Asymmetric synthesis of 4-ethoxy-1-p-tolylsulfonyl-3,6-dioxabicyclo[3.1.0]hexan-2-ones

Article abstract of DOI:10.1016/j.tet.2009.10.106

Optically pure sulfinylfuranones undergo oxidation at sulfur followed by a totally stereoselective epoxidation at the electron deficient double bond by treatment with MCPBA at room temperature to afford, in good yields, enantiomerically pure 4-ethoxy-5-al

Full text of DOI:10.1016/j.tet.2009.10.106

Tetrahedron 66 (2010) 235–241
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Asymmetric synthesis of 4-ethoxy-1-p-tolylsulfonyl-3,6-
dioxabicyclo[3.1.0]hexan-2-ones
*
*
´
´
´
Alberto Fraile, Jose Luis Garcıa Ruano , M. Rosario Martın , Amelia Tito
´
´
Departamento de Qu´ımica Organica, Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Optically pure sulfinylfuranones undergo oxidation at sulfur followed by a totally stereoselective epox-
idation at the electron deficient double bond by treatment with MCPBA at room temperature to afford, in
good yields, enantiomerically pure 4-ethoxy-5-alkyl-1-p-tolylsulfonyl-3,6-dioxabicyclo[3.1.0]hexan-2-
ones. These epoxyfuranones are obtained along with cyclopropanefuranones by reaction of 4-ethoxy-6-
p-tolylsulfinylfuro[3,4-c]pyrazolin-6-ones with MPCBA. In both cases, the formation of the sulfonyl
epoxylactones takes place by oxidation of the sulfonylfuran-2(5H)-one resulting from the starting ma-
terials. This reaction is completely stereoselective (controlled by the configuration of C-5 of furanone)
and results from the nucleophilic attack of the peroxycarboxylate generated by interaction of the reagent
with weak basic centres at the substrates.
Received 18 September 2009
Received in revised form 27 October 2009
Accepted 29 October 2009
Available online 1 November 2009
Keywords:
Asymmetric synthesis
Epoxylactones
Sulfoxides
Ó 2009 Elsevier Ltd. All rights reserved.
Sulfones
Sulfonylfuranones
1. Introduction
starting from furanones, which could be opened by the base. The
key for the success of these reactions derived from the nucleophilic
The
a
,
b
-epoxy-
g
-lactone (3,6-dioxabicyclo[3.1.0]hexan-2-one)
character of the epoxidating reagent (perbenzoate anion, instead of
the electrophilic attack of the MCPBA), and the strong deactivation
of double bonds. In that reference we also reported that MCPBA
without base was able to produce the epoxidation of 5-ethoxy-3-p-
tolylsulfonylfuran-2(5H)-one, although such reactions were not
investigated in detail. However, the negative influence of the basic
reagents, able to interact with the furanone rings and other struc-
tural moieties, prompted us to consider the study of scope of
MCPBA as reagent for the preparation of epoxyfuranones from
subunit is present in many natural products with biomedical in-
terest (Fig. 1) such as diterpenoides Lophotoxin1 briaranes (cyto-
toxicity against L1210 murine leukaemia and KB human
epidermoid carcinoma cell in vitro),2 Bipinnatin Q (significant cy-
totoxic activity)3 or nortriterpenoids (propindilactone L shows anti-
HBV activity in vitro).4
Simple 3,6-dioxabicyclo[3.1.0]hexan-2-ones have been used as
intermediates in synthesis of Epolactaene and derivatives5 and
Cerulenin,6 which exhibit antibiotic activity and are inductors of
apoptosis in human cancer cell lines.
The epoxidation of non-activated furan-2(5H)-ones has been
described as notoriously difficult,7 and only the specific protocol
developed by Tishler and co-workers6 (NaOCl, pyridine) and other
analogous,8–10 work satisfactorily. Moreover, there are few pro-
tocols available for effecting the epoxidation of tri or tetrasub-
stituted alkenes bearing two electron-withdrawing groups.11
Therefore 4-alkoxy-3,6-dioxabicyclo[3.1.0]hexan-2-ones are not
easily obtained in good yields.12 We have recently reported that
epoxidation of sulfur-deactivated furanones could be accomplished
with MCPBA in basic medium.13 The nature and proportion of the
employed base proved to be highly important, especially when
* Corresponding authors. Tel.: þ34 91 497 4701; fax: þ34 91 497 3966.
´
Figure 1. Natural products and synthesis intermediates with epoxyfuranone moiety.
E-mail address: joseluis.garcia.ruano@uam.es (J.L. Garcıa Ruano).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.106

236
A. Fraile et al. / Tetrahedron 66 (2010) 235–241
deactivated furanones. The fact that the number of reported pro-
cesses involving the formation of epoxides by MCPBA oxidation of
alkenes bearing two electron-withdrawing groups is rather
scarce,14–17 increased the interest of this research. In this paper we
report our studies aiming at establishing the scope of the reactions
of 3-sulfinyl and sulfonyl furan-2(5H)-ones with MCPBA in the
synthesis of enantiomerically pure sulfonyl epoxyfuranones, as
well as their competition with other processes affecting the ex-
trusion reactions of furopyrazolines involved in the preparation of
the starting products.
been used for synthesizing 4-ethyl derivatives 7a and 7b. These
compounds were obtained from pyrazolynes 9 (adducts of fur-
anones 2a and 2b with diazoethane) or 10 (adducts of furanones 6a
and 6b with diazomethane).19 The best results were obtained from
pyrazolines 9. Compounds 5a and 5b were obtained from 11 by
reaction with MCPBA.
Next we tried to obtain sulfonyl derivative 3b by oxidation of
sulfoxide 6b19a with z2.5 equiv amounts of MCPBA at 0 ꢀC for 5 h.
Under these conditions a 1:1 mixture of sulfonyl epoxylactone 17b
and sulfonylfuranone 3b was obtained (Scheme 3). Sulfinyl epoxy
lactone was not detected, which suggests that oxidation of the
sulfur function is much faster than epoxidation of the sulfinylated
double bonds, thus generating the sulfonylfuranones, whose ep-
oxidation must take place at a rate similar to that of the oxidation of
the sulfinyl group. This result indicates that MCPBA, without any
base, is able to epoxidize 3-sulfonylfuran-2(5H)-ones.
2. Results and discussion
Both enantiomers of 5-ethoxy-3-p-tolylsulfonylfuran-2(5H)-
ones (1, R¼H in Scheme 1)13 were obtained by oxidation of the
corresponding sulfoxides (2). In order to prepare the optically pure
sulfonylfuranones RsH (3–5 in Scheme 1), which will be used as
the substrates for our MCPBA oxidation studies, we designed the
two strategies shown in Scheme 1. The first route involves the
oxidation of the sulfinyl derivatives 6–7, obtained by thermal ex-
trusion of nitrogen from compounds 8–11. In the second one, the
order of the steps is inverted and the oxidation of the sulfinyl
compounds 8–11 into the sulfonyl ones 12–15 would be previous to
the thermal extrusion of nitrogen.
Scheme 3. Reaction of sulfinylfuranone 6b with MCPBA after 5 h.
In order to develop a good synthetic procedure for preparing
epoxysulfonylfuranones (our target molecules), we increased the
reaction times. Under the conditions indicated in Table 1 the sul-
fonylated epoxyfuranones were obtained as the exclusive products
from sulfinylfuranones 2, 6–7 and sulfonylfuranones 5.
All the reactions were completely stereoselective only yielding
the epoxylactones, which exhibit an anti-relationship between the
oxirane ring and the OEt group (>98% ee). The yields for com-
pounds 16–18 were very high whereas the isopropyl sulfone 5 did
not react, presumably due to steric reasons, thus precluding the
preparation of compounds 19 by this procedure. 5-Methoxyfuran-
2(5H)-one20 was recovered when treated with MCPBA under the
conditions indicated in Table 1. Therefore the epoxidation of fur-
anones with this oxidant reagent only evolved when the furanone
bear an electron-withdrawing substituent at C-3.
Scheme 1. Strategies for preparation of 3-sulfonylfuran-2(5H)-ones.
We assume that the transformation of the sulfoxide into sulfonyl
group is previous to the epoxidation at the double bond because
epoxy sulfoxides were never detected in these reactions (see
above). Accordingly, the stereoselectivity control must be exerted
by the configuration at C-5 (the only stereogenic element at the
intermediate sulfones 1, 3–5). The approach of the reagent to the
Compounds (5S,SS)-2a and (5R,SS)-2b,18 differ only in the con-
figuration at stereogenic C-5 (Scheme 2). Their reactions with
diazomethane were completely stereoselective affording cyclo-
adducts 8a and 8b, respectively. They were easily transformed into
6a and 6b by thermal extrusion (Scheme 2). A similar procedure has
Scheme 2. Synthesis of 5-ethoxy-3-sulfonylfuran-2(5H)-ones.

A. Fraile et al. / Tetrahedron 66 (2010) 235–241
237
Table 1
nitrogen. When compound 8a (Scheme 4) reacted with MCPBA,
sulfonylpyrazoline 12a was detected by 1H NMR, but it could not be
isolated chemically pure. When a chloroform solution of the crude
of oxidation was kept at room temperature in the presence of silica
gel, surprisingly a 68:32 mixture of epoxy sulfonylfuranone 17a and
cyclopropyl derivative 20a was obtained in high combined yield.
The formation of cyclopropanes by extrusion of nitrogen from
pyrazolines is a well-known process22 that we have recently
reported from the adducts resulting from the reaction of diazo-
alkanes with sulfinylcycloalkenones and sulfinyllactones, by treat-
ment with some types of acids.23 According to these precedents,
the obtained results suggest that after oxidation of 8a into sulfo-
nylpyrazoline 12a, it is quickly decomposed into cyclopropyl de-
rivative 20a and the sulfonylfuranone 3a, which is immediately
transformed by MCPBA into the epoxyderivative 17a (Scheme
4).24,25
After these preliminary results, we studied the reactions of the
sulfinylfuropyrazolines 8b and 9–11 under the conditions depicted
in Scheme 4, to evaluate the influence of the structure of the ad-
ducts on the reaction course, mainly on the competition of both
extrusion reactions. The results are indicated in Table 2. In all cases
mixtures of epoxysulfonylfuranones 17–19 and 1-p-tolylsulfonyl-3-
oxabicyclo[3.1.0]hexan-2-ones 20–22 (dimethylcyclopropyl de-
rivative 23 was not detected) or sulfonylfuranones 5 were formed.
The composition of the mixture, nature and ratio of the obtained
products, depends on the nature of R1, R2 and on the stereochem-
istry of the starting compounds.
As it can be seen in Table 2, the presence of a methyl group at C-3
of furopyrazoline (entries 3 and 4) diminishes the amount of
cyclopropyl derivative, whereas it is completely inhibited when
there is an additional methyl group at 3a position (entries 7 and 8).
In the latter cases, the major products of the reaction mixtures are
the 4-isopropyl-3-sulfonylfuranones 5 (>65%), which is a conse-
quence of their difficult epoxidation (see above). The negative in-
fluence of the methyl groups at C-3 and C-3a of the bicyclic systems
on the relative rate of cyclopropane or alkene formation by extru-
sion of nitrogen, had been previously evidenced and explained
from steric grounds.23b,26 A worth mentioning result, is easier for-
mation of cyclopropanes from cycloadducts 8–10 with respect to
the formation of olefins by extrusion of nitrogen, when they have
configuration 4R (compare entries 1 and 2, 3 and 4, or 5 and 6 in
Table 2).
Another interesting aspect is the formation of compounds 19a
and 19b starting from pyrazolines 11a and 11b (entries 7 and 8,
Table 2), whereas they could not be obtained by epoxidation with
MCPBA of sulfonylfuranones 5a and 5b (entries 7 and 8, Table 1). By
assuming that sulfones 5 are the precursors of 19 in both cases,
these results could be explained taking into account the higher
basicity of pyrazolines 11 that furanones 5, which increases the
concentration of the actual oxidizing reagent.
Reactions of furan-2(5H)-ones 2, 5, 6 and 7 with MCPBA (2.5 equiv)
Entry
n
Furanone
R
Epoxide
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
2
2
2a
2b
6a
6b
7a
7b
5a
5b
H
H
Me
Me
Et
Et
i-Pr
i-Pr
16a
16b
17a
17b
18a
18b
(S)-19a
(R)-19b
3
80
75
89
88
86
86
d
1.5
8.5
8.5
2.5
2.5
18
18
d
face opposite to that occupied by the OEt group at C-5, would ex-
plain the exclusive formation of the oxiranes exhibiting the anti
arrangement with respect to the alkoxy group. This assumption is
supported by the fact that epimeric sulfoxides afford enantiomeric
sulfonyloxiranes.
Concerning the nature of the actual reagent in these reactions,
we propose that it is the m-chloroperbenzoate anion, generated by
dissociation of MCPBA. In addition to the autoprotolysis, which
provides very low concentration of the reagent, the carbonyl oxy-
gen at sulfonylfuranones 1, 3–5 can also act as a basic centre for
promoting the dissociation.21 In any case, as the concentration of
these anions must be very small, they will only be able to attack
double bonds strongly activated for nucleophilic additions, such as
sulfonylfuranones. In order to check the influence of the base on
these reactions we have studied the behaviour of compounds 6 in
the presence of MCPBA/K2CO3, conditions, which had proved op-
timum in the formation of oxiranes from other cyclic substrates.13
After 8.5 h the reaction of 6 with MCPBA/K2CO3 (1.0:3.2:1.6 ratio
6:MCPBA:K2CO3) afforded epoxysulfones 17 in 67% yield (lower
than the yield indicated in Table 1 only with MCPBA).
We have finally attempted the synthesis of sulfonylfuranones 3–
5 by using the second strategy shown in Scheme 1, consisting in the
MPCBA oxidation of cycloadducts 8,19b 9,19a 1019b and 1119a into
their sulfonyl derivatives 12–15, followed by thermal extrusion of
The structures of both enantiomers of 4-ethoxy-1-(p-toly
lsulfonyl)-3,6-dioxabicyclo[3.1.0]hexan-2-ones 16,13 17, 18 and 19,
[(S1,S4,R5)-a and (R1,R4,S5)]-b] were unequivocally determined
from their analysis elemental, [a] values and IR and NMR data
(Table 3). The absolute configuration of epoxides 16a,b (Table 3)
was determined by the value J4,5¼0 Hz, indicating that both H are in
a trans relationship,19,27 and the configuration at C-5 of starting
furanones.
The absolute configuration at C-1, C-4 and C-5 of epoxides 17a,b,
18a,b and 19a,b was assigned on the assumption that the attack of
the oxidant to 5-ethoxy-3-p-tolylsulfonylfuran-2(5H)-ones is anti
with respect to the alkoxy group and the configuration of the
acetalic carbon is the same in the epoxide and in the starting fur-
anone. These hypotheses are in agreement with the configuration
of epoxides 16 and the observed formation of a different enantio-
mer from each epimer at C-5 of sulfinylfuranones.
Scheme 4. Reaction of sulfinylfuropyrazoline 8a with MCPBA.

238
A. Fraile et al. / Tetrahedron 66 (2010) 235–241
Table 2
Reactions of 4-ethoxy-6a-p-tolylsulfinylfuro[3,4-c]pyrazolines with MCPBA
Entry
Furopyrazoline
R1
R2
Time step 2 (h)
Products (% isolated yield)
Products ratio
1
2
3
4
5
6
7
8
8a
8b
9a
9b
H
H
Me
Me
H
H
Me
Me
H
H
H
H
Me
Me
Me
Me
9
9
d
17a (53) 20a (20) 3a (0)
17b (19) 20b (43) 3b (0)
18a (72) 21a (8) 4a (0)
18b (60) 21b (11) 4b (0)
18a (46) 22a (23) 4a (0)
18a (37) 22b (40) 4b (0)
19a (21) 23a (0) 5a (52)
19b (12) 23b (0) 5b (62)
68:32:0
36:64:0
90:10:0
60:11:0
61:39:0
47:53:0
34:0:66
21:0:79
8
10aa
10bb
11a
11bc
48
48
39
90
a
From a 95:5 mixture of 9a syn-exo/anti-exo.
From a 15:85 mixture of syn-exo/9b anti-exo.
From a 66:34 mixture of 11b anti-exo/anti-endo.
b
c
The structures of cyclopropanefuranones (4-ethoxy-1-p-toly
3. Experimental section
3.1. General methods
lsulfonyl-3-oxabicyclo[3.1.0]hexan-2-ones) 20–22 were determined
from their analysis elemental, and their IR and NMR data (Table 3).
The cis or trans relationship of H5 with respect to H4 and H6 of cy-
clopropanes 20 and 21 is based on the value of J4,5 and J5,6. Accord-
Flash chromatography was carried out with silica gel Merck 60
(230–400 mesh ASTM). NMR spectra were determined in CDCl3
solutions at 300 and 75 MHz for 1H and 13C NMR, respectively; J
values are given in hertz. Melting points were measured using
a Gallenkamp apparatus in open capillary tubes and are un-
corrected. The optical rotations were measured at room tempera-
ingly, J4,5¼0 Hz showed
a trans relationship between these
protons19,27 (compounds 20b and 21b), whereas aw4 Hz value in-
dicated a cis relationship (20a and 21a). Taking into account that the
relative stereochemistry of these cyclopropanefuranones is the same
that of the starting furopyrazolines, we can assume that the config-
uration of acetalic carbon of furanone remains unaltered. Both facts
allowed us to assign the absolute configuration of above-mentioned
cyclopropanes and that of 22a and 22b, with no proton at C-5.
In summary, we have reported that sulfonylepoxyfuranones can
be obtained by MCPBA oxidation of the corresponding sulfinylfur-
anones. Additionally, we have demonstrated that this reagent is
efficient only for oxidizing strongly deactivated double bonds,
which suggests that it is acting as a nucleophile and therefore is
indicative that the m-chloroperbenzoate anion, generated by dis-
sociation of the acid with some basic centre at the substrate, is the
actual oxidizing agent.
ture (20–23 ꢀC) using
a Perkin–Elmer 241 MC polarimeter
(concentration in g/100 mL). Compounds 1,13 2,18 619 and 8–11,19
were synthesized and purified following the reported procedures.
The ee’s of compounds 16–19 were determined by chiral HPLC on
Chiralcel OD column using i-PrOH/hexane (13:87) as the eluent.
3.2. 3-Ethyl-5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-ones (7)
A 0.03 M solution of furopyrazolines 9 or 10 in toluene was
heated at 100 ꢀC for 60 min or 24 h, respectively. The evolution of
the reaction was followed by TLC. After evaporation of the solvent
Table 3
NMR data for compounds of structure
No
X
Y
1H NMR
H4
13C NMR
H5
H6ex
H6en
J4,5
J5,6en
J5,6ex
C1
C2
C4
99.0
C5
C6
16
17
18
19
20a
20b
21a
21b
22a
22b
O
O
O
O
CH2
CH2
CHMe
CHMe
CH2
CH2
H
Me
Et
i-Pr
H
H
H
H
Me
Me
5.42
5.25
5.34
5.36
5.63
5.24
5.66
5.25
5.26
5.13
4.67
d
d
d
0
d
d
d
d
d
8.8
8.8
d
d
d
d
65.8
73.6
77.0
79.1
48.0
45.2
52.6
49.9
49.9
47.7
163.1
164.4
164.6
164.8
165.9
166.9
166.9
167.9
166.5
167.8
62.6
68.1
68.9
69.4
29.2
31.7
34.1
36.8
38.7
39.7
d
d
d
d
d
d
4.1
0
d
101.4
100.5
101.8
100.0
100.2
100.9
100.4
104.0
102.2
d
d
d
d
d
d
d
d
d
d
d
3.18
3.06
3.00
2.94
d
2.04
2.16
d
1.86
1.44
2.11
1.71
1.88
1.50
5.2
5.5
5.3
5.5
d
17.1
18.5
26.6
28.9
22.4
24.3
4.0
0
d
2.07
2.11
d
d
d
d

A. Fraile et al. / Tetrahedron 66 (2010) 235–241
239
under reduced pressure the residue was purified by column chro-
matography (hexane/ethyl acetate 3:1).
tR¼10.28 min). Anal. Calcd for C13H14O6S: C 52.34, H 4.73, S 10.75.
Found: C 52.37, H 4.63, S 10.99.
3.2.1. (5S,SS)-4-Ethyl-5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-one
(7a). It was obtained after heating for 1 h a 95:5 mixture of syn-
exo-9a:anti-exo-9a. Yield 85%. Colourless oil. IR (film) 1760, 1639,
3.3.4. (1S,4S,5R)-4-Ethoxy-5-methyl-1-p-tolylsulfonyl-3,6-dioxabi-
cyclo[3.1.0]hexan-2-one [(þ)-17a]. This compound was obtained
from 6a after 8.5 h, purified by column chromatography (75:20:5
hexane/CH2Cl2/Et2O) and isolated in 89% yield. It was also obtained
from sulfinylpyrazoline 8a in 53% yield. White solid, mp 114–115 ꢀC.
1084,1060. 1H NMR : 7.69 and 7.33 (AA0BB0 system, 4H), 5.71 (s,1H,
d
H5), 3.90 (m, 1H), 3.74 (m, 1H), 3.22 (m, 1H), 2.67 (m, 1H), 2.40 (s,
3H), 1.28 (t, 3H, J¼7.0), 1.22 (t, 3H, J¼7.6). 13C NMR
d
: 169.4 (C), 165.5
IR (KBr) 1790, 1596, 1190. 1H NMR : 7.99 and 7.41 (AA0BB0 system,
d
(C), 142.2 (C), 138.6 (C) 132.3 (C), 130.0 (CH), 124.7 (CH), 101.8 (C5),
66.4 (CH2), 21.4 (CH3), 18.9 (CH2), 14.8 (CH3), 12.5 (CH3).
4H), 5.25 (s, 1H, H4), 3.93 (m, 1H), 3.68 (m, 1H), 2.47 (s, 3H), 2.02 (s,
3H), 1.27 (t, 3H, J¼7.0). 13C NMR
d: 164.4 (C2), 146.6 (C), 133.8 (C),
129.9 (CH), 129.8 (CH), 101.4 (C4), 73.6 (C1), 68.1 (C5), 66.5 (CH2),
[
a
]D¼þ195.5 (c¼1.35, CHCl3). Anal. Calcd for C15H18O4S: C 61.20, H
6.16, S 10.89. Found: C 61.48, H 6.50, S 11.17.
21.8 (CH3), 14.7 (CH3), 10.0 (CH3). [
a
]D¼þ226.8 (c 1, CHCl3), ee 98.4%
(flow 0.8 mL/min, tR¼12.10 min). Anal. Calcd for C14H16O6S: C 53.84,
3.2.2. (5R,SS)-4-Ethyl-5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-one
(7b). It was obtained after heating for 30 min a 15:85 mixture of
syn-exo-9b:anti-exo-9b. Yield 75%. Colourless oil. IR (film): 1765,
H 5.16, S 10.27. Found: C 53.84, H 5.15, S 10.55.
3.3.5. (1R,4R,5S)-4-Ethoxy-5-methyl-1-p-tolylsulfonyl-3,6-dioxabi-
cyclo[3.1.0]hexan-2-one [(ꢁ)-17b]. It was obtained from 6b after
8.5 h, purified by column chromatography (75:20:5 hexane/CH2Cl2/
Et2O) and isolated in 88% yield. It was also obtained from sulfi-
nylpyrazoline 8b in 19% yield. White solid, mp 114–115 ꢀC.
1639, 1084, 1058. 1H NMR : 7.69 and 7.33 (AA0BB0 system, 4H), 5.74
d
(s,1H, H5), 3.88 (m,1H), 3.73 (m,1H), 3.24 (m,1H), 2.66 (m,1H), 2.41
(s, 3H), 1.25 (t, 3H, J¼7.0), 1.23 (t, 3H, J¼7.6). 13C NMR
d: 169.1 (C),
165.7 (C), 142.3 (C), 138.9 (C), 132.3 (C), 130.2 (CH), 125.0 (CH), 101.9
(C5), 66.7 (CH2), 21.5 (CH3), 18.8 (CH2), 14.9 (CH3), 12.4 (CH3).
[
a
]D¼ꢁ220.0 (c 0.5, CHCl3), ee 96% (flow 0.8 mL/min, tR¼8.67 min).
[
a
]D¼þ140.6 (c¼0.35, CHCl3). Anal. Calcd for C15H18O4S: C 61.20, H
Anal. Calcd for C14H16O6S: C 53.84, H 5.16, S 10.27. Found: C 53.93, H
5.24, S 10.53.
6.16, S 10.89. Found: C 61.12, H 6.28, S 11.18.
3.3.6. (1S,4S,5R)-4-Ethoxy-5-ethyl-1-p-tolylsulfonyl-3,6-dioxabicy-
clo[3.1.0]hexan-2-one [(þ)-18a]. It was obtained from sulfinylfur-
anone 7a after 2.5 h, purified by column chromatography (80:15:5
hexane/CH2Cl2/Et2O) and isolated in 86% yield. It was also obtained
from sulfinylpyrazolines 9a or 10a in 72% and 46% yields, re-
spectively. White solid, mp 141–143 ꢀC. IR (KBr) 1794,1594,1150. 1H
3.3. Oxidation of 5-ethoxy-3-p-tolylsulfinyllfuran-2(5H)-ones.
General procedure
To a stirred solution of 0.38 mmol of sulfinylfuranone (2, 6 or 7),
in dichloromethane (5 mL) under argon atmosphere at 0 ꢀC, was
added dropwise a solution of MCPBA (162 mg, 0.84 mmol, w90%)
in dichloromethane (10 mL). The reaction mixture was stirred at
room temperature for the time indicated in each case, and then it
was washed with saturated aqueous sodium bicarbonate until pH 7.
The aqueous layer was extracted with several portions of
dichloromethane. The combined organic layers were dried over dry
sodium sulfate and the solvent removed in vacuo. The crude
product was chromatographied on silica gel (hexane/CH2Cl2/Et2O
in the ratio indicated in each case) to give the pure epoxide.
NMR d
: 7.99 and 7.41 (AA0BB0 system, 4H), 5.34 (s, 1H, H4), 3.94 (m,
1H), 3.69 (m, 1H), 2.50 (q, 2H, J¼7.6), 2.47 (s, 3H), 1.29 (t, 3H, J¼7.0),
1.24 (t, 3H, J¼7.6). 13C NMR
d: 164.6 (C2), 146.5 (C), 133.8 (C), 130.0
(CH), 129.8 (CH), 100.5 (C4), 77.0 (C1), 68.9 (C5), 66.6 (CH2), 21.8
(CH3), 17.9 (CH2), 14.7 (CH3), 9.5 (CH3). [
a
]D¼þ233.6 (c 0.5, CHCl3),
ee 98.8% (flow 0.7 mL/min, tR¼11.79 min). Anal. Calcd for
C15H18O6S: C 55.20, H 5.56, S 9.83. Found: C 55.21, H 5.58, S 10.22.
3.3.7. (1R,4R,5S)-4-Ethoxy-5-ethyl-1-p-tolylsulfonyl-3,6-dioxabicy-
clo[3.1.0]hexan-2-one [(ꢁ)-18b]. It was obtained from 7b after 2.5 h,
purified by column chromatography (80:15:5 hexane/CH2Cl2/Et2O)
and isolated in 86% yield. It was also obtained from sulfinylpyr-
azolines 9b and 10b in 60% and 37% yields, respectively. White
3.3.1. (5R)-5-Ethoxy-4-methyl-3-p-tolylsulfonylfuran-2(5H)-one
(3b). It was obtained by reaction of (5R,SS)-5-ethoxy-4-methyl-3-
p-tolylsulfinylfuran-2(5H)-one (6b) with MCPBA for 5 h at room
temperature. It was isolated by column chromatography (6:1 hex-
solid, mp 142–143 ꢀC. [
a
]D¼ꢁ234.0 (c 0.3, CHCl3), ee 99.5% (flow
ane/ethyl acetate). 1H NMR
d
: 7.95 and 7.35 (AA0BB0 system, 4H),
0.7 mL/min, tR¼8.51 min). Anal. Calcd for C15H18O6S: C 55.20, H
5.62 (s, 1H, H5), 3.90 (m, 1H), 3.75 (m, 1H), 2.50 (s, 3H), 2.44 (s, 3H),
5.56, S 9.83. Found: C 55.16, H 5.35, S 10.13.
1.26 (t, 3H, J¼7.0).
3.4. Transformation of 6-p-tolylsulfinylfuro[3,4-c]pyrazolin-
6-ones to sulfonylcyclopropanefuranones and
sulfonylepoxyfuranones. General procedure
3.3.2. (1S,4S,5R)-4-Ethoxy-1-p-tolylsulfonyl-3,6-dioxabicyclo[3.1.0]-
hexan-2-one [(þ)-16a]9. It was obtained from 2a after 3 h, purified
by column chromatography (60:35:5 hexane/CH2Cl2/Et2O) and
isolated in 80% yield. White solid, mp 152–153 ꢀC. IR (KBr) 1796,
To
a stirred ice-cooled solution of furopyrazoline 8–11
1596, 1158. 1H NMR
d
: 7.99 and 7.43 (AA0BB0 system, 4H), 5.42 (s, 1H,
(0.75 mmol) in dichloromethane (16 mL), was added dropwise
a solution of MCPBA (360 mg, z90%, 1.9 mmol) in dichloromethane
(15 mL). The mixture was stirred under argon atmosphere at room
temperature for 4 h, and then it was washed with saturated
aqueous sodium bicarbonate until pH 7. The aqueous layer was
extracted several times with dichloromethane. The combined or-
ganic layers were dried over dry sodium sulfate and the solvent
removed at reduced pressure. The residue was dissolved in 23 mL
of chloroform and then 954 mg of silica gel were added. The mix-
ture was stirred at room temperature for the time indicated in each
case, and the evolution of reaction was followed by TLC. The silica
gel was filtered off and the solvent was removed under reduced
pressure. 1H NMR analysis of the crude product showed the
H4), 4.67 (s, 1H, H5), 3.96 (m, 1H), 3.72 (m, 1H), 2.48 (s, 3H), 1.29 (t,
3H, J¼7.1); 13C RMN
d: 163.1 (C2), 146.8 (C), 132.6 (C), 130.0 (CH),
129.8 (CH), 99.0 (C4), 66.7 (CH2), 65.8 (C1), 62.6 (C5), 21.8 (CH3), 14.7
(CH3). [
a
]D¼þ184.8 (c 0.5, CHCl3), ee 99.4% (flow 0.8 mL/min,
tR¼12.36 min). Anal. Calcd for C13H14O6S: C 52.34, H 4.73, S 10.75.
Found: C 52.38, H 4.66, S 10.99.
3.3.3. (1R,4R,5S)-4-Ethoxy-1-p-tolylsulfonyl-3,6-dioxabicyclo[3.1.0]-
hexan-2-one [(ꢁ)-16b]. It was obtained from 2b after 1.5 h, purified
by column chromatography (60:35:5 hexane/CH2Cl2/Et2O) and
isolated in 75% yield. White solid, mp 150–152 ꢀC. [
a]D¼ꢁ162.6 (c
0.5, CHCl3), ee 87% (from a 95:5 mixture of 3b:3a) (flow 0.8 mL/min,

240
A. Fraile et al. / Tetrahedron 66 (2010) 235–241
presence of compounds indicated in Table 2. The products were
separated by flash column chromatography and purified as in-
dicated in each case.
22.4 (C6), 21.7 (CH3), 14.8 (CH3), 13.1 (CH3). [
CHCl3). Anal. Calcd for C15H18O5S: C 58.05, H 5.85, S 10.33. Found: C
58.13, H 5.72, S 10.68.
a
]D¼ꢁ17.8 (c 0.5,
3.4.1. (1R,4S,5S)-4-Ethoxy-1-p-tolylsulfonyl-3-oxabicyclo[3.1.0]hexan-
2-one (20a). Compound 20a was obtained from 8a and purified by
column chromatography (5:1 hexane/ethyl acetate). Yield 20%.
White solid, mp 130–131 ꢀC. IR (KBr) 1770, 1596, 1155, 1085. 1H
3.4.6. (1R,4R,5S)-4-Ethoxy-5-methyl-1-p-tolylsulfonyl-3-ox-
abicyclo[3.1.0]hexan-2-one (22b). It was obtained from 10b and
purified by column chromatography (4:1 hexane/ethyl acetate).
Yield 40%. White solid, mp 80–82 ꢀC. IR (KBr) 1780,1597,1159, 1060.
NMR
d
: 7.92 and 7.38 (AA0BB0 system, 4H), 5.63 (d, 1H, H4, J4,5¼4.1),
1H NMR : 7.89 and 7.35 (AA0BB0 system, 4H), 5.13 (s, 1H, H4), 3.78
d
3.81 (m, 1H), 3.66 (m, 1H), 3.18 (ddd, 1H, H5, J5,4¼4.1, J5,6endo¼5.2
(m, 1H), 3.54 (m, 1H), 2.44 (s, 3H), 2.11 (d, 1H, H6exo, J¼5.1), 1.71 (s,
and J5,6exo¼8.8), 2.46 (s, 3H), 2.04 (dd, 1H, H6exo, J6exo,6endo¼5.3 and
3H), 1.50 (d, 1H, H6endo, J¼5.1), 1.16 (t, 3H, J¼7.0). 13C NMR
d: 167.8
J6exo,5¼8.8), 1.86 (t, 1H, H6endo, J¼5.2), 1.22 (t, 3H, J¼7.1). 13C NMR
d
:
(C2), 145.2 (C), 135.9 (C), 129.6 (CH), 128.9 (CH), 102.2 (C4), 65.2
(CH2), 47.7 (C1), 39.7 (C5), 24.3 (C6), 21.6 (CH3), 14.7 (CH3), 11.0 (CH3).
165.9 (C2), 145.6 (C),135.1 (C),129.8 (CH), 129.1 (CH),100.0 (C4), 67.0
20
(CH2), 48.0 (C1), 29.2 (C5), 21.7 (CH3), 17.1 (C6), 14.8 (CH3); [
a
]
[
a
]D¼ꢁ160.0 (c 0.5, CHCl3). Anal. Calcd for C15H18O5S: C 58.05, H
D
ꢁ16.6 (c 0.5, CHCl3). Anal. Calcd for C14H16O5S: C 56.74, H 5.44, S
5.85, S 10.33. Found: C 58.18, H 5.90, S 10.78.
10.82. Found C 56.56, H 5.44, S 10.80.
3.4.7. (1S,4S,5R)-4-Ethoxy-5-isopropyl-1-p-tolylsulfonyl-3,6-dioxa-
bicyclo[3.1.0]hexan-2-one [(þ)-19a]. It was obtained from sulfi-
nylfuropyrazoline 11a and purified by column chromatography
(85:10:5 hexane/dichloromethane/ethyl ether). Yield 21%. White
solid, mp 149–151 ꢀC. IR (KBr) 1796, 1595, 1341, 1160, 1123, 1006. 1H
3 . 4 . 2 . ( 1 R , 4 R , 5 S ) - 4 - E t h o x y - 1 - p - t o l y l s u l f o n y l - 3 - o x -
abicyclo[3.1.0]hexan-2-one (20b). Compound 20b was obtained
from 8b and purified by column chromatography (50:45:5 hexane/
dichloromethane/ethyl ether). Yield 43%. White solid, mp 128–
129 ꢀC. IR (KBr) 1782, 1598, 1150. 1H NMR
d
: 7.93 and 7.37 (AA0BB0
system, 4H), 5.24 (s, 1H, H4), 3.81 (m, 1H), 3.58 (m, 1H), 3.06 (dd, 1H,
H5, J5,6endo¼5.5 and J5,6exo¼8.8), 2.46 (s, 3H, CH3), 2.16 (dd, 1H, H6exo
NMR d
: 8.00 and 7.40 (AA0BB0 system, 4H), 5.36 (s, 1H, H4), 3.95 (m,
1H), 3.67 (m, 1H), 2.78 (sept, 1H, J¼7.1), 2.47 (s, 3H), 1.42 (d, 3H,
,
J¼7.2), 1.31 (t, 3H, J¼7.1), 1.30 (d, 3H, J¼7.0). 13C NMR
d: 164.8 (C2),
J6exo,6endo¼5.5 and J6exo,5¼8.8), 1.44 (t, 1H, H6endo, J¼5.5), 1.18 (t, 3H,
146.5 (C), 133.9 (C), 130.1 (CH), 129.7 (CH), 101.8 (C4), 79.1 (C1), 69.4
(C5), 66.9 (CH2), 28.3 (CH), 21.8 (CH3), 19.6 (CH3), 17.9 (CH3), 14.8
J¼7.1). 13C NMR
d: 166.9 (C2), 145.5 (C), 135.0 (C), 129.7 (CH), 129.0
(CH), 100.2 (C42)0, 65.0 (CH2), 45.2 (C1), 31.7 (C5), 21.7 (CH3), 18.5 (C6),
(CH3). [
a
]D¼þ258.8 (c 0.25, CHCl3), ee 97.6% (flow 1 mL/min,
14.7 (CH3). [
a
]
D
ꢁ121.2 (c 0.5, CHCl3). Anal. Calcd for C14H16O5S: C
tR¼10.93 min). Anal. Calcd for C16H20O6S: C 56.46, H 5.92, S 9.42.
56.74, H 5.44, S 10.82. Found: C 56.78, H 5.31, S 11.08.
Found: C 56.63, H 6.03, S 9.11.
3.4.3. (1R,4S,5S,6R)-4-Ethoxy-6-methyl-1-p-tolylsulfonyl-3-ox-
abicyclo[3.1.0]hexan-2-one (21a). Compound 21a was obtained
from a 95:5 mixture of 9a-syn-exo:anti-exo furopyrazolines and
purified by column chromatography (60:35:5 hexane/dichloro-
methane/ethyl ether). Yield 8%. White solid, mp 100–103 ꢀC. IR
3.4.8. (1R,4R,5S)-4-Ethoxy-5-isopropyl-1-p-tolylsulfonyl-3,6-dioxa-
bicyclo[3.1.0]hexan-2-one [(ꢁ)-19b]. It was obtained from a mixture
of sulfinylfuropyrazolines 11b-anti-exo:anti-endo and purified by
column chromatography (85:10:5 hexane/dichloromethane/ethyl
ether). Yield 12%. White solid, mp 148–150 ꢀC; [
a
]D¼ꢁ259.9 (c 0.24,
(KBr) 1777, 1595, 1322, 1153. 1H NMR
d
: 7.99 and 7.37 (AA0BB0 sys-
CHCl3), ee 98% (flow 1 mL/min, tR¼7.29 min). Anal. Calcd for
tem, 4H), 5.66 (d, 1H, H4, J4,5¼4.0), 3.80 (m, 1H), 3.66 (m, 1H), 3.00
(dd, 1H, H5, J4,5¼4.0 and J5,6¼5.3), 2.46 (s, 3H), 2.11 (qd, 1H, H6,
J6,5¼5.3 and J6,Me¼6.5), 1.50 (d, 3H, CH3-6, JMe,6¼6.5), 1.22 (t, 3H,
C16H20O6S: C 56.46, H 5.92, S 9.42. Found: C 56.75, H 6.02, S 9.11.
3.4.9. (5S)-5-Ethoxy-4-isopropyl-3-p-tolylsulfonylfuran-2(5H)-one
J¼7.1). 13C NMR
d
: 166.9 (C2), 145.3 (C), 136.3 (C), 129.7 (CH), 128.8
[(þ)-5a]. It was obtained from 11a in 52% yield. Colourless oil. IR
(CH), 100.9 (C4), 66.9 (CH2), 52.6 (C1), 34.1 (C5), 26.6 (C6), 21.7 (CH3),
(film) 1778, 1626, 1597, 1158. 1H NMR : 7.93 and 7.33 (AA0BB0
d
14.8 (CH3), 10.6 (CH3). [
C15H18O5S: C 58.05, H 5.85, S 10.33. Found: C 58.06, H 5.83, S 10.56.
a
]D¼þ15.2 (c 0.25, CHCl3). Anal. Calcd for
system, 4H), 5.78 (s, 1H, H5), 4.03 (sept, 1H, J¼7.0), 3.91 (m, 1H), 3.74
(m, 1H), 2.41 (s, 3H), 1.32 (d, 3H, J¼7.0), 1.25 (t, 3H, J¼7.1), 1.22 (d,
3H, J¼7.0). 13C NMR
d: 175.7 (C), 164.1 (C), 145.6 (C), 135.9 (C), 129.7
(CH), 129.0 (C), 128.8 (CH), 101.2 (C5), 67.2 (CH2), 27.2 (CH), 21.6
(CH3), 21.4 (CH3), 19.0 (CH3), 14.8 (CH3).
3.4.4. (1R,4R,5S,6R)-4-Ethoxy-6-methyl-1-p-tolylsulfonyl-3-ox-
abicyclo[3.1.0]hexan-2-one (21b). It was obtained from a 85:15
mixture of 9b-anti-exo:syn-exo and purified by column chroma-
tography (50:45:5 hexane/dichloromethane/ethyl ether). Yield 11%.
White solid, mp 129–131 ꢀC. IR (KBr) 1775, 1595, 1332, 1156. 1H
3.4.10. (5R)-5-Ethoxy-4-isopropyl-3-p-tolylsulfonylfuran-2(5H)-one
[(ꢁ)-5b]. It was obtained from a 66:34 mixture of sulfinylfuropyr-
azoline 11b-anti-exo:anti-endo and purified by column chroma-
tography (60:35:5 hexane/dichloromethane/ethyl ether). Yield
NMR d
: 7.98 and 7.35 (AA0BB0 system, 4H), 5.25 (s, 1H, H4), 3.80 (m,
1H), 3.58 (m, 1H), 2.94 (d, 1H, H5, J5,6¼5.5), 2.45 (s, 3H), 1.71 (qd, 1H,
H6, J6ndo,5¼5.5 and J6,Me¼6.3), 1.53 (d, 3H, JMe,6¼6.3), 1.19 (t, 3H). 13
C
62%. Colourless oil, [
Acknowledgements
We thank DGICYT (Grant CTQ2006-06741/BQU) and Comunidad
a
]D¼ꢁ40.5 (c 1.68, CHCl3).
NMR d: 167.9 (C2), 145.2 (C), 136.3 (C), 129.5 (CH), 128.9 (CH), 100.4
(C4), 64.9 (CH2), 49.9 (C1), 36.8 (C5), 28.9 (C6), 21.7 (CH3), 14.8 (CH3),
10.8 (CH3). [
a
]D¼ꢁ74.0 (c 0.25, CHCl3). Anal. Calcd for C15H18O5S: C
58.05, H 5.85, S 10.33. Found: C 58.08, H 5.86, S 10.53.
´
Autonoma de Madrid (CCG08-UAM/PPQ-4151) for financial
3.4.5. (1R,4S,5S)-4-Ethoxy-5-methyl-1-p-tolylsulfonyl-3-ox-
abicyclo[3.1.0]hexan-2-one (22a). Compound 22a was obtained
from 10a and purified by column chromatography (50:45:5 hex-
ane/dichloromethane/ethyl ether). Yield 23%. White solid, mp 82–
support.
References and notes
84 ꢀC. IR (KBr) 1777, 1599, 1155, 1071. 1H NMR
d: 7.90 and 7.36
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