Chemoenzymatic synthesis of (5S)- and (5R)-hydroxymethyl-3,5-dimethyl-4-(methoxymethoxy)-5H-thiophen-2-one: a precursor of thiolactomycin and determination of its absolute configuration

Article abstract of DOI:10.1016/j.tetasy.2006.10.032

A convenient enantioselective synthesis of (5S)- and (5R)-hydroxymethyl-3,5-dimethyl-4-(methoxymethoxy)-5H-thiophen-2-one, a key intermediate in the synthesis of thiolactomycin has been carried out by a Carica papaya lipase-mediated resolution protocol to

Full text of DOI:10.1016/j.tetasy.2006.10.032

Tetrahedron: Asymmetry 17 (2006) 2890–2895
Chemoenzymatic synthesis of (5S)- and (5R)-hydroxymethyl-
3
,5-dimethyl-4-(methoxymethoxy)-5H-thiophen-2-one:
a precursor of thiolactomycin and determination
I
of its absolute configuration
*
Ahmed Kamal, Ahmad Ali Shaik, Shaik Azeeza, M. Shaheer Malik and Mahendra Sandbhor
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 31 August 2006; accepted 20 October 2006
Abstract—A convenient enantioselective synthesis of (5S)- and (5R)-hydroxymethyl-3,5-dimethyl-4-(methoxymethoxy)-5H-thiophen-2-
one, a key intermediate in the synthesis of thiolactomycin has been carried out by a Carica papaya lipase-mediated resolution protocol
to provide (R)-2 in a 94% ee and its enantiomer (S)-9 in a 98% ee. The absolute configuration at the C-5 position has been determined by
Mosher’s method.
ꢀ
2006 Elsevier Ltd. All rights reserved.
1. Introduction
based analogues, among which some analogues have
shown promising activity against M. tuberculosis cul-
1
0
Naturally occurring (5R)-thiolactomycin 1 (TLM) is a thio-
lactone antibiotic initially isolated from Nocardia sp. found
in a Japanese soil sample. It exhibits broad-spectrum anti-
tures. There are only a few synthetic strategies that have
been developed for the synthesis of thiolactomycin. Wang
and Salvino reported the first total synthesis of racemic
2
1
1
biotic activity in vitro against Gram +ve and Gram ꢀve
thiolactomycin in lower yields. Later Thomas et al. devel-
oped an asymmetric synthesis of (5S)-thiolactomycin and
Townsend and co-workers synthesized (5R)-thiolactomycin
from (2R)-alanine. Recently, Ohata et al. also developed
3
4
12
bacteria, Mycobacterium tuberculosis, the malarial
5
a–e
parasite, Plasmodium falciparum
and African trypano-
TLM inhibits bacterial and plant type II fatty
5
a,d
13
somes.
acid synthase (FAS II) but not mammalian or yeast type
I fatty acid synthase (FAS I). In Escherichia coli, TLM
an asymmetric synthesis of naturally occurring thiolacto-
mycin and its 3-dimethyl derivative. In view of our inter-
6
14
inhibits both b-ketoacyl-ACP synthase I–III and acetyl
est in the development of chemoenzymatic methodologies,
it was considered of interest to develop a chemoenzymatic
route for the preparation of optically active (5R)-hydroxy-
methyl-3,5-dimethyl-4-(methoxymethoxy)-5H-thiophen-2-
one 2 and its enantiomer, which is a key intermediate for
the synthesis of thiolactomycin. Herein, we report a chemo-
enzymatic procedure for the synthesis of (5R)-2 and (5S)-2
starting from methyl propionylacetate and involving a
Carica papaya lipase-mediated resolution protocol.
coenzyme A (CoA):ACP transacylase activities in in vivo
7
and in vitro conditions. Thiolactomycin’s favourable
physical and pharmacokinetic properties, that is, low
molecular weight, high water solubility, appropriate lipo-
8
philicity and low toxicity profile in mice made it an attrac-
9
tive lead molecule for tuberculosis.
Based on TLM’s unique selectivity and inherent potential
for analogues of TLM to be potent therapeutic agents,
we have recently synthesized a new class of thiolactomycin
S
S
S
O
O
O
OH
OH
q
See Ref. 1.
OMOM
OMOM
(S)-2
*
Corresponding author. Tel.: +91 40 27193157; fax: +91 40 27193189;
e-mail: ahmedkamal@iict.res.in
OH
R)-1
(
(R)-2
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.10.032

A. Kamal et al. / Tetrahedron: Asymmetry 17 (2006) 2890–2895
2891
2
. Results and discussion
lactone acetate (S)-9 in a 98% ee and the corresponding hy-
droxy methyl thiolactone (R)-2 in a 94% ee. It was
observed that lipase-mediated alcoholysis of compound
(± )-9 with 1 equiv (w/w) of Carica papaya gave thiolactone
acetate (S)-9 in a 89% ee and the corresponding alcohol
(R)-2 in a 79% ee in 2 days. The results obtained during
the present investigation are summarized in Table 1. On
the basis of the results obtained from the screening of var-
ious lipases, it was observed that Carica papaya lipase with
2 equiv (w/w) provided high conversions with an excellent
enantioselectivity for this alcoholysis process. Therefore,
based on these preliminary results, Carica papaya lipase
was selected for further studies.
In the present synthetic scheme methyl propionylacetate 3
is employed as a starting material. The methylation of b-
keto ester 3 using CH I and anhydrous K CO affords
the corresponding methylated b-keto ester 4. Selective
bromination of compound 4 with Br in CHCl yields c-
brominated product 5, which is followed by thioacetyla-
tion and cyclization to provide thiolactone 7 in moderate
to good yields (Scheme 1).
3
2
3
1
5
2
3
1
6
1
0
Compound (± )-5-hydroxymethyl-3,5-dimethyl-4-(methoxy-
methoxy)-5H-thiophen-2-one 2 was prepared from thio-
lactone 7 via a two-step procedure.
1
7
The primary
hydroxyl group of compound 2 has been acetylated with
acetic anhydride in DMAP to provide the desired (± )-5-
methylacetate-3,5-dimethyl-4-(methoxymethoxy)-5H-thio-
phen-2-one 9 in good yields (Scheme 2). In view of our
interest in enzyme-mediated kinetic resolution of chiral
2
.2. Effect of alcohol
Lipase-mediated alcoholysis of (± )-5-methylacetate-3,5-
dimethyl-4-(methoxymethoxy)-5H-thiophen-2-one 9 was
attempted by employing two different alcohols, namely
n-butanol and 2-propanol with Carica papaya 2 equiv
1
8
building blocks, we performed the resolution of (± )-2
and (± )-9 by employing different lipases.
(
w/w). Carica papaya lipase in n-butanol gave better results
where as this alcoholysis process in 2-propanol required
6 h to provide alcohol (R)-2 in a 67% ee and acetate
S)-9 in a 72% ee as shown in Table 1. Therefore, n-butanol
2
.1. Lipase screening and enzyme concentration
3
(
The selection of a suitable lipase is an important aspect for
developing an efficient resolution protocol. Eleven com-
mercially available lipases from different sources have been
screened for this lipase-mediated alcoholysis of racemic
thiolactone acetate (± )-9 in diisopropyl ether and n-buta-
nol. Lipases from Pseudomonas cepacia (PS) and their
immobilized forms lipase PS-C (immobilized on ceramic
particles) and lipase PS-D (immobilized on diatomaceous
earth), Candida antarctica, Candida cylindracea, AK-20
Pseudomonas fluorescens (PFL) and lipase from Porcine
pancrease (PPL) did not show any significant conversions,
even after prolonged reaction times. The lipases Mucor
miehei (lipozyme) and Candida rugosa (CRL) gave moder-
ate results, when 4 equiv (w/w) of lipases have been used.
Both of these lipases (Mucor miehei and Candida rugosa)
provide thiolactone acetate (S)-9 in 56% and (R)-9 in a
was selected as a suitable alcohol for this resolution
process.
2.3. Lipase-mediated transesterification
The lipase-mediated transesterification of (± )-5-hydroxy-
methyl-3,5-dimethyl-4-(methoxymethoxy)-5H-thiophen-2-
one 2 was attempted with the above-mentioned 11 lipases
employing isopropenyl acetate. The transesterification of
compound (± )-2 by employing Carica papaya 2 equiv
(w/w) in isopropenyl acetate provides alcohol (S)-2 in a
59% ee and the corresponding acetate (R)-9 in a 72% ee.
The immobilized forms of lipases from Pseudomonas cepa-
cia, that is, PS-C and PS-D gives moderate enantioselectiv-
ities of acetate (R)-9 in 81% and 69%, respectively, whereas
the corresponding alcohols (S)-2 were obtained in low
enantioselectivities. The lipases from Mucor miehei and
Candida rugosa provided thiolactone acetate (R)-9 in 39%
and (S)-9 in 43% ee and the corresponding hydroxymethyl
thiolactone in low enantioselectivities, that is, (S)-2 in 27%
and (R)-2 in 28%. Other lipases did not show any signifi-
cant conversion even after prolonged reactions time.
Therefore, the lipase-mediated transesterification process
4
8% ee and the corresponding hydroxymethyl thiolactone
in moderate enantioselectivities, that is, (R)-2 in 68% and
S)-2 in 61%, respectively. However, Carica papaya lipase-
(
mediated alcoholysis of racemic thiolactone acetate (± )-9
has shown interesting results with good conversions and
high enantioselectivities. The lipase-mediated alcoholysis
of compound (± )-9 by employing Carica papaya (2 w/w
equiv) in diisopropyl ether, n-butanol at 40 ꢁC gave thio-
Br
i
ii
OCH3
OCH3
OCH3
O
O
O
O
O
O
3
4
5
SAc
O
S
O
iii
iv
OCH3
O
OH
6
7
2 3 3 2 3 3 2 2 2
Scheme 1. Reagents and conditions: (i) anhydrous K CO , CH I, dry THF, reflux; (ii) Br , CHCl , rt; (iii) AcSH, Et N, CH Cl , rt; (iv) KOH, H O–
EtOH, rt.

2892
A. Kamal et al. / Tetrahedron: Asymmetry 17 (2006) 2890–2895
S
S
S
S
O
O
O
O
OH
iii
OAc
i
ii
OH
OMOM
OMOM
(±)-2
OMOM
(±)-9
7
8
Scheme 2. Reagents and conditions: (i) MOMCl, N,N-diisopropylethylamine, dry CH
dry CH Cl , rt.
2
Cl
2
, rt; (ii) LDA, (HCHO)
n
2
, dry THF, ꢀ78 ꢁC; (iii) Ac O, DMAP,
2
2
a
Table 1. Enzymatic alcoholysis of compound (± )-9 by employing different lipases and alcohols
b
c
Lipase
Equiv (w/w)
Alcohol
Time (h)
ee (%)
Conversion (%)
Alcohol-2 (Config.)
Acetate-9 (Config.)
Carica papaya
Carica papaya
Mucor miehei
Candida rugosa
Carica papaya
2
1
4
4
2
n-Butanol
n-Butanol
n-Butanol
n-Butanol
2-Propanol
18
48
38
40
36
94 (R)
79 (R)
68 (R)
61 (S)
67 (R)
98 (S)
89 (S)
56 (S)
48 (R)
72 (S)
51
53
45
44
52
a
b
c
Conditions: 9 (1 mmol), diisopropyl ether (10 mL), alcohol (10 mmol) at 40 ꢁC.
Time taken for alcoholysis.
Enantiomeric excess of alcohol 2 and acetate 9 is determined by chiral HPLC analysis employing Daicel Chiralcel AS-H column (0.46 · 25 cm); eluent:
hexane–isopropanol = 90:10; flow rate: 0.5 mL/min; UV detection: 254 nm.
was not considered as a practical route for achieving good
enantiopurities for these required intermediates.
2.4. Determination of the absolute configuration by Mosher’s
method
Thus, lipase-catalyzed alcoholysis of (± )-5-methylacetate-
Over the course of our study, the absolute configuration of
both the alcohols of 5-hydroxymethyl-3,5-dimethyl-4-
(methoxymethoxy)-5H-thiophen-2-one 2 was determined
by H NMR spectra of their esters with a-methoxy-a-(tri-
fluoromethyl)phenylacetic acid (MTPA) and correlated
3
,5-dimethyl-4-(methoxymethoxy)-5H-thiophen-2-one
was carried out by employing Carica papaya lipase 2 equiv
w/w) and n-butanol in diisopropyl ether at 40 ꢁC. The
9
1
(
reaction progress was monitored on chiral HPLC employ-
ing a Chiralcel AS-H column. In order to obtain good
enantioselectivities and yields, the reaction was stopped
when it reached about 50% conversion. The pure products
are isolated by silica gel column chromatography to obtain
acetate (S)-9 in a 98% ee and a 48% yield, while the corre-
sponding alcohol (R)-2 in a 94% ee and a 46% yield
with the proposed model for 9-anthrylmethoxyacetic acid
1
9
(9-AMA) by Riguera et al. The enantiomerically enriched
both 5-hydroxymethyl-3,5-dimethyl-4-(methoxymethoxy)-
5H-thiophen-2-one 2 alcohols were derivatized to their cor-
responding (R)- and (S)-MTPA esters by the condensation
with (R)- and (S)-MTPA. The alcohol obtained during the
lipase-mediated alcoholysis was designated as alcohol-I
while the other alcohol, which was obtained by Candida
rugosa lipase-mediated deacetylation procedure, was desig-
nated as alcohol-II.
(
Scheme 3).
Deacetylation of (S)-9 was carried out under different reac-
tion conditions by using anhydrous K CO in methanol
2
3
and with LiOH, to give a complex mixture of products.
The successful deacetylation of (S)-9 was carried out by
using Candida rugosa lipase in n-butanol for 5 days to pro-
vide (S)-2 in a 98% ee and with a 90% yield (Scheme 4).
The condensation of (R)- and (S)-a-methoxy-a-(trifluoro-
methyl)phenylacetic acid (MTPA) with alcohol-I by
employing DCC gave (R)-MTPA ester-I and (S)-MTPA
1
ester-I. Based on the chemical shift differences in the H
NMR spectra of (R)-MTPA ester-I and (S)-MTPA ester-
I, a proposed model was demonstrated. According to
Riguera’s proposed empirical conformational model, the
S
S
S
O
O
O
OAc
OMOM
OH
OAc
OMOM
i
+
substitutent (shifted to higher field in the (R)-MTPA ester),
OMOM
RS
(
±)-9
(R)-2
(S)-9
placed above the plane (Dd
<0) and the substitutent
shifted to higher field in the (S)-MTPA ester is placed
Scheme 3. Reagents and conditions: (i) Carica papaya lipase, n-butanol,
diisopropyl ether, 40 ꢁC.
RS
1
below the plane (Dd >0). Based on the H NMR spectra
of (R)-MTPA ester-I 10 and (S)-MTPA ester-I 11 of alco-
hol-I, which was obtained by lipase-mediated alcoholysis
possessing an (R)-configuration at the asymmetric centre,
and proposed model is as shown in Figure 1.
S
S
O
O
OAc
OMOM
OH
i
1
OMOM
The chemical shift differences in H NMR spectra of (R)-
(
S)-9
(S)-2
MTPA ester-II 12 and (S)-MTPA ester-II 13 indicated that
alcohol-II, which was obtained by Candida rugosa lipase-
mediated deacetylation procedure possesses the (S)-config-
Scheme 4. Reagents and conditions: (i) lipase Candiada rugosa, n-butanol,
diisopropyl ether, 40 ꢁC.

A. Kamal et al. / Tetrahedron: Asymmetry 17 (2006) 2890–2895
2893
+
0.018
dzu LC-10AT system controller, SPD-10A fixed wave-
length UV monitor as the detector. Specific rotations
were recorded on SEPA-300 Horiba high sensitive polari-
meter, fixed with sodium lamp of wavelength 589 nm.
S
O
RO
O
-
0.032
-
0.109
-
0.081
O
4.2. Chemicals and enzymes
-0.004
R = MTPA
Methyl propionylacetate, (R)- and (S)-a-methoxy-a-(tri-
fluoromethyl)phenylacetic acid, thioacetic acid, bromine,
n-BuLi, diisopropyl amine, N,N-diisopropylethylamine,
sodium hydroxide and solvents were obtained commer-
cially and used without purification. Pseudomonas cepacia
lipase immobilized on ceramic particles (PS-C) and Pseudo-
monas cepacia lipase immobilized on diatomaceous earth
(PS-D) were purchased from Amano (Nagoya, Japan),
Carica papaya lipase was purchased from Sigma–Aldrich.
RS
Figure 1. Dd values for MTPA derivatives of alcohol-I.
-0.011
S
O
RO
O
+
0.041
+
0.1155
+
0.091
O
+0.013
4.2.1. Methyl-2-methyl-3-oxopentanoate 4. To a solution
R = MTPA
of methyl propionylacetate 3 (5.2 g, 40 mmol) in dry
THF (70 mL) was added anhydrous K CO (16.6 g,
RS
Figure 2. Dd values for MTPA derivatives of alcohol-II.
2
3
1
20 mmol) under an N atmosphere. The mixture was then
2
refluxed for 3 h after which it turned to a pale yellow col-
our. The resulting mixture was cooled to 0 ꢁC and CH I
uration at the asymmetric centre, and the proposed model
is shown in Figure 2.
3
(
3 mL, 48 mmol) was added dropwise and stirred for 6–
8
h. The reaction was filtered through a Celite pad and
the collected filtrate concentrated under reduced pressure
to obtain an oily residue, which was purified by silica gel
column chromatography to obtain 5.3 g of pure methyl-
ated b-ketoester 4. Yield: 92%; IR (neat): 2995, 2910,
3
. Conclusion
In conclusion, a facile lipase-mediated resolution protocol
to obtain 5-hydroxymethyl-3,5-dimethyl-4-(methoxymeth-
oxy)-5H-thiophen-2-one, a key intermediate in the synthe-
sis of thiolactomycin, has been achieved. The Carica
papaya lipase-mediated alcoholysis has provided a good
enantiomeric excess for alcohol (R)-2 in a 94% ee as well
as the corresponding acetate (S)-9 in a 98% ee. The deacet-
ylation process has been carried out by employing Candida
rugosa lipase to provide the corresponding (5S)-alcohol
under extremely mild reaction conditions. Furthermore,
the absolute configuration of both the alcohols has been
determined by the application of Mosher’s method. In this
connection the application of the MTPA ester method has
been extended for the determination of absolute configura-
tion of primary alcohols. Both enantiomers have been syn-
thesized in a high enantiomeric excess, which will assist
researchers to design and synthesize novel analogues in
the desired stereochemical forms.
ꢀ1
1
1
746, 1710 cm ; H NMR (200 MHz; CDCl ) d 1.03
3
(3H, t, J = 7.03 Hz), 1.30 (3H, d, J = 7.03 Hz), 2.4–2.6
(
2H, m), 3.5 (1H, q, J = 7.03 Hz), 3.75 (3H, s); EIMS
+
(m/z): 144 (M ); Anal. Calcd for C H O : C, 58.32; H,
7
12
3
8.39. Found: C, 58.24; H, 8.29.
4.2.2. Methyl-4-bromo-2-methyl-3-oxopentanoate 5. To a
solution of compound 4 (5.0 g, 34.7 mmol) in CHCl3
60 mL), Br (1.78 mL, 34.7 mmol) in CHCl (20 mL) was
(
2
3
added at 0 ꢁC and the reaction mixture was stirred at room
temperature for 10 h. A stream of air was then passed
through the solution for 1 h. After drying over anhydrous
Na SO , the solvent was removed in vacuo and subjected
2
4
to silica gel column chromatography to yield 4.8 g of pure
c-bromo b-ketoester 5. Yield: 61.7%; IR (neat): 2990, 2920,
ꢀ1
1
1
760, 1730 cm ; H NMR (200 MHz; CDCl ) d 1.29 (3H,
3
d, J = 7.03 Hz), 1.76 (3H, d, J = 7.03 Hz), 3.75 (3H, s),
.06 (1H, q, J = 7.03 Hz), 4.89 (1H, q, J = 7.03 Hz);
4
+
FABMS (m/z): 224 (M +2); Anal. Calcd for C H BrO :
7
11
3
C, 37.69; H, 4.97. Found: C, 37.59; H, 4.91.
4. Experimental
4
.2.3. Methyl-4-(acetylsulfanyl)-2-methyl-3-oxopentanoate
6. To a stirred solution of thioacetic acid (1.57 mL,
2 mmol) in 30 mL of dry CH Cl was added triethylamine
4
.1. Material and methods
2
2
2
Enzymatic reactions were carried out on ‘New Brunswick-
shaker’ at 220 rpm. Infrared spectra of neat samples are
reported in wave numbers (cm ). H NMR was recorded
(3.3 mL, 24 mmol) under an N atmosphere and left for
2
20 min. The reaction mixture was then cooled to 0 ꢁC
and compound 5 (4.5 g, 20 mmol) added in 10 mL of dry
CH Cl dropwise over a period of 30 min. The resulting
ꢀ
1
1
as solutions in CDCl and chemical shifts are reported in
3
2
2
parts per million (PPM, d) on a 200 MHz instrument. Cou-
pling constants are reported in Hertz (Hz). LSIMS mass
spectra were recorded on Autospec M. with 7 kV accelera-
tion voltage and 25 kV gun voltage. HPLC analysis was
performed on an instrument, which consisted of a Shima-
mixture was stirred at room temperature for 6 h. The reac-
tion mixture was diluted with water and extracted with
CH Cl (2 · 10 mL). The combined organic layers were
2
2
dried over anhydrous Na SO . The solvent was removed
2
4
in vacuo and the residue subjected it for silica gel column

2894
A. Kamal et al. / Tetrahedron: Asymmetry 17 (2006) 2890–2895
chromatography to afford 4 g of pure 6. Yield: 91%; IR
compound (± )-2. Yield: 89%; IR (neat): 3426, 2971,
ꢀ
1
1
ꢀ1
1
(
neat): 2980, 1750, 1715 cm
;
H NMR (200 MHz;
1744, 1617 cm ; H NMR (200 MHz; CDCl ) d 1.59
3
CDCl ) d 1.38 (3H, d, J = 7.03 Hz), 1.41 (3H, d,
(3H, s), 1.89 (3H, s), 3.56 (3H, s), 3.65 (1H, d,
3
J = 7.03 Hz), 2.4 (3H, m), 3.75 (3H, s), 3.8 (1H, m), 4.3
J = 11.12 Hz), 3.86 (1H, d, J = 11.54 Hz), 5.28 (1H, d,
+
13
(
1H, m); FABMS (m/z): 219 (M +1); Anal. Calcd for
J = 5.98 Hz), 5.34 (1H, d, J = 5.98 Hz);
C NMR
C H O S: C, 49.53; H, 6.46. Found: C, 49.46; H, 6.39.
(50 MHz, CDCl ) 9.28, 22.04, 57.05, 59.72, 66.73, 72.21,
9
14
4
3
9
6.19, 111.27, 175.53, 195.28; FABMS (m/z): 219
+
4
.2.4. 3,5-Dimethyl-4-hydroxy-5H-thiophen-2-one 7. Potas-
(M +1); Anal. Calcd for C H O S: C, 49.53; H, 6.46.
9 14 4
sium hydroxide (2 g, 35.7 mmol) in water (10 mL) was
Found: C, 49.46; H, 6.41.
added dropwise to a stirred solution of thioacetate 6
(
3.9 g, 17.8 mmol) in ethanol (20 mL) at an ambient
4.2.7. (±)-5-Methylacetate-3,5-dimethyl-4-(methoxymeth-
oxy)-5H-thiophen-2-one 9. To a solution of compound 2
(2.5 g, 11.46 mmol) in dry CH Cl (20 mL), Et N
temperature. The resulting solution was stirred at room
temperature for 3 h. Ethanol was then evaporated and
water (10 mL) added. The aqueous layer was washed with
diethyl ether (2 · 10 mL) and acidified to pH 1 with the
addition of 2 M HCl (10 mL). The aqueous layer was
extracted with ethyl acetate. The organic layers were
washed with brine, dried over anhydrous Na SO and the
2
2
3
(5.6 mL, 40.13 mmol) and a pinch of DMAP were added.
The reaction mixture was then cooled to 0 ꢁC, acetic anhy-
dride (2.7 mL, 28.66 mmol) added dropwise and the reac-
tion mixture warmed to room temperature and left for
1 h. The reaction mixture was quenched with water and
extracted with CH Cl . The organic layers were combined,
2
4
solvent removed in vacuo. The crude residue was purified
2
2
by flash column chromatography to obtain 2.3 g of 7 as a
washed with brine and dried over anhydrous Na SO . The
2 4
1
1
white solid. Mp 130–132 ꢁC (lit. mp 128–130 ꢁC); Yield:
organic layer was evaporated under reduced pressure to
give crude oil, which was purified by column chromato-
graphy to give pure 2.8 g of compound (± )-9. Yield:
ꢀ
1
1
8
9%; IR (neat): 3200, 2994, 1650, 1610 cm ; H NMR
(
(
200 MHz; DMSO-d ) d 1.52 (3H, d, J = 7.03 Hz), 1.7
3H, s), 4.1 (1H, q, J = 7.03 Hz); EIMS (m/z): 144 (M );
6
+
ꢀ1
1
94%; IR (neat): 2935, 1747, 1678, 1630 cm ; H NMR
Anal. Calcd for C H O S: C, 49.98; H, 5.59. Found: C,
(200 MHz; CDCl ) d 1.64 (3H, s), 1.94 (3H, s), 2.06 (3H,
6
8
2
3
4
9.89; H, 5.46.
s), 3.53 (3H, s), 4.15 (1H, d, J = 10.57 Hz), 4.40 (1H, d,
J = 10.57 Hz), 5.24–5.31 (2H, m); C NMR (50 MHz,
1
3
4
8
.2.5. 3,5-Dimethyl-4-(methoxymethoxy)-5H-thiophen-2-one
To a solution of thiolactone 7 (2.2 g, 15.27 mmol) in
CDCl ) 9.40, 20.81, 22.83, 56.14, 57.29, 66.32, 67.82,
3
.
96.18, 113.76, 170.50, 174.39, 194.94; ESIMS (m/z): 261
+
dry CH Cl (20 mL) was added N,N-diisopropylethyl-
(M +1). Anal. Calcd for C H O S: C, 50.76; H, 6.20.
2
2
11 16
5
amine (3.2 mL, 18.33 mmol) at room temperature. To this
solution MOMCl (1.4 mL, 18.33 mmol) was added drop-
wise at 0 ꢁC. The reaction mixture was stirred at 0 ꢁC for
Found: C, 50.67; H, 6.12.
4.3. General procedure for lipase-mediated alcoholysis
2
–3 h, quenched with water and concentrated. The aqueous
layer was extracted with CH Cl . The combined organic
To a solution of 5-methylacetate-3,5-dimethyl-4-methoxy-
methoxy-5H-thiophen-2-one 9 (2.8 g, 10.76 mmol) in diiso-
propyl ether (80 mL) were added n-butanol (9.9 mL,
107.6 mmol) and lipase Carica papaya [5.6 g, 2 equiv
(w/w)]. The suspension was shaken at 220 rpm at 40 ꢁC.
The reaction monitored on chiral HPLC analysis, reached
50% conversion after 18 h. The reaction mixture was fil-
tered and the solvent was evaporated. The residue was
chromatographed on silica gel. The enantiopure products
were analyzed by chiral HPLC and compared with the cor-
responding racemic products. Thiolactone acetate (S)-9
1.34 g was obtained. Yield: 48%; 98% ee, determined by
HPLC analysis using Chiralcel AS-H column (hexane–
2
2
layers were washed with brine, dried over anhydrous
Na SO , filtered and concentrated. The crude mixture
2
4
was chromatographed on silica gel to give 2.64 g of pure
compound 8. Yield: 83%; IR (neat): 2964, 1720,
ꢀ
1 1
1
670 cm ; H NMR (200 MHz; CDCl3) d 1.59 (3H, d,
J = 6.6 Hz), 1.83 (3H, s), 3.51 (3H, s), 4.23 (1H, q,
J = 7.2 Hz), 5.12 (1H, d, J = 6.6 Hz), 5.30 (1H, d,
+
J = 6.6 Hz); EIMS (m/z): 188 (M ); Anal. Calcd for
C H O S: C, 51.05; H, 6.43. Found: C, 50.91; H, 6.40.
8
12
3
4
.2.6. (±)-5-ꢀydroxymethyl-3,5-dimethyl-4-(methoxymeth-
oxy)-5H-thiophen-2-one 2. To a solution of diisopropyl
amine (2.3 mL, 15.95 mmmol) in dry THF (65 mL) was
added n-BuLi (9.9 mL, 15.95 mmmol) at ꢀ78 ꢁC dropwise
for 10–20 min. The reaction mixture was warmed to 0 ꢁC
and stirred at that temperature for 30 min. The solution
turned to a yellow colour indicating the generation of
LDA. To this solution was added MOM protected thiolac-
tone 8 (2.5 g, 13.29 mmol) in dry THF (10 mL) dropwise at
isopropanol, 90:10) with 0.5 mL/min flow rate (t
=
major
2
5
29.06, tminor = 27.79 min); ½aꢁ ¼ ꢀ27:9 (c 1.03, CHCl )
D
3
and 1.28 g of the corresponding alcohol (R)-2. Yield:
46%, 94% ee; determined by the HPLC analysis using
Chiralcel AS-H column (hexane–isopropanol, 90:10) with
0.5 mL/min flow rate (t
= 56.13, tminor = 35.93 min);
major
2
5
½aꢁ ¼ ꢀ17:73 (c 1.02, CHCl3).
D
ꢀ
78 ꢁC. After 30 min, 2.5 g of para-formaldehyde at the
same temperature and the reaction mixture were slowly
warmed to room temperature and left for 12 h. The reac-
tion mixture was quenched with a saturated solution of
4.3.1. (5S)-ꢀydroxymethyl-3,5-dimethyl-4-(methoxymeth-
oxy)-5H-thiophen-2-one 2. To a solution of (5S)-methyl-
acetate-3,5-dimethyl-4-(methoxymethoxy)-5H-thiophen-2-
one 9 (1.3 g, 5 mmol) in diisopropyl ether (25 mL) were
added n-butanol (4.5 mL, 50 mmol) and lipase Candida
rugosa [2.6 g, 2 equiv (w/w)]. The suspension was shaken
at 220 rpm at 40 ꢁC. The reaction was monitored on TLC
NH Cl and extracted with ethyl acetate. The organic layer
4
was washed with brine, dried over anhydrous Na SO and
2
4
concentrated under reduced pressure. The crude mixture
was chromatographed on silica gel to give pure 2.6 g of

A. Kamal et al. / Tetrahedron: Asymmetry 17 (2006) 2890–2895
2895
and was completed in 5 days. The reaction mixture was
Acknowledgement
then filtered and then the solvent evaporated. The residue
was chromatographed on silica gel to give 0.98 g of pure
The authors (A.A.S., S.A., M.S.M. and M.S.) are thankful
to the CSIR, New Delhi, for the award of research
fellowship.
(
S)-2. Yield. 90%; 98% ee; determined by the HPLC anal-
ysis using Chiralcel AS-H column (hexane–isopropanol,
9
5
0:10) with 0.5 mL/min flow rate (t
4.21 min); ½aꢁD ¼ þ15:8 (c 1.0, CHCl3).
= 32.86, tminor =
major
25
References
4.4. General procedure for the preparation of MTPA esters
of 5-hydroxymethyl-3,5-dimethyl-4-(methoxymethoxy)-5H-
thiophen-2-one
1. Part of the work presented at International Symposium on
Advances in Organic Chemistry, Kottayam, India, January
9
–12, 2006.
2
. Oishi, H.; Noto, T.; Sasaki, H.; Suzuki, K.; Hayashi, T.;
Okazaki, H.; Ando, K.; Sawada, M. J. Antibiot. (Tokyo)
To
a
solution of 5-hydroxymethyl-3,5-dimethyl-4-
(
methoxymethoxy)-5H-thiophen-2-one 2 (1 mmol) in di-
1
982, 35, 391.
chloromethane (10 mL) were added a pinch of DMAP,
a-methoxy-a-(trifluoromethyl)phenylacetic acid (1 mmol)
and DCC (1.05 mmol) at 0 ꢁC. The reaction mixture was
stirred at room temperature for 2–3 h, filtered, evaporated,
to give the crude product, which on purification by column
chromatography gave oily liquids as products.
3
4
. Noto, T.; Miyakawa, S.; Oishi, H.; Endo, H.; Okazaki, H. J.
Antibiot. (Tokyo) 1982, 35, 401.
. Douglas, J. D.; Senior, S. J.; Morehouse, C.; Phetsukiri, B.;
Campbell, I. B.; Besra, G. S.; Minnikin, D. E. Microbiology
2002, 148, 3101.
5. (a) Jones, S. M.; Urch, J. E.; Brun, R.; Harwood, J. L.; Berry,
C.; Bilbert, I. H. Bioorg. Med. Chem. 2004, 12, 683; (b)
Prigge, S. T.; He, X.; Gerena, L.; Waters, N. C.; Reynolds, K.
A. Biochemistry 2003, 42, 1160; (c) Waters, N. C.; Kopyd-
lowski, K. M.; Guszczynski, T.; Wei, L.; Sellers, P.; Ferlan, J.
T.; Lee, P. J.; Li, Z.; Woodard, C. L.; Shallom, S.; Gardner,
M. J.; Prigge, S. T. Mol. Biochem. Parasitol. 2002, 123, 85; (d)
Morita, Y. S.; Paul, K. S.; Englund, P. T. Science 2000, 288,
4
.4.1.
[(5R)-4-(Methoxymethoxy)-3,5-dimethyl-5H-thio-
phen-2-one]methyl (2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-
propanoate 10. Prepared from the above-mentioned DCC
25
coupling procedure. Yield: 69%; ½aꢁ ¼ þ21:9 (c 1.55,
D
1
CHCl ); H NMR (500 MHz; CDCl ) d 1.653 (3H, s),
3
3
1
.848 (3H, s), 3.446 (3H, s), 3.510 (3H, s), 4.436 (1H, d,
1
40; (e) Waller, R. F.; Keeling, P. J.; Donald, R. G. K.;
J = 7.2 Hz), 4.598 (1H, d, J = 7.2 Hz), 5.096 (1H, d,
J = 6.6 Hz), 5.186 (1H, d, J = 6.3 Hz), 7.37–7.395 (3H,
m), 7.491–7.502 (2H, m); FABMS (m/z): 435 (M +1).
Striepen, B.; Handman, E.; Lang-Unnasch, N.; Cowman, A.
F.; Besra, G. S.; Roos, D. S.; McFadden, G. I. Proc. Natl.
Acad. Sci. U.S.A. 1998, 95, 12352.
. Hayashi, T.; Yamamoto, O.; Sasaki, H.; Kawaguchi, A.;
Okazaki, H. Biochem. Biophys. Res. Commun. 1983, 115,
+
6
7
4
.4.2.
[(5R)-4-(Methoxymethoxy)-3,5-dimethyl-5H-thio-
1
108.
phen-2-one]methyl (2S)-3,3,3-trifluoro-2-methoxy-2-phenyl-
propanoate 11. Prepared from the above-mentioned DCC
. Tsay, J. T.; Rock, C. O.; Jackowski, S. J. Bacteriology 1992,
174, 508.
8. Miyakawa, S.; Suzuki, K.; Noto, T.; Harada, Y.; Okazaki, H.
J. Antibiot. (Tokyo) 1982, 35, 411.
. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.
25
coupling procedure. Yield: 72%; ½aꢁ ¼ ꢀ7:9 (c 1.95,
D
1
CHCl ); H NMR (500 MHz; CDCl ) d 1.635 (3H, s),
3
3
1
.880 (3H, s), 3.489 (3H, s), 3.514 (3H, s), 4.431 (1H, d,
9
J = 7.2 Hz), 4.661 (1H, d, J = 7.2 Hz), 5.205 (1H, d,
J = 6.6 Hz), 5.267 (1H, d, J = 6.3 Hz), 7.376–7.401 (3H,
m), 7.486–7.499 (2H, m); FABMS (m/z): 435 (M +1).
Adv. Drug Delivery Rev. 2001, 46, 3.
10. Kamal, A.; Shaik, A. A.; Sinha, R.; Yadav, J. S.; Arora, S. K.
+
Bioorg. Med. Chem. Lett. 2005, 15, 1927.
1
1. Wang, C. L. J.; Salvino, J. M. Tetrahedron Lett. 1984, 25,
243.
2. Chambers, M. S.; Thomas, E. J. J. Chem. Soc., Perkin Trans.
1997, 417.
5
4
.4.3.
[(5S)-4-(Methoxymethoxy)-3,5-dimethyl-5H-thio-
1
phen-2-one]methyl (2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-
propanoate 12. Prepared from the above-mentioned DCC
1
25
13. McFadden, J. M.; Frehywot, G. L.; Townsend, C. A. Org.
Lett. 2002, 4, 3859.
14. Ohata, K.; Terashima, S. Tetrahedron Lett. 2006, 47,
coupling procedure. Yield: 63%; ½aꢁ ¼ þ11:4 (c 1.08,
D
1
CHCl ); H NMR (500 MHz; CDCl ) d 1.640 (3H, s),
3
3
1
.888 (3H, s), 3.493 (3H, s), 3.520 (3H, s), 4.4325 (1H, d,
J = 10.80 Hz), 4.6685 (1H, d, J = 10.80 Hz), 5.213 (d,
H, J = 6.3 Hz), 5.2755 (1H, d, J = 6.3 Hz), 7.392–7.411
2
787.
15. Royals, E. E. J. Am. Chem. Soc. 1948, 70, 489.
16. Svendsen, A.; Boll, P. M. Tetrahedron 1973, 29, 4251.
17. Kim, P.; Barry, C. E., III; Dowd, C. S. Tetrahedron Lett.
1
+
(
3H, m), 7.481–7.501 (2H, m); FABMS (m/z): 435 (M +1).
2
006, 47, 3447.
1
8. (a) Kamal, A.; Shaik, A. A.; Sandbhor, M.; Malik, M. S.;
Kaga, H. Tetrahedron Lett. 2004, 45, 8057; (b) Kamal, A.;
Shaik, A. A.; Sandbhor, M.; Malik, M. S. Tetrahedron:
Asymmetry 2005, 16, 1855; (c) Kamal, A.; Shaik, A. A.;
Sandbhor, M.; Malik, M. S. Tetrahedron: Asymmetry 2004,
15, 935; (d) Kamal, A.; Khanna, G. B. R.; Ramu, R.;
Krishnaji, T. Tetrahedron Lett. 2003, 44, 4783; (e) Kamal, A.;
Ramana, K. V.; Rao, M. V. J. Org. Chem. 2001, 66, 997.
4
.4.4. [(5S)-4-(Methoxymethoxy)-3,5-dimethyl-5H-thio-
phen-2-one]methyl (2S)-3,3,3-trifluoro-2-methoxy-2-phenyl-
propanoate 13. Prepared from the above-mentioned DCC
25
coupling procedure. Yield: 75%; ½aꢁ ¼ ꢀ24:9 (c 2.45,
D
1
CHCl ); H NMR (500 MHz; CDCl ) d 1.651 (s, 3H),
3
3
1
.847 (3H, s), 3.438 (3H, s), 3.507 (3H, s), 4.435 (1H, d,
J = 10.80 Hz), 4.602 (1H, d, J = 11.70 Hz), 5.0975 (1H,
d, J = 6.3 Hz), 5.1845 (1H, d, J = 6.3 Hz), 7.379–7.384
19. Ferreiro, M. J.; Latypov, Sh. K.; Qulnoa, E.; Riguera, R.
+
(
3H, m), 7.393–7.479 (2H, m); FABMS (m/z): 435 (M +1).
Tetrahedron: Asymmetry 1996, 7, 2195.