Remote regiocontrol by a thioether group in Diels-Alder reactions of naphthazarin: Regioselective access to tetracyclic polyhydroxyquinones

Article abstract of DOI:10.1021/jo960855n

The synthesis of tetracyclic polyhydroxyquinones 5a and 5b was achieved through a sequence involving two Diels-Alder reactions with 1-methoxy-1,3-cyclohexadiene: the first with 2-(p-tolylthio)naphthazarin and the second on the resulting tricyclic derivative previously transformed into a (p-tolylsulfinyl)naphthazarin. The success of this strategy stemmed from the efficient remote regiocontrol exerted by the thioether substituent in the first step.

Full text of DOI:10.1021/jo960855n

6136
J . Org. Chem. 1996, 61, 6136-6138
Rem ote Regiocon tr ol by a Th ioeth er Gr ou p in Diels-Ald er
Rea ction s of Na p h th a za r in : Regioselective Access to Tetr a cyclic
P olyh yd r oxyqu in on es
M. Carmen Carren˜o,* J ose´ L. Garc´ıa Ruano,* and Antonio Urbano
Departamento de Quı´mica Orga´nica (C-I), Universidad Auto´noma, Cantoblanco, 28049-Madrid, Spain
Received May 8, 1996X
The synthesis of tetracyclic polyhydroxyquinones 5a and 5b was achieved through a sequence
involving two Diels-Alder reactions with 1-methoxy-1,3-cyclohexadiene: the first with 2-(p-
tolylthio)naphthazarin and the second on the resulting tricyclic derivative previously transformed
into a (p-tolylsulfinyl)naphthazarin. The success of this strategy stemmed from the efficient remote
regiocontrol exerted by the thioether substituent in the first step.
The possibility of achieving double Diels-Alder cy-
cycloaddition at the substituted ring it was necessary to
oxidize the thioether function into a sulfoxide or sulfone,
which increased the dienophilic reactivity of the substi-
tuted double bond.
cloadditions on naphthazarin derivatives1 has been suc-
cessfully exploited in the total synthesis of anthra-
cyclinones.2-4 The construction of the tetracyclic frame-
work with the adequate substitution required an efficient
control of the regiochemistry in both cycloadditions. The
solution of the regiochemical problem in these Diels-
Alder reactions has been found in the introduction of
different substituents on the two reactive double bonds2
or in the derivatization of the 5,8-dihydroxy-1,4-naph-
thoquinone system through a monoester3,4 or quinone-
monoimine formation.5
These results suggested a ready access to tetracyclic
hydroxyquinones from 1 by a sequence involving two
Diels-Alder reactions: the first with 2-(p-tolylthio)-
naphthazarin (1) and the second on the resulting tricyclic
derivative previously transformed into a (p-tolylsulfinyl)-
naphthazarin. The success of this strategy to construct
the tetracyclic framework would be mainly dependent on
the regioselectivity of the first cycloaddition between 1
and an asymmetric diene. The regiocontrol of the second
cyloaddition on an appropriate sulfinylnaphthazarin was
warranted from the well-documented behavior of sul-
finylquinones.7c
In this paper we report the remote control exerted by
the thioether group on the regioselectivity of Diels-Alder
reactions of 2-(p-tolylthio)naphthazarin (1) and 1-meth-
oxy-1,3-cyclohexadiene as well as its application to the
regiocontrolled formation of a polyhydroxy tetracyclic
quinone, taking advantage of the efficient control that a
thioether and a sulfoxide can exert on both ring selectiv-
ity and regioselectivity of the two cycloadditions.
The first cycloaddition of 1 and 1-methoxy-1,3-cyclo-
hexadiene was carried out at 40 °C for 24 h in different
solvents, and the results obtained are collected in Scheme
1 and Table 1.
Two regioisomeric adducts 2a and 2b, resulting from
the exclusive reaction of the diene on tautomer 1B, were
formed in all cases. The major component of the reaction
mixture was dependent on the nature of the solvent
(Table 1). The observed ring selectivity was expected
after our previous research results,9 but the high regio-
selectivity achieved was surprising taking into account
that in the reactive tautomer 1B the p-tolylthio group
was not directly linked to the reactive dienophilic double
bond. A similar remote regiocontrol in a Diels-Alder
reaction exerted by a substituent situated far from the
dienophilic double bond has been already pointed out by
Kraus et al.10
In the course of our work related to the synthesis6 and
Diels-Alder reactions6a,7 of enantiomerically pure sulfi-
nylquinones, we recently reported the preparation of
sulfenyl-, sulfinyl-, and sulfonylnaphthazarins.8 The
study of their Diels-Alder reactions with cyclopentadi-
ene9 revealed a ring selectivity for the cycloadditions
mainly dependent on the oxidation state at sulfur,
regardless the composition of the tautomeric equilibria
in the involved naphthazarins. In the case of 2-(p-
tolylthio)naphthazarin (1) (see Scheme 1), both thermal
and Lewis acid-catalyzed cycloadditions took place ex-
clusively on the unsubstituted double bond of tautomer
1B9 in spite of its scarce participation in the equilibrium.8
Thus, the ring selectivity of the cycloaddition was mainly
determined by the reactivity of the dienophilic double
bond, higher in tautomer 1B than in 1A, which bears an
electron-donating substituent. In order to achieve the
X Abstract published in Advance ACS Abstracts, August 1, 1996.
(1) Farin˜a, F.; Vega, J . C. Tetrahedron Lett. 1972, 1655.
(2) Echavarren, A.; Prados, P.; Farin˜a, F. Tetrahedron 1984, 40,
4561.
(3) (a) Kelly, T. R.; Gillard, J . W.; Goerner, R. N., J r.; Lyding, J . M.
J . Am. Chem. Soc. 1977, 99, 5513. (b) Kelly, T. R.; Vaya, J .; Anantha-
subramanian, L. J . Am. Chem. Soc. 1980, 102, 5983.
(4) de Bie, J . F. M.; Peperzak, R. M.; Daenen, M. J .; Scheeren, H.
W. Tetrahedron 1993, 49, 6463.
(5) (a) Farin˜a, F.; Noheda, P.; Paredes, M. C. Tetrahedron Lett. 1991,
32, 1109. (b) Farin˜a, F.; Noheda, P.; Paredes, M. C. J . Org. Chem. 1993,
58, 7406.
(6) (a) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Urbano, A. Tetrahedron
Lett. 1989, 30, 4003. (b) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Mata, J .
M.; Urbano, A. Tetrahedron 1991, 47, 605. (c) Carren˜o, M. C.; Garc´ıa
Ruano, J . L.; Urbano, A. Synthesis 1992, 651.
As can be seen in Table 1, the best result corresponded
to the reaction carried out in CH2Cl2 where compound
2a was the major adduct formed in a 90:10 ratio (Table
1, entry 1). Excellent regiocontrol is thus exerted by the
remote thioether function in the cycloaddition. A similar
(7) (a) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Urbano, A. J . Org. Chem.
1992, 57, 6870. (b) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Toledo, M. A.;
Urbano, A. Tetrahedron Lett. 1994, 35, 9759. (c) Carren˜o, M. C.; Garc´ıa
Ruano, J . L.; Toledo, M. A.; Urbano, A.; Remor, C. Z.; Stefani, V.;
Fischer, J . J . Org. Chem. 1996, 61, 503. (d) Carren˜o, M. C.; Garc´ıa
Ruano, J . L.; Urbano, A.; Hoyos, M. A. J . Org. Chem. 1996, 61, 2980.
(8) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Urbano, A. Tetrahedron
1994, 50, 5013.
(9) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Urbano, A. Tetrahedron Lett.
1994, 35, 3789.
(10) Kraus, G. A.; Li, J .; Gordon, M.; J ensen, J . H. J . Org. Chem.
1994, 59, 2219.
S0022-3263(96)00855-9 CCC: $12.00 © 1996 American Chemical Society

Access to Tetracyclic Polyhydroxyquinones
J . Org. Chem., Vol. 61, No. 18, 1996 6137
Sch em e 1a
F igu r e 1.
lower when other solvents, such as ethyl ether (Table 1,
entry 3) and acetonitrile (Table 1, entry 4), were used.
Moreover, when water was the solvent of choice, the
reaction took place very quickly, being completed in 2 h
at rt, but with a total lack of regioselectivity (Table 1,
entry 6).
The changes observed in the regioselectivity under the
different conditions used could be rationalized from the
different polarization of the dienophilic double bond of 1
as a result of the intramolecular hydrogen bonds strongly
affected by the nature of the solvent. Thus, when the
solvent was unable to be associated with the substrate
through hydrogen bonds (CH2Cl2 and CHCl3), only the
intramolecular associations should be responsible of the
double bond polarization. As can be seen in Figure 1,
considering only the reactive tautomer 1B, the associa-
tion of the OH at C-8 with the carbonyl group at C-1 must
be stronger than the one between the OH at C-5 and the
carbonyl at C-4 due to the competition of the latter with
the sulfur atom at C-6. As a consequence, the dienophile
is mainly polarized as indicated for 1B′ in Figure 1
leading to the major formation of 2a in the cycloaddition.
When the solvents used were able to form hydrogen
bonds with the OH (ethyl ether and acetonitrile) and
carbonyl (ethanol) groups of the substrate, the intermo-
lecular associations could compete with the intramolecu-
lar ones modifying the polarization of the dienophilic
double bond. The presence of the STol group at C-6
would make difficult the intermolecular association of the
solvent with the close OH at C-5 preserving the intramo-
lecular hydrogen bonding shown in 1B′′. The polariza-
tion of the dienophilic double bond in 1B′′ could explain
the major formation of adduct 2b. Finally, the high
ability of water to form hydrogen bonds determined the
breaking of all intramolecular associations, giving rise
to the nonpolarized species 1B′′′ that evolved in the
cycloaddition without any regioselectivity.
a
Key: (a) 1-methoxy-1,3-cyclohexadiene (10 equiv), 40 °C, 24
The major regioisomeric adduct 2a was isolated pure
by flash chromatography (eluent: CH2Cl2) in 79% yield,
and its structural assignment could only be unequivocally
established after the synthesis of the tetracyclic system
shown in Scheme 1.
h; (b) K2CO3 THF, H2O, rt, 24 h, 70-88%; (c) m-CPBA, CH2Cl2, 0
°C, 2 h, 92-95%; (d) 1-methoxy-1,3-cyclohexadiene (2 equiv),
CHCl3, rt, 24 h, 80-82%.
Ta ble 1. Diels-Ald er Rea ction s of 1 a n d
1-Meth oxy-1,3-cycloh exa d ien e a t 40 °C
Thus, the treatment of adducts 2a or 2b (as a 75:25
mixture of 2b:2a ) with potassium carbonate in a mixture
THF/H2O at rt afforded, respectively, pure (p-tolylthio)-
naphthazarin 3a in 78% yield, and a 75:25 mixture of
3b and 3a . Compound 3b could be isolated pure after
flash chromatography (eluent: CH2Cl2) in a 70% yield.
The m-CPBA controlled oxidation of 3a and 3b gave the
corresponding sulfoxides 4a and 4b as a 50:50 mixture
of sulfur epimers. Finally, the Diels-Alder reaction of
4a with 1-methoxy-1,3-cyclohexadiene at rt for 24 h gave
the tetracyclic derivative 5a in 82% yield. In a similar
reaction, 4b yielded exclusively compound 5b (80% yield).
In both cycloadditions, the adduct initially formed suf-
fered a spontaneous pyrolysis of the sulfoxide, giving rise
entry
solvent
yield (%)
2a :2b
1
2
3
4
5
6
dichloromethane
chloroform
ethyl ether
acetonitrile
ethanol
82
77
75
80
78
85
90:10
80:20
40:60
35:65
25:75
50:50
watera
a
Room temperature, 2 h.
result,
a 80:20 mixture of 2a and 2b , was ob-
served when the cycloaddition was carried out in chloro-
form (Table 1, entry 2). The best opposite regioselectiv-
ity, a 25:75 mixture of 2a and 2b, was achieved in ethanol
(Table 1, entry 5). The observed regioselectivity was

6138 J . Org. Chem., Vol. 61, No. 18, 1996
Carren˜o et al.
to the quinonic framework in the same synthetic step.7c,11
As expected, the regiochemistry of this second cycload-
dition was in both cases fully controlled by the sulfinyl
group.7c,12
After workup and flash chromatography (eluent: CH2Cl2)
compound 3a was obtained as a red solid (88% yield): mp 120-
121 °C (MeOH); 1H-NMR δ 13.60 and 12.62 (2H, 2s), 7.41 and
7.30 (4H, AA′BB′ system), 6.70 (1H, dd, J ) 1.4, 8.0 Hz), 6.46
(1H, dd, J ) 6.1, 8.0 Hz), 6.09 (1H, s), 4.58 (1H, m), 3.72
(3H, s), 2.42 (3H, s), 1.9-1.4 (4H, m); 13C-NMR δ 182.1, 181.3,
158.1, 157.1, 155.3, 146.7, 142.5, 141.0, 135.5 (2C), 135.3,
131.6, 131.1 (2C), 127.0, 123.5, 110.0, 109.7, 85.4, 55.4, 33.2,
30.8, 24.9, 21.3.
The unequivocal regiochemical assignment of both 5a
1
and 5b was based on their H-NMR spectra. Compound
5a showed the two associated hydroxyl groups at the
same chemical shift (δ ) 13.59 ppm) due to the C2
symmetry present in this molecule. On the contrary, in
compound 5b both phenolic groups were nonequivalent
and appeared at 13.02 and 14.12 ppm, respectively.
In summary, we have shown that the thioether func-
tion on the naphthazarin system is able to exert an
effective remote control on the regioselectivity of the
Diels-Alder cycloadditions with 1-methoxy-1,3-cyclo-
hexadiene. Moreover, this regioselectivity can be in-
verted by changing the reaction medium. This ability
has allowed the highly regioselective formation of tetra-
cyclic quinonic compounds by two consecutive Diels-
Alder reactions. We are currently extending this meth-
odology to the synthesis of adequately functionalized
derivatives related to anthracyclinones.
9,10-Dih yd r oxy-8-m eth oxy-2-(p-tolylth io)-5,8-d ih yd r o-
1,4-a n th r a qu in on e (3b). Compound 3b was obtained as
above from 2b as a red solid (70% yield): mp 160-162 °C
1
(MeOH); H-NMR δ 13.25 and 12.94 (2H, 2s), 7.41 and 7.30
(4H, AA′BB′ system), 6.71 (1H, dd, J ) 1.5, 8.0 Hz), 6.45
(1H, dd, J ) 6.1, 8.0 Hz), 6.09 (1H, s), 4.57 (1H, m), 3.75
(3H, s), 2.43 (3H, s), 1.9-1.4 (4H, m); 13C-NMR δ 182.8, 181.8,
156.1, 156.0, 155.9, 145.2, 144.3, 141.1, 135.6 (2C), 135.4,
131.8, 131.2 (2C), 128.2, 123.5, 110.0, 109.7, 85.6, 55.6, 33.2,
30.9, 25.0, 21.4.
5,8-Dih yd r oxy-1-m eth oxy-6-(p-tolylsu lfin yl)-1,4-d ih y-
d r o-1,4-a n th r a qu in on e (4a ). To a solution of 3a (42 mg, 0.1
mmol) in 5 mL of CH2Cl2 cooled at -20 °C was slowly added
m-CPBA (30 mg, 0.1 mmol) in 5 mL of CH2Cl2. After the
addition, the temperature was raised to 0 °C and the reaction
was continued for 2 h. Then, the mixture was treated with
NaHCO3 saturated solution, and after workup, compound 4a
was obtained pure by 1H-NMR as a 50:50 mixture of sulfur
epimers (92% yield): 1H-NMR δ 13.10, 13.00, 12.66 and 12.63
(4H, 4s), 7.88 and 7.87 (2H, 2s), 7.68 and 7.25 (8H, 2 AA′BB′
systems), 6.65 and 6.62 (2H, 2dd, J ) 1.5, 6.2 Hz), 6.41 and
6.38 (2H, 2dd, J ) 4.7, 6.2 Hz), 4.49 (2H, m), 3.70 and 3.68
(6H, 2s), 2.37 and 2.36 (6H, 2s), 1.9-1.2 (8H, m).
5,8-Dih yd r oxy-1-m eth oxy-7-(p-tolylsu lfin yl)-1,4-d ih y-
d r o-1,4-a n th r a qu in on e (4b). Compound 4b was obtained
as above from 3b as a 50:50 mixture of sulfur epimers (95%
yield): 1H-NMR δ 13.10, 13.09, 12.56 and 12.55 (4H, 4s), 7.86
and 7.85 (2H, 2s), 7.69 and 7.25, 7.68 and 7.25 (8H, 2 AA′BB′
systems), 6.65 and 6.61 (2H, 2dd, J ) 1.5, 6.2 Hz), 6.43 and
6.39 (2H, 2dd, J ) 4.7, 6.2 Hz), 4.53 (2H, m), 3.68 and 3.65
(6H, 2s), 2.36 (6H, 2s), 1.9-1.2 (8H, m).
6,11-Dih yd r oxy-1,7-d im et h oxy-1,4,7,10-t et r a h yd r o-5,-
12-n a p h th a cen equ in on e (5a ). To a solution of compound
4a (44 mg, 0.1 mmol) in 5 mL of dry CHCl3 was added
1-methoxy-1,3-cyclohexadiene (40 µL, 0.2 mmol, 2 equiv) under
argon. After 24 h at rt, the solvent was evaporated and the
residue was purified by flash chromatography (eluent: CH2-
Cl2/EtOAc 90/10) to obtain the tetracyclic quinone 5a (80%
yield): 1H-NMR δ 13.59 (2H, s), 6.67 (2H, dd, J ) 1.0, 7.8 Hz),
6.44 (2H, dd, J ) 6.0, 7.8 Hz), 4.57 (2H, m), 3.72 (6H, s), 1.9-
1.3 (8H, m).
6,11-Dih yd r oxy-1,10-d im eth oxy-1,4,7,10-tetr a h yd r o-5,-
12-n a p h th a cen equ in on e (5b). Compound 5b was obtained
as above from 4b (82% yield): 1H-NMR δ 14.12 and 13.02 (2H,
2s), 6.67 (2H, dd, J ) 1.1, 7.9 Hz), 6.43 (2H, dd, J ) 6.1, 7.9
Hz), 4.54 (2H, m), 3.72 (6H, s), 1.9-1.3 (8H, m); 13C-NMR δ
169.9 (2C), 167.9 (2C), 147.6 (2C), 147.5 (2C), 146.4, 146.3,
135.4 (2C), 131.4 (2C), 85.60 (2C), 55.7 (2C), 33.1 (2C), 31.1-
(2C), 25.0 (2C).
Exp er im en ta l Section
Melting points were obtained in open capillary tubes and
are uncorrected. 1H- and 13C-NMR spectra were recorded in
CDCl3 at 200.1 and 50.3 MHz, respectively. Diastereoisomeric
adduct ratios were established by integration of well-separated
signals of the diastereoisomers 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. CH2Cl2 was dried over P2O5. All other
reagent quality solvents were used without purification. For
routine workup, hydrolysis was carried out with water, extrac-
tions with CH2Cl2, and solvent drying with Na2SO4.
5,8-Dih yd r oxy-1-m eth oxy-6-(p-tolylth io)-1,4,4a ,9a -tet-
r a h yd r o-9,10-a n t h r a qu in on e (2a ). To a solution of 2-(p-
tolylthio)naphthazarin (1) (100 mg, 0.3 mmol) in 10 mL of
refluxing CH2Cl2 was added 1-methoxy-1,3-cyclohexadiene (0.6
mL, 3 mmol, 10 equiv). After 24 h, the solvent was evaporated
and the residue purified by flash chromatography (eluent:
CH2Cl2) to afford 2a as a brown solid (79% yield): mp 168-
170 °C (MeOH); 1H-NMR δ 12.97 and 12.36 (2s, 2H), 7.43 and
7.27 (4H, AA′BB′ system), 6.45 (1H, s), 6.13 (1H, dd, J ) 5.6,
8.7 Hz), 6.06 (1H, dd, J ) 1.8, 8.7 Hz), 3.49 (3H, s), 3.39 (1H,
d, J ) 9.1 Hz), 3.33 (1H, m), 3.26 (1H, dd, J ) 2.8, 9.1 Hz),
2.42 (3H, s), 2.1-1.4 (4H, m); 13C-NMR δ 203.6, 198.7, 155.4,
150.8, 140.6, 135.9 (2C), 135.8, 131.4, 131.2, 131.1 (2C), 124.5,
121.7, 113.2, 112.3, 80.1, 51.3, 50.9, 50.6, 36.4, 29.3, 24.2, 21.3.
5,8-Dih yd r oxy-1-m eth oxy-7-(p-tolylth io)-1,4,4a ,9a -tet-
r a h yd r o-9,10-a n th r a qu in on e (2b). Compound 2b was ob-
tained as above in EtOH at 40 °C as an unseparable 75:25
mixture with 2a (78% yield): 1H-NMR δ 12.78 and 12.46 (2H,
2s), 7.44 and 7.27 (4H, AA′BB′ system), 6.41 (1H, s), 6.08 (2H,
m), 3.50 (3H, s), 3.41 (1H, d, J ) 9.0 Hz), 3.30 (1H, m), 3.22
(1H, dd, J ) 2.8, 9.0 Hz), 2.42 (3H, s), 2.1-1.4 (4H, m).
9,10-Dih yd r oxy-5-m eth oxy-2-(p-tolylth io)-5,8-d ih yd r o-
1,4-a n th r a qu in on e (3a ). To a solution of 2a (85 mg, 0.2
mmol) in 5 mL of THF was added K2CO3 (280 mg, 2 mmol, 10
equiv) in 5 mL of H2O. After 24 h at rt, the reaction mixture
was hydrolyzed with 10% HCl and extracted with ethyl ether.
Ack n ow led gm en t. We thank Direccio´n General de
Investigacio´n Cient´ıfica y Te´cnica (Grants PB92-0161,
PB92-0162, and PB95-0174) and Comunidad Auto´noma
de Madrid (Grants AE 00144/94 and AE00244/95) for
financial support.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H-NMR
spectra of all compounds (8 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
(11) Kraus, G. A.; Woo, S. H. J . Org. Chem. 1986, 51, 114.
(12) Boeckmann, R. K., J r.; Dolak, T. M.; Culos, K. O. J . Am. Chem.
Soc. 1978, 100, 7098.
J O960855N