On the mechanism and diastereoselectivity of 2,3-dihydrobenzofuran formation from sulfinylbenzoquinones and 2-trimethylsilyloxyfuran

Article abstract of DOI:10.1016/S0957-4166(99)00460-7

A mechanistic study of the reactions between 2-trimethylsilyloxyfuran 1 and (SS)-2-(arylsulfinyl)-1,4-benzoquinones 2a and 2b, giving rise to the diastereoselective formation of [3aS,8bS,SS]-3a,8b-dihydro-7-hydroxy-8- (arylsulfinyl)furo[3,2-b]benzofuran-2(3H)-ones 3a and 3b, is reported. The detection and ¹H NMR characterization of several precursors of 3a and 3b accounts for a Michael-type initial reaction which dictates the final diastereoselection of the process. A significant improvement of the stereoselectivity (up to 96% de) in the formation of the tert-butylsulfinyl substituted derivative 3c was achieved by using 2-(tert-butylsulfinyl)-1,4- benzoquinone 2c as the starting quinone. (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00460-7

Pergamon
Tetrahedron: Asymmetry 10 (1999) 4357–4367
On the mechanism and diastereoselectivity of
2,3-dihydrobenzofuran formation from sulfinylbenzoquinones
and 2-trimethylsilyloxyfuran
M. Carmen Carreño,∗ José L. García Ruano,∗ Antonio Urbano, Cynthia Z. Remor † and
Yolanda Arroyo ‡
Departamento de Química Orgánica (C-I), Universidad Autónoma, Cantoblanco, 28049 Madrid, Spain
Received 8 October 1999; accepted 19 October 1999
Abstract
A mechanistic study of the reactions between 2-trimethylsilyloxyfuran 1 and (SS)-2-(arylsulfinyl)-1,4-
benzoquinones 2a and 2b, giving rise to the diastereoselective formation of [3aS,8bS,SS]-3a,8b-dihydro-7-
1
hydroxy-8-(arylsulfinyl)furo[3,2-b]benzofuran-2(3H)-ones 3a and 3b, is reported. The detection and H NMR
characterization of several precursors of 3a and 3b accounts for a Michael-type initial reaction which dictates
the final diastereoselection of the process. A significant improvement of the stereoselectivity (up to 96% de) in
the formation of the tert-butylsulfinyl substituted derivative 3c was achieved by using 2-(tert-butylsulfinyl)-1,4-
benzoquinone 2c as the starting quinone. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
The 2,3-dihydrobenzofuran moiety is found in a number of natural products1 which show significant
biological properties. Two general synthetic approaches are available to date to construct this fragment.
One of them, mainly exploited by Engler,2 is based on a Lewis acid promoted reaction between a methoxy
substituted p-benzoquinone and a styrene or stilbene derivative. The other relies on the reaction between
a benzoquinone bearing an electron-withdrawing substituent and an electron-rich diene and has been
studied by different research groups.3 With 2-trimethylsilyloxyfuran 1, this reaction gives rise to a cis-
3a,8b-dihydrofuro[3,2-b]benzofuran-2(3H)-one4 (Scheme 1). An asymmetric version of this process has
been studied by Brimble using quinones bearing differently substituted esters as chiral auxiliaries5 or
in the presence of chiral catalysts.6 Although optically active derivatives were obtained in all cases, the
∗
†
‡
Corresponding authors. E-mail: carmen.carrenno@uam.es
On leave from Instituto de Química/UFRGS, Porto Alegre (RS), Brazil.
On leave from Departamento de Química Orgánica (E.T.S.I.I.), Universidad de Valladolid, Spain.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00460-7

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diastereoselectivities achieved were not good enough for preparative purposes. When the reaction was
carried out between 1 and enantiopure (SS)-2-(p-tolylsulfinyl)-1,4-benzoquinone 2a7 in acetonitrile, a
77:23 mixture of diastereomers 3a and 4a was obtained (Scheme 1). To date, such diastereoselectivity has
not been improved due to the unknown mechanistic and stereochemical course of the process, since either
an initial Diels–Alder reaction3b,d,f or a Michael-type addition process is consistent with the observed
results.5b
Scheme 1.
In the course of our studies devoted to asymmetric Diels–Alder reactions with enantiomerically pure
(SS)-2-(p-tolylsulfinyl)-1,4-quinones,8 we had observed excellent levels of π-facial diastereoselection
for cycloadditions with a wide range of dienes. Based on our results, the stereoselectivity reported for
the reaction of 2a with 2-trimethylsilyloxyfuran 1 was suggesting a non concerted reaction course in
the initial step. To clarify the mechanism, we undertook a detailed study of the reaction between 2a
and 2-substituted furan derivatives with the aim of gaining an improvement of the diastereoselectivity
obtained previously. We report herein evidence of a Michael-type initial reaction which dictates the
stereoselectivity of the process as well as the way to improve the final diastereoselection.
2. Results and discussion
We first carried out the reaction of 2a9 with 2-methoxyfuran 5 (Scheme 2). Working under very mild
conditions (CH2Cl2, rt, 30 min), (SS)-3-(5-methoxy-2-furanyl)-2-(p-tolylsulfinyl)-1,4-dihydroxybenzene
6 could be isolated in 63% yield, after flash chromatography. The formation of compound 6 must be the
consequence of a Michael-type attack of the furan from its nucleophilic C-5 position to the more deficient
C-3 of the quinone, followed by aromatization of the initial intermediate.
Scheme 2.
We then repeated the reaction reported by Brimble7 between (SS)-2-(p-tolylsulfinyl)-1,4-
benzoquinone 2a and 2-trimethylsilyloxyfuran 1 in CH2Cl2 at rt and obtained a complex reaction
mixture which, after flash chromatography, evolved into a 80:20 ratio of 3a10 and 4a10 in 59% yield
1
(Scheme 1, Table 1, entry 1). The course of the reaction was then monitored by H NMR (CD3CN at
rt), recording a spectrum every 10 min until the disappearance of 2a signals (1 h 40 min). The evolution
showed the progressive formation of epimeric compounds 7a and 8a in a 75:25 ratio (Scheme 3), which
were stable enough to be characterized. The mixture of 7a and 8a could be transformed into desilylated

M. C. Carreño et al. / Tetrahedron: Asymmetry 10 (1999) 4357–4367
4359
Table 1
Reactions of 2-trimethylsilyloxyfuran 1 and sulfinylbenzoquinones 2a–c
1
derivatives 9a and 10a (75:25) by treatment with 10% HCl. When the same H NMR monitoring was
effected in CDCl3, a mixture of compounds 9a and 10a (80:20) was detected. This evolution could be
a consequence of the acid traces always present in CDCl3. After flash chromatography, both mixtures
of 7a–8a and 9a–10a evolved into 3a and 4a as a consequence of an intramolecular conjugate addition
to the α,β-unsaturated butyrolactone moiety, which also occurs stereoselectively, giving rise to the
corresponding cis-fused compounds (Scheme 3).
In accordance with these observations, the diastereoselectivity achieved must be initially defined in the
Michael-type starting reaction. The stereochemical course of the process could be explained taking into
account a sterically favored approach of 2-trimethylsilyloxyfuran 1 to sulfinylquinone 2a from the less
hindered face which supports the lone electron pair at sulfur. Three conformers A, B and C (Scheme 4)
could participate in the conformational equilibrium of 2a. Nevertheless, only A and C show a steric
differentiation between both diastereotopic faces of 2a. Thus, the attack of 2-trimethylsilyloxyfuran
1 would preferentially occur from the upper face of conformation A and from the bottom one of
conformation C. Although rotamer B could also be considered,11 steric and stereoelectronic grounds
suggest a lower participation. The conjugate addition through transition states TSI and TSII, with an
antiperiplanar relationship between the nucleophilic and electrophilic double bonds, must be favored over
the approach shown as TSIII with an antiperiplanar arrangement of the furan oxygen and the quinonic
double bond. The latter must be strongly destabilized by electronic repulsions between proximal oxygens.
The expected higher reactivity of s-cis conformation A12 as well as its higher stability due to minimum
electrostatic repulsions allowed us to assume its preferred evolution. Moreover, a higher stability of TSI
can be predicted since steric interactions between the approaching furan and the sulfinylic oxygen must
be lower than those existing in TSII, where furan is interacting with the bulky tolyl ring. Thus, reaction
through TSI accounts for the major formation of diastereoisomer 7a, a precursor of compound 3a bearing
the (S,S) absolute configuration in the new stereogenic centers.
According with this mechanism, all factors increasing the population of conformer A in the confor-
mational equilibrium of sulfinylquinone 2a or steric interactions in the corresponding transition states
would improve the diastereoselectivity of the process. As shown in Table 1, a decrease in the reaction
temperature (CH2Cl2, −78°C) slightly improved the diastereoselectivity in favor of 3a (83:17, entry 2),
as could be expected assuming an increased participation of A in the conformational equilibrium shown
in Scheme 4. The use of chelating Lewis acids such as Eu(fod)3 and ZnBr2 (Table 1, entries 3 and 4)

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Scheme 3.
decreased the diastereoselection as a consequence of the higher participation of an s-trans conformation
such as C.
In order to evaluate the role of steric effects in the relative stability of the different transition states,
we reasoned that the use of quinones bearing a sulfinyl substituent bulkier than the tolyl group could
be appropriate. With this aim, (SS)-2-(20-methoxynaphthylsulfinyl)-1,4-benzoquinone 2b and 2-(tert-
butylsulfinyl)-1,4-benzoquinone 2c were prepared (Scheme 5). The synthesis of (+)-2b was carried out
following the two-step general methodology described previously by us9 for the synthesis of (+)-2a,
based on Andersen’s synthesis.13 Thus, the direct metallation of 1,4-dimethoxybenzene with n-BuLi at
rt, followed by reaction with (−)-(SS)-menthyl-2-methoxy-1-naphthylsulfinate14 as sulfinylating agent,
afforded derivative (+)-11 in 60% yield (Scheme 5). Ammonium cerium (IV) nitrate (CAN) cleanly
oxidized compound 11 at rt into enantiopure sulfinylquinone (+)-2b in 90% yield.
The tert-butylsulfinyl derivative 2c was prepared in racemic form as outlined in Scheme 5 from
the corresponding thioether 12. Thus, 2-(tert-butylthio)-1,4-benzoquinone 12 was prepared in 50%
isolated yield according to an old reported procedure15 based on the reaction between 2 equiv. of 1,4-
benzoquinone and tert-butylthiol. Direct controlled oxidation of compound 12 with 1 equiv. of m-CPBA
in CHCl3 at 0°C yielded a 75% yield of 2-(tert-butylsulfinyl)-1,4-benzoquinone 2c. The results obtained
in the reactions of sulfinylbenzoquinones (+)-2b and 2c and 2-trimethylsilyloxyfuran 1 are collected in
Table 1.
As expected, reaction of quinone (+)-2b in CH2Cl2 at rt gave, after flash chromatography, a better
diastereoselection (85:15) of the corresponding derivatives (+)-3b and (+)-4b (Scheme 1, Table 1, entry
5) if compared with the same reaction with quinone 2a (entry 1). The use of a polar solvent such as EtOH

M. C. Carreño et al. / Tetrahedron: Asymmetry 10 (1999) 4357–4367
4361
Scheme 4.
Scheme 5. (a) (i) n-BuLi, THF, rt, 1 h; (ii) (−)-(SS)-menthyl-2-methoxy-1-naphthalenesulfinate, THF, −78°C, 2 h, 60%; (b)
CAN, CH3CN, H2O, rt, 1 h, 90%; (c) EtOH, rt, 4 h, 50%; (d) m-CPBA, CH2Cl2, 0°C, 1 h, 93%
decreased the diastereoselectivity (69:31, Table 1, entry 6). This result is in agreement with a diminished
presence of conformation A (Scheme 4) due to minimization of dipolar repulsion between the C_O and
S_O groups induced by polar solvents. The best result, 90:10 ratio of 3b and 4b, was obtained working
in CHCl3 at −20°C (Table 1, entry 7). The mechanistic pathway proposed for the formation of 3a and
1
4a could be corroborated for 3b and 4b in a similar H NMR monitoring of the reaction between 2b
and 1 (Scheme 3). In this case, compounds 7b and 8b (80:20 ratio) were initially detected in CD3CN
and 9b and 10b (90:10) in CDCl3. Derivatives 7b and 8b can be transformed into 9b and 10b after
hydrolysis with 10% HCl and compounds 3b and 4b were obtained diastereoisomerically pure after flash

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M. C. Carreño et al. / Tetrahedron: Asymmetry 10 (1999) 4357–4367
Figure 1. 1H NMR parameters and NOE experiment used for configurational assignment
chromatography of the mixtures of 7b–8b or 9b–10b. The assignment of the correct stereochemistry at
the bridgehead positions of 3b and 4b was effected taking into account the fixed s-trans conformation of
the sulfinyl group in both derivatives due to the hydrogen bonding formed between the phenolic proton
and the sulfinyl oxygen (Fig. 1).16 In this conformation, the bulky 2-methoxynaphthyl substituent of the
sulfoxide is directed to the upper face of the dimethoxy substituted aromatic ring and the lone electron
pair to the lower one. In this situation, protons H3a and H8b in diastereoisomer 3b are shielded by the
naphthalene ring appearing further upfield in the 1H NMR spectrum relative to the equivalent protons in
the other diastereoisomer 4b (0.25 ppm shielding for H3a and 0.43 for H8b, see Fig. 1).
Finally, reaction of 2-(tert-butylsulfinyl)-1,4-benzoquinone 2c with 1 was effected in CHCl3 at −20°C
(Scheme 1, Table 1, entry 8). Under these conditions and after flash chromatography, a 98:2 mixture
of derivatives 3c and 4c was formed, allowing us to isolate compound 3c diastereoisomerically pure in
52% yield. This excellent result demonstrates that steric effects are essential in controlling the π-facial
diastereoselectivity of the initial conjugate addition. Configurational assignment of 3c was mainly based
on an NOE experiment.17 Thus, selective irradiation on bridgehead hydrogen H8b showed a relevant 4.6%
NOE enhancement between this proton and the tert-butyl substituent of the sulfinyl moiety, indicating
the spatial closeness of both groups in the fixed s-trans conformation of the tert-butyl sulfinyl substituent
depicted for 3c in Fig. 1.
3. Conclusion
We have proposed a mechanistic and stereochemical rationale for the diastereoselective formation
of [3aS,8bS,SS]-3a,8b-dihydro-7-hydroxy-8-(aryl- and tert-butylsulfinyl)furo[3,2-b]benzofuran-2(3H)-
ones 3a–c based on a sterically controlled diastereoselective conjugate addition of 2-trimethylsilyloxy-
furan on sulfinylquinones as the key step. A significant improvement of the stereoselectivity (up to 96%
de) was achieved by using the tert-butylsulfinyl group on the starting quinone. We are now proceeding
to apply these good results to the asymmetric synthesis of natural products.
4. Experimental
4.1. General methods
Melting points were obtained in open capillary tubes and are uncorrected. IR spectra were obtained
1
as CHCl3 solutions and are given in cm−1. H NMR and 13C NMR spectra were recorded in CDCl3 at
300 and 75 MHz, respectively. Diastereoisomeric adducts ratios were established by integration of well-

M. C. Carreño et al. / Tetrahedron: Asymmetry 10 (1999) 4357–4367
4363
separated signals in the crude reaction mixtures and are listed in Table 1. All reactions were monitored
by thin layer chromatography that was performed on precoated sheets of silica gel 60, and flash column
chromatography was done with silica gel 60 (230–400 mesh) of Macherey–Nagel. Eluting solvents are
indicated in the text. Apparatuses for inert atmosphere experiments were dried by flaming in a stream of
dry argon. Dry THF was distilled from sodium/benzophenone ketyl. CH2Cl2 and CHCl3 were dried over
P2O5. For routine workup, hydrolysis was carried out with water, extractions with CH2Cl2, and solvent
dryness with Na2SO4.
4.2. (SS)-2-(5-Methoxy-2-furanyl)-3-(p-tolylsulfinyl)-1,4-dihydroxybenzene 6
To a solution of (SS)-2-(p-tolylsulfinyl)-1,4-benzoquinone 2a (500 mg, 2.0 mmol) in dry CH2Cl2 (10
ml), 2-methoxyfuran (200 µl, 2.2 mmol) was added. After stirring at rt for 30 min, the solvent was
evaporated and the residue purified by flash chromatography (eluent hexane:EtOAc 3:1) to obtain pure
20
1
6 as a solid in 60% yield: mp 126–127°C; [α] =−403 (c 0.5, acetone); H NMR δ 10.54 (s, 1H), 7.55
D
and 7.26 (AA0BB0 system, 4H), 6.98 and 6.82 (AB system, 2H, J=8.6 Hz), 6.41 (d, 1H, J=3.1 Hz), 5.75
(s, 1H), 5.29 (d, 1H, J=3.1 Hz), 3.82 (s, 3H), 2.37 (s, 3H); 13C NMR δ 162.3, 153.8, 147.1, 142.1, 140.6,
134.9, 130.2, 130.0, 126.0, 120.9 (2C), 120.8 (2C), 114.8, 81.6, 57.7, 21.3; IR νmax 3500, 3040, 2960,
2290, 1490, 1460, 1355, 1315, 1150, 790; EI-MS m/z (%) 344 (M+, 21), 328 (9), 285 (100), 269 (37),
193 (18), 165 (18), 139 (13), 123 (14), 91 (28). Anal. calcd for C18H16O5S: C, 62.78; H, 4.69; S, 9.29.
Found: C, 62.47; H, 4.55; S, 8.94.
4.3. (5R,SS)- and (5S,SS)-5-[3-Hydroxy-6-trimethylsilyloxy-2-(p-tolylsulfinylphenyl)]furan-2(5H)-one
7a and 8a
1
These compounds were detected by H NMR monitoring after mixing (SS)-2-(p-tolylsulfinyl)-1,4-
benzoquinone (2a) (10.8 mg, 0.04 mmol) and 2-trimethylsilyloxyfuran 1 (8.1 µl, 0.05 mmol) in CD3CN
1
at rt as a 75:25 mixture of epimers at C5. Compound 7a: H NMR (CD3CN) δ 10.34 (s, 1H), 7.66 and
7.38 (AA0BB0 system, 4H), 7.62 (dd, 1H, J=1.8 and 5.9 Hz), 7.04 and 6.81 (AB system, 2H, J=9.4 Hz),
6.64 (dd, 1H, J=1.8 and 2.4 Hz), 6.31 (dd, 1H, J=2.4 and 5.3 Hz), 2.41 (s, 3H), 0.09 (s, 9H). Compound
8a: 1H NMR (CD3CN) δ 10.26 (s, 1H), 7.72 (dd, 1H, J=1.8 and 5.9 Hz), 7.57 and 7.40 (AA0BB0 system,
4H), 6.95 and 6.80 (AB system, 2H, J=9.4 Hz), 6.58 (dd, 1H, J=1.8 and 2.4 Hz), 6.18 (dd, 1H, J=2.4
and 5.3 Hz), 2.38 (s, 3H), 0.29 (s, 9H); EI-MS (from the mixture of 7a and 8a) m/z (%) 402 (M+, 2), 346
(6), 330 (100), 314 (14), 185 (21), 267 (40), 248 (42), 194 (24), 139 (31), 123 (29), 108 (43), 91 (87), 77
(34).
4.4. (5R,SS)- and (5S,SS)-5-[3,6-Dihydroxy-2-(p-tolylsulfinylphenyl)]furan-2(5H)-one 9a and 10a
To a solution of (SS)-2-(p-tolylsulfinyl)-1,4-benzoquinone 2a (25 mg, 0.1 mmol) in dry CH2Cl2 (5 ml),
2-trimethylsilyloxyfuran 1 (20 µl, 0.12 mmol) was added. The mixture was stirred at rt for 15 min and 5
ml of 10% HCl were added. After workup, compounds 9a and 10a were obtained as an 80:20 mixture of
1
epimers at C5. These compounds were also detected by H NMR after mixing (SS)-2-(p-tolylsulfinyl)-
1,4-benzoquinone 2a (10.8 mg, 0.04 mmol) and 2-trimethylsilyloxyfuran 1 (8.1 µl, 0.05 mmol) in CDCl3
at rt as a 85:15 mixture. Compound 9a: 1H NMR δ 10.43 (s, 1H), 7.72 and 7.31 (AA0BB0 system, 4H),
7.52 (dd, 1H, J=1.8 and 5.9 Hz), 6.92 and 6.79 (AB system, 2H, J=8.8 Hz), 6.64 (dd, 1H, J=1.6 and 2.3
Hz), 6.31 (dd, 1H, J=2.3 and 5.7 Hz), 2.39 (s, 3H). Compound 10a: 1H NMR δ 10.14 (s, 1H), 7.65 (dd,
1H, J=1.6 and 5.7 Hz), 7.56 and 7.31 (AA0BB0 system, 4H), 6.92 and 6.79 (AB system, 2H, J=9.4 Hz),

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6.59 (dd, 1H, J=1.6 and 2.3 Hz), 6.17 (dd, 1H, J=2.3 and 5.7 Hz), 2.39 (s, 3H); EI-MS (from the mixture
of 9a and 10a) m/z (%) 330 (M+, 100), 314 (14), 285 (21), 267 (37), 194 (20), 139 (16), 123 (18).
4.5. (3aS,8bS,SS)-3a,8b-Dihydro-7-hydroxy-8-(20 -methoxy-1-naphthylsulfinyl)furo[3,2-b]benzofuran-
2(3H)-one 3a
To a solution of (SS)-2-(p-tolylsulfinyl)-1,4-benzoquinone 2a (50 mg, 0.20 mmol) in dry CH2Cl2
(5 ml) cooled to −78°C, 2-trimethylsilyloxyfuran 1 (38 µl, 0.22 mmol) was added under argon. The
mixture was stirred at −78°C for 30 min and the solvent evaporated under reduced pressure. After flash
chromatography (eluent CH2Cl2:acetone 40:1), compound (−)-3a was isolated diastereoisomerically
pure in 69% yield: [α]20=−268 (c 0.41, CH2Cl2) [(lit.7 [α]20=−240 (c 0.34, CH2Cl2)].
D
D
4.6. (3aR,8bR,SS)-3a,8b-Dihydro-7-hydroxy-8-(p-tolylsulfinyl)furo[3,2-b]benzofuran-2(3H)-one 4a
Compound (+)-4a was obtained diastereoisomerically pure as above in 13% yield: [α]20=+4.8 (c 0.30,
D
CH2Cl2) [(lit.7 [α]20=+4.2 (c 0.24, CH2Cl2)].
D
4.7. (SS)-1,4-Dimethoxy-2-(20-methoxynaphthylsulfinyl)benzene 11
To a solution of 2.4 M n-BuLi (4.2 ml, 10 mmol) in dry THF (20 ml), 1,4-dimethoxybenzene (1.37 g,
9.9 mmol) in dry THF (20 ml) was added dropwise at rt under argon. The mixture was stirred for 1 h,
cooled to −78°C and then added via cannula to a precooled (−78°C) and vigorously stirred solution of (−)-
(SS)-menthyl-2-methoxy-1-naphthalenesulfinate15 (3.0 g, 10.2 mmol) in dry THF (50 ml). The mixture
was stirred at −78°C for 2 h and quenched with water (200 ml). After workup and crystallization, pure 11
was obtained as a white solid in 60% yield: mp 165–167°C; [α]20=+327 (c 1, CHCl3); 1H NMR δ 8.67
D
(dd, 1H, J=1.1 and 8.6 Hz), 7.92 (d, 1H, J=9.1 Hz), 7.79 (dd, 1H, J=1.1 and 8.1 Hz), 7.75 (d, 1H, J=3.2
Hz), 7.54 (dt, 1H, J=1.1 and 8.1 Hz), 7.37 (dt, 1H, J=1.1 and 8.1 Hz), 7.21 (d, 1H, J=9.1 Hz), 6.87 (dd,
1H, J=3.2 and 8.6 Hz), 6.66 (d, 1H, J=9.1 Hz), 3.90, 3.87 and 3.32 (3s, 9H); 13C NMR δ 157.6, 153.9,
149.2, 134.3, 132.3, 128.7, 128.3, 127.50, 124.1, 123.2, 117.0, 113.7, 112.3, 111.7, 56.5, 56.0, 55.8; IR
νmax 1620, 1590, 1510, 1480, 1460, 1435, 1380, 1350, 1275, 1150, 1140, 1090, 910, 810, 710. Anal.
calcd for C19H18O4S: C, 65.65; H, 5.30; S, 9.35. Found: C, 65.67; H, 5.01; S, 9.15.
4.8. (SS)-2-(20-Methoxynaphthylsulfinyl)-1,4-benzoquinone 2b
To a solution of (+)-11 (752 mg, 2.2 mmol) in CH3CN (50 ml), ammonium cerium (IV) nitrate (5.5 g,
10 mmol) in H2O (150 ml) was added at rt. After stirring for 1 h, workup and crystallization (ethyl ether),
pure 2b was obtained as an orange solid in 90% yield: mp 102–103°C; [α]20=+960 (c 0.1, CHCl3); 1H
D
NMR δ 8.52 (d, 1H, J=8.1 Hz), 8.00 (d, 1H, J=8.9 Hz), 7.81 (d, 1H, J=8.1 Hz), 7.64 (dt, 1H, J=1.2 and
8.1 Hz), 7.59 (d, 1H, J=2.8 Hz), 7.44 (dt, 1H, J=1.2 and 8.1 Hz), 7.27 (d, 1H, J=8.9 Hz), 6.79 (dd, 1H,
J=2.8 and 10.1 Hz), 6.63 (d, 1H, J=10.1 Hz), 4.00 (s, 3H, OCH3); 13C NMR δ 185.0, 183.30, 158.3,
153.0, 136.9, 136.3, 134.0, 132.2, 128.8, 128.6, 128.50, 124.5, 122.5, 113.4, 56.6; IR νmax 1655, 1585,
1500, 1465, 1315, 1270, 1215, 1130, 1070, 980, 810, 720, 670. Anal. calcd for C17H12O4S: C, 65.37; H,
3.87; S, 10.26. Found: C, 65.02; H, 4.14; S, 9.99.

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4.9. (5R,SS)- and (5S,SS)-5-[3-Hydroxy-6-trimethylsilyloxy-2-(20 -methoxynaphthylsulfinyl)phenyl]-
furan-2(5H)-one 7b and 8b
These compounds were detected by 1H NMR monitoring after mixing (SS)-2-(20-
methoxynaphthylsulfinyl)-1,4-benzoquinone 2b (11.0 mg, 0.03 mmol) and 2-trimethylsilyloxyfuran 1
1
(6.5 µl, 0.04 mmol) in CD3CN at rt as a 80:20 mixture of epimers at C5. Compound 7b: H NMR
(CD3CN) δ 11.13 (s, 1H), 8.6–7.4 (m, 6H), 6.9–6.7 (m, 2H), 5.93 (dd, 1H, J=1.8 and 2.3 Hz), 5.78 (dd,
1H, J=2.3 and 5.9 Hz), 5.63 (dd, 1H, J=1.8 and 5.9 Hz), 3.90 (s, 3H), 0.08 (s, 9H). Compound 8b: 1H
NMR (CD3CN) δ 11.27 (s, 1H), 8.7–7.4 (m, 6H), 6.9–6.7 (m, 2H), 6.12 (dd, 1H, J=1.8 and 5.9 Hz),
5.97 (dd, 1H, J=2.3 and 5.9 Hz), 5.86 (dd, 1H, J=1.8 and 2.3 Hz), 3.95 (s, 3H), 0.29 (s, 9H).
4.10. (5R,SS)- and (5S,SS)-5-[3,6-Dihydroxy-2-(20 -methoxynaphthylsulfinyl)phenyl]furan-2(5H)-one
9b and 10b
To a solution of (SS)-2-(20-methoxynaphthylsulfinyl)-1,4-benzoquinone 2b (30.8 mg, 0.10 mmol) in
dry CH2Cl2 (5 ml), 2-trimethylsilyloxyfuran 1 (16.25 µl, 0.11 mmol) was added. The mixture was stirred
at rt for 1 h and 5 ml of 10% HCl were added. After workup, compounds 9b and 10b were obtained
1
as a 85:15 mixture of epimers at C5. These compounds were also detected by H NMR monitoring
after mixing (SS)-2-(20-methoxynaphthylsulfinyl)-1,4-benzoquinone 2b (11.0 mg, 0.03 mmol) and 2-
trimethylsilyloxyfuran 1 (6.5 µl, 0.04 mmol) in CDCl3 at rt as a 90:10 mixture. Compound 9b: 1H NMR
δ 11.10 (s, 1H), 8.6–7.2 (m, 6H), 6.72 and 6.66 (AB system, 2H, J=9.2 Hz), 5.92 (dd, 1H, J=1.6 and 2.1
Hz), 5.73 (dd, 1H, J=2.1 and 5.4 Hz), 5.34 (dd, 1H, J=1.6 and 5.4 Hz), 3.90 (s, 3H). Compound 10b: 1H
NMR δ 11.18 (s, 1H), 8.6–7.2 (m, 6H), 6.79 and 6.73 (AB system, 2H, J=9.2 Hz), 6.15 (dd, 1H, J=1.8
and 5.4 Hz), 5.98 (dd, 1H, J=2.1 and 5.4 Hz), 5.84 (dd, 1H, J=1.8 and 2.1 Hz), 3.85 (s, 3H).
4.11. (3aS,8bS,SS)-3a,8b-Dihydro-7-hydroxy-8-(20 -methoxy-1-naphthylsulfinyl)furo[3,2-b]benzofuran-
2(3H)-one 3b
To a solution of (SS)-2-(20-methoxynaphthylsulfinyl)-1,4-benzoquinone 2b (154 mg, 0.5 mmol) in dry
CHCl3 (10 ml) cooled to −20°C, 2-trimethylsilyloxyfuran 1 (80 µl, 0.55 mmol) was added under argon.
The mixture was stirred at −20°C for 4 h and the solvent evaporated under reduced pressure. After flash
chromatography (eluent CH2Cl2:acetone 20:1), compound (+)-3b was isolated diastereoisomerically
20
1
pure as an oil in 82% yield: [α] =+62 (c 1.5, CHCl3); H NMR δ 10.70 (s, 1H), 8.66. (d, 1H, J=8.2
D
Hz), 8.09 (d, 1H, J=8.8 Hz), 7.86 (d, 1H, J=8.2 Hz), 7.69 (dt, 1H, J=8.2 and 1.2 Hz), 7.47 (dt, 1H, J=8.2
and 1.2 Hz), 7.34 (d, 1H, J=8.8 Hz), 6.91 and 6.78 (AB system, 2H, J=8.8 Hz), 5.06 (d, 1H, J=6.4 Hz),
4.95 (m, 1H), 4.00 (s, 3H), 2.84 (m, 2H); 13C NMR δ 174.1, 158.6, 156.3, 153.5, 136.2, 132.8, 132.6,
129.7, 128.8, 128.3, 124.8, 122.7, 121.5, 117.7, 117.2, 113.9, 113.5, 81.7, 81.0, 56.3, 34.9; IR νmax 3650,
3000, 2910, 1780, 1595, 1460, 1300, 1160, 1140, 1105. Anal. calcd for C21H16O6S: C, 63.63; H, 4.07;
S, 8.09. Found: C, 63.50; H, 4.08; S, 7.95.
4.12. (3aR,8bR,SS)-3a,8b-Dihydro-7-hydroxy-8-(20 -methoxy-1-naphthylsulfinyl)furo[3,2-b]benzo-
furan-2(3H)-one 4b
Compound (+)-4b was obtained diastereoisomerically pure as above in 8% yield: [α]20=+267 (c 0.6,
D
1
CHCl3); H NMR δ 10.82 (s, 1H), 8.57 (d, 1H, J=8.2 Hz), 8.12 (d, 1H, J=9.4 Hz), 7.87 (d, 1H, J=8.2
Hz), 7.60 (dt, 1H, J=8.2 and 1.2 Hz), 7.40 (dt, 1H, J=8.2 and 1.2 Hz), 7.31 (d, 1H, J=9.4 Hz), 6.92 and

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M. C. Carreño et al. / Tetrahedron: Asymmetry 10 (1999) 4357–4367
6.80 (AB system, 2H, J=8.8 Hz), 5.49 (d, 1H, J=5.9 Hz), 5.14 (m, 1H), 3.97 (s, 3H), 2.67 (m, 2H); 13
C
NMR δ 173.1, 158.9, 155.9, 154.1, 136.9, 132.4, 129.3, 128.9, 128.8, 124.3, 122.7, 121.7, 121.2, 118.2,
117.5, 113.9, 113.1, 81.7, 81.1, 56.3, 34.9. Anal. calcd for C21H16O6S: C, 63.63; H, 4.07; S, 8.09. Found:
C, 63.78; H, 4.15; S, 8.23.
4.13. 2-(tert-Butylthio)-1,4-benzoquinone 12
To a suspension of 1,4-benzoquinone (2.36 g, 21.8 mmol) in EtOH (35 ml), 1,1-dimethylethanethiol
(1.23 ml, 10.9 mmol) was added at rt. After stirring for 4 h and evaporation of the solvent, the residue
was purified by flash chromatography (eluent hexane:EtOAc 85:15) to afford pure 12 as a red solid in
1
50% yield: mp 64–65°C (ethyl ether/hexane); H NMR δ 6.8–6.6 (m, 3H), 1.53 (s, 9H); 13C NMR δ
184.4, 184.2, 150.9, 136.9, 136.6, 128.2, 46.5, 30.0 (3C); EI-MS m/z (%) 196 (M+, 11), 174 (10), 142
(25), 57 (100); HRMS (EI) calcd for C10H12O2S 196.05580, found 196.05568.
4.14. (SS*)-2-(tert-Butylsulfinyl)-1,4-benzoquinone 2c
To a solution of thioether 12 (100 mg, 0.5 mmol) in CH2Cl2 (5 ml) cooled at 0°C, m-CPBA (150 mg,
0.5 mmol) in CH2Cl2 (5 ml) was added. The mixture was stirred at 0°C for 1 h and treated with saturated
aqueous solution of NaHCO3. After workup and crystallization (CH2Cl2:hexane), pure 2c was obtained
as an orange solid in 93% yield: mp 139–140°C; 1H NMR δ 7.28 (d, 1H, J=1.7 Hz), 6.87 (dd, 1H, J=1.7
and 9.5 Hz), 6.84 (d, 1H, J=9.5 Hz), 1.26 (s, 9H); 13C NMR δ 184.6, 184.4, 152.9, 137.5, 136.9, 136.7,
52.1, 23.6 (3C); EI-MS m/z (%) 212 (M+, 1), 158 (21), 140 (15), 112 (24), 57 (100); HRMS (EI) calcd
for C10H12O3S 212.05072, found 212.05058.
4.15. (3aS*,8bS*,SS*)-3a,8b-Dihydro-7-hydroxy-8-(tert-butylsulfinyl)furo[3,2-b]benzofuran-
2(3H)-one 3c
To a solution of 2-(tert-butylsulfinyl)-1,4-benzoquinone 2c (28 mg, 0.13 mmol) in dry CHCl3 (5 ml)
cooled to −20°C, 2-trimethylsilyloxyfuran (1) (24 µl, 0.14 mmol) was added under argon. The mixture
was stirred at −20°C for 1 h and the solvent evaporated under reduced pressure. The residue was purified
by flash chromatography (eluent hexane:EtOAc 50:50) to obtain diastereoisomerically pure 3c as a white
solid in 52% yield: mp 168–169°C; 1H NMR δ 10.50 (s, 1H), 6.90 and 6.89 (AB system, 2H, J=9.0 Hz),
5.94 (d, 1H, J=5.9 Hz), 5.32 (dt, 1H, J=5.9 and 3.2 Hz), 4.00 (s, 3H), 2.98 (m, 2H), 1.38 (s, 9H); 13C
NMR δ 174.1, 157.6, 154.1, 124.3, 121.1, 116.1, 114.6, 83.2, 81.7, 61.0, 34.5, 23.6 (3C); EI-MS m/z (%)
296 (M+, 2), 240 (42), 224 (31), 194 (100), 179 (32), 149 (32), 84 (16), 69 (10), 57 (81); HRMS (EI)
calcd for C14H16O5S 296.07185, found 296.07120.
Acknowledgements
We thank Dirección General de Investigación Científica y Técnica (Grants PB95-0174 and PB96-0035)
for financial support.
References
1. Sotheeswaran, S.; Pasupathy, V. Phytochemistry 1993, 32, 1083–1092.
2. (a) Engler, T. A.; Combrink, K. D.; Letavic, M. A.; Lynch Jr., K. O.; Ray, J. E. J. Org. Chem. 1994, 59, 6567–6587. (b)
Engler, T. A.; Wei, D.; Letavic, M. A.; Combrink, K. D.; Reddy, J. P. J. Org. Chem. 1994, 59, 6588–6599. (c) Engler, T. A.;

M. C. Carreño et al. / Tetrahedron: Asymmetry 10 (1999) 4357–4367
4367
Gfesser, G. A.; Draney, B. W. J. Org. Chem. 1995, 60, 3700–3706. (d) Engler, T. A.; Iyengar, R. J. Org. Chem. 1998, 63,
1929–1934. (e) Engler, T. A.; Letavic, M. A.; Iyengar, R.; LaTessa, K. O.; Reddy, J. P. J. Org. Chem. 1999, 64, 2391–2405.
3. (a) Bird, C. W.; Brown, A. L.; Chan, C. C.; Lewis, A. Tetrahedron Lett. 1989, 30, 6223–6226. (b) Fariña, F.; Paredes,
M. C.; Valderrama, J. Synth. Commun. 1989, 19, 3301–3312. (c) Kraus, G. A.; Shi, J.; Reynolds, D. J. Org. Chem. 1990,
55, 1105–1106. (d) Fariña, F.; Paredes, M. C.; Valderrama, J. J. Chem. Soc., Perkin Trans. 1 1990, 48, 2345–2346. (e)
Rupprecht, K. M.; Boger, J.; Hoogsteen, K.; Nachbar R. B.; Springer, J. P. J. Org. Chem. 1991, 56, 6180–6188. (f) Fariña,
F.; Paredes, M. C.; Valderrama, J. Tetrahedron 1992, 48, 4629–4640.
4. Brimble, M. A.; Elliot, R. J. R. Tetrahedron 1997, 53, 7715–7730 and references cited therein.
5. (a) Brimble, M. A.; Duncalf, L. J.; Reid, D. C. W.; Roberts, T. R. Tetrahedron 1998, 6, 5363–5374. (b) Brimble, M. A.;
McEwan, J. F.; Turner, P. Tetrahedron: Asymmetry 1998, 9, 1257–1267.
6. Brimble, M. A.; McEwan, J. F. Tetrahedron: Asymmetry 1997, 8, 4069–4078.
7. Brimble, M. A.; Duncalf, L. J.; Reid, D. C. W. Tetrahedron: Asymmetry 1995, 6, 263–269.
8. For an overview of our work, see: (a) Carreño, M. C. Chem. Rev. 1995, 95, 1717–1760. For more recent references, see:
(b) Carreño, M. C.; García Ruano, J. L.; Toledo, M. A.; Urbano, A.; Remor, C. Z.; Stefani, V.; Fischer, J. J. Org. Chem.
1996, 61, 503–509. (c) Carreño, M. C.; Urbano, A.; Fischer, J. Angew. Chem., Int. Ed. Engl. 1997, 36, 1621–1623. (d)
Carreño, M. C.; Urbano, A.; Di Vitta, C. J. Org. Chem. 1998, 63, 8320–8330. (e) Carreño, M. C.; Hérnandez-Sánchez, R.;
Mahugo, J.; Urbano, A. J. Org. Chem. 1999, 64, 1387–1390. (f) Carreño, M. C.; Urbano, A.; Di Vitta, C. Chem. Commun.
1999, 817–818.
9. Carreño, M. C.; García Ruano, J. L.; Urbano, A. Synthesis 1992, 651–653.
10. The absolute configuration of 3a and 4a had been established previously (see Ref. 7).
11. Kahn, S. D.; Here, W. J. J. Am. Chem. Soc. 1986, 108, 7399–7400.
12. Higher reactivity had been evidenced for the s-cis conformer in Michael additions of vinyl sulfoxides (see Ref. 11) and
Diels–Alder reactions of sulfinyl quinones (see Ref. 8).
13. Andersen, K. K.; Gafield, W.; Papanicolaou, N. E.; Foley, J. W.; Perkins, R. I. J. Am. Chem. Soc. 1964, 86, 5637–5646.
14. Pyne, S. G.; Hajipour, A. R.; Prabakaran, K. Tetrahedron Lett. 1994, 35, 645–648.
15. Snell, J. M.; Weissberger, A. J. Am. Chem. Soc. 1939, 61, 450.
16. The presence of this hydrogen bonding was evident from the H NMR spectra of 3b and 4b, where the phenolic proton
1
appears very deshielded at 10.70 and 10.82 ppm, respectively.
17. This NOE experiment was performed in CDCl3 at 500 MHz.