-H
g
ydroxy-3-ox
f
o-carbo
u
xylates Xu, Yonghui Zhang, Chengye Yuan*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai, 200032, P. R. China
Fax +86(21)64166128; E-mail: yuancy@mail.sioc.ac.cn
Received 17 December 2003
alkoxide complex to give optical active 5-alkoxy-3-oxo-
carboxylates;8j,k Soriente et al. described an efficient
asymmetric aldol condensation of 1,3-bis(trimethylsilyl-
oxy)-1-methoxy-buta-1,3-diene promoted by Ti(IV)/
BINOL complex.8l,m
Abstract: Enzymatic hydrolysis was applied to the preparation of
certain chiral 5-hydroxy-3-oxo-carboxylates that are potential pre-
cursors for natural product synthesis via the formation of lactone
derivatives and tetrahydropyran rings.
Key words: 5-hydroxy-3-oxo-carboxylates,
6-substituted-4-hy-
droxy lactones, tetrahydropyran-4-ones, Candia Rugosa lipase
(CRL), enzymatic hydrolysis
The drawbacks of the above synthetic routes are signifi-
cant, including harsh reaction conditions, expensive re-
agents, low chemical yields and low optical purity.8 A
convenient procedure for the preparation of the title com-
pounds is therefore needed as an alternative method. The
utility of lipases for efficient resolution of alcohols and re-
lated compounds is of great importance in organic synthe-
sis.9 It is known that lipase catalyzed kinetic resolution of
racemic secondary alcohols in organic media can over-
come the limitations of the traditional procedure, such as
instability of enzymes, time consuming experimental pro-
cedures, comparably lower selectivity, etc. Our group
have developed Candida Antarctia lipase B (CALB) cata-
lyzed acetylation and crude Candia Rugosa lipase (CRL)
catalyzed hydrolysis in diisopropyl ether for preparing op-
tical 1- or 2-hydroxyalkanephophonates and 4-hydroxy-3-
oxoalkanephophonates.10 As an extension of our study,
we herein wish to report a chemoenzymatic approach to
chiral 5-hydroxy-3-oxo-carboxylates. In our previous
work, we successively resolve the diethyl 4-hydroxy-3-
oxo-4-arylbutylphosphonates by crude CRL in isopropyl
ether saturated with 1.2 M MgCl2 solution.10a This strate-
gy was successfully applied to resolve 5-hydroxy-3-oxo-
carboxylates.
Methods for the synthesis of optically active alcohols
have been developed to give a variety of precursors of
biologically active natural products,1 among them optical-
ly active 5-hydroxy-3-oxo-carboxylates can be easily
converted to 6-substituted-4-hydroxy lactones which are
an important component of inhibitors of 3-hydroxy-3-me-
thylglutaryl coenzyme A (HMG-CoA) reductase such as
compactin and mevinolin.2 As well as other natural prod-
ucts, such as manoalide,3 compaction and (+)-dihydro-
compaction,4 (–)-pestalotin,5 bryostatin6 etc. 5-Hydroxy-
3-oxo-carboxylates can also react with an equivalent of al-
dehyde by a tandem Knoevenagel reaction in presence of
BF3·Et2O to synthesize single diastereomers of highly
substituted tetrahydropyran-4-ones that are ubiquitous in
natural product area.7
There have been several reports concerning the asym-
metric synthesis of the above compounds.8 For example,
Johnson et al. reported the diastereoselective addition
of 1,3-bis(trimethylsiloxy)-1-methoxybuta-1,3-diene to
chiral actal providing 5-alkoxy-3-oxo-carboxylates in
high optical purity;8d Saburi and coworkers reported the
asymmetric hydrogenation of 3,5-dioxoesters catalyzed
by Ru–BINAP complex, giving 6-substituted-5,6-dihy-
dro-2-pyones in 71–81% optical purity;8f,g Oguni et al. de-
scribed an enantioselective reaction of diketene with
aldehydes promoted by chiral Schiff’s base–titanium
For this purposes, starting from acetoacetates, the racemic
5-hydroxy-3-oxo-carboxylates were resulted through the
following sequence of reactions with high yields. The re-
action conditions were simple and the temperature was
relatively high unlike the traditional reaction that needs
low temperature (such as –78 °C)7 (Scheme 1).
Scheme 1
SYNLETT 2004, No. 3, pp 0485–0488
1
8.
0
2.
2
0
0
4
Advanced online publication: 06.02.2004
DOI: 10.1055/s-2004-817746; Art ID: U28203ST
© Georg Thieme Verlag Stuttgart · New York

486
C. Xu et al.
LETTER
Direct butyrylation of 5-hydroxy-3-oxo-carboxylates us- pentanoic acid methyl ester (3a) was determined based
20
ing DCC/butyric acid system afforded the butyryl deriva- on the optical rotation. [a]D +58.1 (c 1.0, CHCl3),
tives in 90–98% yields. They could be enantioselectively literature8l [a]D25 +57.1 (c 1.0, CHCl3) and literature8m (S)-
25
hydrolyzed to the corresponding (R)-alcohols by CRL in 3a [a]D –46.0 (c 1.0, CHCl3)}, see Scheme 2 and
diisopropyl ether pre-equilibrated with 1.2 M aqueous Table 1.
MgCl2. Because of the similarity of the substrates 2a–n,
the enantioselectivities of these molecules 2a–n catalyzed
by CRL are identical. Consequently, if we determined the
absolute configuration of the products 3a–n and 4a–n),
As demonstrated by our experimental data, in contrast
with the corresponding 4-hydroxy-3-oxobutylphospho-
nates, the overall yields of this optically active oxo-car-
boxylates were dramatically increased and the reaction
the absolute configuration of other molecules could thus
time was sharply shortened. In the meantime, the chemi-
be deduced. Substantially, the absolute configuration of
cal structure of aryl substrates as well as ester groups did
one of hydrolyzed alcohols {5-hydroxy-3-oxo-5-phenyl
not affect the enantioselectivity of CRL.
Scheme 2
Table 1 CRL Catalyzed Enantioselective Hydrolysis of 2a–n
3 (%)
4 (%)
Entry
R
Ar
Yield 2 (%)
Reaction time (h)
Yield
Eea
Yield
Eea
Eb
a
b
c
d
e
f
Me
Me
Me
Me
Me
Me
Me
Me
Et
C6H5
92
91
93
94
91
96
94
93
94
91
92
94
93
93
24
24
24
24
24
24
24
24
24
24
24
24
24
24
46
46
45
54c
47
48
46
46
47
47
45
46
45
45
97.0
98.6
99.9
52.0
99.8
97.7
98.1
99.9d
99.7
98.6
97.2
89.6
99.1
99.8
47
47
46
39c
47
46
47
48
47
46
47
48
49
45
99.9
99.9
96.0
98.1
97.5
97.2
94.9
91.9
99.7
99.9
99.6
84.9
99.9
>200
>200
>200
>80
4-MeC6H4
4-MeOC6H4
2-Furyl
2-BrC6H4
4-FC6H4
2,4-Cl2C6H3
4-O2NC6H4
C6H5
>200
>200
>200
>200
>200
>200
>200
>100
>200
/
g
h
i
j
Et
4-MeC6H4
4-MeOC6H4
2-Furyl
k
l
Et
Et
m
n
Et
2,4-Cl2C6H3
4-O2NC6H4
e
Et
/
a The ee values were determined by the chiral HPLC.11,
b 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).12,
c The reaction time was too long.
d The ee values of 3h was determined by 4h.
e Compound 4n cannot be determined by chiral HPLC.
Synlett 2004, No. 3, 485–488 © Thieme Stuttgart · New York

LETTER
A Chemoenzymatic Approach to Optically Active 5-Hydroxy-3-oxo-carboxylates
487
Scheme 3
Table 2 Conditions of Chiral HPLCa
D
D
E
D
E
A
B
C
E
F
A
B
C
F
A
B
C
F
3a
3b
3c
3d
3e
3f
AD
AD
AD
AD
AD
AD
AD
\
95/5
8/2
8/2
8/2
8/2
95/5
9/1
\
29.81
15.60
19.54
15.87
14.03
52.59
21.83
\
34.54
17.23
17.74
17.85
16.37
57.03
25.05
\
3h
3k
3l
AD
AD
AD
AD
AD
OD
AD
OD
AD
95/5
9/1
95/5
95/5
9/1
8/2
9/1
8/2
8/2
41.29
31.06
47.00
31.52
41.43
54.76
20.04
40.35
52.59
46.70
34.24
53.33
34.93
43.43
37.55
16.04
31.13
57.03
4e
4f
OD
OD
OD
AD
AD
AD
AD
OD
OD
8/2
8/2
9/1
7/3
8/2
8/2
9/1
30.27
23.24
27.21
18.66
14.52
12.57
18.33
13.12
23.32
17.15
22.16
38.18
10.76
10.38
13.69
13.99
25.99
4g
4h
4i
3m
3n
4a
4b
4c
4d
4j
3g
3h
3i
4k
4l
95/5
AD
9/1
23.15
25.70
4m
100/2.5 29.53
a A: Substrate. B: Chiral CHIRALPAK column. C: Ratio of eluents (n-hexane–i-propanol). D: Retention time (min). E: Major enantiomer. F:
Minor enantiomer.
Upon successfully enzymatic resolution of 5-hydroxy-3-
oxo-carboxylates, several optical active substrates were
converted to 4-hydroxy-6-aryl-5,6-dihydro-2-pyones that
are functionalized lactones with potential application in
natural products synthesis and highly substituted tetrahy-
dropyran-4-ones that also have potential application in
natural product synthesis (Scheme 3).13
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Acknowledgment
The project was supported by the National Nature Science Founda-
tions of China (Grant No. 20272075 and 20372076).
Synlett 2004, No. 3, 485–488 © Thieme Stuttgart · New York

488
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LETTER
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Synlett 2004, No. 3, 485–488 © Thieme Stuttgart · New York