Efficient Ce(III)-catalyzed cis-selective synthetic approach to γ-lactones in aqueous media

Article abstract of DOI:10.1080/00397911.2010.540923

The first CeCl₃ ·7H₂O-catalyzed. one-pot synthesis of α-mercapto-γ -lactones via regioselective epoxide ring opening and mercaptoacetylative cyclization cascades in water is reported. The reaction between 2-methyl-2-phenyl-1,3-oxathiolan-5-one and a variety of terminal epoxides was carried out in aqueous media to afford γ-lactones in good to excellent yields (83-94%) with complete cis diastereoselectivity. Acetophenone obtained as a by-product was also recovered and recycled easily for further use. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.540923

This article was downloaded by: [University of Windsor]
On: 17 July 2014, At: 02:23
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Efficient Ce(III)-Catalyzed cis-Selective
Synthetic Approach to γ-Lactones in
Aqueous Media
Vijai K. Rai a , Priya Tiku a & Anil Kumar a
a School of Biotechnology, College of Science, Shri Mata Vaishno Devi
University , Katra , India
Accepted author version posted online: 17 Nov 2011.Published
online: 25 Jan 2012.
To cite this article: Vijai K. Rai , Priya Tiku & Anil Kumar (2012) Efficient Ce(III)-Catalyzed cis-
Selective Synthetic Approach to γ-Lactones in Aqueous Media, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:10, 1489-1499,
DOI: 10.1080/00397911.2010.540923
To link to this article: http://dx.doi.org/10.1080/00397911.2010.540923
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 42: 1489–1499, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.540923
EFFICIENT Ce(III)-CATALYZED cis-SELECTIVE
SYNTHETIC APPROACH TO c-LACTONES IN
AQUEOUS MEDIA
Vijai K. Rai, Priya Tiku, and Anil Kumar
School of Biotechnology, College of Science, Shri Mata Vaishno Devi
University, Katra, India
GRAPHICAL ABSTRACT
Abstract The first CeCl3 ꢀ 7H2O-catalyzed, one-pot synthesis of a-mercapto-c-lactones via
regioselective epoxide ring opening and mercaptoacetylative cyclization cascades in water is
reported. The reaction between 2-methyl-2-phenyl-1,3-oxathiolan-5-one and a variety of
terminal epoxides was carried out in aqueous media to afford c-lactones in good to excellent
yields (83–94%) with complete cis diastereoselectivity. Acetophenone obtained as a
by-product was also recovered and recycled easily for further use.
Keywords Aqueous medium; CeCl3 ꢀ 7H2O; diastereoselectivity; epoxides; c-lactones
INTRODUCTION
Since the pioneering studies by Breslow,[1] organic reactions in water have
gained tremendous importance because of their environmental friendliness.[2] In
addition, CeCl3 ꢀ 7H2O has attracted much attention as a Lewis acid in organic syn-
thesis because of its special attributes, which include water tolerance, nontoxicity,
and easy handling.[3] c-Lactones constitute an important group of natural and syn-
thetic products used as agrochemicals, as pharmaceuticals, and in the food industry
and also possess a wide range of biological activities.[4a–f] In particular, some aryl
substituted c-lactones have shown cancer-preventive and anti-inflammatory activi-
ties.[4g] Moreover, c-lactones are effective as starting materials for the synthesis of
different molecules of biological and medicinal interest.[5–7] It is well known that
the presence of a thiol function in many enzymes (called an –SH enzyme) is essential
for their enzymatic activity. Likewise, incorporation of a thiol function in
Received September 19, 2010.
Address correspondence to Vijai K. Rai (present address), Department of Applied Chemistry,
Institute of Technology, Guru Ghasidas Vishwavidyalaya, Bilaspur, CG, 495 009, India. E-mail:
vijaikrai@hotmail.com
1489

1490
V. K. RAI, P. TIKU, AND A. KUMAR
Scheme 1. Disconnection approach for target a-mercapto-c-lactones.
heterocycles, nucleosides, or nucleotides has led to a number of analogs possessing
interesting biological and therapeutic properties.[8–15]
Because of their unique chemical and biological properties, the synthesis of
substituted c-lactones has been of the great interest to synthetic chemists for several
years. Several routes have been devised to access c-lactones,[16–25] although they tend
to be lengthy and cumbersome if the lactone contains any sort of substitution.[16] In
most of the cases, construction of the c-lactone ring includes ring-closing hydrogen-
ation of diacids,[17] allylboration of aldehyde ring-closing cascades,[18] cyclization of
2-(substituted phenyl)pent-4-enoic,[19] cyclohydrocarbonylation of a-ketoalkynes,[20]
electrophilic cyclization of 3-alkynoate esters=acids,[21] and epoxidation of eno-
ates.[22] Particularly, aryl-c-lactones have been obtained by Baeyer–Villiger reaction
of aryl cyclobutanones,[23] reaction of 2-phenyloxirane with the malonate anion,[24]
or photoinduced tandem Ar-C, C-O bond formation.[25] However, these methods
are not environmentally friendly and suffer from one or more disadvantages such
as the use of hazardous solvents, tedious workup, expensive and large amounts of
catalyst, special treatment for activation, and lengthy reaction times. Recently, litera-
ture records the synthesis of c-lactones using basic ionic liquid, but the method
involves high reaction temperature, long reaction time, mixture of cis=trans diaster-
eomers, and moderate to good yields.[26] These valid facts prompted us to developed
a time-efficient, stereocontrolled, high-yielding, and environmentally benign syn-
thetic approach to aryl-c-lactones bearing a mercapto group on the a-position.
Herein, we report an efficient CeCl3 ꢀ 7H2O-catalyzed, high-yielding (83–94%),
entirely cis-diastereoselective synthesis of a-mercapto-c-lactones in aqueous media
at ambient temperature via regioselective ring-opening of terminal epoxides
(Scheme 1).
At the outset, we tried the mercaptoacetic acid for mercaptoacetylation of
epoxides 2 but were not successful, probably because of the presence of free –COOH
and –SH groups. Then, we turned our attention to blocking the –COOH and –SH
groups of mercaptoacetic acid and thus activating its methylene group by converting
it into 2-methyl-2-phenyl-1,3-oxathiolan-5-one 1 (Scheme 2).[27] The 2-methyl-2-
phenyl-1,3-oxathiolan-5-one not only acted as mercaptoacetyl transfer agent for
the synthesis of a-mercapto acids but also provides a completely new route to
a-mercapto-c-lactones and is the cornerstone in our approach, presenting its novel
utility in furan chemistry.
Scheme 2. Formation of 2-methyl-2-phenyl-1,3-oxathiolan-5-one.

cis-SELECTIVE SYNTHETIC APPROACH TO c-LACTONES
1491
To optimize the reaction condition, several Lewis acid catalysts were used.
Among these, CeCl3 ꢀ 7H2O gave the best result (Table 1, entry 1). K-10 clay afforded
the product 3a in moderate yield, while poor yields of product 3a were obtained in the
case of silica gel and neutral or acidic alumina (Table 1). Next, we estimated the reac-
tivity of epoxide 2a (2 mmol), 2-methyl-2-phenyl-1,3-oxathiolan-5-one 1 (2 mmol),
and CeCl3 ꢀ 7H2O (0.2 mmol) by stirring at room temperature in water for 4h, and
we successfully isolated the corresponding lactone 3a in 91% yield (Table 2, entry
1). The formation of c-lactone 3a was entirely diastereoselective in favor of the cis
isomer. It was noted that a higher reaction temperature, for example, in refluxing
condition instead of room temperature, led to decreased diastereoselectivity without
any appreciable effect on the yield. Next, to investigate the substrate scope for general
validity of the present investigation, a variety of aromatic and aliphatic terminal
epoxides 2 were used, employing the present optimized reaction conditions, and dif-
ferent c-lactones 3 were synthesized. The yields were consistently good (Table 2), and
the greatest yield was 94% (Table 2, entries 3 and 4). To compare its solvent-free
version, we also carried out the reaction in a microwave (Chemical Laboratory
Microwave Oven, model BP-310=50, 230 V, 50 Hz power input) for establishing its
solvent-free version, but a relatively lower yield (43%) was obtained, although time
required for the completion of the reaction was 12 min.
The present optimized synthesis is accomplished by stirring the mixture of
epoxides 2 (1 mmol), 2-methyl-2-phenyl-1,3-oxathiolan-5-ones 1 (1 mmol), and
CeCl3 ꢀ 7H2O (0.1 mmol) in water at room temperature for 4–6 h (Table 2). The iso-
lation and purification steps are very simple and done by filtration with Buchner
funnel followed by washing with water (2 ꢁ 10 mL) and recrystallization from EtOH.
After isolation of the product, the aqueous layer was extracted with EtOAc
(3 ꢁ 10 mL) and acetophenone was easily collected from the organic phase.
Formation of 3 can be rationalized by nucleophilic attack of the active meth-
ylene carbon (C-4) of 10 to the less substituted carbon of epoxide 2 regiselectively,
followed by protonation of epoxide oxygen, leading to the intermediate 4. Herein,
CeCl3 ꢀ 7H2O promotes the enolization step and thus it increases the nucleophilic
character of methylene carbon (C-4) of 1. Presumably, the role of water in the envi-
saged synthetic protocol is not only as a solvent but also to catalyze the reaction
through H-bonding with epoxide oxygen and render them more susceptible to
Table 1. Optimization of catalysts for compound 3a
MW
Aqueous medium
Entry
Catalyst
Time (min)a
Yield (%)b
Time (h)c
Yield (%)b
1
2
3
4
5
CeCl3 ꢀ 7H2O
K-10 clay
Silica gel
12
15
14
20
20
43
38
24
13
18
4
6
91
63
21
10
16
8
Neutral alumina
Acidic alumina
10
10
aTime for completion of the reaction under MW irradiation.
bTime for completion of the reaction at room temperature as indicated by TLC.
cYield of isolated and purified product 3a.

1492
V. K. RAI, P. TIKU, AND A. KUMAR
Table 2. CeCl3 ꢀ 7H2O-catalyzed one-step synthesis of a -mercapto-c-lactones 3
Entry Masked acid 1
Epoxide 2
Time (h)a
c-Lactone 3
Yield (%)b,c
1
4
91
2
3
1
1
4
5
90
94
4
1
4
94
5
6
1
1
4
4
83
90
7
8
1
1
6
5
88
92
9
1
1
5
5
84
83
10
aRefluxing time in water at room temperature.
bYield of isolated and purified products.
cAll compounds gave C, H, and N analyses within ꢂ0.39%, and satisfactory spectral (IR, 1H NMR, 13
C
NMR, and EIMS) data.

cis-SELECTIVE SYNTHETIC APPROACH TO c-LACTONES
1493
Scheme 3. Tentative mechanism for mercaptoacetylation of epoxides.
nucleophilic attack. The adduct 4 undergoes intramolecular nucleophilic attack of
the oxygen atom of the OH group at the carbonyl carbon (C-5) of the oxathiolan-5-
one moiety to yield target compounds 3 with elimination of acetophenone
(Scheme 3), which was easily recovered and reused for the preparation of mercaptoa-
cetyl transfer agent, 2-methyl-2-phenyl-1,3-oxathiolan-5-one 1, by treatment with
LiBr and mercaptoacetic acid as depicted in Scheme 2. This conclusion is based
=
on the observation that the representative intermediate compounds 4a (R Ph), 4b
=
(R ¼ 4-ClC6H4), and 4g (R Me) could be isolated in 49–53% yield. These could
be converted into the corresponding lactones 3a, 3b, and 3g in quantitative yields,
and acetophenone was formed during the reaction (Scheme 3). The spectral data
of compounds 3a, 3b, 4a, and 4b are in good agreement with the reported in
literature.[26]
In the case of epichlorohydrin 2h, excellent chemoselectivity was achieved, and
formation of possible new mercaptoacetylative cyclization in the envisaged synthetic
strategy was obtained (Scheme 3). In case of epichlorohydrin 2h, excellent chemo-
selectivity was achieved and formation of possible new oxirane was not observed
by extrusion of the chlorine atom (path B, Scheme 4),[28] rather we obtained the cor-
responding lactone 3h (path A, Scheme 4). This can be explained: The oxygen of
Scheme 4. Chemoselectivity in the case of epichlorohydrin 2h.

1494
V. K. RAI, P. TIKU, AND A. KUMAR
Figure 1. Determination of the cis stereochemistry by NOE of c-lactones 3.
epoxide prefers to attack at C-5 of 2-methyl-2-phenyl-1,3-oxathiolan-5-one 1 rather
than the carbon containing chlorine, and the driving force for this is the easy opening
of the oxathiolan ring by removal of the acetophenone (Scheme 4). The reactions
1
were clean, and all the syntheized products were characterized by their H NMR,
13C NMR, infrared (IR), and mass spectroscopic data.
The intramolecular cyclization of adducts 4 to c-lactones 3 was entirely diaster-
eoselective in favor of the cis isomers. The relative stereochemistry of lactones 3 was
established by nuclear Overhauser effect (NOE) experiments (Fig. 1). The strong
NOE at 3-H=5-H upon irradiation of Ha combined with the absence of any measur-
able intensity enhancement at 3-H=5-H upon irradiation of Hb indicates that 4-Ha
and 3-H=5-H are located on the same face of the molecule; that is, lactones 3 have
3,5-cis configuration (Fig. 1).
EXPERIMENTAL
Melting points were determined by the open glass capillary method and are
uncorrected. IR spectra in KBr were recorded on a Perkin-Elmer 993 IR spectro-
1
photometer. H NMR spectra were recorded on a Bruker WM-40 C (400 MHz)
Fourier transform (FT) spectrometer in dimethylsulfoxide (DMSO-d6) using tetra-
methyl silane (TMS) as internal reference. 13C NMR spectra were recorded on the
same instrument at 100 MHz in DMSO-d6, and TMS was used as internal reference.
Mass (EI) spectra were recorded on a Jeol D-300 mass spectrometer. Elemental
analyses were carried out in a Coleman automatic carbon, hydrogen, and nitrogen
analyzer. A Chemical Laboratory microwave oven (model BP-310=50, 230 V,
50 Hz power input) was used. All chemicals used were reagent grade and were used
as received without further purification. Silica gel G was used for thin layer chroma-
tography (TLC).
3,5-Disubstitutedfuran-2-ones (3a–j): General Procedure
2-Methyl-2-phenyl-1,3-oxathiolan-5-one 1 (1 mmol), epoxide 2 (1 mmol), and
CeCl3 ꢀ 7H2O (0.1 mmol) were taken in 10 mL water and stirred at room temperature
for 4–6 h (Table 2). After the completion of reaction (monitored by TLC), the reac-
tion mixture was filtered with a Buchner funnel and washed with water (2 ꢁ 10 mL).
The crude product 3 thus obtained was recrystallized from EtOH to afford an

cis-SELECTIVE SYNTHETIC APPROACH TO c-LACTONES
1495
analytically pure sample of 3. The aqueous layer was extracted with EtOAc
(3 ꢁ 10 mL), and acetophenone was easily recovered from the organic phase. Spectral
parameters of some representative compounds are given below.
Compound 3c. Colorless solid. IR (KBr): 2549, 1760 cmꢃ1 1H NMR
.
(400 MHz; DMSO-d6=TMS): d ¼ 1.61 (d, J ¼ 7.7 Hz, 1 H, SH, exchanges with
D2O), 2.69 (ddd, J ¼ 11.1, 9.2, 5.5 Hz, 1 H, 4-Ha), 2.81 (ddd, J ¼ 11.1, 8.0, 2.8 Hz, 1
H, 4-Hb), 3.50 (ddd, J ¼ 9.2, 7.7, 5.5 Hz, 1 H, 3-H), 3.78 (s, 3 H, OMe), 5.51 (dd,
J ¼ 2.8, 8.0 Hz, 1 H, 5-H), 6.89–7.21 (m, 4 Harom). 13C NMR (100 MHz; DMSO-d6=
TMS): 38.8, 50.9, 56.8, 86.2, 121.5, 126.8, 127.5, 151.5, 177.8. MS (EI): m=z ¼ 224
[Mþ]. Anal. calcd. for C11H12O3S: C, 58.91; H, 5.39. Found: C, 58.63; H, 5.61.
Compound 3d. Colorless solid. IR (KBr): 2556, 1763 cmꢃ1 1H NMR
.
(400 MHz; DMSO-d6=TMS): d ¼ 1.60 (d, J ¼ 7.8 Hz, 1 H, SH, exchanges with
D2O), 2.77 (ddd, J ¼ 11.2, 9.5, 5.1 Hz, 1 H, 4-Ha), 2.86 (ddd, J ¼ 11.2, 8.1, 2.9 Hz,
1 H, 4-Hb), 3.58 (ddd, J ¼ 9.5, 7.8, 5.1 Hz, 1 H, 3-H), 5.46 (dd, J ¼ 2.9, 8.1 Hz, 1
H, 5-H), 7.31–7.76 (m, 2 Harom), 7.98–8.11 (m, 2 Harom). 13C NMR (100 MHz;
DMSO-d6=TMS): 38.5, 51.3, 85.8, 125.8, 128.8, 143.2, 146.8, 178.3. MS (EI):
m=z ¼ 239 [Mþ]. Anal. calcd. for C10H9NO4S: C, 50.20; H, 3.97; N, 5.85. Found:
C, 50.51; H, 3.40; N, 5.57.
Compound 3e. Colorless solid. IR (KBr): 2553, 1768 cmꢃ1 1H NMR
.
(400 MHz; DMSO-d6=TMS): d ¼ 1.59 (d, J ¼ 7.6 Hz, 1 H, SH, exchanges with
D2O), 2.75 (ddd, J ¼ 11.2, 9.4, 5.5 Hz, 1 H, 4-Ha), 2.88 (ddd, J ¼ 11.2, 8.0, 2.9 Hz,
1 H, 4-Hb), 3.55 (ddd, J ¼ 9.4, 7.6, 5.5 Hz, 1 H, 3-H), 3.69 (s, 3 H, OMe), 3.72 (s,
3 H, OMe), 5.42 (dd, J ¼ 2.9, 8.0 Hz, 1 H, 5-H), 6.79–7.03 (m, 3 Harom). 13C
NMR (100 MHz; DMSO-d6=TMS): 38.5, 50.5, 55.9, 56.8, 86.7, 121.1, 127.2, 131.2,
135.5, 144.2, 146.8, 178.6. MS (EI): m=z ¼ 254 [Mþ]. Anal. calcd. for C12H14O4S:
C, 56.68; H, 5.55. Found: C, 56.91; H, 5.37.
Compound 3f. Colorless solid. IR (KBr): 2550, 1760 cmꢃ1 1H NMR
.
(400 MHz; DMSO-d6=TMS): d ¼ 1.58 (d, J ¼ 7.8 Hz, 1 H, SH, exchanges with
D2O), 2.73 (ddd, J ¼ 11.0, 9.2, 5.5 Hz, 1 H, 4-Ha), 2.84 (ddd, J ¼ 11.0, 8.5, 2.3 Hz,
1 H, 4-Hb), 3.51 (ddd, J ¼ 9.2, 7.8, 5.5 Hz, 1 H, 3-H), 5.48 (dd, J ¼ 2.3, 8.5 Hz, 1
H, 5-H), 7.30–7.85 (m, 7 Harom). 13C NMR (100 MHz; DMSO-d6=TMS): 39.2,
51.6, 85.6, 125.5, 126.7, 127.4, 128.2, 130.1, 131.5, 132.0, 132.9, 133.5, 134.1,
178.1. MS (EI): m=z ¼ 244 [Mþ]. Anal. calcd. for C14H12O2S: C, 68.83; H, 4.95.
Found: C, 68.51; H, 5.19.
Compound 3g. Colorless solid. IR (KBr): 2551, 1770 cmꢃ1 1H NMR
.
(400 MHz; DMSO-d6=TMS): d ¼ 1.62 (d, J ¼ 7.7 Hz, 1 H, SH, exchanges with
D2O), 2.25 (s, 3 H, Me), 2.51–2.70 (m, 2 H, CH2), 3.60 (ddd, J ¼ 9.5, 7.7, 5.3 Hz,
1 H, 3-H), 4.43–4.51 (m, 1 H, 5-H). 13C NMR (100 MHz; DMSO-d6=TMS): 19.7,
38.5, 50.1, 81.2, 177.9. MS (EI): m=z ¼ 132 [Mþ]. Anal. calcd. for C5H8O2S: C,
45.43; H, 6.10. Found: C, 45.81; H, 5.79.
Compound 3h. Colorless solid. IR (KBr): 2557, 1759 cmꢃ1 1H NMR
.
(400 MHz; DMSO-d6=TMS): d ¼ 1.61 (d, J ¼ 7.7 Hz, 1 H, SH, exchanges with
D2O), 2.58–2.76 (m, 2 H, CH2), 3.52 (ddd, J ¼ 9.5, 7.7, 5.1 Hz, 1 H, 3-H), 3.61
(dd, J ¼ 10.5, 3.9 Hz, 1 H, 10-Ha), 3.85 (dd, J ¼ 10.5, 5.5 Hz, 1 H, 10-Hb),

1496
V. K. RAI, P. TIKU, AND A. KUMAR
4.83–4.92 (m, 1 H, 5-H). 13C NMR (100 MHz; DMSO-d6=TMS): 38.1, 49.7, 51.5,
84.9, 178.5. MS (EI): m=z ¼ 166, 168 [Mþ, M þ 2]. Anal. calcd. for C5H7ClO2S: C,
36.04; H, 4.23. Found: C, 35.83; H, 4.51.
Compound 3i. Colorless solid. IR (KBr): 2553, 1765 cmꢃ1 1H NMR
.
(400 MHz; DMSO-d6=TMS): d ¼ 1.64 (d, J ¼ 7.5 Hz, 1 H, SH, exchanges with
D2O), 2.65–2.81 (m, 2 H, CH2), 3.49 (ddd, J ¼ 9.4, 7.5, 5.1 Hz, 1 H, 3-H), 3.93
(dd, J ¼ 10.9, 3.8 Hz, 1 H, 10-Ha), 4.17 (dd, J ¼ 10.9, 5.5 Hz, 1 H, 10-Hb),
4.91–5.03 (m, 1 H, 5-H), 7.31–7.75 (m, 5 Harom). 13C NMR (100 MHz; DMSO-d6=
TMS): 36.5, 50.7, 72.8, 80.8, 121.2, 126.3, 134.5, 153.7, 178.9. MS (EI): m=z ¼ 224
[Mþ]. Anal. calcd. for C11H12O3S: C, 58.91; H, 5.39. Found: C, 58.62; H, 5.58.
Compound 3j. Colorless solid. IR (KBr): 2550, 1770 cmꢃ1 1H NMR
.
(400 MHz; DMSO-d6=TMS): d ¼ 1.59 (d, J ¼ 7.9 Hz, 1 H, SH, exchanges with
D2O), 2.83–2.89 (m, 2 H, CH2), 3.57 (ddd, J ¼ 9.2, 7.9, 5.5 Hz, 1 H, 3-H), 3.93
(dd, J ¼ 10.9, 3.5 Hz, 1 H, 10-Ha), 4.18 (dd, J ¼ 10.9, 5.2 Hz, 1 H, 10-Hb), 4.95-5.01
(m, 1 H, 5-H), 7.22–7.69 (m, 2 Harom), 7.78–7.83 (m, 2 Harom). 13C NMR
(100 MHz; DMSO-d6=TMS): 37.2, 51.5, 72.0, 81.2, 122.2, 126.2, 128.5, 152.9,
178.8. MS (EI): m=z ¼ 258, 260 [Mþ, M þ 2]. Anal. calcd. for C11H11ClO3S: C,
51.07; H, 4.29. Found: C, 51.45; H, 4.03.
Isolation of 4a (R ¼ Ph), 4b (R ¼ 4-cI), and 4g (R ¼ Me) and Their
Cyclization into c-Lactones 3a, 3b, and 3g
2-Methyl-2-phenyl-1,3-oxathiolan-5-one 1 (1 mmol), epoxide 2 (1 mmol), and
CeCl3 ꢀ 7H2O (0.1 mmol) were taken in 10 mL water and stirred at room temperature
for 2 h. Then the reaction mixture was filtered with a Buchner funnel and washed
with water (2 ꢁ 10 mL). The crude products 4a, 4b, and 4g thus obtained were recrys-
tallized from EtOH to give their respective analytical samples. For converting these
intermediates into final products, 4a, 4b, and 4g were stirred for 2–3 h at room tem-
perature in 10 mL of water. After completion of the reaction (monitored by TLC),
the reaction mixture was filtered with a Buchner funnel and washed with water
(2 ꢁ 10 mL). The crude product 3 thus obtained was recrystallized from EtOH to
afford an analytically pure sample of 3. The aqueous layer was extracted with EtOAc
(3 ꢁ 10 mL), and acetophenone was easily recovered from the organic phase. Spectral
parameters of representative compound 4g are given. Colorless solid. IR (KBr):
3385, 1769 cmꢃ1
.
1H NMR (400 MHz; DMSO-d6=TMS): d ¼ 2.29 (s, 3 H, Me),
2.33 (s, 3 H, Me), 2.63–2.69 (m, 2 H, CH2), 3.28–3.35 (m, 1 H, 20-H), 3.57 (dd,
J ¼ 8.0, 5.5 Hz, 1 H, SCH), 3.65 (d, J ¼ 2.9 Hz, 1 H, OH, exchanges with D2O),
7.01–7.43 (m, 5 Harom). 13C NMR (100 MHz; DMSO-d6=TMS): 20.3, 23.7, 38.8,
49.1, 77.3, 126.8, 129.5, 131.3, 133.7, 178.5. MS (EI): m=z ¼ 252 [Mþ]. Anal. calcd.
for C13H16O3S: C, 61.88; H, 6.39. Found: C, 62.23; H, 6.08.
ACKNOWLEDGMENTS
We sincerely thank Indian Institute of Integrative Medicine (IIIM) Jammu
and Sophisticated Analytical Instrumentation Facility (SAIF), Punjab University,
Chandigarh, for providing microanalyses and spectra.

cis-SELECTIVE SYNTHETIC APPROACH TO c-LACTONES
1497
REFERENCES
1. Breslow, R. Hydrophobic effects on simple organic reactions in water. Acc. Chem. Res.
1991, 24, 159–164; (b) Breslow, R. Determining the geometries of transition states by
use of antihydrophobic additives in water. Acc. Chem. Res. 2004, 37, 471–478.
2. (a) Raj, M.; Singh, V. K. Organocatalytic reactions in water. Chem. Commun. 2009, 6687–
6703; (b) Li, C. J.; Chan, T. H. In Organic Reactions on Aqueous Media; John Wiley
and sons: New York, 1997; (c) Grieco, P. A. Ed., Organic Synthesis in Water; Blacky
Academic and Professional: London, England, 1998.
3. (a) Bose, D. S.; Fatima, L.; Mereyala, H. B. Green chemistry approaches to the synthesis
of 5-alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones by a three-component coup-
ling of one-pot condensation reaction: Comparison of ethanol, water, and solvent-free
conditions. J. Org. Chem. 2003, 68, 587–590; (b) Christoffers, J.; Werner, T.; Unger, S.;
Frey, W. Preparation of acyloins by cerium-catalyzed, direct hydroxylation of b-dicarbo-
nyl compounds with molecular oxygen. Eur. J. Org. Chem. 2003, 425–431; (c) Keh, C. C.
K.; Namboodiri, V. V.; Varma R. S.; Li, C.-J. Direct formation of tetrahydropyranols via
catalysis in ionic liquid. Tetrhedron Lett. 2002, 43, 4993–4996; (d) Warren, S.; Clayden, J.
Stereocontrol in organic synthesis using the diphenylphosphoryl group. Angew. Chem. Int.
Ed. 1996, 35, 241–270.
4. (a) Brown, H. C.; Kulkarni, S. V.; Racherla, U. S. Chiral synthesis via organoboranes. 39.
A facile synthesis of .gamma.-substituted-gamma-butyrolactones in exceptionally high
enantiomeric purity. J. Org. Chem. 1994, 59, 365–369; (b) Yao, Y. S. Chemistry of bute-
nolides. Chem. Rev. 1964, 64, 353–388; (c) Yao, Y. S. Recent advances in the chemistry of
unsaturated lactones. Chem. Rev. 1976, 76, 625–694 (d) Higuchi, Y.; Shimoma, F.; Ando,
M. Synthetic method and biological activities of cis-fused a-methylene c-lactones. J. Nat.
Prod. 2003, 66, 810–817; (e) Hislop, J.-A.; Hunt, M. B.; Fielder, S.; Rowan, D. D. Syn-
thesis of deuterated c-lactones for use in stable isotope dilution assays. J. Agric. Food
Chem. 2004, 52, 7075–7083; (f) Frediani, P.; Rosi, L.; Frediani, M.; Bartolucci, C.;
Bambagiotti-Alberti, M. A convenient route to the synthesis of isotopomeric dihydro-
2(3H)furanones. J. Agric. Food Chem. 2007, 55, 3877–3883; (g) Lambert, J. D.; Rice, J.
E.; Hong, J.; Hou, Z.; Yang, C. S. Synthesis and biological activity of the tea catechin
metabolites, M4 and M6 and their methoxy-derivatives. Bioorg. Med. Chem. Lett. 2005,
15, 873–876.
5. Hanessian, S.; Hou, Y.; Bayrakdarian, M.; Tintelnot-Blomley, M. A convenient route to
the synthesis of isotopomeric dihydro-2(3H)furanones. Stereoselective synthesis of con-
strained oxacyclic hydroxyethylene isosteres of aspartic protease inhibitors: Aldol and
Mukaiyama aldol methodologies for branched tetrahydrofuran 2-carboxylic acids.
J. Org. Chem. 2005, 70, 6735–6745.
6. Asano, M.; Inoue, M.; Katoh, T. Model Studies towards the total synthesis of
GKK1032s, novel antibiotic anti-tumor agents: Enantioselective synthesis of the alkyl aryl
ether portion of GKK1032s. Synlett 2005, 2599–2602.
7. Hanessian, S.; Yun, H.; Hou, Y.; Tintelnot-Blomley, M. Stereoselective Synthesis of
constrained azacyclic hydroxyethylene isosteres as aspartic protease inhibitors: Dipolar
cycloaddition and related methodologies toward branched pyrrolidine and pyrrolidinone
carboxylic acids. J. Org. Chem. 2005, 70, 6746–6756.
8. Holla, B. S.; Poojary, K. N.; Rao, B. S.; Shivananda, M. K. New bis-aminomercaptotria-
zoles and bis-triazolothiadiazoles as possible anticancer agents. Eur. J. Med. Chem. 2002,
37, 511–517.
9. Martin, G.; Lahti, R. A.; Rudzik, A. D.; Duchamp, D. J.; Chidester, C.; Scahill, T. Novel
anxiolytic agents derived from .alpha.-amino-.alpha.-phenyl-o-tolyl-4H-triazoles and
imidazoles. J. Med. Chem. 1978, 21, 542–548.

1498
V. K. RAI, P. TIKU, AND A. KUMAR
10. Thomas, G.; Mehta, D. V.; Tahilramani, R.; Joy, D.; Talwalker, P. K. Synthesis of some
s-triazoles with potential analgesic and antiinflammatory activities. J. Med. Chem. 1971,
14, 335–338.
11. Holla, B. S.; Poojary, K. N.; Kalluraya, B.; Gowda, P. V. Synthesis, characterisation
and antifungal activity of some N-bridged heterocycles derived from 3-(3-bromo-4-
methoxyphenyl)-4-amino-5-mercapto-1,2,4-triazole. Il Farmaco 1996, 51, 793–799.
12. Wnuk, S. F. Sulfur- and seleno-sugar modified nucleosides. Synthesis, chemical transfor-
mations and biological properties. Tetrahedron 1993, 49, 9877–9936.
13. Yuzhakov, A. A.; Chidgeavadze, Z. G.; Beabealashvilli, R. S. 30-Mercapto-20,30-
dideoxynucleotides are high effective terminators of DNA synthesis catalyzed by HIV
reverse transcriptase. FEBS Lett. 1992, 306, 185–188.
14. Yuzhakov, A. A.; Chidgeavadze, Z. G.; Beabealashvilli, R. S.; Kraevskii, A. A.; Galegov,
G. A.; Korneeva, M. N.; Nosik, D. N.; Kilesso, T. Y. 30-Mercapto-30-deoxythymidine-50-
triphosphate as a terminator of DNA synthesis catalyzed by RNA-dependent DNA-
polymerases. Bioorg. Khim. 1991, 17, 504–509, Chem. Abstr. 1991, 115, 84923g.
15. Le Hir de Fallois, L.; Decout, J. L.; Fontecave, M. Synthesis of 20-thio-uridine and -cyti-
dine derivatives aspotential inhibitors of ribonucleoside diphosphate reductase: Thioni-
trites, disulfides and 20-thiouridine 50-diphosphate. J. Chem. Soc. Perkin Trans. 1 1997,
2587–2596.
16. (a) Hughes, M. A.; McFadden, J. M.; Townsend, C. A. Bioorg. Med. Chem. Lett. 2005,
15, 3857–3859; (b) Tong, X.; Li, D.; Zhang, Z.; Zhang, X. Rhodium-Catalyzed Cycloi-
somerization of 1,6-enynes with an intramolecular halogen shift: Reaction scope and
mechanism. J. Am. Chem. Soc. 2004, 126, 7601–7607; (c) Lei, A.; He, M.; Zhang, X.
Highly enantioselective syntheses of functionalized a-Methylene-c-butyrolactones via
Rh(I)-catalyzed intramolecular Alder ene reaction: Application to formal synthesis of
(þ)-pilocarpine. J. Am. Chem. Soc. 2002, 124, 8198–8199; (d) Lee, K.; Jackson, J. A.;
Wiemer, D. F. Stereocontrol in Horner-Wadsworth-Emmons condensations of alpha-
phosphono lactones with aldehydes: A synthesis of integerrinecic acid and senecic acid
lactones. J. Org. Chem. 1993, 58, 5967–5971.
17. Frediani, P.; Rosi, L.; Frediani, M.; Bartolucci, G.; Bambagiotti-Alberti, M. A convenient
route to the synthesis of isotopomeric dihydro-2(3H)furanones. J. Agric. Food Chem.
2007, 55, 3877–3883.
18. (a) Elford, T. G.; Ulaczyk-Lesanko, A.; Pascale, G. D.; Wright, G. D.; Hall, D. G.
Diversity-oriented synthesis and preliminary biological screening of highly substituted
five-membered lactones and lactams originating from an allyboration of aldehydes and
imines. J. Comb. Chem. 2009, 11, 155–168; (b) Elford, T. G.; Arimura, Y.; Yu, S. H.; Hall,
D. G. Triflic acid-catalyzed additions of 2-alkoxycarbonyl allylboronates to aldehydes.
Study of scope and mechanistic investigation of the reaction stereochemistry. J. Org.
Chem. 2007, 72, 1276–1284.
ˇ
ꢀ
19. Pour, M.; Spulak, M.; Buchta, V.; Kubanova, P.; Voprsalova, M.; Wsol, V.; Fakova, H.;
Koudelka, P.; Pourova, H.; Schiller, R. 3-Phenyl-5-acyloxymethyl-2H,5H-furan-2-ones:
`
`
`
´
´
´
´
Synthesis and biological activity of a novel group of potential antifungal drugs. J. Med.
Chem. 2001, 44, 2701–2667.
20. Hoven, B. G. V.-d.; Ali, B. E.; Alper, H. Chemo- and regioselective cyclohydrocarbonyla-
tion of a-keto alkynes catalyzed by a zwitterionic rhodium complex and triphenyl
phosphite J. Org. Chem. 2000, 65, 4131–4137.
21. Just, Z. W.; Larock, R. C. Synthesis of 2(3H)-furanones via electrophilic cyclization.
J. Org. Chem. 2008, 73, 2662–2667.
´
´
´
22. Lopez, I.; Rodrıguez, S.; Izquierdo, J.; Gonzalez, F. V. Highly stereoselective epoxidation
of a-methyl-c-hydroxy-a,b-unsaturated esters: Rationalization and synthetic applications
J. Org. Chem. 2007, 72, 6614–6617.

cis-SELECTIVE SYNTHETIC APPROACH TO c-LACTONES
1499
23. Murahashi, S.-I.; Ono, S.; Imada, Y. Asymmetric Baeyer–Villiger reaction with hydrogen
peroxide catalyzed by a novel planar-chiral bisflavin. Angew. Chem., Int. Ed. 2002, 41,
2366–2368.
24. Sato, M.; Kosasayama, A.; Uchimaru, F. Psychotropic Agents. IV. Syntheses of b-phenyl-
c-butyrolactone derivatives. Chem. Pharm. Bull. 1981, 29, 2885–2892.
25. Protti, S.; Fagnoni, M.; Albini, A. Benzyl (Phenyl) c- and d-lactones via photoinduced
Tandem ArꢃC, CꢃO Bond formation. J. Am. Chem. Soc. 2006, 128, 10670–10671.
26. Patel, R.; Srivastava, V. P.; Yadav, L. D. S. Epoxides to c-mercapto-c-lactones via ionic
liquid promoted mercaptoacetylative ring-opening–ring-closing cascade. Synlett 2010,
1797–1802.
27. Yadav, L. D. S.; Yadav, S.; Rai, V. K. Mercaptoacetic acid based expeditious synthesis of
polyfunctionalised 1,3-thiazines. Tetrahedron 2005, 61, 10013–10017.
28. McClure, D. E.; Arison, B. H.; Baldwin, J. J. Mode of nucleophilic addition to epichloro-
hydrin and related species: Chiral aryloxymethyloxiranes. J. Am. Chem. Soc. 1979, 101,
3666–3668.