Preparation of enantiomerically pure (3E)-alkyl-4-(hetero-2-yl)-2-hydroxybut-3-enoates by Candida parapsilosis ATCC 7330 mediated deracemisation and determination of the absolute configuration of (3E)-ethyl-4-(thiophene-2-yl)-2-hydroxybut-3-enoate

Article abstract of DOI:10.1016/j.tetasy.2007.04.029

Deracemisation of racemic (3E)-alkyl-4-(hetero-2-yl)-2-hydroxybut-3-enoates using Candida parapsilosis ATCC 7330 resulted in the formation of one enantiomer in high enantiomeric excess [up to >99% ee] and isolated yields [up to 79%]. The absolute configur

Full text of DOI:10.1016/j.tetasy.2007.04.029

Tetrahedron: Asymmetry 18 (2007) 1077–1084
Preparation of enantiomerically pure (3E)-alkyl-4-(hetero-2-yl)-2-
hydroxybut-3-enoates by Candida parapsilosis ATCC 7330 mediated
deracemisation and determination of the absolute configuration
of (3E)-ethyl-4-(thiophene-2-yl)-2-hydroxybut-3-enoate
T. Vaijayanthia and Anju Chadhab,*
aDepartment of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, India
bLaboratory of Bioorganic Chemistry, Department of Biotechnology and National Center for Catalysis Research,
Indian Institute of Technology Madras, Chennai 600 036, India
Received 14 March 2007; accepted 26 April 2007
Available online 1 June 2007
Abstract—Deracemisation of racemic (3E)-alkyl-4-(hetero-2-yl)-2-hydroxybut-3-enoates using Candida parapsilosis ATCC 7330 resulted
in the formation of one enantiomer in high enantiomeric excess [up to >99% ee] and isolated yields [up to 79%]. The absolute configu-
ration of the enantiomerically pure (3E)-ethyl-4-(thiophene-2-yl)-2-hydroxybut-3-enoate as determined by 1H NMR of the Mosher esters
was found to be (S).
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
(S)-hydroxy esters in high chemical yields (up to 85%)
and up to >99% ee by C. parapsilosis ATCC 7330 was pre-
viously reported by our group.2c,d–i The asymmetric syn-
thesis of (3E)-isopropyl-4-(furan-2-yl)-2-hydroxybut-3-
enoate and (3E)-isopropyl-4-(thiophene-2-yl)-2-hydroxy-
but-3-enoate using the asymmetric catalyst Ru-TsDPEN
gives low ee (59–65%).10 Herein we report the deracemisa-
tion, by C. parapsilosis ATCC 7330, of hetero-aryl com-
pounds, that is, (3E)-alkyl-4-(hetero-2-yl)-2-hydroxybut-3-
enoates, where the hetero atom is either oxygen, sulfur or
nitrogen. These chiral synthons are required for the synthe-
sis of important pharmaceutical compounds such as 6-(1-
arylmethylpyrrol-2-yl)-1,4-dioxo-5-hexenoic acids, 4-[5-
(benzoylamino)thien-2-yl]-2,4-dioxobutanoic acid and 1-
[5-(4-fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-1,2,4-tria-
zol-3-yl)propene which are found to possess antiviral activ-
ity.11–13 The synthesis of racemic (3E)-alkyl-4-(hetero-2-yl)-
2-hydroxybut-3-enoates is included along with the biocata-
lytic deracemisation to obtain the enantiomerically pure
(3E)-alkyl-4-(hetero-2-yl)-2-hydroxybut-3-enoates in high
yields. The determination of the absolute configurations
of enantiomerically pure (3E)-ethyl-4-(thiophene-2-yl)-2-
hydroxybut-3-enoate, which is obtained from its racemate
by C. parapsilosis ATCC 7330 mediated deracemisation is
reported here for the first time.
Several chemical1 and enzymatic2 methods are known for
the synthesis of enantiomerically pure a-hydroxy esters,
which are important and useful chiral synthons.3 Of these,
the resolution of racemates can result in a maximum theo-
retical yield of only 50% for each enantiomer.4 In order to
increase the yield of one enantiomer beyond 50%, the race-
mic substrate can be deracemised.5 Deracemisation is a
methodology, which can, in principle, provide a single
enantiomer from a racemate in high yield and high enantio-
meric excess.6 Deracemisation can be carried out by re-rac-
emisation, dynamic kinetic resolution or stereoinversion,
chemically, chemo-enzymatically or enzymatically by using
either isolated enzymes or whole cells.2c–i,7 Among the
other strategies for deracemisation,8 stereoinversion using
Candida parapsilosis has been well illustrated for 1,2-diols
and 1,3-diols.9 Deracemisation of racemic aryl a- and b-hy-
droxy esters to the corresponding enantiomerically pure
*
Corresponding author. Tel.: +91 44 2257 4106; fax: +91 44 2257 4102;
e-mail: anjuc@iitm.ac.in
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.04.029

1078
T. Vaijayanthi, A. Chadha / Tetrahedron: Asymmetry 18 (2007) 1077–1084
2. Results and discussion
2.2. Deracemisation of racemic (3E)-alkyl-4-(hetero-2-yl)-2-
hydroxybut-3-enoates using C. parapsilosis ATCC 7330
2.1. Synthesis of substrates
The deracemisation of the ethyl and methyl esters of race-
mic (3E)-4-(hetero-2-yl)-2-hydroxybut-3-enoic acids 3a–3i
(Scheme 2, Tables 2 and 3) by C. parapsilosis ATCC
7330 provided the enantiomerically pure ethyl and methyl
esters of (S)-(3E)-4-(hetero-2-yl)-2-hydroxybut-3-enoic
acids, respectively, 4a–4i (Scheme 2, Tables 2 and 3) in
excellent enantiomeric excess (90–>99%) and good isolated
yields (52–79%) as described in Section 4. At the end of the
reaction, that is, after the ee reached a constant value, as
monitored by HPLC, the cells were filtered and the aque-
ous layer extracted with ethyl acetate. The enantiomeric
excess of products 4a–4i (Scheme 2, Tables 2 and 3) was
determined by HPLC using a chiral stationary phase.
Racemic (3E)-alkyl-4-(hetero-2-yl)-2-hydroxybut-3-enoates
3a–3i (Table 1, Scheme 1) were synthesised by reported
procedures14 to obtain high yields of the target esters.
(3E)-4-(Hetero-2-yl)-2-oxobut-3-enoic acids 1a–1i (Scheme
1) were obtained in 90–95% yields by condensing the pre-
cursor aldehydes with pyruvate. Previous reports on the
synthesis of (3E)-ethyl-4-(furan-2-yl)-2-oxobut-3-enoate,
(3E)-methyl-4-(furan-2-yl)-2-oxobut-3-enoate, (3E)-ethyl-
4-(thiophene-2-yl)-2-oxobut-3-enoate and (3E)-methyl-4-
(thiophene-2-yl)-2-oxobut-3-enoate 2a–2d (Scheme 1,
Table 1) had used the Wittig reaction.15–17 In order to
improve the above reaction conditions such as refluxing
with triphenyl phosphine for 3 days, various (3E)-alkyl-4-
(hetero-2-yl)-2-oxobut-3-enoates 2a–2i (Scheme 1, Table
1) were prepared within 3 h by esterification of the corre-
sponding acids using concentrated hydrochloric acid as a
catalyst. With the exception of (3E)-ethyl-4-(furan-2-yl)-2-
hydroxybut-3-enoate 3a and its derivatives which are
known,18 the synthesis of the racemic a-hydroxy heteroaryl
carbonyl compounds 3b–3i (Scheme 1, Table 1) is reported
here for the first time. The sodium borohydride reduction
of the (3E)-alkyl-4-(hetero-2-yl)-2-oxobut-3-enoates 2a–2i
(Scheme 1, Table 1) resulted in the corresponding racemic
C. parapsilosis ATCC 7330 mediated deracemisation of the
methyl and ethyl esters of racemic (3E)-4-(furan-2-yl)-
2-hydroxybut-3-enoic acid, (3E)-4-(thiophene-2-yl)-2-
hydroxybut-3-enoic acid and (3E)-4-(pyrrole-2-yl)-2-hydr-
oxybut-3-enoic acid 3a–3d and 3i (Scheme 2, Tables 2 and
3) gave only one enantiomer in good yields (52–70%) and
ee (95–>99%) 4a–4d and 4i (Scheme 2, Tables 2 and 3).
The introduction of a 5-methyl group in the methyl and
ethyl esters of (3E)-4-(furan-2-yl)-2-hydroxybut-3-enoic
acid and (3E)-4-(thiophene-2-yl)-2-hydroxybut-3-enoic
acid 3e–3h (Scheme 2, Tables 2 and 3) improved the yields
of the product enantiomer to 75–79% with good ee (92–
97%) 4e–4h (Scheme 2, Tables 2 and 3). Thus the biocata-
lyst C. parapsilosis ATCC 7330 deracemises (3E)-alkyl-4-
(hetero-2-yl)-2-hydroxybut-3-enoates 3a–3i (Scheme 2, Ta-
bles 2 and 3) into their enantiomerically pure product enan-
tiomers 4a–4i (Scheme 2, Tables 2 and 3) in good isolated
yields (52–79%) and high ee (90–>99%), accepting the
methyl substituents on these heteroaryl esters thus suggest-
ing a wide substrate tolerance of the enzyme. In addition to
the high enantioselectivity, the biocatalyst displays che-
moselectivity in that the C. parapsilosis ATCC 7330 medi-
ated deracemisation of b,c-unsaturated a-hydroxy esters
occurs without affecting the C@C bond. Hence, multifunc-
tional enantiomerically pure chiral synthons (3E)-alkyl-4-
(3E)-alkyl-4-(hetero-2-yl)-2-hydroxybut-3-enoates
3a–3i
(Scheme 1, Table 1) in moderate to good yields (75–90%).
Table 1. Synthesis of racemic (3E)-alkyl-4-(hetero-2-yl)-2-hydroxybut-3-
enoates 3a–3i
Entry
X
R
R0
Yield (%) 2
Yield (%) 3
a
b
c
d
e
f
O
O
S
H
H
H
H
5-Me
5-Me
5-Me
5-Me
H
Et
Me
Et
Me
Et
Me
Et
85
87
92
90
75
72
84
86
73
80
75
85
83
85
82
90
89
76
S
O
O
S
S
NH
g
h
i
Me
Et
O
O
ONa
O
O
O
R'OH, Toluene
Conc HCl
OR'
OH
H
KOH, aq methanol
X
X
X
R
R
O
R
O
1
2
3 h
0-10oC, 2-3 h
reflux
yield 90-95%
yield 72-92%
NaBH4, EtOH
0-10 oC, 0.5h
OH
R= H, CH3
R'= CH3, CH2CH3
X= O, S, NH
OR'
R
X
O
3
yield 75-90%
Scheme 1. Synthesis of racemic (3E)-alkyl-4-(hetero-2-yl)-2-hydroxybut-3-enoates 3a–3i.

T. Vaijayanthi, A. Chadha / Tetrahedron: Asymmetry 18 (2007) 1077–1084
1079
O
O
Candida parapsilosis ATCC 7330
OR'
X
R
OR'
X
25 oC, 3 h
R
OH
H
4a-4i
(S)
OH
3a-3i
(RS)
R= H, CH3
R= CH3,CH2CH3
X= O, S, NH
Scheme 2. Deracemisation of racemic (3E)-alkyl-4-(hetero-2-yl)-2-hydroxybut-3-enoates 3a–3i.
Table 2. Deracemisation of racemic (3E)-alkyl-4-(hetero-2-yl)-2-hydroxybut-3-enoates 4a–4i
25
Compound
X
R
R0
Yield
eea
½aꢀD
Lit. value
Abs conf
4a
4b
4c
4d
4e
4f
O
O
S
H
H
H
H
5-Me
5-Me
5-Me
5-Me
H
Et
Me
Et
Me
Et
Me
Et
70
52
70
65
78
75
77
79
60
>99
>99
>99
>99
90
92
95
97
95
+25.6 (c 1, MeOH)b
+25.1 (c 1, MeOH)b
+97.6 (c 1, MeOH)b
+96.9 (c 1, MeOH)b
+35.2 (c 1, MeOH)
+41.7 (c 1, MeOH)
+61.4 (c 1, MeOH)
+65.9 (c 1, MeOH)
+52.1 (c 1, MeOH)
ꢁ28.2 (MeOH, 200 mM)c
(S)
(S)
(S)
ꢁ28.2 (MeOH, 200 mM)c
ꢁ98.0 (MeOH, 97 mM)c
S
ꢁ98.0 (MeOH, 97 mM)c
(S)
O
O
S
S
NH
—
—
—
—
—
(S)d
(S)d
(S)d
(S)d
(S)d
4g
4h
4i
Me
Et
a Enantiomeric excess was determined by using chiral HPLC (Chiracel ODH, solvent: hexane–IPA (98:2), flow rate: 1 ml/min).
b Specific rotations were measured after hydrolysis of the esters and compared with literature reported values.
c Ref. 19.
d Compounds 4e–4i showed that the deracemised product had the same elution profile as compounds 4a–4d, that is, the ‘R’ enantiomer is the late eluting
enantiomer, while ‘S’ is the early eluting enantiomer (refer Table 3).
Table 3. Retention times of enantiomerically pure (3E)-alkyl-4-(heteroar-
2-yl)-2-hydroxybut-3-enoates 4a–4i
The mechanism of the deracemisation of the racemic
(3E)-alkyl-4-(hetero-2-yl)-2-hydroxybut-3-enoates 3a–3i
R0
Elution of HPLC peaks
(retention time in minutes)
(Scheme 2, Tables 2 and 3) as seen in aryl-2-hydroxy es-
ters,2g which may involve a keto ester as an intermediate
can be explained by a redox mechanism (stereoinversion)
mediated by oxidoreductases. In order to verify the mech-
anism the following experiment was carried out with (3E)-
ethyl-4-(furan-2-yl)-2-hydroxybut-3-enoate 3a (Scheme 2,
Tables 2 and 3). The time course of the deracemisation of
the racemic (3E)-ethyl-4-(furan-2-yl)-2-hydroxybut-3-eno-
ate 3a (Scheme 2, Tables 2 and 3) was monitored by HPLC
using a reverse phase column. Aliquots of the reaction mix-
ture were taken every 15 min for 3 h. The keto ester inter-
mediate was detected at 15 and 30 min, after which time it
did not show up as a peak in the HPLC. The possible rea-
sons for this observation could be (i) the first step which
involves the formation of a keto ester intermediate is
irreversible and (ii) the second step (reversible) which
involves the enantioselective reduction of the keto ester
intermediate (forward reaction) is considerably faster than
the backward reaction, leading to a negligible concentra-
tion of the keto ester intermediate at any point during
the reaction.20 The presence of (3E)-ethyl-4-(furan-2-yl)-
2-oxobut-3-enoate was confirmed by spiking it with the
standard substrate 2a (Scheme 1, Table 2).
Entry
X
R
Early (major)
Later (minor)
4a
4b
4c
4d
4e
4f
O
O
S
H
H
H
H
5-Me
5-Me
5-Me
5-Me
H
Et
Me
Et
Me
Et
Me
Et
13.95
19.71
15.89
22.35
13.44
17.41
20.27
20.55
14.56
17.19
23.85
19.60
28.76
14.56
18.88
22.53
22.53
17.58
S
O
O
S
S
NH
4g
4h
4i
Me
Et
(hetero-2-yl)-2-hydroxybut-3-enoates 4a–4i (Scheme 2,
Tables 2 and 3) are obtained after 3 h.
It was observed that upon deracemisation, the racemic (3E)-
ethyl-4-(furan-2-yl)-2-hydroxybut-3-enoate 3a (Scheme 2,
Tables 2 and 3) results in the predominant formation of
the (S)-enantiomer and a small amount (27%) of the corre-
sponding (3E)-4-(furan-2-yl)-2-hydroxybut-3-enoic acid
25
[92% ee]19 {½aꢀD ¼ þ23:0 (c 1.0 CH3OH)} as a side product.
2.3. Determination of the absolute configuration of (3E)-
ethyl-4-(thiophene-2-yl)-2-hydroxybut-3-enoate 4c
A control experiment revealed that the ester was stable
under experimental conditions and in all likelihood enzy-
matic hydrolysis follows the deracemisation resulting in
the formation of acid.
Circular dichroism21 and lanthanide shift reagents22
can be employed for the determination of the absolute

1080
T. Vaijayanthi, A. Chadha / Tetrahedron: Asymmetry 18 (2007) 1077–1084
1
configuration, but H NMR of Mosher esters is still the
most widely used method.23 In the present study, the abso-
lute configuration of enantiomerically pure (3E)-ethyl-4-
(thiophene-2-yl)-2-hydroxybut-3-enoate 4c (Tables 2 and
and the enantiomer (3E)-ethyl-4-(thiophene-2-yl)-2-
hydroxybut-3-enoate 4c, of which the absolute config-
uration was to be determined, is the thiophene moiety
instead of a benzene ring which was assumed to have
no effect on the protons under consideration for this
study.
1
3) was determined by a detailed H NMR study of the
Mosher derivatives of 4c. (R)-MTPA esters of (RS)-(3E)-
ethyl-4-(thiophene-2-yl)-2-hydroxybut-3-enoate 3c (Table
2) and enantiomerically pure ethyl-4-(thiophene-2-yl)-
2-hydroxybut-3-enoate 4c, whose absolute configuration
was unknown, were also prepared (Scheme 3). The struc-
ture of the diastereomer [MTPA-(S,R or R,R)-4c, Scheme
3] was confirmed by 1H NMR spectroscopy as per the
following discussion:
(b) Figure 1a and b represent the absolute configurations
of the diastereomers of MTPA-(R,R)-3c and MTPA-
(S,R)-3c obtained from (S)-Mosher’s acid chloride
with (RS)-3c. The benzene ring of the Mosher’s ester
moiety can be assigned either cis or trans with regards
to the olefinic protons (Ha and Hb) of (R)-3c and (S)-
3c. Thus in MTPA-(R,R)-3c (Fig. 1a) the benzene ring
is cis and in MTPA-(S,R)-3c (Fig. 1b) it is trans with
respect to the olefinic protons—Ha and Hb. In the
ester MTPA-(R,R)-3c, Ha (d 5.95–6.01 ppm) and Hb
(d 6.70–6.74 ppm) are more shielded when compared
to the Ha (d 6.02–6.08 ppm) and Hb (d 6.75–
6.79 ppm) in MTPA-(S,R)-3c (Fig. 1, Table 4). This
is due to the diamagnetic effect of the phenyl ring of
Mosher’s ester, as shown in Figure 1a and b.
MeO
Cl
Ph
O
MeO
O
Ph
CF3
O
O
CF3
(S)
Pyridine, rt, 24 h
Hb
O
Ha
OH
S
O
(c) The 1H NMR spectrum of MTPA ester-(S,R or R,R)-
4c [Ha (d 6.02–6.08 ppm), Hb (d 6.75–6.79 ppm)] was
S
O
1
compared with the H NMR spectrum of the MTPA
Scheme 3. Synthesis of (R)-MTPA esters of (R,S)-3c and (R or S)-4c.
esters of the racemic mixture (R,R and S,R)-3c [Ha
(d 5.95–6.01 and 6.02–6.08 ppm), Hb (d 6.70–6.74
and 6.75–6.79 ppm)]. The chemical shift (d) values
for Ha and Hb protons of MTPA-(S,R or R,R)-4c
match with those of the MTPA-(S,R)-3c (less shielded
or where benzene and olefinic protons Ha and Hb are
trans) as shown in Figure 2 indicating that the enantio-
merically pure deracemised product 4c is the (S)-
enantiomer (Table 4).
(a) Determination of the absolute configuration of enantio-
merically pure aryl b,c-unsaturated a-hydroxy esters
1
using H NMR of Mosher esters is reported.24 The
only structural difference between the reported24
ethyl-2-hydroxy-4-phenyl-but-3-enoate
enantiomer
b
a
more shielded
(d) The specific rotation values for esters 4a–4b and 4d
were measured after hydrolysis and compared with
those reported in the literature19 based on which the
absolute configuration was assigned as (S). For com-
pounds 4e–4i, the specific rotations are reported herein
for the first time. The other deracemised compounds
4e–4i (Scheme 2, Tables 2 and 3) have identical chro-
matographic behaviour (elution order on the chiral
stationary phase column) as the suggested (S)
enantiomer.
Ph
MeO
O
H3C
O
S
CF3
Ha
Hb
MeO
O
Ph
CF3
O
H
Hb
H3C
Ha
less shielded
H
O
O
S
O
MTPA-(R,R)-3c
MTPA-(S,R)-3c
Figure 1. (R)-MTPA derivatives of ester (R,R and S,R)-3c.
Table 4. Chemical shift values of Ha and Hb in MTPA ester-(R,R and S,R)-3c, MTPA ester-(R,R or S,R)-4c (refer Scheme 3)
Entry
Product Mosher’s ester
Absolute configuration
Ha (d ppm)
Hb (d ppm)
O
MeO
O
Ph
O
CF3
Hb
O
Ha
MTPA ester-3c
(R,R) and (S,R)
5.95–6.01 and 6.02–6.08
6.70–6.74 and 6.75–6.79
S
O
MeO
O
Ph
O
CF3
MTPA ester-4c
(R,R) or (S,R)
6.02–6.08
6.75–6.79a
Hb
O
Ha
S
a These values are very similar to the ethyl-2-hydroxy-4-phenyl-but-3-enoate. Hence, we established that is was most likely (S).

T. Vaijayanthi, A. Chadha / Tetrahedron: Asymmetry 18 (2007) 1077–1084
1081
4.2. Synthesis of substrates
4.2.1. Preparation of (3E)-4-(hetero-2-yl)-2-oxobut-3-enoic
acids 1a–1i. Typical reaction procedure of compound
1a. Treatment of furan-2-aldehyde (0.862 ml, 0.010 mol)
with sodium pyruvate (1.145 g, 0.010 mol) with 50% aque-
ous methanolic potassium hydroxide (0.841 g, 0.015 mol)
at 0–10 ꢁC with stirring for 3 h, resulted in the production
of yellow salts that were neutralised with dilute HCl and
extracted using ethyl acetate (3 · 10 ml). The combined
organic extracts were dried over anhydrous sodium sulfate,
then concentrated to afford (3E)-4-(furan-2-yl)-2-oxobut-3-
enoic acid as a yellow solid in 90% yield. The same proce-
dure was followed for compounds 1b–1i (Scheme 1).
Figure 2. 1H NMR signals of Ha and Hb in MTPA-(R,R and S,R)-3c,
MTPA-(R,R or S,R)-4c.
4.2.2. Preparation of (3E)-alkyl-4-(hetero-2-yl)-2-oxobut-3-
enoates 2a–2i. Typical reaction procedure of compound
2a. Esterification of (3E)-4-(furan-2-yl)-2-oxobut-3-enoic
acid 1a (Scheme 1) (3 mmol, 500 mg) was carried out with
ethanol (5 ml) in the presence of concentrated hydrochloric
acid (0.2 ml) as a catalyst in dry toluene (10 ml) for 3 h at
95 ꢁC. After esterification was complete, the toluene and
excess ethanol were removed. Compound (3E)-ethyl-4-(fur-
an-2-yl)-2-oxobut-3-enoate 2a was obtained as a brownish
yellow solid in 85% yield (2.5 mmol, 495 mg) after column
purification using hexane–ethyl acetate (95/5) as solvent.
The same procedure was followed for compounds 2b–2i
(Scheme 1 and Table 1).
3. Conclusion
Deracemisation by the biocatalyst, C. parapsilosis ATCC
7330 was found to be highly chemo- and enantioselective
towards heteroaryl b,c-unsaturated a-hydroxy esters
resulting in the synthesis of multifunctional important chi-
ral synthons, enantiomerically pure (S)-(3E)-alkyl-4-(het-
ero-2-yl)-2-hydroxybut-3-enoates 4a–4i (Scheme 2, Tables
2 and 3) in high yields (up to 79%) and in high ee (up to
>99%). The absolute configuration of the enantiomerically
pure (3E)-ethyl-4-(thiophene-2-yl)-2-hydroxybut-3-enoate
4.2.3. Preparation of (3E)-alkyl-4-(hetero-2-yl)-2-hydroxy-
but-3-enoates 3a–3i. Typical reaction procedure of com-
1
4c was determined as (S) using H NMR of the Mosher
ester.
pound
(3E)-ethyl-4-(furan-2-yl)-2-hydroxybut-3-enoate
3a. Reduction of (3E)-ethyl-4-(furan-2-yl)-2-oxobut-3-
enoate 2a (Scheme 1) (2.3 mmol, 450 mg) was carried out
with sodium borohydride (2.3 mmol, 86 mg) in ethanol
(5 ml) for 0.5 h at 0–10 ꢁC. After completion of the reac-
tion, the ethanol was removed. Compound (3E)-ethyl-4-
(furan-2-yl)-2-hydroxybut-3-enoate 3a was obtained as a
brownish yellow liquid in 80% yield (1.8 mmol, 362 mg)
after column purification using hexane–ethyl acetate (95/
5) as the solvent. The same procedure was followed for
compounds 3b–3i (Scheme 1 and Table 1).
4. Experimental
4.1. General methods
C. parapsilosis ATCC 7330 was purchased from ATCC,
Manassas, VA 20108, USA. All chemicals used for media
preparation were purchased locally. All substrates were
synthesised as shown in the given schemes. H and 13C
1
NMR spectra were recorded in CDCl3 on a JEOL
GSX400 and Bruker AV-400 spectrometers operating at
400 MHz. Chemical shifts are expressed in ppm values
using TMS as an internal standard. Infrared spectra were
recorded on a Shimadzu IR 470 Instrument. Mass spectra
were recorded on a Q TOF micromass spectrometer. The
enantiomeric excess (ee%) were determined by HPLC anal-
ysis. HPLC using a chiral column analysis was done on a
Jasco PU-1580 liquid chromatograph equipped with PDA
detector. The chiral column used was Chiralcel OD-H
(Daicel, 4.6 · 250 mm). The solvent used was hexane/iso-
propanol (98/2) at a flow rate of 1 ml minꢁ1 and the absor-
bance monitored using a PDA detector at 254 nm. The
formation of the keto ester as intermediate in the mechanis-
tic study was detected by HPLC using a reverse phase col-
umn (Rt: 3.97 min; column: Sil C-18, solvent system:
acetonitrile–water (70/30), flow rate: 1 ml minꢁ1, detector:
PDA). Optical rotations were determined on an AutopalR
digital polarimeter. TLC was done using Kieselgel 60 F254
aluminium sheets (Merck 1.05554).
4.3. Deracemisation of various racemic (3E)-alkyl-4-(hetero-
2-yl)-2-hydroxybut-3-enoates
4.3.1. Culture medium for the growth of C. parapsilosis
ATCC 7330. Cells of the yeast, C. parapsilosis ATCC
7330 were grown as reported earlier2i and harvested after
44 h and used for the deracemisation reaction.
4.3.2. A typical procedure for the deracemisation reaction of
(3E)-ethyl-4-(furan-2-yl)-2-hydroxybut-3-enoate 3a using the
whole cells of C. parapsilosis ATCC 7330. Deracemisation
of racemic (3E)-ethyl-4-(furan-2-yl)-2-hydroxybut-3-enoate
3a (3 mg, 0.015 mmol) mediated by resting cells of C. par-
apsilosis ATCC 7330 was carried out using the reported
procedure.2i In order to determine the isolated chemical
yield, the deracemisation of 3a was carried out with 72 mg
of the substrate. The rest of the racemic (3E)-alkyl-4-(het-
ero-2-yl)-2-hydroxybut-3-enoates 3b–3i were also used as
substrates in the same manner (Scheme 2 and Table 2).

1082
T. Vaijayanthi, A. Chadha / Tetrahedron: Asymmetry 18 (2007) 1077–1084
4.4. Preparation of MTPA esters
(100 MHz, CDCl3) d ppm: 16.1, 53.0, 117.7, 127.4, 135.0,
137.8, 141.1, 147.4, 162.6, 181.6; IR mmax: 498.1, 544.3,
663.2, 706.5, 795.0, 971.5, 1050.1, 1083.3, 1198.4, 1256.0,
(R)-MTPA esters of (RS)-(3E)-ethyl-4-(thiophene-2-yl)-2-
hydroxybut-3-enoate 3c (Table 2) and enantiomerically
pure ethyl-4-(thiophene-2-yl)-2-hydroxybut-3-enoate 4c
(Table 2) were prepared (Scheme 3) by using the reported
method.24
1528.9, 1582.1, 1654.4, 1682.0, 1731.3, 2953.1 cmꢁ1
;
HRMS (ESI): m/z 233.0247, C10H10O3SNa [M+Na]+
requires 233.0248.
4.4.1.6. (3E)-Ethyl-4-(pyrrole-2-yl)-2-oxobut-3-enoate 2i.
Brown yellow liquid; 1H NMR (400 MHz, CDCl3) d
ppm: 1.31 (t, J = 7.2 Hz, 3H), 4.15 (q, J = 7.2 Hz, 2H),
4.92 (s, br, 1H), 6.08–6.18 (m, 2H), 6.57 (d, J = 3.1 Hz,
1H), 6.72 (d, J = 15.4 Hz, 1H), 7.60 (d, J = 15.4 Hz, 1H);
13C NMR (100 MHz, CDCl3) d ppm: 14.1, 61.0, 109.2,
4.4.1. Analytical data
4.4.1.1. (3E)-Ethyl-4-(furan-2-yl)-2-oxobut-3-enoate 2a.
Yellow solid: mp 70 ꢁC; H NMR (400 MHz, CDCl3) d
1
ppm: 1.31 (t, J = 7.4 Hz, 3H), 4.29 (q, J = 7.4 Hz, 2H),
6.45 (dd, J = 2.0, 3.5 Hz, 1H), 6.75 (d, J = 3.5 Hz, 1H),
7.12 (d, J = 15.6 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.52
(d, J = 15.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
ppm: 13.8, 62.2, 113.0, 117.7, 118.5, 133.3, 146.2, 150.8,
161.8, 182.1; IR mmax: 625.4, 705.1, 801.0, 1023.8, 1086.8,
114.8, 120.4, 130.4, 131.5, 147.4, 162.6, 181.6; IR mmax
:
498.1, 544.3, 663.2, 706.5, 795.0, 971.5, 1050.1, 1083.3,
1198.4, 1256.0, 1528.9, 1582.1, 1654.4, 1682.0, 1731.3,
2953.1 cmꢁ1; HRMS (ESI): m/z 216.0010, C10H11NO3Na
[M+Na]+ requires 216.0007.
1377.9, 1561.9, 1603.0, 1733.7, 2956.0 cmꢁ1
;
HRMS
(ESI): m/z 195.0657, C10H11O4 [M+H]+ requires 195.0649.
4.4.1.7. (3E)-Methyl-4-(furan-2-yl)-2-hydroxybut-3-eno-
ate 3b. Yellow liquid; 1H NMR (400 MHz, CDCl3) d
ppm: 3.11 (s, 1H), 3.82 (s, 3H), 4.82 (d, J = 5.4 Hz, 1H),
6.21 (dd, J = 5.4 and 15.7 Hz, 1H), 6.28 (d, J = 3.2 Hz,
1H), 6.36 (dd, J = 1.2 and 3.2 Hz, 1H), 6.63 (d,
J = 15.7 Hz, 1H), 7.35 (d, J = 1.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d ppm: 53.0, 70.8, 109.0, 111.3, 120.1,
123.7, 142.3, 159.0, 173.1; IR mmax: 594.4, 702.1, 731.0,
884.0, 923.9, 965.0, 1013.8, 1125.3, 1264.8, 1438.4,
1735.8, 2359.8, 2955.5, 3480.7 cmꢁ1; HRMS (ESI): m/z
205.0476, C9H10O4Na [M+Na]+ requires 205.0477.
4.4.1.2.
(3E)-Ethyl-4-(5-methylfuran-2-yl)-2-oxobut-3-
enoate 2e. Orange yellow solid: mp 87 ꢁC; 1H NMR
(400 MHz, CDCl3) d ppm: 1.30 (t, J = 7.0 Hz, 3H), 2.30
(s, 3H), 4.28 (q, J = 7.0 Hz, 2H), 6.08 (d, J = 3.6 Hz,
1H), 6.65 (d, J = 3.6 Hz, 1H), 7.05 (d, J = 15.6 Hz, 1H),
7.46 (d, J = 15.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d ppm: 13.0, 14.4, 61.2, 109.0, 115.3, 119.7, 132.5, 148.8,
156.7, 161.3, 181.3; IR mmax: 623.1, 733.1, 879.5, 1045.1,
1086.8, 1377.9, 1560.9, 1604.2, 1737.6, 2883.3,
2972.7 cmꢁ1; HRMS (ESI): m/z 231.0638, C11H12O4Na
[M+Na]+ requires 231.0633.
4.4.1.8. (3E)-Ethyl-4-(thiophen-2-yl)-2-hydroxybut-3-eno-
ate 3c. Yellow liquid; 1H NMR (400 MHz, CDCl3) d
ppm: 1.21 (t, J = 6.9 Hz, 3H), 3.1 (s, br, 1H), 4.1 (q,
J = 6.9 Hz, 2H), 4.70 (d, J = 5.2 Hz, 1H), 5.90 (dd,
J = 5.2 and 15.6 Hz, 1H), 6.83 (d, J = 1.6 Hz, 1H), 6.88
(d, J = 15.6 Hz, 1H), 6.90 (dd, J = 1.6 and 5.2 Hz, 1H),
7.10 (d, J = 5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
ppm: 16.2, 53.1, 70.8, 124.6, 124.9, 125.5, 126.6, 127.3,
141.1, 173.6; IR mmax: 486.7, 545.4, 698.7, 753.4, 826.3,
855.2, 957.1, 1020.5, 1040.7, 1040.7, 1118.9, 1199.4,
4.4.1.3. (3E)-Methyl-4-(5-methylfuran-2-yl)-2-oxobut-3-
enoate 2f. Yellow solid: mp 84 ꢁC; H NMR (400 MHz,
1
CDCl3) d ppm: 2.46 (s, 3H), 3.85 (s, 3H), 6.08 (d,
J = 3.5 Hz, 1H), 6.65 (d, J = 3.5 Hz, 1H), 7.05 (d, J =
15.6 Hz, 1H), 7.46 (d, J = 15.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d ppm: 14.1, 52.9, 110.1, 116.1, 121.0,
133.7, 149.8, 157.8, 162.6, 181.8; IR mmax: 625.4, 705.1,
801.0, 973.5, 1023.8, 1085.3, 1141.0, 1184.3, 1249.1,
1285.4, 1370.3, 1437.5, 1515.9, 1561.1, 1603.3, 1682.5,
1733.7, 2956.0 cmꢁ1
;
HRMS (ESI): m/z 217.0480,
1257.1, 1368.6, 1644.9, 1728.8, 2981.5, 3466.0 cmꢁ1
;
C10H10O4Na [M+Na]+ requires 217.0477.
HRMS (ESI): m/z 235.0408, C10H12O3SNa [M+Na]+
requires 235.0405.
4.4.1.4. (3E)-Ethyl-4-(5-methylthiophen-2-yl)-2-oxobut-3-
enoate 2g. Yellow solid: mp 102 ꢁC; 1H NMR (400 MHz,
CDCl3) d ppm: 1.32 (t, J = 6.7 Hz, 3H), 2.45 (s, 3H), 4.29
(q, J = 6.7 Hz, 2H), 6.70 (d, J = 2.9 Hz, 1H), 6.93 (d,
J = 15.6 Hz, 1H), 7.15 (d, J = 2.9 Hz, 1H), 7.83 (d,
J = 15.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d ppm:
14.0, 16.0, 62.3, 117.9, 127.3, 134.7, 137.8, 140.9, 147.1,
162.2, 182.0; IR mmax: 466.1, 592.8, 733.2, 781.7, 790.2,
848.4, 862.6, 882.4, 913.4, 989.6, 1048.1, 1083.4, 1092.4,
1202.0, 1237.8, 1261.6, 1283.3, 1311.4, 1372.6, 1420.7,
1586.9, 1731.7, 2957.0 cmꢁ1; HRMS (ESI): m/z 247.0409,
C11H12O3SNa [M+Na]+ requires 247.0405.
4.4.1.9. (3E)-Methyl-4-(thiophen-2-yl)-2-hydroxybut-3-
enoate 3d. Yellow liquid; H NMR (400 MHz, CDCl3)
1
d ppm: 3.89 (s, 3H), 4.86 (d, J = 5.2 Hz, 1H), 6.14 (dd,
J = 5.2 and 15.6 Hz, 1H), 6.99 (d, J = 15.6 Hz, 1H), 7.02
(d, J = 1.6 Hz, 1H), 7.05 (dd, J = 1.6, 4.7 Hz, 1H), 7.24
(d, J = 4.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
ppm: 53.0, 70.9, 124.5, 124.8, 125.4, 126.5, 127.4, 141.0,
173.5; IR mmax: 494.4, 699.2, 809.2, 852.9, 956.7, 1040.6,
1119.6, 1206.2, 1435.2, 1585.2, 1656.5, 1727.4, 2952.0,
3436.4 cmꢁ1; HRMS (ESI): m/z 221.0245, C9H10O3SNa
[M+Na]+ requires 221.0248.
4.4.1.5. (3E)-Methyl-4-(5-methylthiophen-2-yl)-2-oxobut-
3-enoate 2h. Yellow solid: mp 95 ꢁC; 1H NMR
(400 MHz, CDCl3) d ppm: 2.46 (s, 3H), 3.85 (s, 3H), 6.71
(d, J = 2.8 Hz, 1H), 6.95 (d, J = 15.6 Hz, 1H), 7.19 (d,
J = 2.8 Hz, 1H), 7.85 (d, J = 15.6 Hz, 1H); 13C NMR
4.4.1.10. (3E)-Ethyl-4-(5-methylfuran-2-yl)-2-hydroxy-
but-3-enoate 3e. Yellow liquid; 1H NMR (400 MHz,
CDCl3) d ppm: 1.37 (t, J = 7.1 Hz, 3H), 3.09 (s, br, 1H),
3.72 (s, 3H), 4.2 (q, J = 7.1 Hz, 2H), 4.82 (d, J = 5.2 Hz,
1H), 6.0–6.21 (2H, m), 6.47 (dd, J = 5.2 and 15.6 Hz,

T. Vaijayanthi, A. Chadha / Tetrahedron: Asymmetry 18 (2007) 1077–1084
1083
1H), 6.59 (d, J = 15.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d ppm: 13.6, 14.1, 62.2, 70.9, 107.4, 110.2, 120.3,
122.1, 150.4, 150.8, 173.3; IR mmax: 701.4, 729.7, 785.4,
858.2, 1021.2, 1081.0, 1243.5, 1370.4, 1444.5, 1467.6,
1514.2, 1563.4, 1603.8, 1642.0, 1727.3, 2983.2,
3452.4 cmꢁ1; HRMS (ESI): m/z 211.0969, C11H15O4
[M+H]+ requires 211.0970.
15.2 Hz, 1H), 6.77 (d, J = 15.2 Hz, 1H), 6.90–7.65 (m,
16H).
4.4.1.16. MTPA-(S,R)-4c. Yellow liquid; 1H NMR
(400 MHz, CDCl3) d ppm: 1.28 (t, J = 6.9 Hz, 3H), 3.62
(s, 3H), 4.25 (q, J = 6.9 Hz, 2H), 5.79 (d, J = 5.1 Hz,
1H), 6.06 (dd, J = 5.1 and 15.2 Hz 1H), 6.76 (d,
J = 15.2 Hz, 1H), 7.0–7.7 (m, 8H).
4.4.1.11. (3E)-Methyl-4-(5-methylfuran-2-yl)-2-hydroxy-
but-3-enoate 3f. Yellow liquid; 1H NMR (400 MHz,
CDCl3) d ppm: 2.0 (s, 3H), 3.75 (s, 3H), 4.71 (d,
J = 5.4 Hz, 1H), 5.88 (d, J = 1.6 Hz, 1H), 6.02 (dd,
J = 5.4 and 15.6 Hz, 1H), 6.08 (d, J = 1.6 Hz, 1H), 6.47
(d, J = 15.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
ppm: 13.6, 52.9, 70.9, 107.5, 110.3, 120.4, 121.9, 150.3,
152.4, 173.7; IR mmax: 701.6, 732.2, 786.1, 965.8, 1021.3,
1086.1, 1265.2, 1437.8, 1516.7, 1562.6, 1603.2, 1732.6,
Acknowledgements
We thank the DST, Government of India, for providing
financial assistance and Sophisticated Analytical Instru-
mentation Facility (SAIF), Indian Institute of Technology
Madras, Chennai, for NMR data.
2954.9, 3473.7 cmꢁ1
C10H12O4Na [M+Na]+ requires 219.0633.
;
HRMS (ESI): m/z 219.0638,
References
4.4.1.12.
(3E)-Ethyl-4-(5-methylthiophen-2-yl)-2-hydr-
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oxybut-3-enoate 3g. Yellow liquid; H NMR (400 MHz,
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(q, J = 6.8 Hz, 2H), 4.74 (d, J = 5.6 Hz, 1H), 6.25 (dd,
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127.0, 127.5, 127.9, 145.0, 135.2, 172.0; IR mmax: 702.3,
733.2, 801.0, 1021.2, 1106.9, 1192.4, 1266.3, 1448.5,
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249.0565, C11H14O3SNa [M+Na]+ requires 249.0561.
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Enantioselective Synthesis; VCH: Weinhein, Germany, 1997.
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1
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5.5 Hz, 1H), 6.23 (dd, J = 5.5 and 15.4 Hz, 1H), 6.62 (d,
J = 1.7 Hz, 1H), 6.65 (d, J = 15.4 Hz, 1H), 6.69 (d, J =
1.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) d ppm: 16.5,
52.4, 73.0, 126.8, 127.0, 127.5, 127.7, 135.5, 143.6, 173.0;
IR mmax: 750.3, 801.4, 956.2, 1035.2, 1095.6, 1216.7,
1366.4, 1444.4, 1642.9, 1738.7, 1991.2, 2210.0, 2854.1,
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2925.4, 3455.8 cmꢁ1
;
HRMS (ESI): m/z 213.0592,
C10H13O3S [M+H]+ requires 213.0585.
4.4.1.14. (3E)-Ethyl-4-(pyrrole-2-yl)-2-hydroxybut-3-eno-
ate 3i. Brown yellow liquid; 1H NMR (400 MHz, CDCl3)
d ppm: 1.3 (t, J = 7.3 Hz, 3H), 2.8 (s, br, 1H), 4.15 (q,
J = 7.3 Hz, 2H), 4.77 (d, J = 5.5 Hz, 1H), 6.12 (d, J =
2.5 Hz, 1H), 6.14–6.18 (m, 1H), 6.27 (dd, J = 5.5 and
15.6 Hz, 1H), 6.64 (d, J = 15.6 Hz, 1H), 6.68 (d,
J = 2.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) d ppm:
14.2, 16.9, 74.3, 109.5, 112.5, 119.7, 126.8, 127.5, 130.1,
172.0; IR mmax: 702.3, 733.2, 801.0, 1021.2, 1106.9,
1192.4, 1266.3, 1448.5, 1725.7, 2832.6, 2943.4,
3333.7 cmꢁ1; HRMS(ESI): m/z 218.0900, C10H13NO3Na
[M+Na]+ requires 218.0909.
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1
4.4.1.15. MTPA-(R,R and S,R)-3c. Yellow liquid; H
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6H), 3.51 (s, 3H), 3.62 (s, 3H), 4.32 (2q, J = 6.9 Hz, 4H),
5.79 (2d, J = 5.1 Hz, 2H), 5.98 (dd, J = 5.1 and 15.2 Hz,
1H), 6.05 (dd, J = 5.1 and 15.2 Hz, 1H), 6.72 (d, J =
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