Asymmetric organocatalytic anthrone additions to activated alkenes

Article abstract of DOI:10.1016/j.tet.2011.02.032

Asymmetric organocatalytic additions of anthrones to activated alkenes are discussed. The reaction between anthrone or dithranol and α,β- unsaturated aldehydes is catalyzed by diphenylprolinol trimethylsilyl ether in toluene at -40 °C, giving the Michael

Full text of DOI:10.1016/j.tet.2011.02.032

Tetrahedron 67 (2011) 2513e2529
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Asymmetric organocatalytic anthrone additions to activated alkenes
,
a,b,
Alex Zea a, Andrea-Nekane R. Alba a, Natalia Bravo a, Albert Moyano a , Ramon Rios
*
*
a
ꢀ
ꢀ
Departament de Química Organica, Universitat de Barcelona, Facultat de Química, C. Martí i Franques 1-11, 08028 Barcelona, Spain
b ICREA, Pg. Lluís Companys 23, 08019 Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric organocatalytic additions of anthrones to activated alkenes are discussed. The reaction
between anthrone or dithranol and -unsaturated aldehydes is catalyzed by diphenylprolinol trime-
Received 30 December 2010
Accepted 14 February 2011
Available online 18 February 2011
a,b
thylsilyl ether in toluene at ꢀ40 ꢁC, giving the Michael adducts with good yields and enantioselectivities.
Bifunctional amino-thioureas efficiently catalyze the additions of anthrones to both nitroalkenes and
maleimides, and high enantioselectivities can be achieved in both instances at room temperature. In the
case of nitroalkenes, a Michael addition takes exclusively place. Anthrone generally gives DielseAlder
cycloadducts in the reaction with maleimides, while dithranol affords the Michael adducts. Transition
state working models in which the bifunctional catalyst binds simultaneously to the alkene and to the
anthrone enolate account for the stereochemical outcome of these additions.
ꢁ
Dedicated to Professor Carmen Najera on
the occasion of her 60th birthday
Keywords:
Anthrones
Asymmetric catalysis
DielseAlder cycloaddition
Michael addition
Organocatalysis
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
its derivatives have been reported, most of them dealing with its
base-catalyzed DielseAlder reactions. In the light of these pre-
The chemistry of anthrone and its derivatives is an important
topic in modern organic chemistry.1 The parent anthrone (9-[10H]-
anthracenone, 1a) has been classically used as a reagent for the
analytical determination of sugars. Dithranol (1,8-dihydroxy-9-
[10H]-anthracenone, 1b) is a synthetic compound, that is, widely
used in the treatment of psoriasis. Anthrones and their enol tauto-
mers, 9-anthrols, play a central role in the chemistry of anthracenes,
because by oxidation of the central ring they afford 9,10-anthra-
quinones; the reduction of anthrones provides anthracenes, useful
in the preparation of dyestuffs and of optoelectronic materials.2
On the other hand, natural derivatives of anthrone are isolated,
either in free form or as O- or C-glycosides, from a wide variety of
cedents, and given our interest on the development of new meth-
odology for asymmetric organocatalysis,6 we undertook a study of
the chiral amine-catalyzed enantioselective reactions of anthrones
with electron-deficient alkenes such as a,b-unsaturated aldehydes,
nitrostyrenes, and maleimides. We present herein a full account of
our results in this topic.
2. Results and discussion
2.1. Anthrones as nucleophiles in Michael additions
Although the most common reaction of anthrone with electron-
poor alkenes is the DielseAlder cycloaddition,7 the anthracenolate
ion generated from the deprotonation of anthrone by strong bases
like sodium alkoxides usually undergoes a double Michael addition
ꢁ
vegetal sources (plants, shrubs), such as rhubarb, cassia, and ‘cascara
sagrada’ bark, among others.3 Many of these compounds have
interesting biological properties, and are being used either as
antimicrobial, laxative, antipsoriatic or as androgen-receptor and
telomerase inhibitors.4 Recently, it has been shown that some
anthrone- or anthraquinone-based natural products display potent
and selective antitumor activity.5
at C10 when reacted with a,b
-unsaturated esters.8 Therefore, we
decided to study the amine-catalyzed reaction between anthrones
and enals,9 in order to see whether we obtained the DielseAlder or
the Michael adduct (Fig. 1).
We found out that when anthrone 1a was added to cinna-
maldehyde (2a) in toluene using different proline or prolinol de-
rivatives as catalysts, only the single Michael addition product 3a
was observed (Table 1).
The development of efficient methods for the asymmetric syn-
thesis of anthrones appears therefore as a worthy objective. How-
ever, only a few examples of asymmetric reactions of anthrone or
Proline (I, entry 1 in Table 1) was a rather inefficient catalyst for
the reaction, leading to the racemic adduct 3a with low conversion.
* Corresponding authors. Fax: þ34 933397878; e-mail addresses: amoyano@
ub.edu (A. Moyano), rios.ramon@icrea.cat (R. Rios).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.032

2514
A. Zea et al. / Tetrahedron 67 (2011) 2513e2529
entry 7), that clearly enhanced the reaction rates at ꢀ40 ꢁC, did
CHO
H OH
H
not bring about any positive effect in terms of enantioselectivity.
Using the most suitable reaction conditions for the enantiose-
lective addition of anthrone to cinnamaldehyde (diphenylprolinol
trimethylsilyl ether III as the catalyst, toluene, ꢀ40 ꢁC), we studied
R
CHO
R
+
the scope of the reaction with other
a,b-unsaturated aldehydes
Diels-Alder
O
2beg, as shown in Table 3.
O
Gratifyingly, in most instances the anthrone addition took
place with good yields, albeit with prolonged reaction times (5e36
days). Enantioselectivities ranged from good to excellent for
4-substituted cinnamaldehyde derivatives. For example, when
4-nitrocinnamaldehyde 2c was used, the addition product 3c was
obtained with 75% yield and 78% ee after 36 days at ꢀ40 ꢁC (entry 3).
In the case of 4-cyanocinnamaldehyde 2b, the reaction proceeded
extremely well, obtaining the final adduct 3b in 85% yield and 99%
ee after only 5 days at ꢀ40 ꢁC (entry 2). On the other hand,
2-substituted cinnamaldehydes 2d and 2e gave very low yields
and enantioselectivities, even after very prolonged reaction times
1a
CHO
R
Michael
Fig. 1. Possible products of the addition of anthrone to enals.
Table 1
Catalyst screening in the reaction between anthrone (1a) and cinnamaldehyde (2a)a
O
O
Catalyst (20 mol%)
CHO
+
Ph
Toluene, -20ºC, 48 h
2a
CHO
Ph
1a
3a
F C
3
CF
3
CF
3
Ph
Ph
COOH
N
H
N
H
N
H
N
H
OH
OTMS
OTMS
CF
3
I
II
III
IV
Entry
Catalyst
Conversion (%)b
eec
1
2
3
4
I
II
III
IV
8
23
76
<5
0%
0%
48%
n.d.d
a
Experimental conditions: A mixture of 1a (0.30 mmol), 2a (0.25 mmol), and the catalyst (0.05 mmol) in toluene (1 mL) was stirred at ꢀ20 ꢁC during 48 h.
b
c
Determined by 1H NMR analysis of the reaction mixture.
Determined by HPLC analysis.
d
Not determined.
Prolinol II (entry 2) also gave racemic 3a. Best results were obtained
(entries 4 and 5). When aliphatic enals 2fei were used, the reaction
took place with high yields and enantioselectivities after 10 days at
ꢀ40 ꢁC (entries 6e9). Further studies showed that the final adducts
racemize very fast at room temperature, probably due to a retro-
Michael process, especially when aromatic aldehydes are used. This
could account for the better enantioselectivities obtained with
aliphatic aldehydes, as well as for the poor results afforded by ortho-
substituted cinnamaldehydes, that react very slowly.
Spurred on by these results, we tried next to expand this
methodology to dithranol 1b. It is well known that anthranols are
more nucleophilic than anthrones, so that normally only 1,4-addi-
tion is observed. For example, Tan and co-workers reported that
while anthrones reacted with maleimides affording the expected
DielseAlder adducts, dithranol only gave the 1,4-Michael addi-
tion.11 When we performed the amine-catalyzed reaction of
dithranol with cinnamaldehyde derivatives, we obtained however
very complex reaction mixtures, from which we could not isolate
the expected addition products. We were therefore delighted to
with diphenylprolinol trimethylsilyl ether III, that afforded promis-
ing conversion and enantioselectivity (entry 3). JérgenseneHayashi
catalyst IV, on the other hand, showed a very low catalytic activity
(entry 4).
We decided next to optimize the reaction conditions in order to
achieve higher yields and enantioselectivities. In an initial screening
(Table 2), we found that amine III efficientlycatalyzed the reaction in
toluene at room temperature, although no significant enantiose-
lective induction was observed (entry 1; Table 2). For this reason, we
performed the reaction at lower temperatures. At ꢀ30 ꢁC, the re-
action exhibited a reasonable rate in dichloromethane, but the en-
antiomeric excess of the product was much lower than in toluene
(entries 3 and 4, Table 2). We were pleased to find that in toluene
at ꢀ40 ꢁC the enantiomeric excess of the product was increased to
80% (entry 5; Table 2), although the reaction rate was rather low.
Furthermore, the use of different additives, such as acids (benzoic
acid; entry 6) or hydrogen-bond donors (Schreiner’s thiourea;10

A. Zea et al. / Tetrahedron 67 (2011) 2513e2529
2515
Table 2
Solvent and temperature screening in the reaction between anthrone (1a) and cinnamaldehyde (2a) catalyzed by IIIa
O
O
III (20 mol%)
CHO
+
Ph
Solvent, T, time
2a
CHO
Ph
1a
3a
Entry
Solvent
T
Time
Conversion (%)b
ee (%)c
1
2
3
4
Toluene
Toluene
CH2Cl2
Toluene
Toluene
Toluene
Toluene
rt
3 h
100
76
43
48
23
33
23
4
48
14
63
80
54
60
ꢀ20 ꢁC
ꢀ30 ꢁC
ꢀ30 ꢁC
ꢀ40 ꢁC
ꢀ40 ꢁC
ꢀ40 ꢁC
48 h
24 h
72 h
10 days
48 h
48 h
5
6d
7e
a
Experimental conditions: A mixture of 1a (0.30 mmol), 2a (0.25 mmol), and catalyst III (0.05 mmol) in toluene or dichloromethane (1 mL) was stirred at the temperature
specified in the table.
b
Determined by 1H NMR analysis of the reaction mixture.
Determined by HPLC analysis.
Benzoic acid (0.2 mmol) was present in the reaction mixture.
Schreiner’s thiourea (0.2 mmol) was present in the reaction mixture.
c
d
e
Table 3
Scope of the reaction between anthrone (1a) and
a
,
b
-unsaturated aldehydes (2a-i) catalyzed by IIIa
O
O
III (20 mol%)
CHO
R
+
Toluene, -40ºC
2a-i
CHO
R
1a
3a-i
Entry
Aldehyde (R)
Product
Time
Yield (%)b
ee (%)c
1
2
3
4
2a (Ph)
3a
3b
3c
3d
3e
3f
3g
3h
3i
36 days
5 days
88
85
80
99
78
3
2b (4-CNPh)
2c (4-NO2Ph)
2d (2-BrPh)
2e (2-NO2Ph)
2f (Me)
2g (Et)
2h (n-Pr)
2i (n-Bu)
36 days
53 days
53 days
10 days
10 days
10 days
10 days
75
32d
35d
95
7
4
5
6
7
94
96
96
86
82
84
92
a
Experimental conditions: A mixture of 1a (0.30 mmol), 2aei (0.25 mmol), and catalyst III (0.06 mmol) in toluene (2 mL) was stirred at ꢀ40 ꢁC for the time necessary to
achieve full conversion, as determined by 1H NMR analysis of the reaction mixture.
b
Yield of isolated product after chromatographic purification.
Determined by HPLC analysis of the reaction mixture.
Conversion was not complete.
c
d
find that when dithranol was used in our reaction with aliphatic
-unsaturated aldehydes, the products of single Michael addition
was treated with methylmagnesium bromide, affording the corre-
sponding diastereomeric mixture of alcohols 5a and 5a0. Next, the
oxidation of this mixture with pyridinium chlorochromate (PCC)
gave the corresponding ketone 6a (Scheme 1). Comparison of its
specific rotationwith the literature data12 revealed that the absolute
configuration of this compound, and accordingly that of 3a, is (3R):
a,b
4aed were isolated with good yields and with very high enantio-
selectivities after 10 days at ꢀ40 ꢁC (Table 4).
In order to determine the absolute configuration of our com-
pounds, we took advantage of the fact that, after the publication of
our preliminary results on the addition of anthrones to enals,9 Ye co-
[a
]
25 ꢀ1.8 (c 2.7, CH2Cl2), (3S)-6a, lit.: [
a
]
25 þ2.88 (c 1.0, CH2Cl2)].
D
D
workers reported the reaction of anthrones with
b
-aryl-
a
,b
-un-
This stereochemical outcome can be easily rationalized within
saturated ketones catalyzed by Cinchona-alkaloid derived tertiary
amino-thioureas, the corresponding Michael adducts being
obtained with good yields and enantioselectivities.12 Moreover, the
authors were able to ascertain the absolute configuration of their
products from the anomalous X-ray diffraction analysis of a halo-
genated adduct. Therefore, the Michael adduct 3a (80% ee), resulting
from the reaction between anthrone 1a and cinnamaldehyde 2a,
the mechanistic model proposed for other chiral secondary amine-
catalyzed reactions between nucleophiles and enals,13 as exempli-
fied in Scheme 2. Thus, efficient shielding of the Re-face of the chiral
iminium intermediate 7 by the bulky aryl groups of the chiral
pyrrolidine III leads to stereoselective Si-facial nucleophilic conju-
gate attack on the
b-carbon of 7. Hydrolysis of the resulting en-
amine intermediate 8 would regenerate the catalyst and release the

2516
A. Zea et al. / Tetrahedron 67 (2011) 2513e2529
Table 4
Scope of the reaction between dithranol (1b) and aliphatic a,b
-unsaturated aldehydes (2fei) catalyzed by IIIa
OH
O
OH
OH
O
OH
III (20 mol%)
CHO
+
R
Toluene, -40ºC, 10 d
2f-i
CHO
R
1b
4a-d
Entry
Aldehyde (R)
Product
Yield (%)b
ee (%)c
1
2
3
4
2f (Me)
2g (Et)
2h (n-Pr)
2i (n-Bu)
4a
4b
4c
4d
88
95
93
92
97
99
99
99
a
Experimental conditions: A mixture of 1b (0.25 mmol), 2fei (0.37 mmol), and catalyst III (0.05 mmol) in toluene (2 mL) was stirred at ꢀ40 ꢁC during 10 days.
b
c
Yield of isolated product after chromatographic purification.
Determined by HPLC analysis.
O
O
O
O
MeMgBr
PCC
CH Cl rt
THF, -20ºC
2
2,
OH
Me
CHO
Ph
Ph
Ph
(-)-6a
3a
5a + 5a'
Me
Scheme 1. Determination of the absolute configuration of 3a.
(3R)-Michael adduct. A mechanism involving the intermediacy of
the DielseAlder cycloadduct 9, that by a retro-aldol reaction would
lead to 8, can also be envisaged.
Either with the quinine-derived thiourea catalyst VI or with the
quinidine-derived thiourea catalyst VII, the enantiomeric purities of
the adduct 11a were lower thanwith Takemoto’s thiourea catalyst V.
As expected, quasienantiomeric catalysts VI and VII preferently
rendered opposite enantiomers of 11a in the reaction, with total
conversion after 14 h at room temperature in toluene. It is in-
teresting to note that both (R,R)-V and VII (that also has an (R) ab-
solute configuration at the thiourea stereogenic center) show the
same sense of asymmetric induction.
In 2007, Shi and co-workers described a highly efficient addition
of anthrone to nitroalkenes catalyzed by Cinchona alkaloids and
some of their derivatives.14 When using O-benzoylcupreine as
a chiral catalyst, the Michael addition of anthrone 1a to nitro-
alkenes took place with excellent yields and enantioselectivities,
but the reaction had to be performed at low temperature (ꢀ40 ꢁC)
in chlorinated solvents. This methodology was not suitable more-
over for the addition of dithranol 1b, since in a single example
described by the authors, the enantiomeric excess of the adduct
was very low (9% ee).
Having selected the most suitable reaction conditions for the
enantioselective addition of anthrone to nitrostyrene at room
temperature (toluene, Takemoto’s thiourea V as the catalyst), we
studied the scope of the reaction with different trans-b-nitro-
In the past few years, bifunctional amino-thioureas have
emerged as an important class of enantioselectiveorganocatalysts,15
and in particular they have demonstrated their usefulness in
asymmetric Michael additions to nitroolefins.16 We hypothesized
that bifunctional organocatalysts would also lead to good results in
the addition of anthrones to nitroalkenes, due to their ability to
bring together the two reactants in the transition state by hydrogen-
bonding. In order to test this hypothesis, we investigated the re-
styrene derivatives, as shown in Table 7.
Conversion was completed in all instances after 14 h at room
temperature, and the adducts 11aee were isolated in excellent
yields (91e95%) after chromatographic purification. Enantiomeric
purities were also uniformly high (85e92% ee), although electron-
withdrawing para-substituents gave slightly lower enantiose-
lectivities than electron-donating ones (compare entries 4 and 5 in
Table 7).
action between anthrone 1a and trans-
b
-nitrostyrene 10a, using as
As it could be inferred from the precedent reported by Shi,14 the
a catalyst the commercially available thiourea (R,R)-V described by
Takemoto17 in different solvents at room temperature (Table 5).
Independently of the solvent used, conversion was excellent after
14 h. However, the enantioselectivity decreased from a maximum of
89% ee using toluene (entry 1 in Table 5) down to nearly racemic
when the reaction was run in dimethylsulfoxide (entry 6) or in
ethanol (entry 5), probably due to the fact that their interaction with
the catalyst disrupts the hydrogen-bond network in the transition
state.
addition of dithranol (1b) to b-nitrostyrenes was much more
challenging (Table 8).
At room temperature, the reaction between 1b and trans-b-
nitrostyrene 10a was completed after 14 h, but the Michael addition
product 12a was racemic (entry 1 in Table 8). Fortunately, we could
go down to ꢀ40 ꢁC maintaining a reasonable reaction rate, achieving
a 36% ee for this product (entry 3 in Table 8). Under these conditions,
electron-rich styrenes 10c and 10d afforded the corresponding ad-
ducts 12c and 12d with somewhat higher enantioselectivities (38
and 40% ee, respectively; entries 5 and 6). On the other hand, under
We compared next the behavior of V with that of other bi-
functional catalysts bearing a thiourea and a tertiaryamine (Table 6).
these conditions both trans-b-nitro(2-fluorostyrene) 10b (entry 4)

A. Zea et al. / Tetrahedron 67 (2011) 2513e2529
2517
O
1
OH
7
OH
R
N
O
H O
2
2
H O
2
7
R
N
N
H
N
H
R
O
H
R
H
O
O
9
8
H O
2
CHO
R
(R)-3
R = n-Alkyl, aryl
Scheme 2. Mechanistic proposal for the enantioselective addition of anthrones to enals.
and trans-
b
-nitro(4-nitrostyrene) 10d (entry 7) afforded lower
While this work was in progress, Yuan and co-workers reported
on the use of tertiary amines bearing a thiourea moiety as catalysts
for the addition of 1a to nitroalkenes, with similar results.19
enantioselectivities (21% and 13% ee, respectively). These results
suggest that the hydroxyl groups of dithranol 1b might interfere
with the hydrogen-bond network between the catalyst and
nitrostyrene, resulting in a loss of stereoselectivity. Even if the
bifunctional catalyst (R,R)-V affords much better results than
O-benzoylcupreine,14 the high nucleophilic reactivity of dithranol
renders its asymmetric addition to highly reactive Michael accep-
tors such as nitrostyrenes very hard to control.
2.2. Anthrones in DielseAlder reactions
Asymmetric DielseAlder cycloadditions of anthrones were first
disclosed more than twenty years ago. Kinetic studies performed by
Koerner and Rickborn20 on the reaction between anthrone and
N-methylmaleimide showed that this cycloaddition was efficiently
catalyzed by tertiary amines, probably due to the high reactivity of
the anthrone enolate as a diene. Building upon these results, Riant
and Kagan investigated the effect of chiral bases in the same
reaction,21 finding that quinidine and prolinol were the most
enantioselective catalysts (up to 61% ee was achieved with a 10 mol
% of quinidine in chloroform at ꢀ50 ꢁC). More recently, Fache and
Piva used perfluoroalkylated Cinchona-alkaloid derivatives for the
same purpose, obtaining up to 40% ee in trifluorotoluene at room
temperature.22 Later on, Yamamoto and co-workers23 described the
asymmetric cycloaddition of anthrone and maleimides cataly-
zed by C2-chiral 2,5-bis(hydroxymethyl)pyrrolidines, obtaining
variable enantioselectivities (47e87% ee). The enantioselec-
tive DielseAlder cycloaddition of substituted anthrones with
The absolute (R)-configuration of our compounds was easily
ascertained by chemical correlation with those previously described
by Shi.14 Thus, for instance, we determined a specific rotation
[
a
]
25 ꢀ22.8 (c 0.9, CHCl3) for adduct 11a, whose dextrorotatory en-
D
antiomer had been shown to have an (S)-configuration.
This stereochemical result can be accommodated either by
a qualitative model related to that proposed by Takemoto for the
addition of malonates to
b
-nitrostyrenes17 (transition state A in
Fig. 2, in which the thiourea binds the nitro group), or by another
related to the one forwarded by Papai and co-workers18 (transition
ꢁ
state B in Fig. 2, in which the thiourea binds the anthrone enolate
oxygen). As before, the initial formation of a DielseAlder adduct C
(being produced either by transition states A or B) that leads to the
Michael product by a retro-Henry reaction is also possible.

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A. Zea et al. / Tetrahedron 67 (2011) 2513e2529
Table 5
Solvent screening in the reaction between anthrone (1a) and trans-
b
-nitrostyrene (10a) catalyzed by Va
O
O
(R,R)-V (10 mol%)
Solvent, rt, 14 h
NO
2
+
Ph
10a
CF
NO
2
Ph
1a
3
11a
S
F C
N
H
N
H
3
NMe
2
(R,R)-V
Entry
Solvent
Conversion (%)b
ee (%)c
1
2
3
4
5
6
Toluene
CHCl3
CH2Cl2
AcOEt
DMSO
EtOH
100
100
100
100
100
100
89
76
46
64
0
7
a
Experimental conditions: A mixture of 1a (0.25 mmol), 10a (0.28 mmol), and the catalyst (R,R)-V (0.025 mmol) in the solvent specified in the table (1 mL) was stirred at rt
during 14 h.
b
c
Determined by 1H NMR analysis of the reaction mixture.
Determined by HPLC analysis.
Table 6
Catalyst screening in the reaction between anthrone (1a) and trans-b
-nitrostyrene (10a) in toluenea
O
O
Catalyst (10 mol%)
Toluene, rt, 14 h
NO
2
+
Ph
10a
NO
2
Ph
1a
CF
3
11a
H
OMe
F C
3
NH
H
N
H
NH
H
S
NH
H
N
N
N
S
NH
H
VII
VI
OMe
F C
3
CF
3
Entry
Catalyst
Conversion (%)b
ee (%)c
1
2
3
(R,R)-V
VI
VII
100
100
100
89
ꢀ58d
63
a
Experimental conditions: A mixture of 1a (0.25 mmol), 10a (0.28 mmol), and the catalyst (0.025 mmol) in toluene (1 mL) was stirred at rt during 14 h.
b
c
Determined by 1H NMR analysis of the reaction mixture.
Determined by HPLC analysis.
d
Preferential formation of ent-11a.
maleimides catalyzed by chiral bicyclic guanidines, which takes
performed at room temperature. Very recently, the same research
group has reported on the use of an adduct of anthrone and
N-acetoxyphthalimide, obtained in 92% ee, as a precursor of cata-
lysts for the asymmetric aerobic oxidation of organic compounds.24
place with excellent yields and enantioselectivities (85e99% ee)
when run in dichloromethane solution at ꢀ20 ꢁC, was reported in
2006 by Tan and co-workers.11 This reaction showed however
a very strong temperature dependence, and the enantiomeric pu-
rities of the DielseAlder products were much lower when it was
€
In 2008, Gobel and co-workers developed an addition of anthro-
nes to maleimides catalyzed by metal-free bis(oxazolines), with

A. Zea et al. / Tetrahedron 67 (2011) 2513e2529
2519
Table 7
Scope of the addition of anthrone (1a) to nitrostyrenes (10aee) catalyzed by Va
O
O
(R,R)-V (10 mol%)
NO
2
+
Toluene, rt, 14 h
NO
2
R
1a
10a-e
R
11a-e
Entry
Nitrostyrene (R)
Product
Yield (%)b
ee (%)c
1
2
3
4
5
10a (H)
10b (2-F)
10c (4-Me)
10d (4-MeO)
10e (4-NO2)
11a
11b
11c
11d
11e
92
95
92
94
91
89
92
90
90
85
a
Experimental conditions: A mixture of 1a (0.25 mmol), the nitroolefin (0.28 mmol), and the catalyst (R,R)-V (0.025 mmol) in toluene (1 mL) was stirred at rt during 14 h.
Yield of isolated product after chromatographic purification.
Determined by HPLC analysis.
b
c
Table 8
Scope of the addition of dithranol (1b) to nitrostyrenes (10a-e) catalyzed by Va
OH
O
OH
NO
OH
O
OH
(R,R)-V (10 mol%)
NO
2
+
Toluene, T, 14 h
2
R
1b
10a-e
R
12a-e
Entry
Nitrostyrene (R)
Product
T
Yieldb
ee (%)c
1
2
3
4
5
6
7
10a (H)
10a (H)
10a (H)
10b (2-F)
10c (4-Me)
10d (4-MeO)
10e (4-NO2)
12a
12a
12a
12b
12c
12d
12e
rt
n.d.d
n.d.d
77%
89%
85%
70%
87%
0
26
36
21
38
40
13
ꢀ20 ꢁC
ꢀ40 ꢁC
ꢀ40 ꢁC
ꢀ40 ꢁC
ꢀ40 ꢁC
ꢀ40 ꢁC
a
Experimental conditions: A mixture of 1b (0.25 mmol), the nitroolefin (0.28 mmol), and the catalyst (R,R)-V (0.025 mmol) in toluene (1 mL) was stirred at the temperature
specified in the table during 14 h.
b
Yield of isolated product after chromatographic purification.
c
Determined by HPLC analysis.
d
Not determined; 100% conversion by 1H NMR.
moderate enantioselectivities (39e70% ee).25 Similar results were
achieved through the use of chiral bisamidines as catalysts.26
Finally, a chiral ionic liquid derived from lactic acid has been
lately used as an asymmetric inducer in DielseAlder reactions be-
tween anthrone and several maleimides, with moderate success
(up to 37% ee).27
Given the good performance of bifunctional amino-thiourea
catalysts in the addition of anthrones to nitroalkenes, we decided to
assess their usefulness in the DielseAlder cycloaddition of
anthrones with maleimides.28 the reaction of anthrone 1a with
N-phenylmaleimide 13a as the benchmark process, we studied the
effect of the catalyst and of the solvent (Table 9).
Takemoto’s thiourea V was an efficient catalyst for this reaction,
and complete conversion of anthrone to the expected cycloadduct
14a was obtained after 14 h at room temperature in relatively non-
polar solvents (entries 1e3 inTable 9). Toluene (entry 1) provided the
bestenantioselectivity. Not surprisingly, theuse ofdimethylsulfoxide
as a solvent inhibited the catalytic activity of V (entry 4). The Cin-
chona-alkaloid derived thioureas VI and VII also catalyzed the cy-
cloaddition, but with lower enantioselectivities (entries 5 and 6). The
positive effect of the thiourea moiety is evinced by the fact that
quinidine (VIII) was a less enantioselective catalyst than VII (com-
pare entries 6 and 7). The fact that with quinidine VIII the major
product was ent-14a21,23b also allowed us to conclude that the ab-
solute configuration of 14a was (R,R), an assumption that was also
supported by comparison of its specific rotation with that previously
described in the literature.11
The reaction of 1a with other maleimides was then performed
using the conditions of entry 1 in Table 9 (Table 10). The yields of
the reaction were uniformly high (90e94% after direct purification
of the reaction crude by column chromatography in silica gel).
N-arylmaleimides, with the sole exception of the 4-bromophenyl
derivative 13f (entry 6 in Table 10), afforded the corresponding
DielseAlder adducts with excellent enantioselectivities (90e97%

2520
A. Zea et al. / Tetrahedron 67 (2011) 2513e2529
CF
3
S
N
N
H
O
N
H
O
CF
3
Me
Me
N
H
O
H
O
(R)-11
TS A
NO
2
CF
3
S
N
N
CF
3
O
N
O
Me
Me
N
H
H
H
O
H
O
Ph
H
O
N
O
C
TS B
Fig. 2. Transition state working models for the Michael addition of anthrones to nitroalkenes catalyzed by (R,R)-V.
ee, entries 1, 3e5 in Table 10). For these substrates, therefore,
Takemoto’s thiourea V is a much better catalyst at room tempera-
ture than the bicyclic guanidine employed by Tan, that afforded ent-
14a in only 12% ee.11
same diastereomers was obtained in 80% yield. We can estimate an
inthrinsic diastereomeric ratio29 of 3.58:1 (i.e., a 78% de) for catalyst
V in the reaction of anthrone with N-(1-phenylethyl)maleimide.
The stereoselectivity of the cycloaddition therefore decreases with
We were surprised to find that the reaction of anthrone
with N-(4-(trifluoromethyl)phenyl)maleimide 13e furnished the
Michael adduct 140e (94% yield, 97% ee; entry 5 in Table 10) instead
of the DielseAlder product 14e, that had been previously obtained
by Yamamoto with low enantioselectivity (up to 50% ee) using ei-
ther VIII or C2-chiral pyrrolidines as catalysts in chloroform at room
temperature.23b Since it is known that the anthrone/maleimide
DielseAlder cycloadducts readily isomerize to the ‘open’ Michael
products upon treatment with base,11,23 we assume that the ini-
tially formed adduct 14e undergoes a base-promoted retro-aldol
ring-opening reaction to give the thermodynamically more stable
product 140e. This process is probably facilitated by the strongly
electron-withdrawing trifluoromethyl substituent.
increasing bulkiness of the a-substituent.
In line with the previous results of Tan,11 we found that
dithranol 1b afforded exclusively the Michael adducts 15 in its re-
action with maleimides (Table 11). We were pleased to find that,
contrary to what happened in the reaction of 1b with nitroalkenes,
the Michael adducts were obtained not only with high yields, but
generally with good enantioselectivities (entries 1-3 and 5 in
Table 11). Contrary to what happened in the case of anthrone,
maleimide 13f reacted with excellent enantioselectivity (entry 5).
However, the presence of a chlorine atom at the meta-position of
the phenyl ring in maleimide 13c resulted in a low enantiomeric
purity of the corresponding adduct 15c (22% ee, entry 3). The re-
action between 1b and N-benzhydrylmaleimide 13g (entry 6) gave
the corresponding adduct 15g in good yield, but unfortunately we
were not able to find suitable HPLC conditions for the deter-
mination of its enantiomeric excess.
While N-benzylmaleimide 13b gave the cycloadduct 14b with
good enantioselectivity (85% ee; entry 2 in Table 10), N-benzhy-
drylmaleimide 13g afforded 14g with good yield but with a much
lower enantiomeric purity (33% ee; entry 7 in Table 10).
An absolute (S) configuration was assigned to the predominant
enantiomers of these adducts under the assumption that they arise
from the retro-aldol ring-opening of an initially formed (R,R)-
cycloadduct. On the other hand, the specific rotations of com-
pounds 15a and 15b match (both in sign and in magnitude) those
previously reported by Tan.11 We propose that the in the case of the
dithranol-maleimide derivatives the stability of the Michael adduct
with respect to the kinetic DielseAlder product is enhanced by
hydrogen-bonding of the anthrone carbonyl with the neighboring
hydroxyls (Fig. 3).
The deletereous effect of
a-branching in N-benzylmaleimides
for the stereoselectivity of the reaction was also evinced when
(R)-N-(1-phenylethyl)maleimide 13h was reacted with anthrone
(Scheme 3). Under catalysis by DABCO, cycloadduct 14h was
obtained in 85% yield as a 1:1.40 mixture of the (R,R)- and (S,S)-
diastereomers (determined by 1H NMR of the crude reaction mix-
ture), a result that closely matched that previously reported by
Yamamoto co-workers with (S)-13h and with pyrrolidine as the
catalyst23a By using (R,R)-V as the catalyst, a 2.56:1 mixture of the

A. Zea et al. / Tetrahedron 67 (2011) 2513e2529
2521
Table 9
Catalyst and solvent screening in the DielseAlder cycloaddition between anthrone (1a) and N-phenylmaleimide (13a)a
O
O
O
Ph
H
Catalyst (10 mol%)
Solvent, rt, 14 h
N
H
N
+
O
O
HO
13a
14a
1a
H
CF
3
H
OH
H
S
N
N
F C
3
N
H
N
H
NMe
2
(R,R)-V
VIII
OMe
Entry
Catalyst
Solvent
Conversion (%)b
eec
1
2
3
4
5
6
7
(R,R)-V
(R,R)-V
(R,R)-V
(R,R)-V
VI
Toluene
CH2Cl2
CHCl3
100
100
100
0
100
100
100
90%
73%
71%
d
DMSO
Toluene
Toluene
Toluene
75%
VII
VIII
ꢀ51%d
ꢀ34%d
a
Experimental conditions: A mixture of 1a (0.25 mmol), 13a (0.30 mmol), and the catalyst (0.025 mmol) in the solvent specified in the table (1 mL) was stirred at rt during
14 h. See Table 6 for the structures of catalysts VI and VII.
b
Determined by 1H NMR analysis of the reaction mixture.
c
Determined by HPLC analysis.
Preferential formation of ent-14a.
d
Table 10
Scope of the DielseAlder cycloaddition between anthrone (1a) and maleimides (13aee) catalyzed by Va
O
R
H
N
H
O
14a-g
O
O
HO
(R,R)-V (10 mol%)
N
R
+
F C
3
Toluene, rt, 14 h
O
O
H
N
13a-g
1a
14'e
O
O
Entry
Maleimide (R)
Product
Yieldb
eec
1
2
3
4
5
6
7
13a (Ph)
14a
14b
14c
14d
140ed
14f
91%
92%
92%
90%
94%
94%
86%
90%
85%
90%
97%
97%
29%
33%
13b (CH2Ph)
13c (3-ClPh)
13d (4-MeOPh)
13e (4-CF3Ph)
13f (4-BrPh)
13 g (CHPh2)
14 g
a
Experimental conditions: Maleimides 13aeg (0.30 mmol) were added to a solution of 1a (0.25 mmol) and of catalyst (R,R)-V (0.025 mmol) in toluene (1 mL) and the
resulting mixture was stirred at rt for 14 h.
b
Yield of isolated product after chromatographic purification.
Determined by HPLC analysis.
Only the Michael adduct 140e was isolated.
c
d

2522
A. Zea et al. / Tetrahedron 67 (2011) 2513e2529
H
Me
Ph
Me
Ph
H
O
O
H
H
N
O
N
O
Catalyst
H
H
Ph
H
(10 mol%)
O
O
N
+
+
Toluene,
rt, 14 h
Me
OH
(R)-(S,S)
HO
(R)-(R,R)
85%, 1:1.40 dr
80%, 2.56:1 dr
O
(R)-13h
14h
1a
Catalyst = DABCO
Catalyst = (R,R)-V
Scheme 3. Amine-catalyzed DielseAlder cycloaddition between anthrone (1a) and (R)-N-(1-phenylethyl)maleimide 13h.
Table 11
Scope of the reaction between dithranol (1b) and maleimides (13a-d,f,g) catalyzed by Va
OH
O
OH
O
OH
O
OH
O
(R,R)-V (10 mol%)
N
R
+
N
Toluene, rt, 14 h
R
O
O
13a-d,f,g
15a-d,f,g
1b
Entry
Maleimide (R)
Product
Yield (%)b
eec
1
2
3
4
5
6
13a (Ph)
15a
15b
15c
15d
15e
15g
93
92
92
94
91
78
99%
85%
22%
97%
96%
n.d.d
13b (CH2Ph)
13c (3-ClPh)
13d (4-MeOPh)
13f (4-BrPh)
13g (CHPh2)
a
Experimental conditions: Maleimides 13a-d,f,g (0.30 mmol) were added to a solution of 1b (0.25 mmol) and of catalyst (R,R)-V (0.025 mmol) in toluene (1 mL) and the
resulting mixture was stirred at rt for 14 h.
b
Yield of isolated product after chromatographic purification.
Determined by HPLC analysis.
Not determined.
c
d
(R,R)-V was used as a catalyst) can be accounted for by the transition
state working model depicted in Fig. 4. In this transition state, the
thiourea moiety binds to a carbonyl of the maleimide, while the
anthrone enolate interacts, also by hydrogen bonding, with the pro-
tonated amine. Molecular modeling of this transition state (Fig. 5)
O
O
R
R
O
H
N
H
N
H
O
suggests that p-stacking interactions between the N-aryl substituent
of the maleimide and the 3,5-bis(trifluoromethyl)phenyl moiety of
the catalyst may also play a role in the preferred orientation of the
maleimide. The fact that N-(a-branched) benzylmaleimides give low
stereoselectivities with Takemoto’s catalyst V gives support to this
HO
O
HO
O
HO
O
H
H
hypothesis.
Fig. 3. Rationalization of the enhanced thermodynamic stability of the Michael
product in front of the DielseAlder dithranol-maleimide cycloadducts.
3. Conclusions
On the other hand, the reaction of dithranol with (R)-N-
(1-phenylethyl)maleimide 13h gave the Michael adduct 15h as
a diastereomeric mixture (Scheme 4). While catalysis with DABCO
afforded a 1:1.61 diastereomer ratio, when using (R,R)-V as a cata-
lyst the diastereomer ratio changed to 1.25:1. The calculated
inthrinsic diastereomeric ratio for V (2.01:1)29 therefore lower than
in the case of anthrone.
In summary, we have presented full details of three different
organocatalytic asymmetric additions of anthrones to activated
alkenes. The reaction between anthrone (1a) or dithranol (1b) and
a,b-unsaturated aromatic or aliphatic aldehydes is catalyzed by
diphenylprolinol trimethylsilyl ether III, giving the Michael adducts
with good yields and enantioselectivities when low reaction tem-
peratures were used. The absolute configuration of the products,
determined by chemical correlation, can be accounted for within
The stereochemical outcome of the anthrone/maleimide Dielse
Alder reaction (preferentialformationof the (R,R)-cycloadducts when

A. Zea et al. / Tetrahedron 67 (2011) 2513e2529
2523
H
Me
Ph
Me
Ph
H
O
O
H
H
N
OH
O
OH
N
O
Catalyst
Ph
H
(10 mol%)
O
O
N
+
+
Toluene,
rt, 14 h
Me
O
O
O
OH
HO
OH
(R)-(R)
HO
(R)-(S)
(R)-13h
15h
1b
Catalyst = DABCO
85%, 1:1.61 dr
Catalyst = (R,R)-V
77%, 1.25:1 dr
Scheme 4. Amine-catalyzed Michael addition between dithranol (1b) and (R)-N-(1-phenylethyl)maleimide 13e.
CF
3
CF
3
O
S
N
R
O
N
H
N
H
H
HO
(R,R)
Me
Me
O
H
O
N
H
H
N
H
H
O
O
R
N
O
H
O
(S)
H
Fig. 4. Transition state working model for the DielseAlder cycloaddition between anthrones and maleimides catalyzed by (R,R)-V.
the mechanistic framework commonly accepted for chiral sec-
ondary amine-catalyzed Michael additions to enals. On the other
hand, bifunctional amino-thioureas, especially Takemoto’s thiourea
V, have been shown to be extremely preactical organocatalysts for
the additions of anthrones to both nitroalkenes and maleimides,
since high enantioselectivities can be achieved in both instances at
room temperature in non-halogenated solvents (toluene). In the
case of nitroalkenes, the reaction goes exclusively through a Mi-
chael addition. Anthrone generally gives DielseAlder cycloadducts
in the reaction with maleimides (except for N-(4-trifluoromethyl)
phenylmaleimide), while dithranol affords the Michael adducts.
Transition state working models in which the bifunctional catalyst
binds simultaneously to the alkene and to the anthrone enolate
rationalize the stereochemical outcome of these processes.
4. Experimental section
4.1. General materials and methods
Melting points were taken on a Gallenkamp apparatus and are
uncorrected. Specific rotations were measured at room tempera-
ture in a PerkineElmer 241 MC polarimeter, using a sodium lamp
Fig. 5. Ball-and-stick representation of the proposed transition state for the Dielse
Alder cycloaddition between anthrones and maleimides catalyzed by (R,R)-V.

2524
A. Zea et al. / Tetrahedron 67 (2011) 2513e2529
(
l
¼589 nm) and a 1 dm-long 1 mL cell. NMR spectra were recorded
hexane 10:90, flow rate 1 mL/min, UV detection at 254 nm,
tmajor¼60.8 min, tminor¼37.0 min.
in CDCl3 solution. 1H NMR (300 MHz) and 13C NMR (75.5 MHz)
were obtained on a Varian Unity 300 or on a Unity-Innova 300
spectrometer; 1H NMR (400 MHz) and 13C NMR (100.6 MHz) were
4.2.3. (R)-3-(4-Nitrophenyl)-3-(10-oxo-9,10-dihydro-anthracen-9-
obtained on a Mercury 400 spectrometer. Chemical shifts (
quoted in parts per million and referenced to internal TMS for 1H
NMR and to CDCl3
77.0) for 13C NMR; data are reported as fol-
d
) are
yl)-propanal (3c). Obtained in 75% yield and 78% ee from 2c and 1a.
Yellowish oil. 1H NMR (400 MHz)
d
3.17 (ddd, J¼18.0, 8.0, 1.2 Hz,
(d
1H), 3.38 (ddd, J¼18.0, 8.0, 1.2 Hz, 1H), 4.94 (d, J¼4.0 Hz, 1H), 6.77
(m, 2H), 7.63e8.23 (m, 8H), 8.41 (dd, J¼7.6, 1.6 Hz, 1H), 8.46 (dd,
lows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; cou-
pling constants (J) are quoted in hertz. High resolution mass spectra
(HRMS) were obtained with the ESI (þor ꢀ) technique at the ‘Unitat
d’ Espectrometria de Masses’ of the Barcelona University. Enan-
tiomeric purities were determined by HPLC using Daicel ChiralpakÒ
IA, IB or IC columns in a Shimadzu LC-20AD instrument with UV
detection. Reactions were generally run with magnetic stirring in
loosely stoppered glass vials under air. Commercially available re-
agents, catalysts and solvents were used as received. Aldehydes
2b,c30 and maleimides 13cef23a,31 were prepared according to lit-
erature procedures. Catalysts VI and VII were obtained from qui-
nine and from quinidine, respectively, by the method described by
Jérgensen and co-workers.32 Silica gel (0.063e0.200 mm) was used
for chromatographic purifications.
J¼7.6, 1.6 Hz, 1H), 10.05 (m, 1H). 13C NMR (100.6 MHz)
d 46.0, 48.6,
49.7, 123.5, 127.6, 128.0, 128.5, 128.7, 128.9, 129.1, 130.1, 132.9, 133.3,
140.7, 142.5, 146.0, 163.1, 184.2, 199.8. HRMS (ESI) calcd from
C23H18NO4 (MþH)þ: 372.1233; found: 372.1230. HPLC conditions:
Daicel ChiralpakÒ IA column, i-PrOH/hexane 10:90, flow rate 1 mL/
min, UV detection at 254 nm, tmajor¼55.16 min, tminor¼50.29 min.
4.2.4. (R)-3-(2-Bromophenyl)-3-(10-oxo-9,10-dihydro-anthracen-9-
yl)-propanal (3d). Obtained in 32% yield and 3% ee from 2d and 1a.
Colorless oil. 1H NMR (400 MHz)
d
2.41 (dd, J¼17.6, 5.6 Hz, 1H), 2.51
(ddd, J¼17.2, 10.4, 2.0 Hz, 1H), 4.49 (q, J¼4.8 Hz, 1H), 4.82
(d, J¼4.0 Hz, 1H), 6.40 (dd, J¼7.6, 1.6 Hz, 1H), 6.50 (d, J¼7.6 Hz, 1H),
7.19e7.79 (m, 8H), 8.34 (d, J¼1.2 Hz, 1H), 8.36 (d, J¼1.2 Hz, 1H), 9.39
(m, 1H). 13C NMR (100.6 MHz)
d 45.4, 49.0, 49.4, 121.9, 130.8, 131.5,
132.7, 132.8, 133.7,134.3,137.4, 141.4,142.5, 184.3, 200.4. HRMS (ESI)
calcd from C23H18BrO2 (MþH)þ: 405.0487; found: 405.0484. HPLC
conditions: Daicel ChiralpakÒ IC column, i-PrOH/hexane 10:90,
flow rate 1 mL/min, UV detection at 254 nm, tmajor¼68.5 min,
tminor¼76.5 min.
4.2. General experimental procedure for the addition of
anthrones to a,b-unsaturated aldehydes
To a stirred solution of catalyst (S)-III (20 mg, 0.06 mmol) in tol-
uene (2 mL) were added the -unsaturated aldehyde (0.25 mmol)
a,b
and the anthrone (1a or 1b, 0.30 mmol). The reaction crude was
vigorously stirred at ꢀ40 ꢁC until the starting anthrone was not
detected by 1H NMR. After warming up the reaction flask to room
temperature, the reaction crude was directly purified by column
chromatography on silica gel (hexane/ethyl acetate mixtures) to af-
ford the Michael adduct. Racemic products were obtained from the
corresponding substrates by catalysis with an artificially constructed
racemic mixture of III in toluene at room temperature during 5 days.
Enantiomeric purities were directly determined from the crude
reaction mixture immediately after complete conversion, because
racemization took place at room temperature. This fact precluded in
most instances the reliable determination of specific rotations for
adducts 3 and 4.
4.2.5. (R)-3-(2-Nitrophenyl)-3-(10-oxo-9,10-dihydro-anthracen-9-
yl)-propanal (3e). Obtained in 35% yield and 7% ee from 2e and 1a.
Yellowish oil. 1H NMR (400 MHz)
d 2.72 (m, 2H), 4.81 (m, 1H), 4.92
(d, J¼4.0 Hz, 1H), 6.42 (dd, J¼8.0, 1.2 Hz, 1H), 6.87 (d, J¼7.2 Hz, 1H),
7.42e7.98 (m, 8H), 8.32 (d, J¼1.2 Hz, 1H), 8.34 (d, J¼1.2 Hz, 1H), 9.57
(t, J¼1.6 Hz, 1H). 13C NMR (100.6 MHz)
d 43.2, 44.1, 47.8, 125.5, 127.8,
128.0, 128.7, 128.8, 129.0, 129.2, 130.5, 130.9, 132.5, 132.6, 133.6,
140.5, 142.4, 185.1, 199.7. HRMS (ESI) calcd from C23H18NO4
(MþH)þ: 372.1233; found: 372.1230. HPLC conditions: Daicel
ChiralpakÒ IC column, i-PrOH/hexane 10:90, flow rate 1 mL/min,
UV detection at 254 nm, tmajor¼24.0 min, tminor¼28.0 min.
4.2.6. (R)-3-(10-Oxo-9,10-dihydro-anthracen-9-yl)-butanal
(3f). Obtained in 95% yield and 94% ee from 2f and 1a. Colorless oil.
4.2.1. (R)-3-(10-Oxo-9,10-dihydro-anthracen-9-yl)-3-phenyl-propa-
nal (3a). Obtained in 88% yield and 80% ee from 2a and 1a. Col-
1H NMR (400 MHz)
d
0.70 (d, J¼6.8 Hz, 3H), 2.03 (ddd, J¼17.0, 8.6,
1.6 Hz, 1H), 2.42 (ddd, J¼17.3, 5.8, 1.1 Hz, 1H), 2.62e2.72 (m, 1H),
4.28 (d, J¼3.1 Hz, 1H), 7.39e7.52 (m, 4H), 7.56e7.61 (m, 2H), 8.26
(dt, J¼7.7, 1.6 Hz, 2H), 9.65 (t, J¼1.8 Hz, 1H). 13C NMR (100.6 MHz)
orless oil. 1H NMR (400 MHz)
d
2.70 (ddd, J¼17.4, 8.6, 1.8 Hz, 1H),
2.82 (ddd, J¼17.4, 6.8, 1.4 Hz, 1H), 3.76e3.83 (m, 1H), 4.52
(d, J¼4.0 Hz, 1H), 6.28e6.32 (m, 2H), 6.99e7.04 (m, 2H), 7.12e7.21
(m, 2H), 7.38e7.53 (m, 4H), 7.59 (dt, J¼7.5, 1.4 Hz, 1H), 8.00 (dd,
J¼7.7, 1.4 Hz, 1H), 8.06 (dd, J¼7.7, 1.4 Hz, 1H), 9.61 (t, J¼1.5 Hz, 1H).
d
17.0, 38.4, 47.9, 48.0, 127.7, 127.9, 128.0, 128.1, 129.2, 129.3, 133.1,
133.2, 142.7, 143.6, 185.8, 201.9. HRMS (ESI) calcd from C18H17NO2
(MþH)þ: 265.1223; found: 265.1222. HPLC conditions: Daicel
ChiralpakÒ IC column, i-PrOH/hexane 8:92, flow rate 1 mL/min, UV
detection at 254 nm, tmajor¼38.0 min, tminor¼32.2 min.
13C NMR (100.6 MHz)
d 45.0, 48.7, 49.5, 126.6, 127.0, 127.4, 127.6,
127.8, 128.5, 128.7, 132.2, 133.3, 133.9, 134.1, 137.4, 139.8, 141.1, 142.4,
183.9, 200.6. HRMS (ESI) calcd from C46H36O4Na (2MþNa)þ:
675.2505; found: 675.2505. HPLC conditions: Daicel ChiralpakÒ IC
column, i-PrOH/hexane 10:90, flow rate 1 mL/min, UV detection at
254 nm, tmajor¼44.4 min, tminor¼39.2 min.
4.2.7. (R)-3-(10-Oxo-9,10-dihydro-anthracen-9-yl)-pentanal
(3g). Obtained in 82% yield and 96% ee from 2g and 1a. Colorless
oil. 1H NMR (400 MHz)
d
0.91e1.10 (m, 5H), 1.99 (ddd, J¼17.6, 7.3,
1.5 Hz, 1H), 2.22 (ddd, J¼17.6, 6.4, 1.5 Hz, 1H), 2.40e2.50 (m, 1H),
4.42 (d, J¼2.9 Hz, 1H), 7.40e7.50 (m, 4H), 7.56e7.62 (m, 2H),
8.24e8.29 (m, 2H), 9.56 (t, J¼1.5 Hz, 1H). 13C NMR (100.6 MHz)
4.2.2. (R)-3-(4-Cyanophenyl)-3-(10-oxo-9,10-dihydro-anthracen-9-
yl)-propanal (3b). Obtained in 85% yield and 99% ee from 2b and
1a. Colorless oil. 1H NMR (400 MHz)
1H), 2.97 (dd, J¼18.0, 6.9 Hz, 1H), 3.83e3.89 (m, 1H), 4.55 (d,
J¼4.0 Hz, 1H), 6.36 (d, J¼8.3 Hz, 2H), 7.25e7.30 (m, 2H), 7.40e7.70
(m, 6H), 8.02e8.12 (m, 2H), 9.67 (m, 1H). 13C NMR (100.6 MHz)
d
2.76 (ddd, J¼18.0, 8.2 Hz,
d 12.8, 24.2, 45.0, 45.1, 45.5, 127.9, 128.0, 128.1, 129.2, 129.3, 133.1,
133.4, 143.1, 143.8, 185.7, 202.1. HRMS (ESI) calcd from C19H19NO2
(MþH)þ: 279.1380; found: 279.1377. HPLC conditions: Daicel
ChiralpakÒ IC column, i-PrOH/hexane 8:92, flow rate 1 mL/min, UV
detection at 254 nm, tmajor¼42.1 min, tminor¼35.3 min.
d
45.2, 48.1, 49.3, 118.5, 127.0, 127.4, 127.8, 128.1, 128.3, 128.5,
129.4, 131.6, 132.3, 132.6, 140.2, 141.9, 143.3, 172.3, 199.3. HRMS
(ESI) calcd from C24H17NO2Na (MþNa)þ: 374.1151; found:
374.1153. HPLC conditions: Daicel ChiralpakÒ IC column, i-PrOH/
4.2.8. (R)-3-(10-Oxo-9,10-dihydro-anthracen-9-yl)-hexanal
(3h). Obtained in 84% yield and 96% ee from 2h and 1a. Colorless

A. Zea et al. / Tetrahedron 67 (2011) 2513e2529
2525
oil. 1H NMR (400 MHz)
d
0.85 (t, J¼7.0 Hz, 3H), 0.91e1.00 (m, 1H),
(m, 6H), 2.00e2.32 (m, 2H), 2.40e2.51 (m,1H), 4.34 (d, J¼3.1 Hz,1H),
6.83e6.86 (m, 1H), 6.89e6.94 (m, 3H), 7.46e7.51 (m, 2H), 9.55
(t, J¼1.5 Hz, 1H), 12.11e12.13 (m, 2H, OH). 13C NMR (100.6 MHz)
1.24e1.40 (m, 3H), 1.96 (ddd, J¼17.4, 7.1, 1.8 Hz, 1H), 2.21 (ddd,
J¼17.6, 6.3, 1.5 Hz, 1H), 2.51e2.59 (m, 1H), 4.41 (d, J¼2.9 Hz, 1H),
7.41e7.49 (m, 4H), 7.57e7.61 (m, 2H), 8.24e8.29 (m, 2H), 9.54
d
14.0,19.8, 31.3, 33.0, 43.9, 44.3, 45.0,116.3,116.5,119.5,119.6,131.9,
(t, J¼1.4 Hz, 1H). 13C NMR (100.6 MHz)
d
14.5, 21.1, 33.6, 45.0, 43.3,
132.1, 136.0, 136.2, 144.1, 144.9, 162.6, 193.8, 201.3. HRMS (ESI) calcd
from C21H25O4 (MþH)þ: 341.1747; found: 341.1751. HPLC conditions:
Daicel ChiralpakÒ IC column, i-PrOH/hexane 10:90, flow rate 1 mL/
min, UV detection at 254 nm, tmajor¼25.7 min, tminor¼18.7 min.
45.3, 127.8, 128.0, 129.2, 129.3, 133.1,133.3,143.0, 143.8, 185.6, 202.0.
HRMS (ESI) calcd from C20H219NO2 (MþH)þ: 293.1536; found:
293.1535. HPLC conditions: Daicel ChiralpakÒ IC column, i-PrOH/
hexane 8:92, flow rate 1 mL/min, UV detection at 254 nm, tmajor
44.7 min, tminor¼32.7 min.
¼
4.3. Determination of the absolute configuration of 3a
4.2.9. (R)-3-(10-Oxo-9,10-dihydro-anthracen-9-yl)-heptanal
(3i). Obtained in 92% yield and 86% ee from 2i and 1a. Colorless oil.
In an oven-dried, 25 mL round-bottomed flask, 300 mg of
anthrone 1a (1.54 mmol, 1 equiv) were dissolved in 9 mL of
dry toluene. The solution was cooled to ꢀ20 ꢁC under an atmo-
sphere of pre-purified nitrogen and 204 mg of cinnamaldehyde 2a
(1.54 mmol, 1 equiv) and 101 mg of (S)-diphenylprolinol trime-
thylsilyl ether III (0.31 mmol, 0.2 equiv) were added sequentially
via syringe. After 4 days of stirring at this temperature, 0.46 mL
of methylmagnesium bromide solution (3.0 M in diethyl ether,
1.39 mmol, 0.9 equiv) was added. The reaction mixture was allowed
to slowly reach room temperature and was quenched with a satu-
rated aqueous solution of NH4Cl, extracted three times with
dichloromethane and dried over anhydrous MgSO4. The solvent
was evaporated under reduced pressure and the crude was purified
by flash chromatography using mixtures of hexane/ethyl acetate as
eluent, affording 123 mg of the diastereomeric alcohols 5a, 5a0 as
a 1:1 mixture (33% yield).
[
a
]
25 ꢀ3.4 (c 1.0, CHCl3). 1H NMR (400 MHz)
d
0.83 (t, J¼7.1 Hz, 3H),
D
1.20e1.36 (m, 6H), 1.95 (ddd, J¼17.4, 7.2, 1.8 Hz, 1H), 2.20 (ddd,
J¼17.4, 6.3, 1.6 Hz, 1H), 2.49e2.57 (m, 1H), 4.41 (d, J¼2.9 Hz, 1H),
7.40e7.50 (m, 4H), 7.56e7.62 (m, 2H), 8.23e8.30 (m, 2H), 9.53
(t, J¼1.6 Hz, 1H). 13C NMR (100.6 MHz)
d 13.9, 22.5, 29.6, 30.5, 42.9,
44.6, 44.7, 127.1, 127.2, 127.3, 127.4, 128.6, 128.7, 132.5, 132.7, 133.3,
133.4, 142.4, 143.3, 185.0, 201.4. HRMS (ESI) calcd from C21H22O2Na
(MþNa)þ: 329.1512; found: 329.1511. HPLC conditions: Daicel
ChiralpakÒ IC column, i-PrOH/hexane 8:92, flow rate 1 mL/min, UV
detection at 254 nm, tmajor¼38.0 min, tminor¼25.2 min.
4.2.10. (R)-3-(4,5-Dihydroxy-10-oxo-9,10-dihydro-anthracen-9-yl)-
butanal (4a). Obtained in 88% yield and 97% ee from 2f and 1b.
Yellowish oil. 1H NMR (300 MHz)
d
0.72 (d, J¼6.7 Hz, 3H), 2.09 (ddd,
J¼17.0, 7.9, 1.8 Hz, 1H), 2.40e2.65 (m, 2H), 4.21 (d, J¼3.2 Hz, 1H),
6.79e6.83 (m, 1H), 6.91e6.97 (m, 3H), 7.45e7.53 (m, 2H), 9.67
(t, J¼1.5 Hz, 1H), 12.07 (s, 1H, OH), 12.11 (s, 1H, OH). 13C NMR
1H NMR (400 MHz):
d
1.10 (d, J¼6.1 Hz, 3H), 1.11 (d, J¼6.1 Hz,
3H), 1.80e2.04 (m, 4H), 3.16e3.74 (m, 4H), 4.46e4.49 (m, 2H),
6.16e6.20 (m, 4H), 6.69e8.38 (m, 22H).
(100.6 MHz)
d 16.3, 38.9, 47.4, 47.7, 116.3, 116.5, 119.6, 135.9, 136.2,
This alcohol mixture (0.36 mmol, 1 equiv) was dissolved in 1 mL
of dichloromethane in a 5 mL round-bottomed flask, equipped with
magnetic stirring, and 116 mg of pyridinium chlorochromate
(0.54 mmol, 1.5 equiv) was added in one portion. After consump-
tion of starting material (monitored by TLC), diethyl ether (5 mL)
was added and the mixture was filtered through CeliteÒ. Purifica-
tion by column chromatography gave 55 mg of ketone (ꢀ)-6a (45%
yield), whose spectroscopic data matched those previously repor-
143.7, 144.8, 162.5, 162.7, 193.8, 201.1. HRMS (ESI) calcd from
C18H17O4 (MþH)þ: 297.1121; found: 297.1121. HPLC conditions:
Daicel ChiralpakÒ IC column, i-PrOH/hexane 10:90, flow rate 1 mL/
min, UV detection at 254 nm, tmajor¼23.7 min, tminor¼17.0 min.
4.2.11. (R)-3-(4,5-Dihydroxy-10-oxo-9,10-dihydro-anthracen-9-yl)-
pentanal (4b). Obtained in 95% yield and 99% ee from 2g and 1b.
Yellowish oil. 1H NMR (400 MHz)
d
0.92 (t, J¼7.0 Hz, 3H), 0.97e1.30
ted in the literature for (S)-(þ)-6a.12
[
a]
20 ꢀ1.8 (c 2.7, CH2Cl2).
D
(m, 1H), 1.33e1.41 (m, 1H), 2.07 (ddd, J¼16.9, 6.3, 1.6 Hz, 1H),
2.26e2.38 (m, 2H), 4.35 (d, J¼2.7 Hz, 1H), 6.82e6.85 (m, 1H),
6.90e6.95 (m, 3H), 7.46e7.52 (m, 2H), 9.59 (t, J¼1.5 Hz, 1H),
4.4. General experimental procedure for the addition of
anthrones to trans- -nitrostyrenes
12.10e12.12 (m, 2H, OH). 13C NMR (100.6 MHz)
d
12.1, 23.2, 44.3,
b
44.9, 46.3, 116.4, 119.5, 119.6, 128.5, 132.0, 132.1, 136.1, 136.2, 144.3,
144.8, 162.6, 193.8, 201.3. HRMS (ESI) calcd from C19H19O4 (MþH)þ:
311.1278; found: 311.1280. HPLC conditions: Daicel ChiralpakÒ IC
column, i-PrOH/hexane 10:90, flow rate 1 mL/min, UV detection at
254 nm, tmajor¼27.8 min, tminor¼19.0 min.
To a stirred solution of catalyst (R,R)-V (10 mg, 0.025 mmol) in
toluene (1 mL) were added the nitrostyrene (0.30 mmol) and the
anthrone (1a or 1b, 0.25 mmol). The reaction crude was vigorously
stirred at room temperature (anthrone 1a) or at ꢀ40 ꢁC (dithranol
1b) during 14 h. After warming up the reaction flask to room
temperature, the crude product was directly purified by column
chromatography on silica gel (hexane/ethyl acetate mixtures) to
afford the Michael adduct. Racemic products were obtained from
the corresponding substrates by catalysis with DABCO in toluene at
room temperature.
4.2.12. (R)-3-(4,5-Dihydroxy-10-oxo-9,10-dihydro-anthracen-9-yl)-
hexanal (4c). Obtained in 93% yield and 99% ee from 2h and 1b.
20
Yellowish oil. [
a]
ꢀ5.7 (c 1.0, CHCl3). 1H NMR (400 MHz)
d 0.86
D
(t, J¼7.1 Hz, 3H), 1.20e1.38 (m, 4H), 2.03 (ddd, J¼17.4, 6.9, 1.8 Hz,
1H), 2.29 (ddd, J¼17.4, 6.6, 1.6 Hz, 1H), 2.41e2.50 (m, 1H), 4.33
(d, J¼3.1 Hz, 1H), 6.82e6.85 (m, 1H), 6.90e6.95 (m, 3H), 7.46e7.52
(m, 2H), 9.56 (t, J¼1.6 Hz, 1H), 12.11 (s, 1H, OH), 12.13 (s, 1H, OH). 13C
4.4.1. (R)-(ꢀ)-10-(2-Nitro-1-phenyl-ethyl)-10H-anthracen-9-one
(11a)14,19. Obtained in 92% yield and 89% ee from 10a and 1a.
NMR (100.6 MHz)
d 13.9, 20.5, 32.5, 44.1, 44.6, 45.1, 116.3, 116.4,
116.5, 119.5, 119.6, 136.1, 136.2, 144.2, 144.9, 162.6, 193.8, 201.3.
HRMS (ESI) calcd from C20H20NaO4 (MþNa)þ: 347.1254; found:
347.1255. HPLC conditions: Daicel ChiralpakÒ IC column, i-PrOH/
Colorless solid. Mp 147e148 ꢁC. [
a
]
D
25 ꢀ22.8 (c 0.9, CHCl3). 1H NMR
(300 MHz)
d
4.05 (m, 1H), 4.55 (d, J¼3.5 Hz, 1H), 4.57e4.62 (dd,
J¼13.0, 7.0 Hz, 1H), 4.86e4.92 (dd, J¼13.0, 9.0 Hz, 1H), 6.04e6.06
(d. J¼7.0 Hz, 2H), 6.93e6.97 (t, J¼8.0 Hz, 2H), 7.13e7.17 (t, J¼8.0 Hz,
1H), 7.48e7.66 (m, 6H), 7.97e7.99 (d, J¼7.0 Hz, 1H), 8.05e8.07
(d. J¼6.5 Hz, 1H), 8.17e8.19 (d, J¼6.5 Hz, 1H). 13C NMR (100.6 MHz)
hexane 10:90, flow rate 1 mL/min, UV detection at 254 nm, tmajor
27.1 min, tminor¼17.9 min.
¼
4.2.13. (R)-3-(4,5-Dihydroxy-10-oxo-9,10-dihydro-anthracen-9-yl)-
d 46.4, 53.5, 73.4126.7, 127.2, 127.3, 127.4, 127.5, 127.9, 128.1, 128.2,
heptanal (4d). Obtained in 92% yield and 99% ee from 2i and 1b.
128.7,129.1,132.3,133.0,133.5,133.6,139.5,140.7,142.2,183.5. HPLC
Yellowish oil. 1H NMR (400 MHz)
d
0.88 (t, J¼7.1 Hz, 3H), 0.90e1.43
conditions: Daicel ChiralpakÒ IA column, i-PrOH/hexane 10:90,

2526
A. Zea et al. / Tetrahedron 67 (2011) 2513e2529
flow rate 1 mL/min, UV detection at 254 nm, tmajor¼10.7 min,
tminor¼10.0 min.
conditions: Daicel IB column, i-PrOH/hexane 5:95, flow rate 1 mL/
min, UV detection at 254 nm, tmajor¼18.5 min, tminor¼19.5 min.
4.4.2. (ꢀ)-10-[1-(2-Fluorophenyl)-2-nitroethyl]-10H-anthracen-9-
one (11b). Obtained in 95% yield and 92% ee from 10b and 1a.
4.4.7. 1,8-Dihydroxy-10-(1-(2-fluorophenyl)-2-nitroethyl)anthracen-
9(10H)-one (12b). Obtained in 89% yield and 21% ee from 10b and
Colorless waxy solid. [
a
]
25 ꢀ17.8 (c 0.9, CHCl3). 1H NMR (300 MHz)
1b. Yellow solid. 1H NMR (300 MHz)
d 4.11 (m, 1H), 4.53
D
d
4.38 (m, 1H), 4.50e4.56 (dd, J¼12.0, 6.0 Hz, 1H), 4.60 (d, J¼3.0 Hz,
(d, J¼3.0 Hz, 1H), 4.56e4.65 (dd, J¼12.0, 9.0 Hz, 1H), 4.89e4.95
(dd, J¼12.0, 9.0 Hz, 1H), 6.55e6.59 (t, J¼6.0 Hz, 1H), 6.82e6.99
(m, 7H), 7.25e7.27 (d, J¼6.0 Hz, 1H), 7.30e7.32 (d, J¼6.0 Hz, 1H). 13C
1H), 4.71e4.77 (dd, J¼9.0, 6.0 Hz, 1H), 6.04e6.08 (t, J¼6.0 Hz, 1H),
6.78e6.82 (t, J¼6.0 Hz, 1H), 6.84e6.88 (t, J¼6.0 Hz, 1H), 7.09e7.66
(m, 7H), 8.06e8.08 (d, J¼6.0 Hz, 1H), 8.12e8.14 (d, J¼6.0 Hz, 1H). 13C
NMR (100.6 MHz)
d 46.4, 48.3, 75.4, 115.8, 116.0, 116.8, 117.3, 117.7,
NMR (100.6 MHz)
d
45.9, 47.2, 75.6, 115.8, 116.1, 121.7, 121.8, 123.9,
119.8, 121.4, 121.6, 123.9, 130.0, 130.5, 130.6, 136.2, 136.5, 141.3,
142.8, 159.9, 162.5, 162.8, 192.6. HRMS (ESI) calcd from C22H17FNO5
(MþH)þ: 394.1085; found: 394.1088. HPLC conditions: Daicel
ChiralpakÒ IB column, i-PrOH/hexane 5:95, flow rate 1 mL/min, UV
detection at 254 nm, tmajor¼13.7 min, tminor¼15.7 min.
127.3,127.6,128.3,128.9,129.8, 130.3, 132.9,133.2,134.0,140.1,141.1,
159.5, 162.8, 183.7. HRMS (ESI) calcd from C22H16FNNaO3 (MþNa)þ:
384.1006; found: 384.1003. HPLC conditions: Daicel ChiralpakÒ IC
column, i-PrOH/hexane 5:95, flow rate 1 mL/min, UV detection at
254 nm, tmajor¼68.5 min, tminor¼40.5 min.
4.4.8. 1,8-Dihydroxy-10-(2-nitro-1-p-tolylethyl)anthracen-9(10H)-
4.4.3. (ꢀ)-10-(2-Nitro-1-p-tolyl-ethyl)-10H-anhtracen-9-one
one (12c). Obtained in 85% yield and 38% ee from 10c and 1b.
(11c)14,19. Obtained in 92% yield and 90% ee from 10c and 1a. Col-
Yellow solid. 1H NMR (300 MHz)
d 2.34 (s, 3H), 3.91 (m, 1H), 4.45
20
orless solid. Mp 157e159 ꢁC. [
a]
ꢀ17.8 (c 0.8, CHCl3). 1H NMR
(d, J¼3.0 Hz, 1H), 4.52e4.58 (dd, J¼12.0, 6.0 Hz, 1H), 4.88e4.95
(dd, J¼12.0, 9.0 Hz, 1H), 5.97 (d, J¼6.0 Hz, 2H), 6.82 (d, J¼9.0, 2H),
6.92e6.97 (m, 4H), 7.50e7.57 (dd, J¼9.0, 6.0 Hz, 2H). 13C NMR
D
(300 MHz)
d
2.35 (s, 3H), 4.03 (m, 1H), 4.52 (d, J¼3.0 Hz, 1H),
4.53e4.58 (dd, J¼12.0, 6.0 Hz, 1H), 4.87 (dd, J¼9.0, 6.0 Hz, 1H),
5.95e5.97 (d, J¼6.0 Hz, 2H), 6.75e6.77 (d, J¼6.0 Hz, 2H),
7e26e7.65 (m, 4H), 8.01e7.99 (d, J¼6.0 Hz, 1H), 8.07e8.09
(100.6 MHz)
d 21.2, 46.8, 54.1, 76.6, 116.8, 117.4, 119.2, 119.6, 128.6,
128.8, 130.0, 135.9, 136.5, 138.5, 141.0, 144.2, 162.2, 162.6, 192.5.
HRMS (ESI) calcd from C23H18NO5 (MꢀH)ꢀ: 388.1190; found:
388.1193. HPLC conditions: Daicel ChiralpakÒ IB column, i-PrOH/
hexane 5:95, flow rate 1 mL/min, UV detection at 254 nm,
tmajor¼18.2 min, tminor¼24.2 min.
(d, J¼6.0 Hz, 1H), 8.20 (m, 2H). 13C NMR (100.6 MHz)
d 21.3, 46.4,
53.2, 76.8, 127.0, 127.5, 127.9, 128.3, 128.4, 128.6, 128.9, 130.4, 132.5,
132.9, 133.5, 134.1, 138.2, 139.7, 142.2, 185.4. HPLC conditions: Daicel
ChiralpakÒ IA column, i-PrOH/hexane 10:90, flow rate 1 mL/min,
UV detection at 254 nm, tmajor¼7.0 min, tminor¼7.6 min.
4.4.9. 1,8-Dihydroxy-10-(1-(4-methoxyphenyl)-2-nitroethyl)an-
4.4.4. (ꢀ)-10-[1-(4-Methoxyphenyl)-2-nitroethyl]-10H-anthracen-9-
one (11d)14,19. Obtained in 94% yield and 90% ee from 10d and 1a.
thracen-9(10H)-one (12d). Obtained in 70% yield and 40% ee from
10d and 1b. Yellow solid. 1H NMR (300 MHz)
d 3.72 (s, 3H), 3.88
Colorless solid. Mp 122e123 ꢁC. [
a
]
D
20 ꢀ18.9 (c 0.8, CHCl3). 1H NMR
(m, 1H), 4.43 (d, J¼6.0 Hz, 1H), 4.50e4.57 (dd, J¼12.0, 6.0 Hz, 1H),
4.87e4.94 (dd, J¼12.0, 9.0 Hz, 1H), 5.96e5.99 (d, J¼9.0 Hz, 2H),
6.53e6.56 (d, J¼9.0 Hz, 2H), 6.88e6.98 (m, 4H), 7.51e7.57 (m, 2H).
(300 MHz)
d
3.75 (s, 3H), 4.01 (m, 1H), 4.51 (d, J¼3.5 Hz, 1H),
4.52e4.57 (dd, J¼12.0, 6.0 Hz, 1H), 4.81e4.86 (dd, J¼9.0, 6.0 Hz,
1H), 5.95e5.97 (d, J¼7.0 Hz, 2H), 6.47e6.49 (d, J¼7.0 Hz, 2H),
7.40e7.43 (m, 2H), 7.45e7.52 (m, 2H), 7.61e7.65 (m, 2H), 8.00 (d,
13C NMR (100.6 MHz)
d 46.8, 53.8, 55.5, 76.8, 113.6, 116.8, 116.9,
117.5, 117.6, 119.1, 119.6, 124.8, 129.9, 135.8, 136.5, 140.9, 144.3, 159.9,
162.2, 162.6, 192.4. HRMS (ESI) calcd from C23H18NO6 (MꢀH)ꢀ:
404.1140; found: 404.1139. HPLC conditions: Daicel ChiralpakÒ IB
column, i-PrOH/hexane 5:95, flow rate 1 mL/min, UV detection at
254 nm, tmajor¼24.0 min, tminor¼34.9 min.
J¼7.0 Hz, 1H), 8.02 (d, J¼7.0 Hz, 1H). 13C NMR (100.6 MHz)
d 46.5,
52.9, 55.4, 76.8, 113.7, 125.1, 126.8, 127.0, 127.5, 127.9, 128.3, 128.4,
128.7, 129.9, 132.4, 132.5, 132.9, 133.5, 134.5, 139.6, 142.3, 159.6,
183.4. HPLC conditions: Daicel ChiralpakÒ IA column, i-PrOH/
hexane 10:90, flow rate 1 mL/min, UV detection at 254 nm,
tmajor¼11.9 min, tminor¼11.2 min.
4.4.10. 1,8-Dihydroxy-10-[2-nitro-1-(4-nitrophenyl)ethyl]-10H-an-
thracen-9-one (12e). Obtained in 87% yield and 13% ee from 10e and
4.4.5. (ꢀ)-10-[2-Nitro-1-(4-nitrophenyl)ethyl]-10H-anthracen-9-
one (11e)14,19. Obtained in 91% yield and 85% ee from 10e and 1a.
1b. Yellow solid. 1H NMR (300 MHz)
d 4.09 (m, 1H), 4.51
(d. J¼3.0 Hz, 1H), 4.58e4.67 (dd, J¼12.0, 9.0 Hz, 1H), 4.93e4.99
(dd, J¼12.0, 9.0 Hz, 1H), 6.34e6.37 (d, J¼9.0 Hz, 2H), 6.89e6.96
(m, 2H), 7.00e7.03 (d, J¼9.0 Hz, 2H), 7.55e7.61 (t, J¼9.0 Hz, 2H),
Colorless solid. Mp 195e196 ꢁC. [
a
]
D
20 ꢀ20.1 (c 0.9, CHCl3). 1H NMR
(300 MHz)
d
4.19 (m, 1H), 4.60 (d, J¼3.0 Hz, 1H), 4.61e4.66 (dd,
J¼12.0, 9.0 Hz, 1H), 4.93e4.98 (dd, J¼12.0, 5.0 Hz, 1H), 6.25e6.27
(d, J¼6.0 Hz, 2H), 7.45e7.84 (m, 7H), 8.00e8.02 (d, J¼6.0 Hz, 1H),
8.09e8.11 (d, J¼6.0 Hz, 1H), 8.32e8.34 (dd, J¼6.0, 3.0 Hz, 1H). 13C
7.90e7.93 (d, J¼9.0 Hz, 2H). 13C NMR (100.6 MHz)
d 46.6, 54.0, 76.1,
117.7, 118.2, 119.2, 119.6, 123.2, 129.7, 136.4, 136.9, 141.0, 204.8.
HRMS (ESI) calcd from C22H15N2O7 (MꢀH)ꢀ: 419.0885; found:
419.0888. HPLC conditions: Daicel ChiralpakÒ IB column, i-PrOH/
hexane 10:90, flow rate 1 mL/min, UV detection at 254 nm,
tmajor¼24.8 min, tminor¼28.6 min.
NMR (100.6 MHz) d 46.2, 53.2, 76.5, 123.3, 127.4, 127.9, 128.2, 128.5,
128.6, 128.9, 129.7, 132.9, 133.3, 133.4, 134.3, 138.6, 140.9, 141.3,
147.4, 184.8. HPLC conditions: Daicel ChiralpakÒ IA column, i-PrOH/
hexane 10:90, flow rate 1 mL/min, UV detection at 254 nm, tmajor
25.2 min, tminor¼24.8 min.
¼
4.5. General experimental procedure for the addition of
anthrones to maleimides
4.4.6. 1,8-Dihydroxy-10-(1-phenyl-2-nitroethyl)anthracen-9(10H)-
one (12a). Obtained in 77% yield and 35% ee from 10a and 1b.
Yellow solid. 1H NMR (300 MHz)
d
3.95 (m, 1H), 4.47 (d. J¼3.0 Hz,
To a stirred solution of catalyst (R,R)-V (10 mg, 0.025 mmol) in
toluene (1 mL) were added the maleimide (0.30 mmol) and the
anthrone (1a or 1b, 0.25 mmol). The reaction mixture was vigor-
ously stirred at room temperature during 14 h, and the crude
product was directly purified by column chromatography on silica
gel (hexane/ethyl acetate mixtures) to afford the DielseAlder or the
Michael adduct. Racemic products were obtained from the
1H), 4.55e4.61 (dd, J¼12.0, 6.0 Hz, 1H), 4.91e4.99 (dd, J¼12.0,
9.0 Hz, 1H), 6.06e6.09 (d, J¼9.0 Hz, 2H), 6.89e7.04 (m, 5H),
7.16e7.18 (t, J¼6.0 Hz, 2H), 7.57 (m, 2H). 13C NMR (100.6 MHz)
d
46.7, 54.3, 76.5, 116.9, 117.5, 119.1, 119.6, 128.0, 128.1, 128.7, 128.8,
129.2,133.2,135.9,136.6,140.8,144.1,162.2,162.7,192.5. HRMS (ESI)
calcd from C22H16NO5 (MeH)ꢀ: 374.1034; found: 374.1031. HPLC

A. Zea et al. / Tetrahedron 67 (2011) 2513e2529
2527
corresponding substrates by catalysis with DABCO in toluene at
room temperature.
1H), 6.38e6.40 (d, J¼6.0 Hz, 2H), 7.23e7.44 (m, 8H), 7.54e7.56
(d, J¼6.0 Hz, 1H), 7.65e7.67 (d, J¼6.0 Hz, 1H). 13C NMR (100.6 MHz)
d
45.1, 47.9, 51.1, 76.9, 121.2, 121.3, 123.2, 124.0, 125.0, 127.2, 127.3,
4.5.1. (R,R)-(ꢀ)-4-Hydroxy-2-phenyl-3a,4,9,9a-tetrahydro-4, 9-[10,20]-
benzeno-1H-benz[f]isoindole-1,3(2H)-dione (14a)11,23b,25. Obtained in
127.5, 127.6, 128.1, 128.4, 130.1, 132.6, 132.7, 136.8, 139.0, 141.2, 142.4,
175.5, 177.0. HRMS (ESI) calcd from C24H17BrNO3 (MþH)þ:
446.0386; found: 446.0384. HPLC conditions: Daicel ChiralpakÒ IC
column, i-PrOH/hexane 10:90, flow rate 1 mL/min, UV detection at
254 nm, tmajor¼46.1 min, tminor¼47.8 min.
91% yield and 90% ee from 13a and 1a. Colorless solid. Mp
20
209e210 ꢁC.
d
[a]
ꢀ17.8 (c 0.9, CHCl3). 1H NMR (300 MHz)
D
3.26e3.29 (d, J¼9.0 Hz, 1H), 3.47e3.51 (dd, J¼9.0, 3.0 Hz, 1H), 4.54
(s, 1H, OH), 4.84 (d, J¼3.0 Hz, 1H), 6.47e7.36 (m, 10H), 7.40e7.42 (d,
J¼6.0 Hz, 1H), 7.55e7.57 (d, J¼6.0 Hz, 1H), 7.66e7.68 (d, J¼6.0 Hz,
4.5.6. 4-Hydroxy-2-(diphenylmethyl)-3a,4,9,9a-tetrahydro-4,9-
[10,20]-benzeno-1H-benz[f]isoindole-1,3(2H)-dione (14g). Obtained
in 86% yield and 33% ee from 13g and 1a. Colorless solid. 1H NMR
1H). 13C NMR (100.6 MHz)
d 45.1, 47.9, 51.1, 77.7, 121.2, 121.4, 124.0,
125.0, 126.5, 127.1, 127.5, 127.6, 129.2, 129.4, 131.1, 136.9, 139.1, 141.2,
142.6, 176.5, 177.4. HRMS (ESI) calcd from C24H18NO3 (MþH)þ:
368.1281; found: 368.1279. HPLC conditions: Daicel ChiralpakÒ IA
column, i-PrOH/hexane 10:90, flow rate 1 mL/min, UV detection at
254 nm, tmajor¼47.1 min, tminor¼37.5 min.
(300 MHz)
d
3.12 (d, J¼9.0 Hz, 1H), 3.33 (dd, J¼9.0, 3.6 Hz, 1H), 4.44
(s, 1H), 4.74 (d, J¼3.6 Hz, 1H), 6.16 (s, 1H, OH), 6.57 (d, J¼6.0 Hz, 2H),
6.82 (d, J¼6.0 Hz, 2H), 7.14e7.23 (m, 12H), 7.52 (d, J¼7.2 Hz, 1H),
7.66 (d, J¼7.2 Hz, 1H). HPLC conditions: Daicel ChiralpakÒ IA col-
umn, i-PrOH/hexane 10:90, flow rate 1 mL/min, UV detection at
254 nm, tmajor¼27.3 min, tminor¼23.0 min.
4.5.2. (R,R)-(ꢀ)-4-Hydroxy-2-benzyl-3a,4,9,9a-tetrahydro-4,9-
[ 1 0, 2 0] - b e n z e n o - 1 H - b e n z [ f ] i s o i n d o l e - 1, 3 ( 2 H ) - d i o n e
(14b)23b,25. Obtained in 92% yield and 95% ee from 13a and 1a.
4.5.7. (þ)-3-(10-Oxo-9,10-dihydro-anthracen-9-yl)-1-(4-tri-
Colorless solid. Mp 213e214 ꢁC. [
(300 MHz)
a
]
20 ꢀ36.8 (c 0.9, CHCl3). 1H NMR
fluoromethyl-phenyl)-pyrrolidine-2,5-dione (140e)28. Obtained in
D
20
d
3.12e3.15 (d. J¼9.0 Hz, 1H), 3.32e3.35 (dd, J¼9.0,
94% yield and 97% ee from 13e and 1a. Colorless oil. [
a
]
þ54.7
D
3.0 Hz, 1H), 4.27 (s, 2H), 4.40 (s, 1H, OH), 4.70 (d, J¼3.0 Hz, 1H),
6.70e6.72 (d, J¼6.0 Hz, 2H), 6.97e7.01 (t, J¼6.0 Hz, 1H), 7.05e7.09
(t, J¼6.0 Hz, 1H), 7.13e7.27 (m, 6H), 7.34e7.36 (d, J¼6.0 Hz, 1H),
7.38e7.40 (d, J¼6.0 Hz, 1H), 7.66e7.68 (d, J¼6.0 Hz, 1H). 13C NMR
(c 0.4, CHCl3). 1H NMR (300 MHz)
d
2.11 (dd, J¼18.9, 4.8 Hz, 1H),
2.44 (dd, J¼18.9, 9.6 Hz, 1H), 3.65e3.75 (m, 1H), 5.24 (d, J¼2.3 Hz,
1H), 7.25e7.28 (m, 2H), 7.43e7.75 (m, 8H), 8.30e8.42 (m, 2H). 13C
NMR (100.6 MHz)
d 29.5, 42.3, 50.1, 126.50, 126.55, 126.60,
(100.6 MHz)
d
42.5, 44.6, 47.8, 50.8, 121.0, 123.9, 124.6, 126.9, 127.0,
126.65, 126.8, 128.1, 128.2, 128.3, 128.4, 128.5, 129.1, 132.7,
127.4,127.5, 127.7, 128.1,128.7, 134.8, 136.6,139.5, 140.9, 143.0, 176.3,
177.8. HRMS (ESI) calcd from C25H20NO3 (MþH)þ: 382.1438; found:
382.1426. HPLC conditions: Daicel ChiralpakÒ IC column, i-PrOH/
hexane 10:90, flow rate 1 mL/min, UV detection at 254 nm, tma-
133.5, 133.8, 134.1, 136.2, 142.2, 173.6, 176.7, 183.9. 19F NMR
(376 MHz, CDCl3):
d
ꢀ63.2-(-64.1) (br s). HRMS (ESI) calcd from
C25H16F3NNaO3 (MþNa)þ: 458.0974; found: 458.0970. HPLC
conditions: Daicel ChiralpakÒ IB column, i-PrOH/hexane 20:80,
flow rate 1 mL/min, UV detection at 254 nm, tmajor¼34.7 min,
tminor¼24.1 min.
¼59.7 min, tminor¼63.8 min.
jor
4.5.3. (ꢀ)-4-Hydroxy-2-(3-chlorophenyl)-3a,4,9,9a-tetrahydro-4, 9-
[10,20]-benzeno-1H-benz[f]isoindole-1,3(2H)-dione (14c)28. Obtained
4.5.8. 4-Hydroxy-2-(R)-1-phenylethyl-3a,4,9,9a-tetrahydro-4,9-
[ 1 0, 2 0] - b e n z e n o - 1 H - b e n z [ f ] i s o i n d o l e - 1, 3 ( 2 H ) - d i o n e
(14h)23a. Obtained in 80% yield as a 2.56:1 mixture of the (R,R,R)-
and (R,S,S)-diastereomers from (R)-13h and 1a. 1H NMR (300 MHz)
in 92% yield and 90% ee from 13c and 1a. Colorless solid. [
a
]
20 ꢀ9.3
D
(c 0.9, CHCl3). 1H NMR (300 MHz)
d
3.26e3.29 (d, J¼9.0 Hz, 1H),
3.47e3.51 (dd, J¼9.0, 3.0 Hz, 1H), 4.49 (s, 1H, OH), 4.83 (d, J¼3.0 Hz,
1H), 7.23e7.40 (m, 10H), 7.55e7.57 (d, J¼6.0 Hz, 1H), 7.65e7.67
d
1.15e1.18 (d, J¼7.5 Hz, 3H, major diastereomer), 1.25e1.27
(d, J¼6.0 Hz,1H). 13C NMR (100.6 MHz)
d
45.1, 48.0, 51.1, 121.2, 121.4,
(d, J¼7.2 Hz, 3H, minor diastereomer), 2.99e3.02 (d, J¼8.7 Hz, 1H,
major diastereomer), 3.04e3.07 (d, J¼8.7 Hz, 1H, minor di-
astereomer), 3.21e3.26 (dd, J¼9.6, 3.6 Hz, 1H, minor diastereomer),
3.25e3.29 (dd, J¼8.7, 3.6 Hz, 1H, major diastereomer), 4.47 (s, 1H,
minor diastereomer), 4.51 (s, 1H, major diastereomer), 4.69e4.70
(d, J¼3.3 Hz, 1H, major diastereomer), 4.70e4.71 (d, J¼3.3 Hz, 1H,
minor diastereomer), 5.93e5.00 (q, J¼7.2 Hz, both diastereomers),
6.91e7.67 (m, 13H, both diastereomers). 13C NMR (75.5 MHz, di-
123.7, 124.0, 124.8, 125.0, 126.9, 127.2, 127.3, 127.6, 127.7, 129.5,
130.3, 175.4, 177.2. HRMS (ESI) calcd from C24H17ClNO3 (MþH)þ:
402.0891; found: 402.0888. HPLC conditions: Daicel ChiralpakÒ IA
column, i-PrOH/hexane 10:90, flow rate 1 mL/min, UV detection at
254 nm, tmajor¼38.1 min, tminor¼29.0 min.
4.5.4. (ꢀ)-4-Hydroxy-2-(4-methoxyphenyl)-3a,4,9,9a-tetrahydro-4, 9-
[10,20]-benzeno-1H-benz[f]isoindole-1,3(2H)-dione (14d)23b,25. Obtained
astereomer mixture)
d 16.0, 16.1, 44.7, 44.8, 47.3 47.4, 50.1, 50.3,
in 90% yield and 97% ee from 13d and 1a. Colorless solid. Mp
50.4, 76.8, 120.9, 121.0, 121.2, 121.3, 123.8, 124.8, 126.9, 127.0, 127.2,
127.3, 127.4, 127.5, 127.7,127.8, 128.5, 136.8, 138.5, 139.4, 141.2, 142.9,
176.3, 178.0. HRMS (ESI) calcd from C26H22NO3 (MþH)þ: 396.1594;
found: 396.1590.
20
207e209 ꢁC.
[
a
]
ꢀ14.7 (c 0.9, CHCl3). 1H NMR (300 MHz)
D
d
3.24e3.27 (d, J¼9.0 Hz, 1H), 3.45e3.49 (dd, J¼9.0, 3.0 Hz, 1H), 3.75
(s, 3H), 4.55 (s, 1H, OH), 4.83 (d, J¼3.0 Hz, 1H), 6.37e6.39 (d, J¼6.0 Hz,
2H), 6.79e6.81 (d, J¼6.0 Hz, 2H), 7.22e7.32 (m, 5H), 7.40e7.42 (d,
J¼6.0 Hz, 1H), 7.54e7.56 (d, J¼6.0 Hz, 1H), 7.66e7.68 (d, J¼6.0 Hz, 1H).
4.5.9. (þ)-3-(4,5-Dihydroxy-10-oxo-9,10-dihydro-anthracen-9-yl)-
1-phenyl-pyrrolidine-2,5-dione (15a)28. Obtained in 93% yield and
13C NMR (100.6 MHz)
d 45.1, 47.9, 51.0, 55.7, 76.9, 114.7, 121.1, 121.4,
123.7, 124.0, 125.0, 127.1, 127.2, 127.5, 127.6, 127.7, 137.0, 139.1, 141.3,
142.6, 160.0, 176.2, 177.6. HRMS (ESI) calcd from C25H20NO4 (MþH)þ:
398.1387; found: 398.1371. HPLC conditions: Daicel ChiralpakÒ IC
column, i-PrOH/hexane 10:90, flow rate 1 mL/min, UV detection at
254 nm, tmajor¼18.5 min, tminor¼19.9 min.
99% ee from 13a and 1b. Yellow solid. [
NMR (300 MHz)
a
]
20 þ40.2 (c 1.0, CHCl3). 1H
D
d
2.18e2.26 (dd, J¼18.0, 6.0 Hz, 1H), 2.48e2.57
(dd, J¼18.0, 9.0 Hz, 1H), 3.52 (m, 1H), 5.20 (d, J¼3.0 Hz, 1H),
7.07e6.94 (m, 3H), 7.10 (d, J¼6.0 Hz, 2H), 7.48e7.40 (m, 5H), 7.61
(t, J¼6.0 Hz, 1H). 13C NMR (100.6 MHz)
d 29.8, 42.5, 51.3, 116.0,
116.7, 117.3, 118.3, 118.9, 119.3, 126.5, 129.1, 129.5, 131.7, 136.9,
137.5, 139.9, 144.1, 163.3, 163.5, 174.2, 176.6, 193.4. HRMS (ESI)
calcd from C24H16NO5 (MꢀH)ꢀ: 398.1034; found: 398.1024. HPLC
conditions: Daicel ChiralpakÒ IB column, i-PrOH/hexane 10:90,
flow rate 1 mL/min, UV detection at 254 nm, tmajor¼41.5 min,
tminor¼47.1 min.
4.5.5. (ꢀ)-4-Hydroxy-2-(4-bromophenyl)-3a,4,9,9a-tetrahydro-4,9-
[10,20]-benzeno-1H-benz[f]isoindole-1,3(2H)-dione (14f)25. Obtained
in 94% yield and 29% ee from 13f and 1a. Colorless solid. [
a
]
20 ꢀ12.7
D
(c 1.0, CHCl3). 1H NMR (300 MHz)
d
3.25e3.28 (d, J¼9.0 Hz, 1H),
3.46e3.50 (dd, J¼9.0, 3.0 Hz, 1H), 4.49 (s, 1H, OH), 4.83 (d, J¼3.0 Hz,

2528
A. Zea et al. / Tetrahedron 67 (2011) 2513e2529
4.5.10. (þ)-1-Benzyl-3-(4,5-dihydroxy-10-oxo-9,10-dihydro-an-
thracen-9-yl)-pyrrolidine-2,5-dione (15b)28. Obtained in 92% yield
5.07e5.08 (d, J¼3.0 Hz, 1H, major diastereomer), 5.28e5.37 (m, 1H,
both diastereomers), 6.48e6.50 (d, J¼7.5 Hz, 1H, minor di-
astereomer), 6.77e6.80 (d, J¼7.5 Hz, 1H, major diastereomer),
6.84e7.36 (m, 12H, both diastereomers), 7.50e7.55 (t, J¼7.5 Hz, 1H,
and 85% ee from 13b and 1b. Yellow solid. [
a
]
20 þ38.5 (c 1.0, CHCl3).
D
1H NMR (300 MHz)
d
1.98e2.05 (dd, J¼15.0, 6.0 Hz, 1H), 2.30e2.38
(dd, J¼15.0, 9.0 Hz, 1H), 3.31 (m, 1H), 4.56 (s, 1H), 4.58 (s, 1H), 5.08
(d, J¼3.0 Hz, 1H), 6.59e6.56 (d, J¼9.0 Hz, 1H), 6.84e6.81
(d, J¼9.0 Hz, 1H), 6.93e6.96 (d, J¼9.0 Hz, 1H), 7.00e7.03
(d, J¼9.0 Hz, 1H), 7.26e7.33 (m, 6H), 7.51e7.57 (t, J¼9.0 Hz, 1H). 13C
both diastereomers). 13C NMR (100.6 MHz)
d 29.8, 42.6, 51.3, 116.0,
116.7, 117.4, 118.4, 118.9, 119.1, 123.1, 128.0, 130.6, 132.7, 136.9, 137.6,
139.8, 143.8, 163.3, 163.6, 173.8, 176.3, 193.4. HRMS (ESI) calcd from
C26H20NO5 (MꢀH)ꢀ: 426.1347; found: 426.1346.
NMR (100.6 MHz)
d 29.4, 42.0, 42.8, 51.1, 115.8, 116.4, 117.1, 117.8,
118.9, 119.1, 128.3, 128.8, 129.2, 135.5, 137.0, 137.4, 139.6, 144.3, 163.1,
163.3, 174.9, 177.3, 193.3. HRMS (ESI) calcd from C25H20NO5
(MþH)þ: 414.1336; found: 414.1337. Daicel ChiralpakÒ IB column,
i-PrOH/hexane 10:90, flow rate 1 mL/min, UV detection at 254 nm,
tmajor¼30.2 min, tminor¼36.8 min.
Acknowledgements
We thank the Spanish Ministry of Science and Innovation
(MICINN) for financial support (Project AYA2009-13920-C02-02).
We are also grateful to G. Valero for his preliminary work with
ꢀ
4.5.11. (þ)-1-(3-Chlorophenyl)-3-(4,5-dihydroxy-10-oxo-9,10-dihy-
anthrones, and to the ‘Serveis Científico-Tecnics de la Universitat de
dro-anthracen-9-yl)-pyrrolidine-2,5-dione (15c). Obtained in 92%
Barcelona’ for their invaluable technical assistance.
20
yield and 22% ee from 13c and 1b. Yellow solid. [
CHCl3). 1H NMR (300 MHz)
2.53e2.58 (dd, J¼9.0, 6.0 Hz, 1H), 3.52 (m, 1H), 5.18 (d, J¼3.0 Hz,
1H), 7.59e6.91 (m, 10H). 13C NMR (100.6 MHz)
32.4, 45.2, 53.9,
a
]
þ11.6 (c 1.0,
D
d
2.47e2.52 (dd, J¼9.0, 6.0 Hz, 1H),
References and notes
d
1. Rodd’s Chemistry of Organic Compounds; Coffey, S., Ed.; Elsevier: New York, NY,
1979; Vol. III, Part H.
118.6, 119.3, 120.0, 121.1, 121.6, 121.8, 127.4, 129.5, 132.0, 133.1, 135.3,
137.7, 139.6, 140.2, 142.4, 146.5, 165.9, 166.2, 176.4, 178.9, 196.0.
HRMS (ESI) calcd from C24H15ClNO5 (MꢀH)ꢀ: 432.0644; found:
432.0638. HPLC conditions: Daicel ChiralpakÒ IB column, i-PrOH/
2. For two recent references, see: (a) Srinivas, K.; Yesudas, K.; Bhanuprakash, K.;
Rao, J. V.; Giribabu, L. J. Phys. Chem. C 2009, 113, 20117e20126; (b) Iwaura, R.;
Ohnishi-Kameyama, M.; Lizawa, T. Chem.dEur. J. 2009, 15, 3729e3735.
3. See, for instance: (a) Krenn, L.; Pradhan, R.; Presser, A.; Reznicek, G.; Kopp, B.
Chem. Pharm. Bull. 2004, 52, 391e393; (b) Diaz, F.; Chai, H.-B.; Mi, Q.; Su, B.-N.;
Vigo, J. S.; Graham, J. G.; Cabieses, F.; Farnsworth, N. R.; Cordell, G. A.; Pezzuto,
J. M.; Swanson, S. M.; Kinghorn, A. D. J. Nat. Prod. 2004, 67, 352e356.
hexane 10:90, flow rate 1 mL/min, UV detection at 254 nm, tmajor
33.3 min, tminor¼40.8 min.
¼
€
4. (a) Muller, K.; Prinz, H. J. Med. Chem. 1997, 40, 2780e2787; (b) Cameron, D. W.;
4.5.12. (þ)-3-(4,5-Dihydroxy-10-oxo-9,10-dihydro-anthracen-9-yl)-
Skene, C. E. Aust. J. Chem. 1996, 49, 617e624; (c) Huang, H.-S.; Hwang, J.-M.; Jen,
Y.-M.; Lin, J.-J.; Lee, K.-Y.; Shi, C.-H.; Hsu, H.-C. Chem. Pharm. Bull. 2001, 49,
969e973.
5. (a) Hoffman, E. J. Cancer and the Search for Selective Biochemical Inhibitors, 2nd
ed.; CRC: Boca Raton, 2007; (b) Kren, V.; Rezanka, T. FEMS Microbiol. Rev. 2008,
32, 858e889; (c) Bringman, S.; Maksimenka, K.; Knauer, M.; Abegaz, B. M. Nat.
1-(4-methoxyphenyl)-pyrrolidine-2,5-dione (15d)28. Obtained in
20
94% yield and 97% ee from 13d and 1b. Yellow solid. [
a
]
þ74.9
D
(c 1.0, CHCl3). 1H NMR (300 MHz)
d
2.16e2.23 (dd, J¼15.0, 6.0 Hz,
1H), 2.47e2.54 (dd, J¼15.0, 6.0 Hz, 1H), 3.49 (m, 1H), 3.83 (s, 3H),
5.19 (d, J¼3.0 Hz, 1H), 6.94e7.02 (m, 5H), 7.09 (d, J¼6.0 Hz, 1H),
7.46e7.48 (d, J¼6.0 Hz, 1H), 7.49e7.51 (d, J¼6.0 Hz, 1H), 7.57e7.61
€
Prod. Rep. 1999, 25, 696e716; (d) Muller, K. Appl. Microbiol. Biotechnol. 2001, 56,
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Cavaggini, A.; Basso, G.; Diaspro, A.; Salvato, B.; Carli, M.; Pulci, G. Cancer Res.
2000, 60, 2800e2804; (f) Shiono, Y.; Shino, N.; Seo, S.; Oka, S.; Yamazaki, Y.
Z.Naturforsch. 2002, 57c, 923e929; (g) Zuse, A.; Schmidt, D.; Baasner, S.; Bohm,
K. J.; Muller, K.; Gerlach, M.; Gunther, E. G.; Unger, E.; Prinz, H. J. Med. Chem.
2007, 50, 6059e6066; (h) Prinz, H.; Ishii, Y.; Hirano, T.; Stoiber, T.; Camacho
Gomez, J. A.; Schmidt, P.; Dussmann, H.; Burger, A. M.; Prehn, J. H. M.; Gunther,
E. G.; Unger, E.; Umezawa, K. J. Med. Chem. 2003, 46, 3382e3394.
6. (a) Valero, G.; Balaguer, A.-N.; Moyano, A.; Rios, R. Tetrahedron Lett. 2008, 49,
6559e6562; (b) Valero, G.; Schimer, J.; Cisarova, I.; Vesely, J.; Moyano, A.; Rios,
R. Tetrahedron Lett. 2009, 50, 1943e1946; (c) Balaguer, A.-N.; Companyo, X.;
Calvet, T.; Font-Bardía, M.; Moyano, A.; Rios, R. Eur. J. Org. Chem. 2009, 199e203;
(d) Companyo, X.; Valero, G.; Crovetto, L.; Moyano, A.; Rios, R. Chem.dEur. J.
2009, 15, 6564e6568; (e) Companyo, X.; Hejnova, M.; Kamlar, M.; Vesely, J.;
Moyano, A.; Rios, R. Tetrahedron Lett. 2009, 50, 5021e5024; (f) Companyo, X.;
Balaguer, A.-N.; Cardenas, F.; Moyano, A.; Rios, R. Eur. J. Org. Chem. 2009,
3075e3080; (g) Alba, A.-N.; Companyo, X.; Moyano, A.; Rios, R. Chem.dEur. J.
2009, 15, 7035e7038; (h) Alba, A.-N.; Companyo, X.; Moyano, A.; Rios, R.
Chem.dEur. J. 2009, 15, 11095e11099; (i) El-Hamdouni, N.; Companyo, X.; Rios,
R.; Moyano, A. Chem.dEur. J. 2010, 16, 1142e1148; (j) Alba, A.-N. R.; Companyo,
(t, J¼6.0 Hz, 2H). 13C NMR (100.6 MHz)
d 29.7, 42.5, 51.2, 55.7, 114.8,
€
116.7, 117.3, 118.2, 118.9, 119.3, 124.2, 127.7, 136.9, 137.5, 139.9, 144.1,
159.9, 163.2, 163.5, 174.5, 176.9, 193.4. HRMS (ESI) calcd from
C25H20NO6 (MþH)þ: 430.1285; found: 430.1288. HPLC conditions:
Daicel ChiralpakÒ IB column, i-PrOH/hexane 10:90, flow rate 1 mL/
min, UV detection at 254 nm, tmajor¼31.7 min, tminor¼38.8 min.
€
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ꢁ
€
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ꢁ
4.5.13. (þ)-1-(4-Bromophenyl)-3-(4,5-dihydroxy-10-oxo-9,10-dihy-
dro-anthracen-9-yl)-pyrrolidine-2,5-dione (15f)28. Obtained in 91%
ꢁ
ꢁ
ꢁ
20
yield and 96% ee from 13f and 1b. Yellow solid. [
a
]
D
þ35.8 (c 0.9,
ꢁ
CHCl3). 1H NMR (300 MHz)
d
2.17e2.25 (dd, J¼18.0, 6.0 Hz, 1H),
ꢁ
ꢁ
2.48e2.57 (dd, J¼18.0, 9.0 Hz, 1H), 3.47e3.52 (m, 1H), 5.17
(d, J¼3.0 Hz, 1H), 6.89e6.92 (d, J¼9.0 Hz, 1H), 6.98e7.02 (m, 4H),
7.06e7.08 (d, J¼6.0 Hz, 1H), 7.44e7.48 (t, J¼6.0 Hz, 1H), 7.56e7.61
ꢁ
ꢁ
ꢁ
(m, 3H). 13C NMR (100.6 MHz)
d
29.8, 42.6, 51.3, 116.0, 116.7, 117.4,
X.; Valero, G.; Moyano, A.; Rios, R. Chem.dEur. J. 2010, 16, 5354e5361; (k) Alba,
A.-N. R.; Valero, G.; Calvet, T.; Font-Bardía, M.; Moyano, A.; Rios, R. Chem.dEur.
J. 2010, 16, 9884e9889 For an account, see: (l) Valero, G.; Alba, A.-N. R.;
118.4, 118.9, 119.1, 123.1, 128.0, 130.6, 132.7, 136.9, 137.6, 139.8, 143.8,
163.3, 163.6, 173.8, 176.3, 193.4. HRMS (ESI) calcd from C24H15BrNO5
(MꢀH)ꢀ: 476.0139; found: 476.0129. HPLC conditions: Daicel
ChiralpakÒ IB column, i-PrOH/hexane 10:90, flow rate 1 mL/min,
UV detection at 254 nm, tmajor¼37.3 min, tminor¼56.3 min.
ꢁ
Companyo, X.; Bravo, N.; Moyano, A.; Rios, R. Synlett 2010, 1883e1908.
7. cf. (a) Meek, J. S.; Evans, W. B.; Godefroi, V.; Benson, W. R.; Wilcox, M. F.; Clark,
W. G.; Tiedeman, T. J. Org. Chem. 1961, 26, 4281e4285; (b) Cohen, D.; Millar, I. T.;
Richards, K. E. J. Chem. Soc. C 1968, 793e795.
8. Baik, W.; Yoon, C. H.; Koo, S.; Kin, H.; Kim, J.; Kim, J.; Hong, S. Bull. Korean Chem.
Soc. 2004, 25, 491e500.
9. Preliminary communication: Alba, A.-N.; Bravo, N.; Moyano, A.; Rios, R. Tetra-
hedron Lett. 2009, 50, 3067e3069.
4.5.14. 3-(4,5-Dihydroxy-10-oxo-9,10-dihydro-anthracen-9-yl)-1-
((R)-1-phenylethyl)-pyrrolidine-2,5-dione (15h). Obtained in 77%
yield as a 1.25:1 mixture of the (R,S)- and (R,R)-diastereomers from
10. N,N0-Bis(3,5-bis(trifluoromethyl)phenyl) thiourea Kotke, A.; Schreiner, P. R.
Tetrahedron 2005, 61, 434e439.
(R)-13h and 1b. 1H NMR (300 MHz)
d
1.70e1.73 (d, J¼7.2 Hz, 3H,
11. Shen, J.; Nguyen, T. T.; Goh, Y.-P.; Ye, W.; Fu, X.; Xu, J.; Tan, C.-H. J. Am. Chem. Soc.
2006, 128, 13692e13693.
minor diastereomer), 1.72e1.74 (d, J¼7.2 Hz, 3H, major di-
astereomer), 1.91e1.94 (dd, J¼5.1, 2.4 Hz, 1H, minor diastereomer),
1.97e2.00 (dd, J¼5.4, 2.4 Hz, 1H, major diastereomer), 2.24e2.29
(dd, J¼9.6, 3.9 Hz, 1H, major diastereomer), 2.30e2.35 (dd, J¼9.3,
3.9 Hz, 1H, minor diastereomer), 3.22e3.29 (m, 1H, both dia-
stereomers), 5.03e5.04 (d, J¼3.0 Hz, 1H, minor diastereomer),
12. Wu, C.; Li, W.; Yang, J.; Liang, X.; Ye, J. Org. Biomol. Chem. 2010, 8, 3244e3250.
13. For reviews on organocatalysis dealing with enantioselective iminium catalysis,
€
see: (a) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416e5470;
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M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138e6171;
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Jérgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178e2189; (f) Enders, D.; Wang, C.;

A. Zea et al. / Tetrahedron 67 (2011) 2513e2529
2529
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Liebich, J. X. Chem.dEur. J. 2009, 15, 11058e11076; See also: (g) Seebach, D.;
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€
€
€
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