Diels-Alder reactions of masked p-benzoquinones

Article abstract of DOI:10.1016/S0040-4020(00)00276-3

Phenylthiomonoketal 3 works effectively as masked p-benzoquinone in Diels-Alder reactions. These cycloadditions may be performed with certain Lewis acid catalysts and give rise exclusively to endo adducts with a good to excellent anti-facial selectivity. 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00276-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3603±3609
Diels±Alder Reactions of Masked p-Benzoquinones
*
Pedro de March, Marta Figueredo, Josep Font and Sonia Rodrõguez
Â
 Á
Departament de Quõmica, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain
Received 26 November 1999; revised 13 March 2000; accepted 30 March 2000
AbstractÐPhenylthiomonoketal 3 works effectively as masked p-benzoquinone in Diels±Alder reactions. These cycloadditions may be
performed with certain Lewis acid catalysts and give rise exclusively to endo adducts with a good to excellent anti-facial selectivity. q 2000
Elsevier Science Ltd. All rights reserved.
Introduction
several antibiotics of the manumycin family,3,4b,5 bromoxone,6
and aranorosin,7 among others. All these compounds
contain in their skeleton a highly functionalized cyclohex-
enone, as is also the case for 2. In fact, we have tested the
bio-activity of several compounds 1, 2 and derivatives of
both2,8 and many of them present antituberculous activity.9
p-Benzoquinone and its derivatives have been widely used
in synthetic organic chemistry.1 One particular feature of
p-benzoquinone is its high symmetry. Although in some
circumstances this characteristic may be an advantage, in
most cases di-reaction can take place with consequent
formation of product mixtures. Focusing our attention on
this problem, we have recently prepared several compounds
with general structures 1 and 2 (Scheme 1), which are
synthetic equivalents of p-benzoquinone, having respec-
tively one or both pairs of the originally identical functional
groups differentiated.2
Recently, we have demonstrated the utility of compounds of
type 2 as masked p-benzoquinone in 1,3-dipolar cyclo-
additions to nitrones.2b,8 As a continuation of this work,
and considering that p-benzoquinone and its derivatives
have been used extensively in Diels±Alder reactions,10 we
decided to investigate the reactivity of 2 as dienophiles. We
planned to use the strategy shown in Scheme 1, analogous to
that previously developed for the cycloaddition to nitrones,
consisting of masking one of each pair of equivalent func-
tional groups of p-benzoquinone, and unmasking them after
the cycloaddition.
Monoketals of p-benzoquinone have acquired relevant
importance because they have been used as starting materials
for the synthesis of a wide range of bio-active natural
products, including the antitumor antibiotic LL-C10037a,3,4
Scheme 1.
Keywords: benzoquinones; Diels±Alder; acetals; stereocontrol.
* Corresponding author. Tel.: 134-935-811-258; fax: 134-935-811-265; e-mail: pere.demarch@uab.es
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00276-3

3604
P. de March et al. / Tetrahedron 56 (2000) 3603±3609
There are only a few precedents of Diels±Alder reactions
with p-benzoquinone monoketals but none of these mono-
ketals are chiral.11 Diastereoselective Diels±Alder reactions
using other kinds of enantiopure p-benzoquinone equiva-
lents have been reported,12 and there is also a work descri-
bing enantiopure p-benzoquinone adducts derived from
chiral cyclopentadienes.11f
Results and Discussion
We investigated the reaction of racemic ketal 3, which is
also available in enantiopure form for both antipodes,2b,c
with dienes 4, 5 and 6 under different experimental con-
ditions of temperature and Lewis acid catalysts (Table 1,
1
Scheme 2). The reactions were controlled by H NMR
analysis of aliquots and were quenched when all the ketal
3 was consumed or the reaction mixture did not evolve
further.
Our ®nal goal was to prepare new compounds containing the
1,4-dioxaspiro[4,5]decan-2-one bicyclic system due to their
bioactivity and to explore an alternative access to Diels±
Alder adducts of p-benzoquinone derivatives in enantiopure
form. The results are described herein.
Compounds 3 and 4 did not react in the absence of Lewis
acids (entry 1) and dimerization of the diene was exclusively
Table 1. Cycloadditions between ketal 3 and dienes 4±6
Entry
Diene
Lewis acid
Conditions
Yield (%)
Adducts
Ratio
1
2
3
4
5
6
7
8
4
4
4
4
4
4
5
5
5
6
6
6
±
CH2Cl2, 608C, 4 h
CH2Cl2, 2428C, 9 h
CH2Cl2, 258C, 8 days
CH2Cl2, 258C, 5 h
Toluene, 258C, 8 days
±, 258C, 7 days
±
±
±
±
±
±
±
±
±
10:1
33:1
88:1
±
BF3´Et2O
Et2AlCl
AlCl3
TiCl4
SiO2
±
SiO2
AlCl3
±
61
47a
92
±
7/8
7/8
7/8
±
9/10
9/10
11/12/13
±
±, 1808C, 18 h
±, 258C, 5 months
CH2Cl2, 258C, 30 days
1008C, 7 days
CH2Cl2, 258C, 5 h
CH2Cl2, 258C, 5 h
64a
69
96
±
2:1a
5:1
1:11:20
±
9
10
11
12
SiO2
AlCl3
±
±
±
a Determined by 1H NMR analysis.
Scheme 2.

P. de March et al. / Tetrahedron 56 (2000) 3603±3609
3605
Scheme 3.
observed. The addition of BF3´Et2O and Et2AlCl to the
reaction medium (entries 2 and 3) promoted only the
decomposition of 3, but AlCl3, TiCl4, and SiO2 (entries 4±
6) catalysed the Diels±Alder reaction and the cycloadducts
7, endo-anti, and 8, endo-syn, were isolated with a pre-
dominance of the anti-isomer in all the cases (Scheme 2).
The best yield and diastereoselectivity was obtained with
SiO2 without solvent.
The uncatalysed reaction of ketal 3 with the silyl diene 6,
using the diene as solvent (entry 10) gave a mixture of three
cycloaddition products 11, 12 and 13, which were isolated
in 3, 33 and 60% yield, respectively, after column chroma-
tography through silica gel. The high instability of the silyl
cycloadducts 11 and 12 explains the predominance of the
hydroxyketone 13 after chromatographic puri®cation. In
the presence of SiO2 or AlCl3 (entries 11 and 12) no
cycloadducts were detected. Comparison of the signi®cant
chemical shifts and coupling constant values of 11±13 with
those of 9 indicates that they all derive from an anti-
approach and present the same preferred conformation.
With the help of two-dimensional NMR spectra and nOe
experiments all the proton and carbon signals of 7 could be
0
assigned. The ole®nic protons H3 and H2 appear as double
0
0
doublets (dd) at d 6.16 and 6.08, respectively, H6 as a
0
For the major product 13 a positive nOe observed on H6
0
when H4 was irradiated corroborates this assumption. The
0
0
double doublet at d 3.43, and protons H4a and H8a as dd
at d 2.85 and 3.02, respectively. Comparison of the values
0
measured J1 ,8a values of 0, 5.5 and 5.1 Hz in 11, 12 and 13,
0
0
0
0
0
0
0
of the coupling constants J1 ,8a ˆ4.4 Hz, J4 ,4a ˆ2.9 Hz, and
respectively, show that H1 and H8a are trans in 11 and cis in
12 and 13 (vide supra). Since commercial diene 6 contains
small amounts of the cis isomer, we cannot be sure whether
11 derives from an exo-anti transition state of trans-6 or
from an endo-anti approach of cis-6. We assume an endo-
anti transition state of trans-6 for the major adducts 12 and
13.
J4a ,8a ˆ10.2 Hz with literature data,13 shows that the major
adduct 7 derives from an endo transition state. This stereo-
chemistry is corroborated by the high nOe observed
0
0
0
0
between H6 and H3 , which also indicates that 7 derives
from an anti-facial approach. The minor adduct 8 is also
endo, as evidenced by the value of its diagnostic coupling
constants, very similar to those of 7; hence by exclusion 8
should educe from a syn-approach of the reactants.
As a summary of the above experiments, we concluded that
in the Diels±Alder reactions of ketal 3 the thiophenyl group
exerts good control of the facial diastereoselectivity and that
the cycloaddition may be catalysed by several Lewis acids
without decomposition of the ketal 3.
As expected, the uncatalysed reaction between ketal 3 and
the less reactive dimethylbutadiene 5 did not proceed either
(entry 7). For diene 5 the most effective catalyst was AlCl3
(entry 9). In its presence, adducts 9 and 10 were obtained in
58 and 11% yield, respectively. Their stereochemistry was
0
established by nOe. Irradiation of H6 caused enhancement
0
of the signal corresponding to one proton H4 for 9, while no
0
nOe on protons H4 was observed for 10. These experiments
demonstrate that the major isomer 9 results from an anti-
approach of the reactants in the transition state and that the
main conformation is that shown in Scheme 2 with the
thiophenyl group in an equatorial position. The coupling
0
pattern of proton H4a (J values of 12.4, 5.5 and 5.5 Hz) is
consistent with a locked trans-diaxial relationship with one
To test the overall strategy of Scheme 1, we decided to
unmask the functional groups of the original p-benzo-
quinone. With this aim the conversion of cycloadduct 7
into the unmasked equivalent 1410b was undertaken
(Scheme 3). The order of the required deprotections seemed
unimportant and hydrolysis of the ketal was tried ®rst.
Nevertheless, all attempts to hydrolyse 7 under protic acidic
conditions were unsuccessful and the new compound 15
could only be obtained in 30% yield after prolonged
treatment of 7 with ZnBr2. On the contrary, elimination of
thiophenol by treatment of 7 with DBU followed by
hydrolysis of 1611a with 5% HCl proceeded in an overall
92% yield.
0
0
of the protons H4 . In contrast, H8a presents only two
identical coupling constants of 5.8 Hz, and accordingly is
assigned to an equatorial position related to the cyclohexene
ring. A careful analysis of the 1H NMR spectrum allowed us
to infer that cisJ1 ,8a ˆ5.8 Hz and
J
ˆ0 Hz. These data
Next, we intended to apply the optimal cycloaddition con-
ditions to enantiopure (1)-3 and (2)-3. Unfortunately, the
major adduct 7 isolated from the reactions of (1)- and (2)-3
trans
0
0
0
0
1 ,8a
will be helpful for the stereochemical assignment of the
adducts described below.

3606
P. de March et al. / Tetrahedron 56 (2000) 3603±3609
Scheme 4.
with cyclopentadiene in the presence of SiO2 did not present
optical activity. We suspect that racemization of 3 had
occurred under the reaction conditions, probably through
an elimination±addition process.
was allowed to react at room temperature for 7 days. The
silica gel was ®ltered off and washed with methylene
chloride. Flash chromatography of the crude material
(794 mg) using hexane±ethyl acetate (2:1) as eluent
afforded the following fractions: (i) 7 mg (0.02 mmol, 1%
yield) of (10RS,40SR,4a0RS,60SR,8a0SR)-60-phenylthio-10,40,
4a0,60,70,8a0-hexahydrospiro{1,3-dioxolane-2,50(80H)-[10,40]-
methanonaphthalen}-80-one, 8, endo-syn, as a colorless oil;
(ii) 549 mg (1.67 mmol, 88% yield) of its (10RS,
40SR,4a0RS,60RS,8a0SR)-isomer, 7, endo-anti, as a white
solid; and (iii) 16 mg (0.06 mmol, 3%) of 3. 7: mp 80±
828C (AcOEt±hexane); IR (KBr): 3002, 2959, 2889,
As an alternative method of preparing p-benzoquinone
related adducts in enantiopure form, we performed the
cycloaddition of enantiopure ketal 172a with one equivalent
of diene 4 in the presence of SiO2 (Scheme 4). This reaction
was sluggish, but after seven days at room temperature a
mixture of diastereoisomeric cycloadducts 18 and 19 was
obtained in an almost quantitative yield. We assume that 19 is
the major component of the mixture with a ratio close to 2:1.
All attempts to separate these compounds were unsuccessful.
1
1701, 1476, 1307, 1251, 1159, 1061 cm21; H NMR: d
0
7.40±7.30 (m, 2H), 7.25±7.10 (m, 3H), 6.16 (dd, J3 ,2
0
ˆ
0
0
0
0
0
5.9 Hz, J3 ,4 ˆ2.9 Hz, 1H:H3 ), 6.08 (dd, J2 ,3 ˆ5.9 Hz,
J2 ,1 ˆ2.9 Hz, 1H:H2 ), 4.20±4.00 (m, 4H:2H4, 2H5), 3.43
(dd, J6 ,7 ˆ10.2 Hz, J6 ,7 ˆ5.1 Hz, 1H:H6 ), 3.30 (br s,
1H:H1 ), 3.10 (br s, 1H:H4 ), 3.02 (dd, J8a ,4a ˆ10.2 Hz,
J8a ,1 ˆ4.4 Hz, 1H:H8a ), 2.85 (dd, J4a ,8a ˆ10.2 Hz, J4a ,4
0
0
0
In summary, we have demonstrated that the phenylthio-
monoketal 3 works effectively as masked p-benzoquinone
in Diels±Alder reactions. These cycloadditions may be
performed under certain Lewis acid catalysts and give rise
exclusively to endo adducts with good to excellent facial
selectivity. The products may be converted ef®ciently into
the formal cycloadducts of p-benzoquinone, but racemi-
zation of the starting ketal makes this methodology
unsuitable to prepare enantiopure p-benzoquinone related
Diels±Alder adducts. When the origin of chirality is in
the dioxolane ring as in 17 the asymmetric induction is
only moderate. All the new synthesized products present
antituberculous activity and cytotoxicity assays are in
progress.9
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
ˆ
0
0
0
0
0
2.9 Hz, 1H:H4a ), 2.61 (dd, J7 ,7 ˆ17.5 Hz, J7 ,6 ˆ10.2 Hz,
0
0
0
0
0
0
1H:H7 ), 2.49 (dd, J7 ,7 ˆ17.5 Hz, J7 ,6 ˆ5.1 Hz, 1H:H7 ),
13
1.43 (br d, Jˆ8.8 Hz, 1H:CH2), 1.29 (br d, Jˆ8.8 Hz,
0
0
0
1H:CH2); C NMR: d 209.8 (C8 ), 136.2/136.0 (C2 /C3 ),
135.2/131.4/128.9/126.9 (CAr), 109.9 (C2), 66.3/65.0 (C4/
0
C5), 51.8 (C8a ), 49.9 (C6 ), 49.8 (CH2), 48.0 (C4a ), 47.3
0
0
1
0
0
0
(C1 ), 45.5 (C4 ), 45.3 (C7 ); MS (m/z): 328 (M , 21), 219
(49), 153 (28), 126 (100), 99 (23), 98 (58), 91 (32), 66 (30),
65 (22), 55 (29). Anal. Calcd for C19H20O3S: C, 69.49; H,
6.14; S, 9.76. Found: C, 69.45; H, 6.28; S, 9.64. 8: IR (®lm):
3065, 2952, 2924, 2854, 1708, 1476, 1441, 1258, 1202,
1
1181, 1082, 1026 cm21; H NMR: d 7.40±7.30 (m, 2H),
Experimental
0
7.25±7.10 (m, 3H), 6.08 (m, 2H:H3 , H2 ), 4.30±4.00 (m,
0
0
0
0 0
4H:2H4, 2H5), 3.67 (dd, J6 ,7 ˆ13.1 Hz, J6 7 ˆ6.2 Hz,
Ketals 32b,c and 172a were prepared according to previously
described methods. Reaction mixtures were stirred mag-
netically. The organic extracts were dried over anhydrous
magnesium sulfate. Reaction solutions were concentrated
using a rotary evaporator at 15±20 mmHg. Flash column
chromatography was performed using Merck silica gel
(230±400 mesh). Infrared spectra were recorded on a
Nicolet 5 ZDX spectrophotometer. 1H NMR and 13C
NMR spectra were recorded on a Bruker AC-250-WB
instrument in CDCl3 solutions. Mass spectra were
performed on a Hewlett±Packard 5985B instrument at
70 eV; only peaks with higher intensity than 20% are
reported, unless they belong to molecular ions or to signi®-
cant fragments.
0
0
0
0
1H:H6 ), 3.22 (br s, 1H:H1 ), 3.04 (dd, J8a 4a < 11.3 Hz,
0
0
0
0
J8a ,1 <4.0 Hz, 1H:H8a ), 2.98 (br s, 1H:H4 ), 2.90 (dd,
0
0
0
0
0
J4a ,8a ˆ11.3 Hz, J4a ,4 <2.9 Hz, 1H:H4a ), 2.65 (dd,
0
0
0
0
0
0
0
J7 ,7 ˆ18.7 Hz, J7 ,6 ˆ6.2 Hz, 1H:H7 ), 2.35 (dd, J7 ,7
ˆ
0
0
0
18.7 Hz, J7 ,6 ˆ13.1 Hz, 1H:H7 ), 1.43 (br d, Jˆ8.4 Hz,
1H:CH2), 1.27 (br d, Jˆ8.4 Hz, 1H:CH2); HRMS (EI)
(M1) calcd for C19H20O3S 328.1133, found 328.1148.
AlCl3 as Lewis acid. A mixture of 3 (49 mg, 0.19 mmol)
and AlCl3 (11 mg, 0.08 mmol) in anhydrous methylene
chloride (1.5 mL) under nitrogen atmosphere was stirred
for 10 min. Cyclopentadiene (33 mL, 0.40 mmol) was
added and the reaction mixture was allowed to react at
room temperature for 5 h. The mixture was washed with
saturated NaHCO3 solution, neutralized with aqueous 5%
HCl and washed with water. Flash chromatography of the
crude material (51 mg) using hexane±ethyl acetate (2:1) as
eluent afforded 37 mg of a 10:1 mixture of 7 and 8 (61%
yield) as a white solid.
Reactions between ketal 3 and diene 4
SiO2 as Lewis acid. A mixture of 3 (500 mg, 1.91 mmol),
cyclopentadiene (630 mL, 7.62 mmol), and silica gel (5.0 g)

P. de March et al. / Tetrahedron 56 (2000) 3603±3609
3607
TiCl4 as Lewis acid. Toluene (1 mL), 3 (50 mg, 0.19
mmol), and TiCl4 (1 mL of a 0.08 M solution in toluene,
0.08 mmol) were introduced in a 5 mL Schlenk reactor at
2788C. The mixture was stirred at room temperature for
15 min, 4 (32 mL, 0.39 mmol) was added, and the mixture
was maintained at the same temperature for 8 days. H
NMR analysis revealed the formation of only 47% of a
33:1 mixture of 7 and 8, along with unreacted 3.
5 months. 1H NMR analysis revealed the formation of only
64% of a mixture ca 2:1 of 9 and 10, along with unreacted 3.
Reaction between ketal 3 and diene 6
1
In a sealed reactor, a mixture of 3 (528 mg, 2.01 mmol) and
6 (3.50 mL, 19.55 mmol) was allowed to react at 1008C for
7 days. Flash chromatography of the crude material (2.97 g)
using hexane±ethyl acetate (4:1) as eluent afforded the
following fractions: (i) 23 mg (0.06 mmol, 3% yield) of
(10RS,4a0RS,60RS,8a0RS)-10-trimethylsilyloxy-60-phenylthio-
10,40,4a0,60,70,8a0-hexahydrospiro[1,3-dioxolane-2,50(80H)-
naphthalen]-80-one, 11, as a colorless oil; (ii) 267 mg
(0.66 mmol, 33% yield) of its (10RS,4a0SR,60SR,8a0SR)-
isomer, 12, as a colorless oil; and (iii) 401 mg (1.21
mmol, 60% yield) of (10RS,4a0SR,60SR,8a0SR)-10-hydroxy-
60-phenylthio-10,40,4a0,60,70,8a0-hexahydrospiro[1,3-dioxo-
lane-2,50(80H)-naphthalen]-80-one, 13. 11: IR (®lm): 3037,
Reactions between ketal 3 and diene 5
AlCl3 as Lewis acid. A mixture of 3 (100 mg, 0.38 mmol)
and AlCl3 (31 mg, 0.23 mmol) in anhydrous methylene
chloride (3 mL) was stirred for 30 min under nitrogen
atmosphere. Butadiene 5 (150 mL, 1.33 mmol) was added
and the reaction mixture was allowed to react at room
temperature for 30 days. The mixture was washed with
saturated NaHCO3 solution, neutralized with aqueous 5%
HCl and washed with water. Flash chromatography of the
crude material (159 mg) using hexane±ethyl acetate (4:1) as
eluent afforded the following fractions: (i) 51 mg
(0.15 mmol, 39% yield) of (4a0RS,60RS,8a0SR)-20,30-
dimethyl-60-phenylthio-10,40,4a0,60,70,8a0-hexahydrospiro-
[1,3-dioxolane-2,50(80H)-naphthalen]-80-one, 9, anti, as a
white solid; (ii) 10 mg (0.03 mmol, 8% yield) of its
(4a0RS,60SR,8a0SR)-isomer, 10, syn, as a yellow oil; and
(iii) 31 mg (0.12 mmol, 31%) of 3. With respect to
recovered 3, adducts 9 and 10 are isolated in 58 and 11%
yield, respectively. 9: 114±1178C (AcOEt±hexane); IR
(KBr): 2966, 2910, 1715, 1581, 1476, 1441, 1370, 1138,
1
2959, 2924, 1722, 1258, 1145, 1124, 1054, 1019 cm21; H
NMR: d 7.40±7.30 (m, 2H), 7.25±7.05 (m, 3H), 5.70±5.50
0
0
0
0
0
(m, 2H:H2 , H3 ), 4.45 (d, J1 ,2 ˆ4.0 Hz, 1H:H1 ), 4.30±3.90
(m, 4H:2H4, 2H5), 3.62 (dd, J6 ,7 ˆ13.2 Hz, J6 ,7 ˆ5.8 Hz,
1H:H6 ), 2.99 (br d, J8a ,4a ˆ5.5 Hz, 1H:H8a ), 2.70 (td,
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
J7 ,7 ˆJ7 ,6 ˆ13.2 Hz, J7 ,8a ˆ1.1 Hz, 1H:H7 ), 2.55 (dd,
0
0
0
0
0
0
0
0
0
J7 ,7 ˆ13.2 Hz, J7 ,6 ˆ5.8 Hz, 1H:H7 ), 2.45 (dt, J4a ,4
ˆ
ˆ
ˆ
0
0
0
0
0
0
12.4 Hz, J4a ,4 ˆJ4a ,8a ˆ5.5 Hz, 1H:H4a ), 2.21 (dt, J4 ,4
0
0
0
0
0
0
18.6 Hz, J4 ,3 <J4 ,4a <5.0 Hz, 1H:H4 ), 1.54 (br dd, J4 ,4
18.6 Hz, J4 ,4a ˆ12.4 Hz, 1H:H4 ), 0.00 (s, 9H:3CH3); 13C
0
0
0
0
NMR: d 207.0 (C8 ), 135.0/132.0/129.0 (CAr), 127.6/
0
127.2/127.0 (CAr/C2 /C3 ), 109.6 (C2), 66.2/66.0 (C4/C5),
0
0
0
0
0
0
0
62.0 (C1 ), 53.2/52.7/46.5/38.7/24.5 (C4 /C4a /C6 /C7 /C8a ),
0.0 (CH3); HRMS (EI) (M1) calcd for C21H28O4SSi
404.1478, found 404.1484. 12: IR (®lm): 3030, 2959,
1
1120, 1047, 745 cm21; H NMR: d 7.45±7.35 (m, 2H),
7.25±7.10 (m, 3H), 4.36±4.26 (m, 2H:2H4/2H5), 4.14±
0
2924, 2854, 1708, 1258, 1145, 1117, 1047, 1019 cm21; H
1
0
0
0
4.03 (m, 2H:2H4/2H5), 3.78 (dd, J6 ,7 ˆ12.4 Hz, J6 ,7
ˆ
0
0
6.6 Hz, 1H:H6 ), 3.08 (br t, J<5.8 Hz, 1H:H8a ), 2.76 (t,
NMR: d 7.40±7.28 (m, 2H), 7.22±7.05 (m, 3H), 5.57 (br0d,
0
0
0
0
0
0
0
J7 ,7 <J7 ,6 <13.0 Hz, 1H:H7 ), 2.67 (dd, J7 ,7 <13.0 Hz,
0
0
0
0
0
J2 ,3 ˆ10.0 Hz, 1H:H2 ), 5.41 (ddt, J3 ,2 ˆ10.0 Hz, J ˆ
00
2H5, H1 ), 4.08±3.90 (m, 2H:2H4/2H5), 3.65 (dd, J6 ,7
000
0
0
0
0
0
0
J7 ,6 ˆ6.6 Hz, 1H:H7 ), 2.45 (br d, J1 ,1 <17.5 Hz, 1H:H1 ),
0
4.8 Hz, J ˆJ ˆ2.5 Hz, 1H:H3 ), 4.30±4.12 (m, 3H:2H4/
0
0
0
0
0
0
0
2.34 (dt, J4a ,4 <12.4 Hz, J4a ,4 ˆJ4a ,8a ˆ5.5 Hz, 1H:H4a ),
0
0
0
ˆ
0
0
0
2.08 (br d, J4 ,4 ˆ16.8 Hz, 1H:H4 ), 1.88 (very br d,
0
0
0
0
0
0
0
13.2 Hz, J6 ,7 ˆ5.8 Hz, 1H:H6 ), 3.26 (br t, J8a ,4a <J8a ,1
<
0
0
0
0
0
J1 ,1 <17.5 Hz, 1H:H1 ), 1.64 (br d, J4 ,4 ˆ16.8 Hz,
0
0
0
0
0
0
5.5 Hz, 1H:H8a ), 2.71 (t, J7 ,7 ˆJ7 ,6 ˆ13.2 Hz, 1H:H7 ), 2.52
1H:H4 ), 1.61 (br s, 3H:CH3), 1.54 (br s, 3H:CH3); 13C
0
0
0
0
0
0
0
0
(dd, J7 ,7 ˆ13.2 Hz, J7 ,6 ˆ5.8 Hz, 1H:H7 ), 2.34 (dt, J4a ,4
<
ˆ
0
NMR: d 207.4 (C8 ), 135.2/131.8/128.9/127.2 (CAr),
0
0
0
0
0
0
0
11.0 Hz, J4a ,4 <J4a ,8a <5.5 Hz, 1H:H4a ), 2.14 (br d, J4 ,4
0
123.9/122.5 (C2 /C3 ), 110.1 (C2), 66.3/66.1 (C4/C5), 52.6
0
0
0
0
0
0
18.6 Hz, 1H:H4 ), 1.65 (ddq, J4 ,4 ˆ18.6 Hz, J4 ,4a <11.8 Hz,
J4 ,3 <J4 ,2 <J4 ,1 <3.5 Hz, 1H:H4 ), 0.00 (s, 9H:3CH3); 13C
NMR: d 203.5 (C8 ), 134.8/132.0/130.8/128.9 (CAr), 127.1/
0
0
0
0
0
(C6 ), 46.5 (C7 ), 45.0 (C8a ), 43.5 (C4a ), 30.8 (C4 ), 29.1
0
0
0
0
0
0
0
1
(C1 ), 19.1/18.6 (2CH3); MS (m/z): 344 (M , 16), 235
0
0
(11), 179 (100), 107 (20), 55 (24). Anal. Calcd for
C20H24O3S: C, 69.74; H, 7.02; S, 9.31. Found: C, 69.75;
H, 7.12; S, 9.20. 10: IR (®lm): 2966, 2910, 2850, 1715,
0
0
123.9 (C2 /C3 ), 109.3 (C2), 67.4/66.2/66.1 (C4/C5/C1 ), 53.8/
0
0
0
0
0
0
50.4/47.6/44.2/24.4 (C4 /C4a /C6 /C7 /C8a ), 0.0 (CH3); MS
(m/z): 404 (M1, 1), 183 (24), 167 (20), 149 (20), 142 (25),
99 (21), 79 (24), 75 (63), 73 (100), 70 (20), 69 (21), 55 (23);
HRMS (EI) (M1) calcd for C21H28O4SSi 404.1478, found
404.1468. 13: mp 137±1398C (methylene chloride±pentane);
IR (KBr): 3492, 2892, 1697, 1413, 1151, 1117, 1044, 1021,
1
1476, 1441, 1293, 1138, 1096, 1026, 962, 745 cm21; H
NMR: d 7.43±7.30 (m, 2H), 7.30±7.10 (m, 3H), 4.20±
0
0
0
0
3.90 (m, 4H:2H4, 2H5), 3.58 (dd, J6 ,7 ˆ4.5 Hz, J6 ,7
2.6 Hz, 1H:H6 ), 3.00 (dd, J7 ,7 ˆ14.6 Hz, J7 ,6 ˆ4.5 Hz,
1H:H7 ), 2.65±2.35 (m, 3H:H4a , H7 , H8a ), 2.30±1.90 (m,
ˆ
0
0
0
0
0
692 cm21; H NMR: d 7.50±7.35 (m, 2H), 7.30±7.15 (m,
1
0
0
0
0
4H:2H1 , 2H4 ), 1.54 (br s, 6H:2CH3); 13C NMR: d 208.2
0
0
0
0
0
3H), 5.74 (br d, J2 ,3 ˆ10.2 Hz, 1H:H2 ), 5.58 (ddt,
0
4.15 (m, 2H:2H4/2H5), 4.15±4.00 (m, 3H:2H4/2H5, H1 ),
00
000
0
0
0
(C8 ), 133.7/129.1/127.8 (CAr), 124.0/123.8 (C2 /C3 ), 109.6
0
0
0
J3 ,2 ˆ10.2 Hz, J ˆ4.8 Hz, J <J <2.3 Hz, 1H:H3 ), 4.40±
0
0
0
(C2), 65.9/65.6 (C4/C5), 52.7 (C6 ), 47.3 (C8a ), 43.6 (C7 ),
0
0
0
0
41.3 (C4a ), 31.2/30.8 (C1 /C4 ), 19.0/18.7 (2 CH3); MS (m/z):
344 (M1, 9), 179 (100); HRMS (EI) (M1) calcd for
C20H24O3S 344.1446, found 344.1448.
0
0
0
0
0
3.77 (dd, J6 ,7 ˆ13.5 Hz, J6 ,7 ˆ6.2 Hz, 1H:H6 ), 3.72 (d,
JOH,1 ˆ12.1 Hz, 1H:OH), 3.47 (br t, J8a ,4a <J8a ,1 <5.1 Hz,
1H:H8a ), 2.81 (td, J7 ,7 ˆJ7 ,6 ˆ13.5 Hz, Jˆ1.1 Hz, 1H:H7 ),
2.66 (dd, J7 ,7 ˆ13.5 Hz, J7 ,6 ˆ6.2 Hz, 1H:H7 ), 2.43 (dt,
J4a ,4 ˆ11.3 Hz, J4a ,4 <J4a ,8a ˆ5.6 Hz, 1H:H4a ), 2.27 (br d,
J4 ,4 ˆ18.6 Hz, 1H:H4 ), 1.76 (ddq, J4 ,4 ˆ18.6 Hz, J4 ,4a
11.5 Hz, J4 ,3 <J4 ,2 <J4 ,1 <3.5 Hz, 1H:H4 ); 13C NMR: d
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
SiO2 as Lewis acid. In a sealed reactor, a mixture of 3
(106 mg, 0.40 mmol), 5 (175 mL, 1.52 mmol), and silica
gel (1.08 g) was allowed to react at room temperature for
0
0
0
0
0
0
0
0
0
0
0
0
0
0
ˆ
0
0
0
0
0
0
0

3608
P. de March et al. / Tetrahedron 56 (2000) 3603±3609
0
210.1 (C8 ), 134.9/132.0/131.2/129.1 (CAr), 127.4/124.7 (C2 /
0
react at room temperature for 6 days. The silica gel was
®ltered off and washed with methylene chloride. Flash
chromatography of the crude material (330 mg) using
toluene±methylene chloride (5:1) as eluent afforded the
following fractions: (i) 115 mg (0.38 mmol, 45%) of 17;
(ii) 167 mg (0.45 mmol, 54% yield) of a 1:2 (or 2:1) mixture
of (4R,5R,10R,40S,4a0R,8a0S)-4,5-diphenyl-10,40,4a0,8a0-tetra-
hydrospiro[1,3-dioxolane-2,50(80H)-[1,4]methanonaphthalen]-
80-one and its (4R,5R,10S,40R,4a0S,8a0R)-isomer, 18 and 19,
as a white solid. With respect to recovered 17 the yield is
97%. Mixture 18 and 19: mp 101±1058C; IR (KBr): 3050,
0
C3 ), 109.3 (C2), 67.8/66.4/66.3 (C4/C5/C1 ), 52.9/49.2/47.3/
0
1
0
0
0
0
0
43.7/24.6 (C4 /C4a /C6 /C7 /C8a ); MS (m/z): 332 (M , 6), 167
(100), 149 (26), 99 (39), 73 (21), 55 (46). Anal. Calcd for
C18H20O4S: C, 65.04; H, 6.06; S, 9.64. Found: C, 64.85; H,
6.05; S, 9.68.
(1RS,4SR,4aRS,6RS,8aSR)-6-Phenylthio-1,4,4a,6,7,8a-
hexahydro[1,4]methanonaphthalen-5,8-dione, 15.
A
suspension of 7 (103 mg, 0.31 mmol) and ZnBr2 (150 mg,
0.67 mmol) in methylene chloride (4 mL) was stirred at
room temperature for 3 months. Water was added and the
mixture was extracted with methylene chloride. Flash
chromatography of the crude material (58 mg) using
hexane±ethyl acetate (4:1) as eluent afforded 15 (27 mg,
0.09 mmol, 30% yield) as a colorless oil: IR (KBr): 2995,
2966, 2931, 2875, 1708, 1581, 1476, 1441, 1258, 1068,
3036, 2931, 2878, 1744, 1670, 1260, 1127, 755, 678 cm21
;
1H NMR (M: major isomer; m: minor isomer): d 7.35±7.05
m
0
0
0
0
0
(m, 10H), 6.62 (d, J6 ,7 ˆ10.2 Hz, 1H:H6 ), 6.51 (d, J6 ,7
ˆ
M
0
0
0
0
10.2 Hz, 1H:H6 ), 6.04 (m, 1H:H3 ), 5.97 (d, J7 ,6 ˆ10.2 Hz,
m
m
0
0
1H:H7 ), 5.85 (m, 1H:H2 ), 4.85 (d, J4,5ˆ8.4 Hz, 1H:H4 /H5 ),
5.73 (d, J4,5ˆ8.4 Hz, 1H:Hm4 /H5m), 4.71 (s, 2H:H4M, HM5 ), 3.50
737 cm21
;
1H NMR: d 7.35±7.15 (m, 5H), 6.18 (dd,
0 0
(br s)13.40±3.20 (m)13.15±3.00 (m) (total: 4H:H1 , H4 ,
Jˆ5.5 Hz, J0ˆ2.9 Hz, 1H:H2/H3), 6.01 (dd, Jˆ5.5 Hz,
J0ˆ2.2 Hz, 1H:H2/H3), 3.75 (dd, J6,7ˆ4.4 Hz, J6,7ˆ3.7 Hz,
1H:H6), 3.45±3.30 (m, 4H:H1, H4, H4a, H8a), 2.66 (dd,
J7,7ˆ17.2 Hz, J7,6ˆ3.7 Hz, 1H:H7), 2.52 (dd, J7,7ˆ17.2 Hz,
J7,6ˆ4.4 Hz, 1H:H7), 1.44 (br d, Jˆ8.8 Hz, 1H:CH2), 1.32
(br d, Jˆ8.8 Hz, 1H:CH2); 13C NMR: d 207.6/204.5 (C5/
C8), 137.9/135.1/132.0/131.6/129.3/128.4 (C2/C3/CAr),
52.5/50.9/49.4/48.72/48.68/46.1/42.7 (C1/C4/C4a/C6/C7/C8a/
CH2); MS (m/z): 284 (M1, 31), 218 (41), 175 (21), 136 (51),
135 (44), 110 (34), 109 (100), 91 (46), 66 (50), 65 (27), 55
(26). Anal. Calcd for C17H16O2S: C, 71.80; H, 5.67; S,
11.27. Found: C, 71.54; H, 5.64; S, 11.23.
H4a , H8a ), 1.50±1.30 (m, 2H:CH2); 13C NMR: d 136.0±
0
0
0
0
0
0
0
125.0 (CAr, C2 , C3 , C7 ), M: 200.2 (C8 ), 145.1 (C6 ),
104.5 (C2), 85.7/84.4 (C4/C5), 50.1/48.9/47.5/47.3/46.9
0
(C1 /C4 /C4a /C8a /CH2), m: 199.7 (C8 ), 146.5 (C6 ), 104.4
0
0
0
0
0
0
(C2), 86.1/85.8 (C4/C5), 49.4/48.4/47.9/47.4/46.3 (C1 /C4 /
0
1
0
0
C4a /C8a /CH2); MS (m/z, CI/NH3): 388 (M 118, 8), 371
(M111, 46), 214 (100), 196 (44). Anal. Calcd for
C25H22O3: C, 81.06; H, 5.99. Found: C, 81.04; H, 6.09.
Acknowledgements
We gratefully acknowledge ®nancial support of DGES
(project PB97-0215) and CIRIT (SGR97-00003). We also
Á
thank the Universitat Autonoma de Barcelona for a grant to
S. R.
(10RS,40SR,4a0RS,8a0SR)-10,40,4a0,8a0-Tetrahydrospiro-
{1,3-dioxolane-2,50(80H)-[10,40]methanonaphthalen}-80-
one, 16. A solution of 7 (449 mg, 1.37 mmol) and DBU
(410 mL, 2.75 mmol) in methylene chloride (5 mL) was
kept at room temperature for 20 min. The organic phase
was washed with aqueous 1% HCl and water. Flash
chromatography of the crude material (477 mg) using
hexane±ethyl acetate (2:1) as eluent afforded compound
1611a (289 mg, 1.32 mmol, 97% yield) as a colorless oil:
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0
0
0
0
0
0
0
0
0
0
1H:H6 ), 6.02 (dd, J3 ,2 ˆ5.8 Hz, J3 ,4 ˆ2.9 Hz, 1H:H3 ),
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0
0
0
5.89 (d, J7 ,6 ˆ10.2 Hz, 1H:H7 ), 5.84 (dd, J2 ,3 ˆ5.8 Hz,
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0
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0
0
0
0
0
0
J8a ,1 ˆ4.0 Hz, 1H:H8a ), 2.81 (dd, J4a ,8a ˆ8.8 Hz, J4a ,4
ˆ
0
4.0 Hz, 1H:H4a ), 1.39 (br d, Jˆ8.8 Hz, 1H:CH2), 1.28 (br
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0
0
0
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0
0
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0
0
0
0
C5), 49.7/48.6/47.5/46.6/46.0 (C1 /C4 /C4a /C8a /CH2).
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temperature for 1 h. The solution was extracted with ether
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acetate±hexane). Lit.10b mp 76±78.58C.
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Reaction between ketal 17 and diene 4
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P. de March et al. / Tetrahedron 56 (2000) 3603±3609
3609
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Â
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Â
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