Enantioselective Diels-Alder reaction of anthrone and maleimide catalyzed by a simple chiral tertiary amine

Article abstract of DOI:10.1016/j.tet.2012.11.011

Simple chiral tertiary amines with a special imide skeleton were first successfully applied to catalyze the enantioselective D-A reaction of anthrone and maleimides in excellent yields (up to 96%) and enantioselectivities (up to 95% ee).

Full text of DOI:10.1016/j.tet.2012.11.011

Tetrahedron 69 (2013) 1229e1233
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective DielseAlder reaction of anthrone and maleimide
catalyzed by a simple chiral tertiary amine
,
,
,
,
a,
*
Jian-Fei Bai a b, Yun-Long Guo a b, Lin Peng a, Li-Na Jia a b, Xiao-Ying Xu a , Li-Xin Wang
*
a Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
b Graduate University of Chinese Academy of Sciences, Beijing 10039, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 June 2012
Received in revised form 22 October 2012
Accepted 2 November 2012
Available online 16 November 2012
Simple chiral tertiary amines with a special imide skeleton were first successfully applied to catalyze the
enantioselective DeA reaction of anthrone and maleimides in excellent yields (up to 96%) and enan-
tioselectivities (up to 95% ee).
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
DielseAlder reactions
Anthrones
Maleimide
Chiral tertiary amine
1. Introduction
N-R
The DielseAlder reaction is one of the most straightforward and
atom economical methods to construct chiral six-membered car-
bocyclic compounds in organic chemistry.1 Among all the dienes,
anthrone has been considered as one of the powerful diene com-
ponent and can react with a variety of dienophiles.2 Particularly, the
cycloadditions of anthrone with N-substituted maleimide to con-
struct anthrone derivatives, which are key intermediates for the
preparations of some unsaturated lactams with antipsoriatic and
antiproliferative biological activities, have been studied exten-
sively.3 Chiral bases, such as cinchona alkaloids,4 pyrrolidine de-
rivatives,5 cyclic guanidines,6 bisoxazolines,7 and tertiary amine
thioureas8 have been used to promote those reactions in moderate
to excellent enantioselectivities (Scheme 1). However either sub-
strate scopes or enantioselectivities in this reaction were limited in
most cases.
In the past years, chiral amines have been widely used as
powerful promoters in asymmetric catalyses.9 In particular, chiral
1,2-diphenylethane-1,2-diamine and cyclohexane-1,2-diamine are
frequently used in asymmetric catalysis.10 Imide protected tertiary
amines with these chiral scaffolds, the key intermediates for the
preparation of chiral catalysts, have drawn less attention as cata-
lysts.11 Recently, our group has successfully applied chiral
Scheme 1. Base-catalyzed DielseAlder reaction of anthrones and maleimides.
monoimide protected cyclohexane-1,2-diamines to catalyze enan-
tioselective double Michael reaction of N-Boc-3-nonsubstituted
oxindoles with dienones in up to 98% yield and 89% ee.12 Based on
this backgrounds and our everlasting interests in development of
new catalytic system for the enantioselective reaction of mal-
eimide,13 and the constructions of complex spiro- and bridged
chiral moieties.14 We wish to report our study on DielseAlder
* Corresponding authors. Tel./fax: þ86 28 85255208; e-mail addresses: xuxy@
cioc.ac.cn (X.-Y. Xu), wlxioc@cioc.ac.cn (L.-X. Wang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.011

1230
J.-F. Bai et al. / Tetrahedron 69 (2013) 1229e1233
reactions of anthrones and maleimides catalyzed by a simple chiral
tertiary amine with a special and less reported imide skeleton.
used (Table 1, entries 7 and 8). After a brief screening, catalyst 1a
was chosen for further optimizations.
The effects of the solvents and reaction temperature were also
investigated and the results were listed in Table 2. All solvents gave
moderate to good yields (50e91%), whereas the enantioselectivities
varied strikingly (1e86% ee, Table 2, entries 1e9). When the re-
action was carried out in chlorinated solvents, good yields and
moderate to good enantioselectivities (89e91% yield, 55e86% ee,
Table 2, entries 1e3) were observed. Aromatic hydrocarbon and
ether solvents gave only moderate yields and moderate enantio-
selectivities (50e78% yield, 25e43% ee; Table 2, entries 4e7), and
particularly, acetonitrile and DMF gave poor enantioselectivities
(13% and 1% ee; Table 2, entries 8 and 9). 1,2-Dichloroethane, which
gave the highest enantioselectivity with good conversion (86% ee,
90% yield; Table 2, entry 2), was chosen as the best suitable solvent
for further screening of temperature. When the reaction tempera-
ture was decreased from room temperature to ꢀ10 ꢁC, the enan-
tioselectivities increased slightly (Table 2, entries 10e12). Further
decreasing the temperature to ꢀ20 ꢁC led to lower yield and
enantioselectivity (83% yield, 84% ee, Table 2, entry 13). Through
those screenings, the optimized reaction conditions were found to
be reaction of 1.2 equiv 3a with 1.0 equiv 2a in the presence of
20 mol % of catalyst 1a in 1,2-dichloroethane at ꢀ10 ꢁC.
2. Results and discussion
We first found that the reaction of anthrone 2a and N-phenyl-
maleimide 3a were performed smoothly with 20 mol % chiral ter-
tiary amine 1a in good yield and moderate enantioselectivity (90%
yield, 55% ee; Table 1, entry 1). A series of chiral tertiary amine
catalysts 1beg were then prepared via simple procedures (Fig. 1),
and in an initial screening of catalytic activity, anthrone 2a and N-
phenylmaleimide 3a were used as model reactants and the results
were summarized in Table 1.
Table 1
Catalyst screeningsa
Entry
Catalyst
Time (h)
Yieldb (%)
ee (%)c,d
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
6
6
91
75
85
Nd
83
78
81
77
55
23
11
Nd
47
50
35
51
Table 2
Solvent screeningsa
30
48
20
20
6
1g
1h
18
a
Unless otherwise specified, all reactions were carried out using maleimide 3a
(0.24 mmol), anthrone 2a (0.2 mmol), and catalyst (20 mol %) in CH2Cl2 (0.6 mL) at
room temperature.
Entry
Solvent
Temp (ꢁC)
Time (h)
Yieldb (%)
ee (%)c
b
Isolated yield.
c
1
2
3
4
5
6
7
8
CH2Cl2
ClCH2CH2Cl
CHCl3
Toluene
Xylene
Et2O
THF
Acetonitrile
DMF
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
rt
rt
rt
rt
rt
rt
rt
rt
6
6
6
91
90
89
50
75
60
78
77
58
91
92
90
83
55
86
60
35
28
25
43
13
1
90
90
93
84
Enantiomeric excess was determined by HPLC using Chiralpak AD-H column.
The absolute configuration of the product was determined as (S,S) by comparing
d
with reported data.6
7
10
10
10
10
10
6
12
12
18
9
rt
10
0
10
11
12
13
ꢀ10
ꢀ20
a
Unless otherwise specified, all reactions were carried out using maleimide 3a
(0.24 mmol), anthrone 2a (0.2 mmol), and catalyst (20 mol %) in the solvent (0.6 mL)
at room temperature.
b
Isolated yield.
c
Enantiomeric excess was determined by HPLC using Chiralpak AD-H column.
Under the optimized reaction condition,
a range of N-
substituted maleimides were broadened and the results were listed
in Table 3. In general, all the N-substituted maleimides reacted
smoothly and gave moderate to good yields and moderate to ex-
cellent enantioselectivities (70e97% yield, 40e93% ee; Table 3,
entries 1e13). The positions of the substituents on the maleimides
phenyl ring have some influences on the enantioselectivities. The
meta-position substituted maleimides gave good yields and enan-
tioselectivities (85% yield, 85% ee, Table 3, entry 2), whereas the
para-position substituted, the enantioselectivity decreased sharply
to only 40e76% ee (Table 3, entries 3e9). For less reactive N-alkyl
maleimides, good yields and moderate enantioselectivities were
obtained (70e95% yield, 43e70% ee; Table 3, entries 10e13). A
series of substituted anthrones were also evaluated. Anthrones 2b
and 2c gave good yields and moderate to good enantioselectivities
Fig. 1. Chiral tertiary amine catalysts studied.
All the cases afforded good yields (75e91% yields) and moderate
enantioselectivities (11e55% ee) except catalyst 1d. Chiral tertiary
amine 1a with (R,R)-1,2-cyclohexanediamine chiral scaffold affor-
ded excellent yield and moderate enantioselectivity (91% yield, 55%
ee; Table 1, entry 1). Catalyst 1b with (1R,2R)-1,2-diphenyldiamine
moiety gave a relatively lower yield and enantioselectivity (75%
yield, 23% ee; Table 1, entry 2). The effects of the substituents on
nitrogen atom of the catalyst were then examined. Catalysts 1cef
gave negative effects on the enantioselectivities (Table 1, entries
3e6). No further improvements on yields and enantioselectivities
were observed when catalysts 1g and 1h with bulkier substituents

J.-F. Bai et al. / Tetrahedron 69 (2013) 1229e1233
1231
Table 3
enolate would attack the maleimide from two possible directions,
and thus lead to the corresponding product with (S,S)-configuration.
Scope of substratesa
3. Conclusions
In summary, simple chiral tertiary amines with a special imide
skeleton were first successfully applied to catalyze the enantiose-
lective DeA reaction of anthrones and maleimide in excellent yields
(up to 96%) and enantioselectivities (up to 95% ee). This protocol
provided a potential and effective method for the construction of
optically active unsaturated lactams.
4. Experimental
4.1. General
Entry
2
R3
Product
Yieldb (%)
ee (%)c
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2c
2c
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
90
85
91
97
84
91
95
87
92
70
95
80
85
85
87
88
96
96
93
85
51
40
76
46
46
43
44
70
47
54
43
95
73
87
62
62
3-NO2eC6H4
4-CH3eC6H4
4-CH3OeC6H4
4-OHeC6H4
4-NO2eC6H4
4-CleC6H4
4-FeC6H4
4-BreC6H4
Bn
All reagent were obtained from commercial supplier without
further purification. Commercial grade solvent was dried and puri-
fied bystandard procedures as specified in Purification of Laboratory
Chemicals, fourth Ed (Armarego, W. L. F.; Perrin, D. D. Butterworth
Heinemann: 1997). NMR spectra were recorded with tetrame-
thylsilane (TMS) as internal standard.1H NMR spectrawere recorded
at 300 MHz, and 13C NMR spectra at 75 MHz (Bruker Avance).
9
10
11
12
13
14
15
16
17
18
CH3
Cyclohexyl
Allyl
Chemical shifts (d) are reported in parts per million downfield from
CDCl3
resonance (
(
d
¼7.26 ppm) for 1H NMR and relative to the central CDCl3
Ph
4-CH3eC6H4
2-FeC6H4
Ph
d
¼77.0 ppm) for 13C NMR spectroscopy. Flash column
chromatography was carried out using silica gel eluting with ethyl
acetate and petroleum ether. Reactions were monitored by TLC and
visualized with ultraviolet light. Enantiomeric excess was de-
termined by HPLC analysis on chiralpak AD-H. The absolute con-
figurations of the known products were assigned by HPLC and
optical rotation comparisons with the reported data,6 and those of
other adduct were deduced on the basis of those results.
4-CH3eC6H4
a
Unless otherwise specified, all reactions were carried out using maleimide 3
(0.24 mmol), anthrone 2 (0.2 mmol), and catalyst 1a (20 mol %) in ClCH2CH2Cl
(0.6 mL) at ꢀ10 ꢁC.
b
Isolated yield.
c
Enantiomeric excess was determined by HPLC using Chiralpak AD-H column.
(85e96% yield, 62e95% ee; Table 3, entries 14e18). While 1,8-
dihydroxy-9-anthrone 2d afford only the Michael adducts in 90%
yield and 91% ee, no DielseAlder adduct was separated (Scheme 2).
On the basis of the above results and commonly accepted mech-
anism,8 we proposed theplausible transition state modelasshownin
Scheme 3. The tertiary amine severed as a base to form anthrone
enolate, which is bound to the protonated chiral amine. Thus the
4.2. Representative experimental procedure for DeA reaction
A mixture of maleimide 3 (0.24 mmol), anthrone 2 (0.2 mmol),
and the catalyst (20 mol %) in 1,2-dichloroethane (0.6 mL) at ꢀ10 ꢁC
was stirred for 12 h (monitored by TLC). After evaporation under
reduced pressure, the residue was purified through column chro-
matography on silica gel (petroleum ether/ethyl acetate¼3/1) to
yield pure products.
4.2.1. (15S)-10-Hydroxy-13-phenyl-10,11-dihydro-9H-9,10-[3,4]epi-
pyrroloanthracene-12,14(13H,15H)-dione (4a). Known compound;6
20
white solid; 90% yield; [
a
]
þ29.7 (c 0.7, CH2Cl2); 1H NMR
D
(300 MHz, CDCl3)
d
7.75e7.40 (m, 3H), 7.32e7.22 (m, 8H), 6.50e6.47
(m, 2H), 4.84 (d, J¼3.48 Hz, 1H), 3.49 (dd, J¼3.54, 8.63 Hz, 1H), 3.27
(d, J¼8.61 Hz, 1H) ppm; HRMS (ESI) for C24H17NNaO3 ([MþNa]þ)
calcd 390.1101, found 390.1107; enantiomeric excess: 93%, de-
termined by HPLC (Chiralpak AD-H column, hexane/2-propanol¼80/
20, 1.0 mL/min, 230 nm), tR (major)¼27.9 min, tR (minor)¼36.1 min.
Scheme 2. The Michael reaction of 1,8-dihydroxy-9-anthrone 2d with N-phenyl-
maleimide.
4.2.2. (15S)-10-Hydroxy-13-(3-nitrophenyl)-10,11-dihydro-9H-9,10-
[3,4]epipyrroloanthracene-12,14(13H,15H)-dione (4b). Known com-
pound;8c white solid; 85% yield; [
a
]
D
20 þ6.0 (c 0.33, CH2Cl2); 1H NMR
(300 MHz, DMSO-d6)
d
8.18 (d, J¼1.3 Hz, 1H), 7.67e7.49 (m, 4H),
7.34e7.21 (m, 6H), 7.0 (s, 1H), 6.95 (m, 1H), 4.83 (d, J¼3.29 Hz, 1H),
3.52 (dd, J¼3.43, 8.40 Hz, 1H), 3.29 (d, J¼8.43 Hz, 1H) ppm; HRMS
(ESI) for C24H16N2NaO5 ([MþNa]þ) calcd 435.0951, found 435.0956;
enantiomeric excess: 85%, determined by HPLC (Chiralpak AD-H
column, hexane/2-propanol¼80/20, 1.0 mL/min, 230 nm), tR
(major)¼61.7 min, tR (minor)¼65.4 min.
4.2.3. (15S)-10-Hydroxy-13-(p-tolyl)-10,11-dihydro-9H-9,10-[3,4]ep-
Scheme 3. Plausible transition state models.
ipyrroloanthracene-12,14(13H,15H)-dione (4c). White solid; 80%

1232
J.-F. Bai et al. / Tetrahedron 69 (2013) 1229e1233
20
yield; [
d
a
]
D
þ9.5 (c 0.53, CH2Cl2); 1H NMR (300 MHz, DMSO-d6)
2-propanol¼80/20, 1.0 mL/min, 230 nm), tR (major)¼24.6 min, tR
7.57e7.47 (m, 3H), 7.28e7.17 (m, 5H), 7.12 (d, J¼8.06 Hz, 2H), 6.87
(minor)¼33.8 min.
(s, 1H), 6.30 (d, J¼8.06 Hz, 2H), 4.77 (d, J¼3.17 Hz, 1H), 3.46 (dd,
J¼3.05, 8.32 Hz, 1H), 3.23 (d, J¼8.43 Hz, 1H), 2.25 (s, 3H) ppm; 13C
4.2.9. (15S)-13-(4-Bromophenyl)-10-hydroxy-10,11-dihydro-9H-
9,10-[3,4]epipyrroloanthracene-12,14(13H,15H)-dione (4i). Known
NMR (75 MHz, CDCl3)
d
177.2, 175.7, 142.2, 140.9, 139.0, 138.8, 136.6,
129.7, 128.1, 127.2, 127.1, 126.8, 126.7, 125.9, 124.6, 123.7, 121.0, 120.8,
77.2, 50.7, 47.6, 44.7, 21.1 ppm; HRMS (ESI) for C25H19NNaO3
([MþNa]þ) calcd 404.1257, found 404.1255; enantiomeric excess:
51%, determined by HPLC (Chiralpak AD-H column, hexane/2-
propanol¼80/20, 1.0 mL/min, 230 nm), tR (major)¼29.7 min, tR
(minor)¼35.8 min.
compound;7 white solid; 92% yield; [
a
]
20 þ11.3 (c 0.40, CH2Cl2); 1H
D
NMR (300 MHz, CDCl3)
d
7.75 (d, J¼7.3 Hz, 1H), 7.56 (d, J¼6.8 Hz,
1H), 7.44e7.40 (m, 3H), 7.34e7.23 (m, 5H), 6.40 (d, J¼8.6 Hz, 2H),
4.83 (d, J¼3.4 Hz, 1H), 4.52 (s, 1H), 3.49 (dd, J¼8.6, 3.5 Hz, 1H), 3.27
(d, J¼8.6 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3)
d 176.7, 175.2,
142.1,140.8,138.6,136.5,132.3,129.7,127.7,127.3,127.2,126.9,126.9,
124.6, 123.7, 122.9, 121.0, 120.9, 77.2, 50.8, 47.6, 44.7 ppm; enan-
tiomeric excess: 44%, determined by HPLC (Chiralpak AD-H col-
umn, hexane/2-propanol¼80/20, 1.0 mL/min, 230 nm), tR (major)¼
17.6 min, tR (minor)¼21.3 min.
4.2.4. (15S)-10-Hydroxy-13-(4-methoxyphenyl)-10,11-dihydro-9H-
9,10-[3,4]epipyrroloanthracene-12,14(13H,15H)-dione (4d). Known
compound;7 white solid; 97% yield; [
a
]
20 þ5.0 (c 0.48, CH2Cl2); 1H
D
NMR (300 MHz, DMSO-d6)
d 7.57e7.47 (m, 3H), 7.27e7.16 (m, 5H),
6.92e6.86 (m, 3H), 6.31 (d, J¼8.78 Hz, 2H), 4.77 (d, J¼3.20 Hz, 1H),
3.71 (s, 3H), 3.44 (dd, J¼3.27, 8.47 Hz, 1H), 3.22 (d, J¼8.42 Hz,
1H) ppm; enantiomeric excess: 40%, determined by HPLC (Chir-
alpak AD-H column, hexane/2-propanol¼80/20, 1.0 mL/min,
230 nm), tR (major)¼36.6 min, tR (minor)¼43.6 min.
4.2.10. (15S)-13-Benzyl-10-hydroxy-10,11-dihydro-9H-9,10-[3,4]epi-
pyrroloanthracene-12,14(13H,15H)-dione (4j). Known compound;7
20
white solid; 70% yield; [
a
]
þ10.8 (c 0.47, CH2Cl2); 1H NMR
D
(300 MHz, DMSO-d6)
d
7.51 (d, J¼7.17 Hz, 1H), 7.44 (d, J¼6.51 Hz,
2H), 7.24e7.04 (m, 8H), 6.85 (s, 1H), 6.23 (d, J¼7.08 Hz, 2H), 4.73 (d,
J¼3.15 Hz, 1H), 4.24 (s, 2H), 3.41 (dd, J¼3.33, 8.94 Hz, 1H), 3.19 (d,
J¼8.73 Hz, 1H) ppm; enantiomeric excess: 70%, determined by
HPLC (Chiralpak AD-H column, hexane/2-propanol¼80/20, 1.0 mL/
min, 230 nm), tR (major)¼16.8 min, tR (minor)¼18.8 min.
4.2.5. (15S)-10-Hydroxy-13-(4-hydroxyphenyl)-10,11-dihydro-9H-
9,10-[3,4]epipyrroloanthracene-12,14(13H,15H)-dione
(4e). White
20
solid; 84% yield; [
a
]
ꢀ10.4 (c 0.21, CH2Cl2); 1H NMR (300 MHz,
D
DMSO-d6)
d
9.66 (s, 1H), 7.84e7.46 (m, 3H), 7.27e7.18 (m, 5H), 6.79
(d, J¼8.73 Hz, 1H), 6.65 (d, J¼8.76 Hz, 2H), 6.18 (d, J¼8.55 Hz, 2H),
4.2.11. (15S)-10-Hydroxy-13-methyl-10,11-dihydro-9H-9,10-[3,4]epi-
4.78 (d, J¼3.27 Hz, 1H), 3.47 (dd, J¼3.39, 8.46 Hz, 1H), 3.20 (d,
pyrroloanthracene-12,14(13H,15H)-dione (4k). Known compound;4
20
J¼8.46 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3)
d
175.8, 174.2, 157.3,
white solid; 95% yield; [
a
]
þ23.4 (c 0.46, CH2Cl2); 1H NMR
D
144.7, 141.2, 139.7, 137.3, 127.7, 126.4, 126.3, 126.2, 126.0, 124.3,
123.6, 122.9, 121.1, 120.8, 115.2, 76.6, 50.5, 47.4, 43.7 ppm; enan-
tiomeric excess: 76%, determined by HPLC (Chiralpak AD-H column,
hexane/2-propanol¼80/20, 1.0 mL/min, 230 nm), tR (minor)¼
22.7 min, tR (major)¼32.6 min.
(300 MHz, DMSO-d6)
d
7.68 (d, J¼7.32 Hz, 1H), 7.44e7.35 (m, 2H),
7.24e7.14 (m, 6H), 4.72 (d, J¼3.45 Hz, 1H), 3.32 (dd, J¼3.51, 8.53 Hz,
1H), 3.11 (d, J¼8.52 Hz, 1H), 2.50 (s, 3H) ppm; HRMS (ESI) for
C
19H15NNaO3 ([MþNa]þ) calcd 328.0944, found 390.0958; enan-
tiomeric excess: 47%, determined by HPLC (Chiralpak AD-H column,
hexane/2-propanol¼80/20, 1.0 mL/min, 230 nm), tR (minor)¼
11.6 min, tR (major)¼14.6 min.
4.2.6. (15S)-10-Hydroxy-13-(4-nitrophenyl)-10,11-dihydro-9H-9,10-
[3,4]epipyrroloanthracene-12,14(13H,15H)-dione (4f). Known com-
20
pound;2h white solid; 91% yield; [
a
]
D
ꢀ11.5 (c 0.19, CH2Cl2); 1H
4.2.12. (15S)-13-Cyclohexyl-10-hydroxy-10,11-dihydro-9H-9,10-[3,4]
NMR (300 MHz, DMSO-d6)
d
8.23 (d, J¼8.79 Hz, 2H), 7.58e7.48 (m,
epipyrroloanthracene-12,14(13H,15H)-dione
(4l). Known
com-
3H), 7.28e7.16 (m, 5H), 6.99 (s, 1H), 6.82 (d, J¼8.79 Hz, 2H), 4.81 (d,
J¼3.24 Hz, 1H), 3.52 (dd, J¼3.36, 8.43 Hz, 1H), 3.28 (d, J¼8.46 Hz,
1H) ppm; HRMS (ESI) for C24H16N2NaO5 ([MþNa]þ) calcd 435.0951,
found 435.0968; enantiomeric excess: 46%, determined by HPLC
(Chiralpak AD-H column, hexane/2-propanol¼80/20, 1.0 mL/min,
230 nm), tR (major)¼55.2 min, tR (minor)¼60.6 min.
pound;7 white solid; 80% yield; [
(300 MHz, DMSO-d6)
a]
D
20 þ1.5 (c 0.34, CH2Cl2); 1H NMR
d
7.51 (d, J¼7.04 Hz,1H), 7.44 (d, J¼6.77 Hz, 2H),
7.23e7.09 (m, 5H), 6.69 (s,1H), 4.66 (d,J¼3.21 Hz,1H), 3.24 (dd, J¼3.41,
8.42 Hz,1H), 3.02 (d, J¼8.45 Hz,1H),1.60e1.45 (m, 6H),1.03e0.96 (m,
3H), 0.76e0.65 (m, 2H) ppm. HRMS (ESI) for C24H23NNaO3 ([MþNa]þ)
calcd 396.1570, found 396.1580; enantiomeric excess: 54%, de-
termined by HPLC (Chiralpak AD-H column, hexane/2-propanol¼80/
20, 1.0 mL/min, 230 nm), tR (major)¼9.8 min, tR (minor)¼11.9 min.
4.2.7. (15S)-13-(4-Chlorophenyl)-10-hydroxy-10,11-dihydro-9H-
9,10-[3,4]epipyrroloanthracene-12,14(13H,15H)-dione
(4g). White
20
solid; 95% yield; [
DMSO-d6)
a
]
D
þ9.8 (c 0.57, CH2Cl2); 1H NMR (300 MHz,
4.2.13. (15S)-13-Allyl-10-hydroxy-10,11-dihydro-9H-9,10-[3,4]epi-
d
7.57e7.50 (m, 3H), 7.47e7.41 (m, 2H), 7.28e7.16 (m, 5H),
pyrroloanthracene-12,14(13H,15H)-dione (4m). White solid; 85%
6.92 (s,1H), 6.47 (d, J¼8.58 Hz, 2H), 4.78 (d, J¼3.24 Hz,1H), 3.47 (dd,
yield; [
a
]
20 þ15.8 (c 0.40, CH2Cl2); 1H NMR (300 MHz, CDCl3)
d 7.70
D
J¼3.38, 8.43 Hz,1H), 3.24 (d, J¼8.45 Hz,1H) ppm; 13C NMR (75 MHz,
(d, J¼7.3 Hz, 1H), 7.50 (d, J¼7.3 Hz, 1H), 7.37 (d, J¼7.1 Hz, 1H),
7.24e7.14 (m, 5H), 4.92e4.79 (m, 2H), 4.74 (d, J¼3.4 Hz, 1H), 4.61 (s,
1H), 4.56 (d, J¼1.3 Hz, 1H), 4.49 (s, 1H), 3.70 (d, J¼5.3 Hz, 2H) ppm;
13C NMR (75Mz, CDCl3) 177.3, 175.9, 142.5, 140.8, 139.0, 136.5, 129.5,
127.1, 127.0, 126.7, 126.6, 124.5, 123.6, 120.9, 120.6, 118.0, 77.0, 50.5,
47.4, 44.4, 40.6 ppm; HRMS (ESI) for C21H17NNaO3 ([MþNa]þ) calcd
354.1101, found 354.1099; enantiomeric excess: 43%, determined
by HPLC (Chiralpak OD-H column, hexane/2-propanol¼80/20,
1.0 mL/min, 230 nm), tR (minor)¼10.1 min, tR (major)¼14.5 min.
CDCl3)
d 176.7, 175.3, 142.1, 140.8, 138.6, 136.5, 134.8, 129.3, 129.2,
127.4, 127.3, 127.2, 126.9, 126.8, 124.6, 123.7, 121.0, 120.8, 77.2, 50.7,
47.6, 44.7 ppm; HRMS (ESI) for C24H16ClNNaO3 ([MþNa]þ) calcd
424.0711, found 424.0723; enantiomeric excess: 46%, determined by
HPLC (Chiralpak AD-H column, hexane/2-propanol¼80/20, 1.0 mL/
min, 230 nm), tR (major)¼30.7 min, tR (minor)¼33.5 min.
4.2.8. (15S)-13-(4-Fluorophenyl)-10-hydroxy-10,11-dihydro-9H-
9,10-[3,4]epipyrroloanthracene-12,14(13H,15H)-dione (4h). Known
compound;5b white solid; 87% yield; [
a
]
20 þ8.0 (c 0.47, CH2Cl2); 1H
4.2.14. (9R,10S,15S)-4,5-Dichloro-10-hydroxy-13-phenyl-10,11-
dihydro-9H-9,10-[3,4]epipyrroloanthracene-12,14(13H,15H)-dione
D
NMR (300 MHz, DMSO-d6)
d 7.55e7.47 (m, 3H), 7.29e7.16 (m, 7H),
6.91 (s, 1H), 6.47e6.43 (m, 2H), 4.78 (d, J¼3.33 Hz, 1H), 3.47 (dd,
J¼3.42, 8.45 Hz, 1H), 3.24 (d, J¼8.43 Hz, 1H) ppm; enantiomeric
excess: 43%, determined by HPLC (Chiralpak AD-H column, hexane/
(4n). Knowncompound;7 white solid; 85% yield; [
a]
20 þ12.5 (c 0.43,
D
CH2Cl2); 1H NMR (300 MHz, CDCl3)
d 7.65e7.45 (m, 2H), 7.33e7.24
(m, 7H), 6.59e6.56 (m, 2H), 5.93 (d, J¼3.62 Hz,1H), 4.66 (s,1H), 3.51

J.-F. Bai et al. / Tetrahedron 69 (2013) 1229e1233
1233
(dd, J¼3.65, 8.73 Hz, 1H), 3.26 (d, J¼8.73 Hz, 1H) ppm; 13C NMR
d 12.2 (s, 1H), 12.1 (s, 1H), 7.58e7.40 (m, 5H), 7.09e6.93 (m, 6H), 5.18
(75 MHz, CDCl3)
d
176.7, 174.2, 144.5, 143.1, 135.5, 133.9, 131.0, 130.7,
(d, J¼2.88 Hz, 1H), 3.52e3.49 (m, 1H), 2.52 (dd, J¼9.42, 18.62 Hz,
130.1, 129.2, 129.0, 128.3, 128.2, 128.1, 127.6, 126.1, 119.9, 119.6, 76.5,
49.8, 46.1, 37.6 ppm; enantiomeric excess: 95%, determined by HPLC
(Chiralpak AD-H column, hexane/2-propanol¼80/20, 1.0 mL/min,
230 nm), tR (major)¼25.8 min, tR (minor)¼46.0 min.
1H), 2.21 (dd, J¼5.01, 18.59 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3)
d
193.2, 176.4, 173.9, 163.3, 163.0, 143.8, 139.6, 137.2, 136.7, 131.4,
129.2, 128.9, 126.3, 119.0, 118.6, 118.0, 117.0, 116.4, 115.7, 51.0, 42.2,
29.5 ppm; enantiomeric excess: 91%, determined by HPLC (Chir-
alpak AD-H column, hexane/2-propanol¼80/20, 1.0 mL/min,
230 nm), tR (major)¼26.9 min, tR (minor)¼32.6 min.
4.2.15. (9R,10S,15S)-4,5-Dichloro-10-hydroxy-13-(p-tolyl)-10,11-
dihydro-9H-9,10-[3,4]epipyrroloanthracene-12,14(13H,15H)-dione
(4o). Known compound;6 white solid; 87% yield; [
a
]
D
20 ꢀ40.2 (c 0.5,
Supplementary data
CH2Cl2); 1H NMR (300 MHz, CDCl3)
d 7.65e7.62 (m, 2H), 7.47e7.23
(m, 4H), 7.13e7.11 (m, 2H), 6.45 (d, J¼8.27 Hz, 2H), 5.93 (d,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.11.011. These data include MOL files
and InChIKeys of the most important compounds described in this
article.
J¼3.63 Hz, 1H), 4.67 (s, 1H), 3.50 (dd, J¼3.65, 8.72 Hz, 1H), 3.24 (d,
J¼8.72 Hz, 1H), 2.31 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3)
d 176.7,
174.3, 144.6, 143.2, 139.2, 135.6, 134.0, 131.0, 130.1, 129.8, 128.2,
128.1, 128.1, 127.6, 125.8, 119.9, 119.6, 77.4, 49.8, 46.2, 37.7, 21.1 ppm;
enantiomeric excess: 73%, determined by HPLC (Chiralpak AD-H
column, hexane/2-propanol¼80/20, 1.0 mL/min, 230 nm), tR
(major)¼24.7 min, tR (minor)¼42.2 min.
References and notes
1. For selected reviews: (a) Takao, K.; Munakata, R.; Tadano, K. Chem. Rev. 2005, 105,
ꢀ
ꢀ
4779; (b) Pellissier, H. Tetrahedron 2009, 65, 2839; (c) Merino, P.; Marques-Lopezb,
E.; Tejeroa, T.; Herrera, R. P. Synthesis 2010, 1; (d) Palomo, J. M. Eur. J. Org. Chem.
2010, 6303.
4.2.16. (9R,10S,15S)-4,5-Dichloro-13-(2-fluorophenyl)-10-hydroxy-
10,11-dihydro-9H-9,10-[3,4]epipyrroloanthracene-12,14(13H,15H)-di-
€
2. Selected examples: (a) Muller, K.; Prinz, H. J. Med. Chem.1997, 40, 2780; (b) Dagne,
one (4p). Known compound;6 white solid; 88% yield; [
a]
20 ꢀ39.5 (c
D
E.; Bisrat, D.; Viljoen, A.; Van, B. E. Curr. Org. Chem. 2000, 4,1055; (c) Prinz, H.; Ishii,
0.44, CH2Cl2); 1H NMR (300 MHz, DMSO-d6)
d 8.20 (m, 1H), 7.83 (s,
ꢀ
ꢀ
Y.; Hirano, T.; Stoiber, T.; Camacho, J.; Gomez, A.; Schmidt, F.; Dossmann, H.;
€
Burger, A. M.; Prehn, J. H. M.; Gunter, E. G.; Umezawa, K. J. Med. Chem. 2003, 46,
1H), 7.74e7.31 (m, 8H), 7.00 (d, J¼8.79 Hz,1H), 5.60(d, J¼3.57 Hz,1H),
3.68 (dd, J¼3.36, 8.49 Hz, 1H), 3.46 (d, J¼8.50 Hz, 1H) ppm; 13C NMR
3382; (d) Krenn, L.; Pradhan, R.; Presser, A.; Reznicek, G.; Kopp, B. Chem. Pharm.
Bull. 2004, 52, 391; (e) Lin, J.-H.; Elangovan, A.; Ho, T.-I. J. Org. Chem. 2005, 70,
7397; (f) Iwaura, R.; Ohnishi-Kameyama, M.; Lizawa, T. Chem.dEur. J. 2009, 15,
3729; (g) Liao, Y.-H.; Zhang, H.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C.
Tetrahedron: Asymmetry 2009, 20, 2397; (h) Goh, Y.; White, J. Aust. J. Chem. 2009,
62, 419.
3. Selected examples: (a) Knapp, S.; Ornaf, R. M.; Rodriques, K. E. J. Am. Chem. Soc.
1983, 105, 5494; (b) Koerner, M.; Rickborn, B. J. Org. Chem. 1989, 54, 6; (c)
Koerner, M.; Rickborn, B. J. Org. Chem. 1990, 55, 2662; (d) Bunnage, M. E.;
Nicolaou, K. C. Angew. Chem., Int. Ed. 1996, 35, 1110; (e) Burgess, K. L.; Corbett,
M. S.; Eugenio, P.; Lajkiewicz, N. J.; Liu, X.; Sanyal, A.; Yan, W. L.; Yuan, Q.;
Snyder, J. K. Bioorg. Med. Chem. 2005, 13, 5299.
(75 MHz, CDCl3) d 172.4, 172.0, 145.5, 142.3, 134.5, 132.9, 129.8,129.1,
128.2, 127.6, 127.0, 126.7, 126.4, 126.0, 123.4, 119.4, 118.9, 118.2, 115.3,
115.0, 76.0, 49.0, 45.8, 39.7 ppm; enantiomeric excess: 87%, de-
terminedbyHPLC(ChiralpakAD-Hcolumn, hexane/2-propanol¼80/
20, 1.0 mL/min, 230 nm), tR (major)¼18.0 min, tR (minor)¼31.5 min.
4.2.17. (9S,10R,15S)-1,8-Dichloro-10-hydroxy-13-phenyl-10,11-
dihydro-9H-9,10-[3,4]epipyrroloanthracene-12,14(13H,15H)-dione
(4q). Known compound;6 white solid; 96% yield; [
a
]
D
20 þ88.4 (c 0.5,
4. Fache, F.; Piva, O. Tetrahedron Lett. 2001, 42, 5655.
5. Tokioka, K.; Masuda, S.; Fujii, T.; Hata, Y.; Yamamoto, Y. Tetrahedron: Asymmetry
1997, 8, 101; (b) Uemae, K.; Masuda, S.; Yamamoto, Y. J. Chem. Soc., Perkin Trans.
1 2001, 1002.
CH2Cl2); 1H NMR (300 MHz, CDCl3)
d 7.76 (m, 2H), 7.33e7.24 (m,
7H), 6.59e6.56 (m, 2H), 5.93 (d, J¼3.64 Hz, 1H), 4.66 (s, 1H), 3.51
(dd, J¼3.65, 8.73 Hz, 1H), 3.25 (d, J¼8.72 Hz, 1H) ppm; 13C NMR
6. Shen, J.; Nguyen, T. T.; Goh, Y. P.; Ye, W.-P.; Fu, X.; Xu, J.-Y.; Tan, C.-H. J. Am. Chem.
Soc. 2006, 128, 13692.
(75 MHz, CDCl3) d 176.6, 174.1, 144.5, 143.2, 135.6, 133.9, 131.0, 130.7,
€
€
7. Akalay, D.; Durner, G.; Gobel, M. W. Eur. J. Org. Chem. 2008, 2365.
8. Zea, A.; Valero, G.; Alba, A. R.; Moyano, A.; Riosa, R. Adv. Synth. Catal. 2010, 352,
1102; (b) Zea, A.; Alba, A. R.; Bravo, N.; Moyano, A.; Rios, R. Tetrahedron 2011, 67,
2513; (c) Hau, C.-K.; He, H.; Lee, A. W. M.; Chik, D. T. W.; Cai, Z.-W.; Wong, H. N.
C. Tetrahedron 2010, 66, 9860.
130.1, 129.1, 129.0, 128.3, 128.1, 128.0, 127.6, 126.1, 119.9, 119.6, 77.4,
49.9, 46.1, 37.6 ppm; enantiomeric excess: 62%, determined by
HPLC (Chiralpak AD-H column, hexane/2-propanol¼80/20, 1.0 mL/
min, 230 nm), tR (major)¼25.3 min, tR (minor)¼44.5 min.
9. Selected examples: (a) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev.
2003, 103, 2985; (b) Peng, F.-Z.; Shao, Z.-H. J. Mol. Catal. A e Chem. 2008, 285, 1;
(c) Xu, L.-W.; Lu, Y. Org. Biomol. Chem. 2008, 2047; (d) Chen, Y.-C. Synlett 2008,
1919; (e) Xu, L.-W.; Luo, J.; Lu, Y.-X. Chem. Commun. 2009, 1807.
4.2.18. (9S,10R,15S)-1,8-Dichloro-10-hydroxy-13-(p-tolyl)-10,11-
dihydro-9H-9,10-[3,4]epipyrroloanthracene-12,14(13H,15H)-dione
10. Selected examples: (a) Kim, H.; Yen, C.; Preston, P.; Chin, J. Org. Lett. 2006, 8,
5239; (b) Yang, H.-M.; Li, L.; Jiang, K.-Z.; Jiang, J.-X.; Lai, G.-Q.; Xu, L.-W. Tet-
(4r). Known compound;6 white solid; 96% yield; [
a]
20 ꢀ45.5 (c 0.4,
D
CH2Cl2); 1H NMR (300 MHz, CDCl3)
d 7.64e7.62 (m, 2H), 7.47e7.21
ꢀ
rahedron 2010, 66, 9708; (c) Rogozinska, M.; Adamkiewicz, A.; Mlynarski, J.
Green Chem. 2011, 13, 1155; (d) Menjo, Y.; Hamajima, A.; Sasaki, N.; Hamada, Y.
Org. Lett. 2011, 13, 5744; (e) Byeon, S. R.; Park, H.; Kim, H.; Hong, J. Y. Org. Lett.
2011, 13, 5816.
(m, 4H), 7.12 (d, J¼8.08 Hz, 2H), 6.45 (d, J¼8.23 Hz, 2H), 5.93 (d,
J¼3.58 Hz, 1H), 4.67 (s, 1H), 3.50 (dd, J¼3.64, 8.70 Hz, 1H), 3.24 (d,
J¼8.70 Hz, 1H), 2.31 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3)
d 176.6,
ꢀ
11. Kaik, M.; Gawronski, J. Tetrahedron: Asymmetry 2003, 14, 1559.
12. Luo, X.-Y.; Wang, L.-L.; Peng, L.; Bai, J.-F.; Jia, L.-N.; He, G.-Y.; Tian, F.; Xu, X.-Y.;
Wang, L.-X. Chin. J. Chem. 2012, 30, 1185.
174.3, 144.5, 143.1, 139.2, 135.5, 133.9, 131.0, 130.0, 129.8, 128.2,
128.1, 127.5, 125.8, 119.9, 119.6, 77.4, 49.8, 46.1, 37.6, 21.1 ppm; en-
antiomeric excess: 62%, determined by HPLC (Chiralpak AD-H col-
umn, hexane/2-propanol¼80/20, 1.0 mL/min, 230 nm), tR (major)¼
25.1 min, tR (minor)¼43.0 min.
13. (a) Bai, J.-F.; Wang, L.-L.; Peng, L.; Guo, Y.-L.; Jia, L.-N.; Tian, F.; He, G.-Y.; Xu, X.-
Y.; Wang, L.-X. J. Org. Chem. 2012, 77, 2947; (b) Bai, J.-F.; Wang, L.-L.; Peng, L.;
Guo, Y.-L.; Ming, J.-N.; Wang, F.-Y.; Xu, X.-Y.; Wang, L.-X. Eur. J. Org. Chem. 2011,
4472; (c) Bai, J.-F.; Peng, L.; Wang, L.-L.; Wang, L.-X.; Xu, X.-Y. Tetrahedron 2010,
66, 8928.
14. (a) Wang, L.-L.; Bai, J.-F.; Peng, L.; Qi, L.-W.; Jia, L.-N.; Guo, Y.-L.; Luo, X.-Y.; Xu, X.-Y.;
Wang, L.-X. Chem. Commun. 2012, 5175; (b) Wang, L.-L.; Peng, L.; Bai, J.-F.; Jia, L.-N.;
Luo, X.-Y.; Huang, Q.-C.; Xu, X.-Y.; Wang, L.-X. Chem. Commun. 2011, 5593; (c)
Wang, L.-L.; Peng, L.; Bai, J.-F.; Huang, Q.-C.; Xu, X.-Y.; Wang, L.-X. Chem. Commun.
2010, 8064.
4.2.19. (R)-3-(4,5-Dihydroxy-10-oxo-9,10-dihydroanthracen-9-yl)-1-
phenylpyrrolidine-2,5-dione (4s). Known compound;6 white solid;
20
90% yield; [
a
]
þ38.7 (c 0.62, CH2Cl2); 1H NMR (300 MHz, CDCl3)
D