Remote regio- and stereocontrol by the sulfinyl group: Diels-Alder reaction of sulfinyl dienols and 8,8-dimethylnaphthalene-1,4,5(8H)-trione

Article abstract of DOI:10.1016/j.tetasy.2012.11.017

Diels-Alder cycloaddition of 8,8-dimethylnaphthalene-1,4,5(8H)-trione with diastereomeric hydroxysulfinyldienes proceeded with high yields and good π-facial and regioselectivities. The hydroxysulfoxide moiety controls the regio- and stereoselectivities, t

Full text of DOI:10.1016/j.tetasy.2012.11.017

Tetrahedron: Asymmetry 24 (2013) 56–61
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Tetrahedron: Asymmetry
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Remote regio- and stereocontrol by the sulfinyl group: Diels–Alder reaction
of sulfinyl dienols and 8,8-dimethylnaphthalene-1,4,5(8H)-trione
Iriux Almodovar a, , Wilson Cardona b, Tomás Delgado-Castro c, Gerald Zapata-Torres d,
⇑
f
f
Marcos Caroli Rezende a, Ramiro Araya-Maturana e, , M. Carmen Maestro , José L. García Ruano
⇑
a Facultad de Química y Biología, Departamento de Ciencias del Ambiente, Universidad de Santiago de Chile, Avenida B. O’Higgins 3363, Estación Central, Santiago, CP 9160000, Chile
b Departamento de Ciencias Químicas, Universidad Andrés Bello, Avenida Concepción, Talcahuano 7100, Concepción, Chile
c Departamento de Ciencias Químicas, Universidad Andrés Bello, República 237, Santiago, Chile
d Departamento de Química Inorgánica y Analítica, Universidad de Chile, Casilla 233, Santiago 1, Chile
e Departamento de Química Orgánica y Físico-Química, Universidad de Chile, Casilla 233, Santiago 1, Chile
f Departamento de Química Orgánica (C-1), Universidad Autónoma 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:
Received 7 November 2012
Accepted 26 November 2012
Diels–Alder cycloaddition of 8,8-dimethylnaphthalene-1,4,5(8H)-trione with diastereomeric hydroxy-
sulfinyldienes proceeded with high yields and good p-facial and regioselectivities. The hydroxysulfoxide
moiety controls the regio- and stereoselectivities, through hydrogen bonds in the suggested transition
state.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
the conformational degrees of freedom of the dienophile, to im-
prove the sulfinyl’s ability to act as a chiral inductor. Following this
The Diels–Alder reaction constitutes as one of the most impor-
tant tools for the synthesis of six-membered rings.1,2 Depending on
the substituents attached to the reactants, it is possible to achieve
high regio- and stereoselectivity, thus controlling the absolute con-
figuration of newly formed asymmetric centers.3,4 Several ele-
ments such as chiral auxiliaries,5 catalysts,6 or solvents7 have
been used to achieve this. Non-classical techniques such as high
pressure reactions or microwave synthesis have also been
utilized.8
suggestion, over the past few decades, several examples of Diels–
Alder reactions of dienophiles containing a sulfinyl and a second
electron-withdrawing group have been reported.12
The remote stereocontrol caused by the chiral sulfinyl group in
asymmetric DA reactions was recently investigated by Maestro
et al.13 The authors concluded that, as was the case for DA reac-
tions where the chiral auxiliary was bound directly to the double
bond, the sulfinyl group by itself was not able to control the selec-
tivity of the reaction. A second electron-withdrawing group, at-
Among these elements, chiral sulfoxides constitute a very
important group of compounds that has been increasingly used
as chiral auxiliaries in asymmetric synthesis.9 This group is consid-
ered as one of the most versatile chiral auxiliaries to build carbon–
carbon and carbon–heteroatom bonds. The sulfinyl group is also
present in many natural compounds with interesting biological
properties.10
tached to the diene, in addition to a chelating agent, was
required to achieve the desired stereocontrol.
The result of attaching a sulfinyl group to the diene in asymmet-
ric DA reactions has been less investigated.14,15 Although the num-
ber of papers in this particular area has increased substantially
over the last decade, the sulfinyl group was always attached di-
rectly to a diene system. In most cases, high endo and
p-facial
The sulfinyl group has been employed in asymmetric Diels–Al-
der reactions generally attached to the dienophile. In a seminal
investigation,11 the influence of a sulfinyl group bound directly to
the dienophile system revealed that this group was not able to effi-
ciently control the endo- and facial selectivity. The authors sug-
gested the introduction of another electron-withdrawing group
attached to the double bond to increase the reactivity and reduce
selectivities were observed. In a recent example of the DA cycload-
ditions of amido-2-sulfinyl-butadienes with N-phenylmaleimide
(NPM), it was shown that the chiral sulfur atom was capable of
controlling the diastereoselectivity of the process.16
To the best of our knowledge, there are no reports of Diels–Al-
der reactions with remote stereocontrol caused by a sulfinyl group
not directly attached to the diene. Herein we report the synthesis
of anthraquinone derivatives from a naphthoquinone and chiral
a
-hydroxy-b-sulfinyldienes. Reactions proceeded with good regio-
⇑
Corresponding authors. Tel.: +56 2 7181161.
E-mail addresses: iriux.almodovar@usach.cl (I. Almodovar), raraya@ciq.uchile.cl
and diastereoselectivities, that are governed by hydrogen-bond
interactions in the transition state.
(R. Araya-Maturana).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.11.017

I. Almodovar et al. / Tetrahedron: Asymmetry 24 (2013) 56–61
57
diastereomeric excess of >99%. When this reduction was carried
out in the presence of ZnBr2 (see Section 4), diene (2R,SR)-1-(p-tol-
ylsulfinyl)-3,5-heptadien-2-ol 2 was obtained stereoselectively in
84% yield with a diastereomeric excess of 90%. Both products were
further purified by column chromatography (silica gel), to obtain
the enantiomerically pure dienes 1 and 2.
The reaction of dienols 1 or 2 with naphthoquinone 3 was car-
ried out in benzene at room temperature. The product mixture was
enolized readily on silica, leading to a mixture of tricyclic hydro-
quinones 4–7 (Scheme 2).
2. Results and discussion
The synthesis of diene 1 and naphthoquinone 3 has already
been reported on.17 Dienes were obtained by the stereoselective
reduction
of
(R)-1-(p-tolylsulfinyl)-3,5-heptadien-2-one18
(Scheme 1). When DIBALH was used, diene (2S,SR)-1-(p-tolylsulfi-
nyl)-3,5-heptadien-2-ol 1 was obtained in 94 % yield and with a
OH
O
DIBALH
2.1. Characterization of the reaction products
S
THF, -78oC
1
O
pTol
The determination of the regioselectivity in both reactions was
achieved by the analysis of the bidimensional NMR spectra (HMQC
and HMBC) of each isolated product.
O
S
pTol
An important feature of this regiochemical assignment was the
intramolecular hydrogen-bond between the C9 hydroxyl group
and the carbonyl oxygen of C1. This allowed ready differentiation
of the phenolic OH groups in the regioisomers 4/5 and 6/7.
For example, in the HMBC spectrum of 6a, the C10 hydroxyl
proton at d 4.73 correlated with a quaternary carbon atom
(C10a), which showed another correlation with the methyl protons
at d 1.43 and with H-C6 (d 6.10). In addition, another quaternary
carbon (C8a) correlated simultaneously with the chelated hydrox-
ylic proton (d 13.39) at C9 and with H-C7 (d 5.81) (Scheme 3).
In an analogous way, the regiochemistry of 7a was established
from the observed correlations between the chelated hydroxylic
proton (d 13.18) at C9 and the quaternary carbon C8a, and between
the latter carbon atom and the methyl group at C8 (d 1.37). In addi-
tion, the hydroxylic proton at C10 (d 8.01) also correlated with the
quaternary carbon atom C10a, which exhibited a correlation with
H-C6 (d 5.67) (Scheme 3).
OH
DIBALH / ZnBr2
THF, -78oC
O
S
pTol
2
O
O
O
3
Scheme 1. Preparation and structures of dienes
naphthoquinone 3.
1 and 2, and structure of
pSOTol
pSOTol
OH
O
HO
OH
O
HO
OH
O
OH
O
*
*
*
*
i. 3 / C6H6
1
+
+
+
ii. SiO2
OH
OH
HO
HO
OH
OH
pSOTol
pSOTol
4a
4b
5a
5b
20%
80%
dr (a:b)= 80%
dr (a:b)= 90%
Total yield of 4 + 5 : 84%
pSOTol
pSOTol
OH
O
HO
HO
OH
O
OH
O
OH
O
*
*
*
3
i. / C6H6
*
+
+
2
+
ii. SiO2
OH
OH
HO
OH
OH
HO
pSOTol
pSOTol
6a
6b
7a
7b
20%
80%
dr (a:b)= 80%
dr (a:b)= 95%
Total yield of 6 + 7 : 72%
Scheme 2. Reactions of sulfinyldienols 1 or 2 with naphthoquinone 3 and the corresponding products.

58
I. Almodovar et al. / Tetrahedron: Asymmetry 24 (2013) 56–61
pSOTol
assigned to the chelated protons of each compound, readily identi-
fied in all spectra (Fig. 2).
OH
9
O
1
H
HO
H
H
8a
OH
O
8
5
2
3
7
6
9a
4a
9
H
H
8a
7
8
5
1
4
2
3
4
1.0
0.9
0.8
0.7
0.6
0.5
0.4
9a
4a
10a
10
H
OH
6
10a
10
HO
OH
pSOTol
7a
6a
Scheme 3. Most important correlations observed in the HMBC spectra of com-
pounds 6a and 7a.
0.3
0.2
13.25
0.1
0
13.10
13.34
9
13.20
Following a similar analysis, the regiochemistry of compounds
4/5 was established from the corresponding bidimensional NMR
spectra.
73
4
14
X-ray analysis of compound 4a, the major product of the reac-
tion of 1 with 3, led to the assignment of its stereogenic centers
(Fig. 1).
13.35
13.30
13.25
13.20
13.15
13.10
Chemical Shift (ppm)
Figure 2. 1H NMR signals assigned to the chelated protons of products 4a, 4b, 5a,
5b from the enolized reaction mixture of 1 and 3.
OH
The total yield of the products of the two cycloadditions was
high, amounting to 84% for the conversion of 1 + 3 ? ? 4 + 5
and to 72% for the reaction 2 + 3 ? ? 6 + 7. Both dienols 1 and 2
reacted with high regioselectivity, with an approximate proportion
of regioisomers of 80:20. In addition, a high
the two major regioisomers 4a and 6a was observed, amounting
to 90–95%.
p-facial selectivity of
OH
O
O
HO
S
Although we did not determine the absolute configurations of
the minor regioisomers 5 and 7, the integrations of the signals as-
signed to their chelated protons allowed the estimation of their rel-
ative proportion of the pairs 5a/5b and 7a/7b in the mixture. In
each pair, the major isomers, 5a and 7a, amounted to approxi-
Figure 1. X-ray structure of compound 4a.
mately 80%. Thus, a p-facial selectivity was observed in the forma-
tion of all regioisomers 4/6 and 5/7. This observation was
important in the analysis of the role of the remote sulfinyl group
in the stereoselective cycloaddition.
The causes of such high selectivities were next investigated, by
an analysis of the probable transition-state geometries of the
reaction.
In order to assign the absolute configurations of the stereogenic
centers of 6a, we next oxidized 4a and 6a to the corresponding
sulfones, thus eliminating the homochiral sulfinyl group in each
compound. The resulting sulfones possessed only three stereogenic
centers, one of which was the hydroxylic carbon atom, while the
other two, carbons C8 and C5, were formed in the Diels–Alder reac-
tion. The requirement of a suprafacial process for the Diels–Alder
reaction led to the expectation that these sulfones should be either
enantiomers or diastereomers. NMR analysis of their spectra
showed that the pair of sulfones were diastereomers, thus leading
to the immediate assignment of the absolute configuration of 6a, as
shown in Scheme 2.
The absolute configurations of compounds 4b and 6b
(Scheme 2) followed from the fact that they were both generated
by the addition of naphthoquinone 3 to the other diastereotopic
faces of dienes 1 and 2, respectively.
Due to the fact that regioisomers 5 and 7 constituted only
approximately 20% of the product mixture, their absolute configu-
rations were not investigated further. Nevertheless, the relative
proportions of the stereoisomeric pairs 5a/5b and 7a/7b could be
obtained from analysis of the 1H NMR spectrum of the product
mixture, as described below.
The observation that the major products of these cycloadditions
were compounds 4a and 6a was consistent with a possible TS
geometry where an intermolecular hydrogen-bond between the
hydroxyl group of the diene and a carbonyl group of the naphtho-
quinone governed the approach of the dienophile to the diene. A
similar argument had been used for the regioselectivity observed
in the cycloaddition of naphthoquinone 3 with a primary dienol.19
In all cases, the dienophile approaches the diene from the same
face of its hydroxyl substituent. This is illustrated in Scheme 4,
which describes the reaction of 1 with 3. Similar arguments can
be applied to the reaction of 2 with 3, as discussed below.
It should be noted that the sulfinyldiene conformation shown in
Scheme 4 is less stable than the one with an axial S-tolyl group and
an equatorial dienyl chain, as proven by the 1H NMR spectrum of
compound 1. Nevertheless, the proposed transition states depict
in all cases the less stable conformer, since it allows an intermolec-
ular hydrogen-bond between the diene and dienophile. This effect
is absent in the TS’s derived from the more stable conformer of 1
(scheme not shown), thus nicely illustrating the Curtin-Hammett
principle.
2.2. Analysis of the cycloaddition selectivities
From our results, we were able to analyze the facial and
regioselectivity of the Diels–Alder cycloaddition. This was based
on the product yields, estimated from the integration of the signals
Scheme 4-I depicts a possible geometry for the endo-approach
of the diene to the dienophile, leading to the major isomer 4a. It
should be noted that the selective formation of this compound is

I. Almodovar et al. / Tetrahedron: Asymmetry 24 (2013) 56–61
59
O
O
O
pSOTol
pSOTol
H
pTol
HO
HO
HO
HO
S
O
H
O
OH
O
O
O
O
H
O
O
OH
I
4a
O
O
O
pSOTol
pSOTol
H
pTol
HO
S
O
H
O
OH
O
(S)
H
O
O
O
OH
4b
II
O
pSOTol
pSOTol
H
pTol
HO
S
O
H
O
OH
O
O
H
O
O
OH
III
4b
Scheme 4. Plausible TS geometries of the reaction of 1 with 3: (I) endo-approach of the diene to the dienophile. (II) exo-approach of the diene to the dienophile. (III) endo-
approach of the diene to the dienophile from the more sterically hindered face.
a consequence of two factors: the intermolecular hydrogen-bond
between the OH group of the diene and the ketone group of the
dienophile, and the presence of the chiral sulfinyl group, which is
dienol 2 is also the one that allows the least sterically hindered ap-
proach of the dienophile, and the formation of an intermolecular
hydrogen-bond in the transition state, in a very similar way to that
responsible for the observed high
p
-facial stereoselectivity. An
suggested for the reaction of 1 with 3. The regio- and p-facial selec-
intramolecular hydrogen bond between the S–O group and the
hydroxylic proton has been described before in an NMR study of
the preferred conformations of similar compounds.20 In the case
of the studied reaction, this hydrogen bond is responsible for the
rather rigid conformations of the dienes 1 and 2, leading to a high
tivities for the reaction of 2 are also dependent on the intermolec-
ular hydrogen-bond and the presence of the neighboring sulfinyl
group, aspects which are common to both dienols.
3. Conclusions
p
-facial selectivity by the approaching dienophile, as shown in
Scheme 4.
The formation of isomer 4b in a smaller amount could be as-
Herein we have demonstrated that a sulfinyl group remotely at-
tached to a diene is capable of controlling the stereoselectivity of a
Diels–Alder reaction with one naphthoquinone, achieving high re-
cribed to the exo-approach of the diene to the dienophile
(Scheme 4-II), a process which is normally less favoured in
Diels–Alder cycloadditions. Alternatively, an endo-approach of
the diene to the dienophile from the more sterically hindered face
would also account for the formation of 4b as the minor product
(Scheme 4-III).
gio- and p-facial selectivities in the products. An additional struc-
tural requirement is the presence of a hydroxy substituent on the
diene, allowing the formation of an intermolecular hydrogen-bond
between the diene and dienophile in the transition state.
The above discussion rationalizes the selectivity in the forma-
tion of the major regioisomers 4/6, and suggests two main factors
for this result: the intermolecular OH–CO hydrogen-bond and the
presence of the sulfinyl group forming an intramolecular hydro-
gen-bond with the OH group of the diene. The role of the latter
4. Experimental
4.1. General
Melting points were obtained with a Kofler hot-stage apparatus
and are not corrected. IR spectra were recorded with a Nicolet
Magna 550 FT-IR spectrometer. 1H and 13C NMR spectra were ob-
tained with a Bruker Avance DRX-300. All chemical shifts in the
NMR spectra are reported as ppm downfield from TMS. The follow-
ing calibrations were used: CDCl3 d 7.26 and 77.00. Optical rota-
tions were measured on a Perkin–Elmer 241 MC polarimeter.
Commercially available starting materials and solvents were used
without further purification. Silica gel 60 (70–230 mesh) and alu-
Foil 60 F254 were used for column chromatography and analytical
TLC, respectively. THF was dried using Na and benzophenone
in the high p-facial selectivity remains uncertain, because it could
be argued that the intermolecular OH–CO bond would be enough
to explain the observed selectivities.
Unequivocal evidence for the role played by the sulfinyl group is
provided by the observation that the formation of the minor regioi-
somers 5 and 7 also exhibited a high
p-facial selectivity. In this
case, the formation of an intermolecular OH–CO bond is no longer
possible, leaving the sulfinyl group as the only factor responsible
for the observed selectivity.
For the reaction of 2 with 3, similar arguments could be made to
explain the observed selectivities. The most stable conformation of

60
I. Almodovar et al. / Tetrahedron: Asymmetry 24 (2013) 56–61
under a nitrogen atmosphere. i-Pr2NH was distilled from KOH. n-
BuLi (2.5 M solution in hexanes) was purchased from Aldrich and
was titrated with N-pivaloyl-o-toluidine21 in THF every time it
was used. (SR)-1-(p-tolylsulfinyl)-3,5-heptadien-2-one and
(2S,SR)-1-(p-tolylsulfinyl)-3,5-heptadien-2-ol 1 were prepared as
previously described.17 The X-ray analysis data of compound 4a
were deposited at the Cambridge Crystallographic Data Centre
and allocated the deposition number CCDC 898239.
(dd, 1H, J = 5.0 Hz, J = 10.0 Hz), 6.23 (d, 1H, J = 10.0 Hz), 6.82 (d,
1H, J = 10.0 Hz), 7.32 (d, 2H, J = 8.0 Hz), 7.51 (d, 2H, J = 8.0 Hz),
13.25 (s, 1H). 13C NMR d (CDCl3, 75 MHz): 21.56, 25.06, 25.27,
30.45, 38.18, 40.56, 60.45, 68.36, 113.07, 121.60, 123.21, 123.94,
124.15, 129.97, 130.00, 132.95, 133.17, 137.69, 141.50, 142.80,
154.7, 161.14, 191.13. Anal. Calcd for C26H28O5S: C, 69.00; H,
6.24; S, 7.08. Found C, 68.25; H, 6.41; S, 6.39.
4.3.2. (5S,8R)-9,10-Dihydroxy-8-{(1S)-1-hydroxy-2-[(4-
methylphenyl)-(R)-sulfinyl]ethyl}-4,4,5-trimethyl-5,8-dihydro-
1(4H)-anthracenone 4b
4.2. (2R,SR)-1-(p-Tolylsulfinyl)-3,5-heptadien-2-ol 2
(SR)-1-(p-Tolylsulfinyl)-3,5-heptadiene-2-one (1.21 mmol) was
dissolved in dry THF (5 mL) under nitrogen. A solution of ZnBr2
(1.7 mmol) in dry THF (5 mL) was then added. The mixture was
stirred for 30 min at 25 °C. The reaction mixture was then cooled
to ꢀ78 °C and 3 mL of DIBALH (1.0 M in hexane) was added drop-
wise. The resulting mixture was stirred at this temperature for
45 min. Methanol (3 mL) was then added, and the reaction mixture
was allowed to warm up to 25 °C. The solvent was removed with a
rotary evaporator and a saturated aqueous solution of NH4Cl
(5 mL) was added to the residue. The resulting mixture was stirred
for 15 min, extracted with ethyl acetate, and the organic extracts
were dried over magnesium sulfate. The solvent was eliminated
under reduced pressure and the residue was purified by column
chromatography (AcOEt:Hex, 1:0.7). Yield: 62%, with 90%de
1H NMR d (CDCl3, 300.13 MHz): 1.38 (d, 3H, J = 7.0 Hz), 1.57 (s,
3H), 1.63 (s, 3H), 2.35 (s, 1H), 2.38 (s, 3H), 2.67 (dd, 1H, J = 1.0 Hz,
J = 13.0 Hz), 3.08 (dd, 1H, J = 11.0 Hz, J = 13.0 Hz), 3.45 (m, 1H), 3.94
(m, 1H), 4.66 (m, 1H), 5.92 (dd, 1H, J = 5.0 Hz, J = 10.0 Hz), 6.12 (dd,
1H, J = 5.0 Hz, J = 10.0 Hz), 6.21 (d, 1H, J = 10.0 Hz), 6.84 (d, 1H,
J = 10.0 Hz), 7.34 (d, 2H, J = 8.0 Hz), 7.39 (d, 2H, J = 8.0 Hz), 13.34
(s, 1H). 13C NMR d (CDCl3, 75 MHz): 21.36, 21.80, 25.14, 25.23,
30.40, 38.17, 60.95, 69.52, 113.05, 121.59, 123.68, 123.89, 124.50,
129.83, 131.84, 133.62, 136.43, 139.85, 141.23, 143.12, 154.32,
161.20, 190.95.
4.3.3. 9,10-Dihydroxy-5-{(1S)-1-hydroxy-2-[(4-methylphenyl)-
(R)-sulfinyl]ethyl}-4,4,5-trimethyl-5,8-dihydro-1(4H)-
anthracenone 5a
½
a 2D0
ꢁ
¼ þ132 (c 1.8, acetone); Mp: 85 °C. IR (KBr) (cmꢀ1): 3328,
Mp: 198–201 °C. IR (KBr) (cmꢀ1): 3418, 2924, 1651, 1601.1H
NMR d (CDCl3, 300.13 MHz): 0.74 (d, 3H, J = 7.0 Hz), 1.58 (s,
3H), 1.65 (s, 3H), 2.40 (s, 1H), 2.80 (d, 1H, J = 14.0 Hz), 3.53 (d,
1H, J = 14.0 Hz), 3.65 (m, 1H), 3.87 (m, 2H), 5.70 (dd, 1H,
J = 5.0 Hz, J = 10.0 Hz), 6.04 (dd, 1H, J = 5.0 Hz, J = 10.0 Hz), 6.15
(s, 1H), 6.23 (dd, 1H, J = 1.0 Hz, J = 10.0 Hz), 6.84 (dd, 1H,
J = 1.0 Hz, J = J = 10.0 Hz), 7.33 (d, 2H, J = 8.0 Hz), 7.40 (d, 2H,
3008, 2962, 2916, 2871, 1653, 1006, 812. 1H NMR d (CDCl3
300.13 MHz): 1.75 (d, 3H, J = 6.7 Hz), 2.42 (s, 3H), 2.80 (dd, 1H,
J = 13.1 Hz, J = 2.9 Hz) 3.03 (dd, 1H, J = 13.1 Hz, J = 9.3 Hz); 3.65 (s,
1H), 4.81 (m, 1H), 5.53 (dd, 1H, J = 15.1 Hz, J = 6.4 Hz) 5.74 (m,
1H), 6.01 (dd, 1H, J = 15.0 Hz, J = 10.5 Hz), 6.28 (dd, 1H,
J = 15.2 Hz, J = 10.4 Hz), 7.34 (d, 2H, J = 8.1 Hz), 7.55 (d, 2H,
J = 8.2 Hz). 13C NMR d (CDCl3, 75 MHz): 18.10, 21.40, 62.63,
69.22, 123.99, 129.67, 130.09, 130.30, 131.22, 131.95, 140.45,
141.96. HRMS (EI). Anal. Calcd for C14H17OS (M-OH) 233.1000,
found 233.0991.
J = 8.0 Hz), 7.99 (s, 1H), 13.15 (s, 1H). 13C NMR
d (CDCl3,
75 MHz):21.35, 21.43, 25.02, 25.45, 29.45, 38.44, 41.65, 55.06,
76.36, 113.53, 122.62, 124.01, 130.26, 134.36, 134.84, 136.20,
136.78, 142.04, 144.95, 153.98, 161.72, 191.57. Anal. Calcd for
C26H28O5S: C, 69.00; H, 6.24; S, 7.08. Found: C, 68.14; H, 6.61;
4.3. Diels–Alder cycloadditions
S, 6.53.
General procedure:
A
solution of sulfinyldienol
1
or
2
4.3.4. 9,10-Dihydroxy-5-{(1S)-1-hydroxy-2-[(4-methylphenyl)-
(R)-sulfinyl]ethyl}-4,4,5-trimethyl-5,8-dihydro-1(4H)-
anthracenone 5b
(0.128 mmol) and dienophile 3 (0.128 mmol) in benzene (5 mL)
was allowed to react at room temperature in the absence of light
for one week. The course of the reaction was followed by TLC.
Evaporation of the solvent left a residue, which did not contain
any starting material, as shown by its 1H NMR spectrum in CDCl3.
The residue was redissolved in benzene, after which silica gel
(60 mg) was added, and the mixture was stirred overnight. The
mixture was then filtered and the silica gel residue was washed
with methanol. The combined filtrates were evaporated to yield a
mixture of anthracenones, which underwent separation by semi-
preparative thin-layer chromatography (AcOEt:Hex 1:2 as eluent).
In this way, pure compounds 4a, 4b, 5a, from sulfinyldienol 1, and
6a, 6b, 7a from sulfinyldienol 2, were obtained. In addition minor
products 5b, from sulfinyldienol 1, and 7b from sulfinyldienol 2,
were also isolated with some contamination, which did not pre-
clude identification by their 1H NMR spectra. These products were
characterized by their IR, 1H and 13C NMR spectra as follows.
1H NMR d (CDCl3, 300.13 MHz): 1.32 (d, 3H, J = 7.0 Hz), 1.56 (s,
3H), 1.68 (s, 3H), 2.47 (s, 3H), 2.61 (d, 1H, J = 14.0 Hz), 2.93 (dd, 1H,
J = 11.0 Hz, J = 14.0 Hz), 3.65 (m, 1H), 4.02 (m, 1H), 4.40 (d, 1H,
J = 11.0 Hz), 5.36 (dd, 1H, J = 5.0 Hz, J = 10.0 Hz), 5.91 (dd, 1H,
J = 5.0 Hz, J = 10.0 Hz), 6.23 (d, 1H, J = 10.0 Hz), 6.66 (s, 1H), 6.85
(d, 1H, J = 10.0 Hz), 7.40 (d, 2H, J = 8.0 Hz), 7.45 (d, 2H, J = 8.0 Hz),
9.23 (s, 1H), 13.21 (s, 1H). 13C NMR d (CDCl3, 75 MHz):20.73,
21.50, 24.99, 25.23, 29.63, 38.54, 42.66, 52.63, 72.49, 113.96,
122.23, 123.81, 124.16, 127.49, 130.08, 130.37, 133.91, 134.26,
136.78, 142.18, 145.41, 153.99, 161.99, 191.61.
4.3.5. (5R,8S)-9,10-Dihydroxy-8-{(1R)-1-hydroxy-2-[(4-
methylphenyl)-(R)-sulfinyl]ethyl}-4,4,5-trimethyl-5,8-dihydro-
1(4H)-anthracenone 6a
½
a 2D0
ꢁ
¼ þ84 (c 1.79, acetone) Mp: 144–147 °C. IR (KBr) (cmꢀ1
)
3416, 3020, 2959, 2937, 1651, 1597, 1029, 809. 1H NMR d (CDCl3,
300.13 MHz): 1.43 (d, 3H, J = 7.0 Hz), 1.58 (s, 3H), 1.63 (s, 3H),
2.42 (s, 3H), 2.98(dd, 1H, J = 12.9 Hz, J = 2.1 Hz), 3.17 (dd, 1H,
J = 12.9 Hz, J = 10.4 Hz), 3.45(m, 1H), 3.56 (d, 1H, J = 4.1 Hz), 3.82
(m, 1H), 4.59 (m, 1H), 4.73 (s, 1H), 5.81 (dd, 1H, J = 9.9 Hz,
J = 5.0 Hz), 6.10 (dd, 1H, J = 10.1 Hz, J = 5 Hz), 6.23 (d, 1H,
J = 10.0 Hz), 6.82 (d, 1H, J = 10.1 Hz), 7.33 (d, 2H, J = 8.2 Hz), 7.56
(d, 2H, J = 8.3 Hz), 13.39 (s, 1H). 13C NMR d (CDCl3, 75 MHz):
21.45, 21.51, 25.03, 25.28, 30.44, 38.19, 40.95, 62.00, 69.75,
4.3.1. (5S,8R)-9,10-Dihydroxy-8-{(1S)-1-hydroxy-2-[(4-
methylphenyl)-(R)-sulfinyl]ethyl}-4,4,5-trimethyl-5,8-dihydro-
1(4H)-anthracenone 4a
Mp: 234–236 °C. IR (KBr) (cmꢀ1): 3431, 2925, 1598, 1423. 1H
NMR d (CDCl3, 300.13 MHz): 1.35 (d, 3H, J = 7.0 Hz), 1.58 (s, 3H),
1.64 (s, 3H), 2.42 (s, 3H), 2.86 (dd, 1H, J = 2.0 Hz, J = 13.0 Hz), 3.18
(dd, 1H, J = 10.0 Hz, J = 13.0 Hz), 3.42 (m, 2H), 3.82 (m, 1H), 4.52
(m, 1H), 4.61 (m, 1H), 5.94 (dd, 1H, J = 5.0 Hz, J = 10.0 Hz), 6.12

I. Almodovar et al. / Tetrahedron: Asymmetry 24 (2013) 56–61
61
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113.08, 121.94, 122.92, 123.85, 124.26, 130.09, 133.35, 133.40,
137.10, 140.32, 140.02, 142.98, 154.14, 161.27, 191.22. HRMS
(ESI-MS): Anal. clacd. for C26H29O5S (M+H)+ 453.1711 found
453.1711.
4.3.6. (5S,8R)-9,10-Dihydroxy-8-{(1R)-1-hydroxy-2-[(4-
methylphenyl)-(R)-sulfinyl]ethyl}-4,4,5-trimethyl-5,8-dihydro-
1(4H)-anthracenone 6b
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Hamada, T.; Iwagawa, T. B. Chem. Soc. Jpn. 2012, 85, 631–633.
Mp: 99 °C (dec). IR (KBr) (cmꢀ1): 3411, 3260, 3040, 2960, 2927,
1655, 1598, 1034, 809. 1H NMR d (CDCl3, 300.13 MHz): 1.18 (d, 3H,
J = 7.2 Hz), 1.58 (s, 3H), 1.64 (s, 3H), 2.38 (s, 3H), 2.81(dd, 1H,
J = 12.8 Hz, J = 1.7 Hz), 3.20 (dd, 1H, J = 12.8 Hz, J = 9.3 Hz), 3.43
(m, 1H), 4.10 (m, 1H), 4.22 (m, 2H), 4.60 (s, 1H), 5.99 (dd, 1H,
J = 9.8 Hz, J = 4.3 Hz), 6.03 (dd, 1H, J = 9.9 Hz, J = 4.2 Hz), 6.26 (d,
1H, J = 10.1 Hz), 6.85 (d, 1H, J = 10.1 Hz), 7.27 (d, 2H, J = 8.2 Hz),
7.51 (d, 2H, J = 8.2 Hz), 13.58 (s, 1H). 13C NMR d (CDCl3, 75 MHz):
21.42, 21.78, 25.07, 25.25, 30.34, 38.18, 40.52, 62.39, 72.27,
113.22, 122.04, 123.91, 124.33, 124.83, 129.95, 131.73, 133.64,
136.36, 140.54, 141.78, 143.16, 154.35, 161.25, 191.12. HRMS
(ESI-MS): Anal. Calcd for C26H28O5NaS (M+Na)+ 475.1549, found
475.1538.
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4.3.7. 9,10-Dihydroxy-5-{(1R)-1-hydroxy-2-[(4-methylphenyl)-
(R)-sulfinyl]ethyl}-4,4,5-trimethyl-5,8-dihydro-1(4H)-
anthracenone 7a
Mp: 248 °C. IR (KBr) (cmꢀ1): 3377, 3020, 2925, 2854, 1655,
1599, 1077, 804.1H NMR d (CDCl3, 300.13 MHz): 1.37 (d, 3H,
J = 7 Hz), 1.57 (s, 3H), 1.65 (s, 3H), 2.45 (s, 3H), 3.09 (dd, 1H
J = 13.1 Hz, J = 9.5 Hz), 3.14 (dd, 1H, J = 12.9 Hz, J = 2.0 Hz), 3.80
(m, 2H), 4.32 (ddd, 1H, J = 9.6 Hz, J = 9.6 Hz, J = 1.9 Hz), 5.67 (dd,
1H, J = J = 9.7 Hz, J = 5.5 Hz), 6.02 (s, 1H), 6.22 (d, 1H, J = 10.1 Hz),
6.24 (dd, 1H, J = 9.6 Hz, J = 5.5 Hz), 6.82 (d, 1H, J = 10.0 Hz), 7.39
(d, 2H, J = 8.2 Hz), 7.60 (d, 2H, J = 8.2 Hz), 8.01 (s, 1H), 13.18 (s,
1H). 13C NMR d (CDCl3, 75 MHz): 21.51, 22.37, 25.04, 25.47,
29.82, 38.42, 42.12, 59.14, 78.34, 113.61, 122.62, 123.90, 123.93,
127.68, 130.46, 134.32, 134.42, 136.83, 139.90, 142.81, 145.00,
154.13, 161.61, 191.52. HRMS (ESI-MS): Anal. Calcd for
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C
26H28O5NaS (M+Na)+ 475.1549, found 475.1547.
4.3.8. 9,10-Dihydroxy-5-{(1R)-1-hydroxy-2-[(4-methylphenyl)-
(R)-sulfinyl]ethyl}-4,4,5-trimethyl-5,8-dihydro-1(4H)-
anthracenone 7b
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Mp: 199–202 °C. IR (KBr) (cmꢀ1): 3421, 3072, 2956, 2929, 1656,
1596, 1066, 813. 1H NMR d (CDCl3, 300.13 MHz): 1.17 (d, 3H,
J = 7.0 Hz), 1.55 (s, 3H), 1.64 (s, 3H), 2.37 (s, 3H), 2.40 (dd, 1H,
J = 13.0 Hz, J = 10.7 Hz), 2.94 (dd, 1H, J = 13.0 Hz, J = 0.8 Hz), 3.65
(m, 1H), 4.20 (m, 1H), 4.79 (m, 1H), 5.78 (ddd, 1H, J = 9.9 Hz,
J = 4.5 Hz, J = 0.8 Hz), 5.96 (s, 1H), 6.08 (ddd, 1H, J = 9.8 Hz,
J = 5.0 Hz, J = 1.0 Hz), 6.19 (d, 1H, J = 9.9 Hz), 6.82 (d, 1H,
J = 10.1 Hz), 7.28 (d, 2H, J = 8.1 Hz), 7.38 (d, 2H, J = 8.2 Hz), 9.10
(s, 1H), 13.13 (s, 1H). 13C NMR d (CDCl3, 75 MHz): 20.64, 21.41,
24.86, 25.19, 29.67, 38.48, 42.45, 56.22, 74.54, 113.95, 122.57,
123.40, 123.73, 127.50, 129.56, 130.40, 133.85, 134.87, 139.23,
142.48, 145.30, 153.84, 161.96, 191.55. HRMS (ESI-MS): Anal.
Calcd for C26H28O5NaS (M+Na)+ 475.1549, found 475.1545.
Acknowledgements
This work was supported by USACH-DICYT, Fondecyt Grant
1110176 and the Deutscher Akademischer Austausch-Dienst
(Grant to I.A. and to W.C.).
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López, B. E. Tetrahedron 1999, 55, 637–648.
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