Asymmetric cycloaddition of anthrone and maleimides catalyzed by C2-chiral pyrrolidines

Article abstract of DOI:10.1039/b100961n

Catalytic asymmetric cycloaddition of anthrone with N-alkyl- and N-arylmaleimides with various substituents in the aromatic ring was carried out in the presence of C₂-chiral pyrrolidines to afford chiral, non-racemic [4 + 2] adducts. Among them, good catalytic activity was observed with the pyrrolidines with a N-(4-pyridyl) methyl group 1h, which was discussed from the viewpoint of conformational analysis. The best stereoselectivity of 87% ee was attained when the reaction of N-(2-tert-butylphenyl) maleimide 4j and anthrone was promoted with 1h.

Full text of DOI:10.1039/b100961n

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Asymmetric cycloaddition of anthrone and maleimides catalyzed
by C2-chiral pyrrolidines
Kouhei Uemae, Satoshi Masuda and Yukio Yamamoto*
1
Graduate School of Human and Environmental Studies, Kyoto University, Sakyo-ku,
Yoshida, Kyoto 606-8501, Japan
Received (in Cambridge, UK) 26th January 2001, Accepted 8th March 2001
First published as an Advance Article on the web 4th April 2001
Catalytic asymmetric cycloaddition of anthrone† with N-alkyl- and N-arylmaleimides with various substituents in the
aromatic ring was carried out in the presence of C2-chiral pyrrolidines to afford chiral, non-racemic [4 ϩ 2] adducts.
Among them, good catalytic activity was observed with the pyrrolidines with a N-(4-pyridyl)methyl group 1h, which
was discussed from the viewpoint of conformational analysis. The best stereoselectivity of 87% ee was attained when
the reaction of N-(2-tert-butylphenyl)maleimide 4j and anthrone was promoted with 1h.
The asymmetric Diels–Alder reaction has been studied exten-
sively and recognized as an efficient method creating up to four
chiral centres at one time. Almost all investigations focus on the
use of stereogenic auxiliaries bound to one of the reactants1
and on the use of chiral Lewis acids2 either stoichiometric or
catalytic amounts. On the other hand, only a few reports of
base-catalyzed asymmetric [4 ϩ 2] cycloaddition closely related
to the Diels–Alder reaction have been published with anthrone3
and 3-hydroxy-2-pyrone.4 In these reports, natural cinchona
alkaloids and proline derivatives were employed as catalysts,
and though the ee’s of the products were moderate the
selectivity was improved by using a chiral auxiliary in the
latter report. Recently, a different type of effective organo-
catalytic Diels–Alder reaction was reported with α,β-
unsaturated aldehydes.5 We have reported the asymmetric
cycloaddition with moderate stereoselectivity catalyzed
by C2-chiral 2,5-bis(hydroxymethyl)pyrrolidine 1b and high
selectivity was attained with chiral N-substituted maleimides.6
Now, we describe the catalytic asymmetric cycloaddition with
up to 87% asymmetric yield with the devised base catalysts.
Scheme 1 Reagents and conditions: i, ArCH2Cl, Pri2EtN, THF, reflux,
9 h; ii, HCl, MeOH, 80 ЊC, 2 days.
Results and discussion
In the design of the catalyst structure, the solubility of catalyst
was taken into account since the catalyst 1b, which exhibited
the best selectivity of 61% ee, has a problem of high solubility
in water and its reuse is difficult. Because the hydroxy groups
in 1b were found to be indispensable for the asymmetric
induction,6 we started the catalyst modification by introducing
substituents on the nitrogen atom in the pyrrolidine ring. First,
we examined the N-benzyl derivative 1d, which turned out
to be practically inactive as a catalyst. On the basis that the
cinchona alkaloids which exhibit high activity are aliphatic
amines with aromatic rings containing a nitrogen atom,
we prepared the chiral pyrrolidine derivatives with the 2-
pyridylmethyl 1f and 4-pyridylmethyl 1h groups as well as
other aromatic groups as catalyst candidates. Among them, the
4-pyridylmethyl derivative 1h exhibited good catalytic activity
for the [4 ϩ 2] cycloaddition.
Fig. 1 The most stable conformation of 1d, 1f and 1h calculated by
PM3. A, benzyl derivative 1d and 2-pyridylmethyl derivative 1f; B,
4-pyridylmethyl derivative 1h.
diols 1d, 1f and 1h, respectively (Scheme 1). The asymmetric
cycloaddition of anthrone 3 with N-methylmaleimide 4a and
N-benzylmaleimide 4b was carried out in chloroform at room
temperature by using the 2-pyridylmethyl derivative 1f, the
4-pyridylmethyl derivative 1h and their MOM derivatives 1e
and 1g (Table 1). As a reference, the reaction was also effected
with the unsubstituted pyrrolidine 1b and its MOM derivative
1a as well as quinidine 2 which has been reported previously.6
The reaction periods required for completion with 1h with
the 4-pyridylmethyl group were comparable with 1b although
they were longer than those with 2. The reaction with the
2-pyridylmethyl counterpart 1f was more sluggish. We also
examined other pyrrolidine derivatives with 2-pyridyl, 4-
pyridyl, benzimidazol-2-ylmethyl or 3,5-dimethylisoxazol-4-yl-
methyl groups as well as the bis(pyrrolidine) derivative linked
Starting from methoxymethyl (MOM) ether 1a,7 the N-
benzyl derivative 1c, the N-2-pyridylmethyl derivative 1e and
the 4-pyridylmethyl derivative 1g were obtained by the reaction
with the corresponding arylmethyl chlorides. Compounds 1c, 1e
and 1g were then deprotected with hydrochloric acid to afford
† The IUPAC name for anthrone is 9,10-dihydroanthracen-9-one.
1002
J. Chem. Soc., Perkin Trans. 1, 2001, 1002–1006
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b100961n

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Asymmetric cycloaddition of anthrone with phenyl-
maleimides
Table 1 Catalytic asymmetric cycloaddition of anthrone with N-
benzylmaleimides
Table 2
Yield
(%)
Ee
(%)
Product
R1
H
R2
H
R3
H
Catalyst
t/h
5c
2
1
2
24
0.75
0.25
18
0.25
1
18
0.2
1
18
4
2
24
1.5
2
96
10
5
72
0.25
0.25
3
93
95
91
86
80
85
89
93
88
68
95
96
80
72
55
80
73
56
75
53
50
95
99
97
20
51
61
33
46
50
30
55
57
27
74
62
38
59
63
25
63
52
11
50
47
40
81
87
1b
1h
2
5d
5e
5f
5g
5h
5i
H
H
H
Cl
Br
CF3
F
H
H
H
Cl
H
H
H
1b
1h
2
1b
1h
2
1b
1h
2
1b
1h
2
1b
1h
2
1b
1h
2
R
Product
Catalyst
t/h
0.25
2
2
0.25
8
4
Yield (%)
Ee (%)a
OMe
H
Me
5a
2
99
88
99
99
99
92
30
33
83
91
63
82
35
59
74
45
38
59
—
21
38
12
42
70
1b
1h
2
Bn
5b
1a
1b
1c
1d
1e
1f
1g
1h
Br
48
48
24
48
24
2
Me Me
But
5j
H
1b
1h
a By chiral HPLC analysis.
by a pyridine-2,5-diyl group, but their catalytic activity was
poor.
groups were prepared by heating the corresponding substituted
anilines with maleic anhydride and zinc chloride.8 Quinidine
was also employed as a reference. It took longer for the reaction
to complete with 1h. The catalysts 1b and 1h always afforded
higher ee’s than 2. The ee’s of the N-phenyl adduct 5c were
rather poorer than those of the N-alkyl adducts (Table 1). The
substituents on the aromatic ring, with the exception of 2-But
group 4j, did not affect the selectivity. The best asymmetric
induction of 87% ee was attained when 1h with an N-4-pyridyl-
methyl group was used in the reaction with 4j. The con-
figuration of 5j was the same as the N-alkyl analogues 5a
and 5b, and is described later. The ee of 5j with 1b with no N-
substituent was also high, 81% ee. The high selectivity with 4j
with the 2-But group is partly ascribed to the conformation of
4j. The aromatic ring stands perpendicular to the maleimide
ring and one face of the latter is shielded with the But group.
For the determination of the absolute configuration, we
employed the (Ϫ)-isomers ent-5c and ent-5j while the products
of the present asymmetric synthesis were the (ϩ)-isomers
5c and 5j. The adducts ent-5a3 and 76 were employed as the
reference compounds whose R,R-configuration had been
established. Compounds ent-5a, ent-5c, ent-5j and 7 were con-
verted to ketones 6a, 6c, 6j and 8, respectively, by the action of
triethylamine (Scheme 2). Their CD spectra showed the same
pattern, a positive maximum at 243–249 nm and a negative
maximum at 211–215 nm (Table 3), and the R,R-configuration
was assigned to ent-5c and ent-5j based on this fact. Con-
sequently, the S,S-configuration of 5c (R = Ph) and 5j (R =
(2-But)Ph) from the present asymmetric cycloaddition was
established. This conclusion was also supported by the obser-
vation in the chiral HPLC analysis that the major isomers of
5a, 5c and 5j eluted faster (the retention times are given in the
Experimental section). The S,S-configuration was also assigned
to the other products based on the chiral HPLC analysis as well
as the fact that they showed positive rotations.
The best activity among the pyrrolidine derivatives examined
was found for 1h and was rationalized by conformational
analysis. We estimated the most stable conformation of 1d,
1f and 1h by PM3 calculations starting from systematically
created initial structures. In the most stable conformation A of
1d,f and B of 1h, the dihedral angles around C1–N2–C3–C4
are quite different and the aromatic groups orient in opposite
directions (Fig. 1). An open space exists around the nitrogen
atom in the pyrrolidine ring in B, which enables anthrone to
approach it. In contrast, the nitrogen atom is shielded by
the phenyl or 2-pyridyl group in A, which hinders the approach.
In order to confirm the consideration that the nitrogen atom
of the catalyst should be unhindered for good activity, we
examined several achiral amines for the [4 ϩ 2]cycloaddition.
Secondary amines accelerated the reaction but tertiary amines,
except 1-azabicyclo[2.2.2]octane, did not exhibit catalytic
activity. This observation can be rationalized by the fact that
the nitrogen atom of the bicyclic amine is naked, and suggests
that the nitrogen atom of pyrrolidine 1h is also naked.
As to the MOM derivatives 1a, 1e and 1g, the stereoselectiv-
ity was moderate and comparable with 2. Diol 1f with a 2-
pyridylmethyl group exhibited poor stereoselection. On the
other hand, the ee’s (74 and 70%) of the products 5a and 5b,
yielded with diol 1h with a 4-pyridylmethyl group, were higher
than those with 2 (35 and 45%) and 1b (59%). Almost the same
results were observed when the reaction was conducted in
toluene and/or at lower temperature. The configuration of the
products 5a and 5b was S,S throughout the entries in Table 1.
In order to attain improved stereoselectivity, we undertook
the reaction between anthrone and various N-arylmaleimides
4c–j catalyzed by 1b and 1h which exhibited good selectivity
forthereactionwithN-alkylmaleimides(Table2).VariousN-aryl-
maleimides having electron-attracting and electron-donating
J. Chem. Soc., Perkin Trans. 1, 2001, 1002–1006
1003

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Table 3 CD spectra of the ketones derived from the cycloaddition
the N-2-pyridylmethyl derivative 1e was reported as a ligand
products
of a rhodium complex for the enantioselective allylation of
arylaldehydes.10 The C2-chiral pyrrolidines prepared herein are
also considered to have potential as chiral ligands.
Ee
[θ]/deg cm2
Ketone
(%)
dmolϪ1 (λ/nm)a
6a
8
6c
6j
52
ϩ4700 (245)
ϩ16000 (249)
ϩ5400 (243)
ϩ15000 (249)
0 (236)
0 (238)
0 (235)
0 (236)
Ϫ62000 (212)
Ϫ117000 (212)
Ϫ7500 (215)
Experimental
b
All mps were measured on a Yanagimoto micro melting
54
71
point apparatus and are uncorrected. H NMR and 13C NMR
1
Ϫ79000 (211)
spectra were recorded with a JEOL-JNM-EX-270 (at 270 MHz
a In MeOH. b 100% de.
1
for H, 68 MHz for 13C) and a JEOL A-500 (at 500 MHz
for 1H, 126 MHz for 13C). J Values are given in Hz. IR spectra
were recorded with a SHIMADZU FTIR-8600PC; absorb-
ances are measured in cmϪ1. Mass spectra were recorded with
a JEOL JMS DX-300. The elemental analyses were performed
by Kyoto University elemental analysis centre. Optical rotation
was measured with a JASCO DIP-1000 (with a 10 cm cell) and
are given in 10Ϫ1 deg cm2 gϪ1. CD spectra were measured with
a JASCO J-720 (with a 0.1 cm cell). Chiral HPLC analyses
were run with Sumipax OA-2000 (4 × 200 mm) on a JASCO
880-PU chromatographic system with an 875-UV detector
(254 nm); eluent: hexane–CH2ClCH2Cl–EtOH = 450 : 50 : 2,
2.0 cm3 minϪ1. PM3 calculations were performed with Chem3D
MOPAC (Cambridge Soft MOPAC version 4.0).
4-[(2R,5R)-2,5-Bis(methoxymethoxymethyl)pyrrolidinyl-
methyl]pyridine 1g—typical procedure for synthesis of the MOM
derivatives 1c, 1e and 1g
Scheme 2 Reagents and conditions: i, Et3N, MeOH, room temp., 1 day.
To a solution of 4-pyridylmethyl chloride hydrochloride
(213 mg, 1.3 mmol) in THF (5 cm3), ethyldiisopropylamine
(260 mg, 2.0 mmol) and (2R,5R)-2,5-bis(methoxymethoxy-
methyl)pyrrolidine6 1a (220 mg, 1.0 mmol) were added. This
mixture was refluxed for 9 h, and then CH2Cl2 (50 cm3) and
water (150 cm3) were added. After the aqueous layer was
made alkaline with 15% NaOH (20 cm3), the organic layer
was separated. The aqueous layer was extracted with CH2Cl2
(2 × 100 cm3). The organic layer and the extracts were com-
bined and washed with saturated NaCl (100 cm3) and dried over
Na2SO4. After evaporation, the residue was purified with flash
column chromatography (silica gel, 15% EtOAc in hexane) to
give 1g (92 mg, 32%); yellow oil; [α]D20 ϩ31.9 (c 0.25, CHCl3);
δH (CDCl3) 1.6–2.1 (m, 4H, CH2CH2), 3.2 (br s, 2H, 2 × CH),
3.32 (s, 6H, 2 × OCH3), 3.95 (d, J 15.4, 1H, NCHH), 4.08 (d,
J 15.4, 1H, NCHH), 4.56 (s, 4H, 2 × OCH2), 7.2–7.3 (m, 2H,
pyridine ring), 8.5–8.6 (m, 2H, pyridine ring); δC (CDCl3) 27.3,
51.5, 55.2, 60.5, 69.5, 96.7, 123.1, 149.6, 150.4; IR (neat) 1216,
1151, 1111, 1045; HRMS (Mϩ) Calcd for C16H26N2O4:
310.1891; Found 310.1884.
Scheme 3 Transition state model for the [4 ϩ 2]cycloaddition.
We now present a tentative transition state model which
affords the (S,S)-products (Scheme 3). The protonated pyrroli-
dine catalyst is considered to link with anthrone enolate
through ionic interactions and hydrogen bonds.3 It is note-
worthy that high enantioselectivity is attained only when the
catalysts have hydroxy groups and the reaction is effected in
aprotic solvents (this report and reference 6). This fact indicates
the importance of another hydrogen bond in the transition
state. When the maleimide approaches from the upper-right
direction, the transition state should be stabilized by the
hydrogen bond between a carbonyl group of the maleimide
and a hydroxy group of the catalyst. On the other hand, such
stabilization cannot be expected when the maleimide attacks
from the upper-left direction. Because the catalysts are of
C2-symmetry, the same stereochemical consideration can be
applied to the approach from the lower side. Consequently, the
(S,S)-products are afforded preferentially.
In conclusion, the asymmetric cycloaddition of anthrone
with N-alkyl- and N-arylmaleimides was performed with
high stereoselectivity by using C2-chiral pyrrolidine 1h with
a N-4-pyridylmethyl group. The best ee of 87% was attained
when maleimide 4j with an N-(2-tert-butyl)phenyl group was
employed. The configuration of the products was S,S through-
out the present asymmetric synthesis with both N-alkyl- and
N-arylmaleimides. The derivative of 4j with a substituent on the
maleimide ring is axially asymmetric and the optically active
compound has been obtained by resolution and proved to be a
useful chiral dienophile.9 The present asymmetric synthesis can
be applied to the kinetic resolution of analogous dienophiles
and is currently under investigation. Recently, an analogue of
4-[(2R,5R)-2,5-Bis(hydroxymethyl)pyrrolidinylmethyl]-
pyridine 1h. To a solution of 1g (91.2 mg, 0.29 mmol) in
CH3OH (10 cm3), 12 M HCl (3 drops) was added. This solution
was refluxed for 2 days and evaporated. The residue was dis-
solved in CH3OH (5 cm3), and the solution was passed through
an ion-exchange resin, IRA-400 (OHϪ). Evaporation gave
1h (50 mg, 76%); yellow oil; [α]D20 ϩ20.9 (c 0.14, CH3OH);
δH (CD3OD) 1.7–2.0 (m, 4H, CH2CH2), 3.1–3.2 (m, 2H,
2 × CH), 3.4–3.6 (m, 6H, 2 × CHCH2, 2 × OH), 4.0–4.1 (m,
4H, 2 × NCH2), 7.4–7.5 (m, 2H, pyridine ring), 8.4–8.5 (m, 2H,
pyridine ring); δC (CD3OD) 28.5, 53.2, 64.5, 64.6, 125.8, 150.6,
154.0; IR (neat) 3197, 1219, 1055; HRMS (Mϩ) Calcd for
C12H18N2O2: 222.1367; Found 222.1382.
1-Benzyl-[(2R,5R)-2,5-bis(hydroxymethyl)]pyrrolidine
1d.
Yield 74% (from 1a); yellow oil; [α]D20 ϩ40.7 (c 0.65, CH3OH);
δH (CD3OD) 1.7–2.1 (m, 4H, CH2CH2), 3.0–3.2 (m, 2H, 2 ×
CH), 3.3–3.4 (m, 2H, 2 × OH), 3.4–3.6 (m, 4H, 2 × CHCH2),
3.92 (s, 2H, NCH2), 7.2–7.4 (m, 5H, Ph); δC (CD3OD) 28.4,
54.4, 64.2, 64.5, 128.6, 130.1, 130.3, 142.4; IR (neat) 3301, 1216,
1004
J. Chem. Soc., Perkin Trans. 1, 2001, 1002–1006

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1030, 700; HRMS (Mϩ) Calcd for C13H19NO2: 221.1415; Found
221.1420.
CHCHCH), 4.52 (s, 1H, OH), 4.82 (d, J 3.5, 1H, CHCH),
6.43–6.48 (m, 2H, Ph), 6.98 (t, J 8.5, 2H, Ph), 7.2–7.3 (m, 4H,
Ph), 7.40 (d, J 6.2, 2H, Ph), 7.55 (d, J 7.6, 1H, Ph), 7.73 (d,
J 7.3, 1H, Ph); δC (CDCl3) 44.8, 47.6, 50.8, 116.0, 116.4, 120.9,
121.1, 123.8, 124.7, 126.7, 126.9, 127.0, 127.2, 127.3, 128.1,
128.2, 136.6, 138.7, 140.9, 142.1, 160.6, 164.2, 175.5, 177.0; IR
(Nujol) 3400, 1774, 1703; HRMS (Mϩ) Calcd for C24H16FNO3:
385.1113; Found 385.1102; HPLC (S,S)-isomer 28.3 min
(major), (R,R)-isomer 31.2 min (minor).
General procedure for base-catalyzed asymmetric cycloaddition
of anthrone and N-substituted maleimides
A mixture of anthrone 3 (19.4 mg, 0.1 mmol), N-substituted
maleimide 4 (0.1 mmol), a catalyst (0.01 mmol) and CHCl3
(1 cm3) was stirred at room temperature during which the
reaction conversion was assessed by TLC. After completion of
the reaction, water (5 cm3) and 3 M HCl (1 cm3) were added.
The mixture was extracted with CH2Cl2 (3 × 15 cm3). The
extracts were washed with saturated NaCl and dried over
Na2SO4. After evaporation, the residue was purified with flash
column chromatography (silica gel, 15% EtOAc in hexane).
4-Hydroxy-2-(4-methoxyphenyl)-3a,4,9,9a-tetrahydro-4,9-
[1Ј,2Ј]benzeno-1H-benz[ f ]isoindole-1,3(2H)-dione 5f. 74% ee;
colorless solid; mp 206–207 ЊC; [α]D20 ϩ29.0 (c 0.5, CHCl3);
δH (CDCl3) 3.24 (d, J 8.3, 1H, HOCHCH), 3.47 (dd, J 3.5, 8.6,
1H, CHCHCH), 3.75 (s, 3H, OCH3), 4.55 (s, 1H, OH), 4.82
(d, J 3.8, 1H, CHCH), 6.38 (d, J 8.4, 2H, Ph), 6.80 (d, J 8.9,
2H, Ph), 7.2–7.3 (m, 5H, Ph), 7.40 (d, J 7.0, 1H, Ph), 7.55 (d,
J 7.0, 1H, Ph), 7.73 (d, J 7.6, 1H, Ph); δC (CDCl3) 44.8, 47.6,
50.7, 55.4, 114.5, 120.9, 121.1, 123.4, 123.7, 124.7, 126.8, 126.9,
127.2, 127.3, 127.5, 136.6, 138.8, 141.0, 142.3; IR (Nujol) 3380,
1695; HRMS (Mϩ) Calcd for C25H19NO4: 397.1313; Found
397.1307; HPLC (S,S)-isomer 58.6 min (major), (R,R)-isomer
67.2 min (minor).
4-Hydroxy-2-methyl-3a,4,9,9a-tetrahydro-4,9-[1Ј,2Ј]benzeno-
1H-benz[ f ]isoindole-1,3(2H)-dione 5a. 74% ee, colorless solid;
mp 189–190 ЊC; [α]D20 ϩ54.3 (c 0.6, CHCl3); δH (CDCl3) 2.49
(s, 3H, NCH3), 3.10 (d, J 8.4, 1H, HOCCH), 3.30 (dd, J 3.5,
8.4, 1H, CHCHCH), 4.52 (s, 1H, OH), 4.72 (d, J 3.5, 1H,
CHCH), 7.1–7.8 (m, 8H, Ph); δC (CDCl3) 24.2, 44.5, 47.6, 50.7,
120.7, 120.8, 123.6, 124.4, 126.7, 126.8, 127.0, 127.2, 136.4,
138.9, 140.6, 142.4, 176.4, 177.8; Anal. Calcd for C19H15NO3: C,
74.74; H, 4.95; N, 4.59; Found C, 74.87: H, 4.83; N, 4.60%.
4-Hydroxy-2-(2,6-dichlorophenyl)-3a,4,9,9a-tetrahydro-4,9-
[1Ј,2Ј]benzeno-1H-benz[ f ]isoindole-1,3(2H)-dione 5g. 63% ee;
colorless solid; mp 229–231 ЊC; [α]D20 ϩ20.6 (c 0.5, CHCl3);
δH (CDCl3) 3.42 (d, J 9.5, 1H, HOCHCH), 3.60 (dd, J 3.2, 9.2,
1H, CHCHCH), 4.39 (s, 1H, OH), 4.86 (d, J 3.2, 1H, CHCH),
7.2–7.4 (m, 9H, Ph), 7.59 (d, J 7.3, 1H, Ph), 7.69 (d, J 7.3, 1H,
Ph); δC (CDCl3) 44.3, 47.7, 50.7, 120.6, 121.6, 123.6, 125.3,
126.7, 126.8, 127.5, 127.6, 128.2, 128.4, 131.2, 133.6, 134.5,
137.0, 141.3, 142.9, 173.7, 175.4; IR (Nujol) 3420, 1773, 1700;
HRMS (Mϩ) Calcd for C24H15Cl2NO3: 435.0428; Found
435.0435; HPLC (S,S)-isomer 22.5 min (major), (R,R)-isomer
27.2 min (minor).
4-Hydroxy-2-benzyl-3a,4,9,9a-tetrahydro-4,9-[1Ј,2Ј]benzeno-
1H-benz[ f ]isoindole-1,3(2H)-dione 5b. 70% ee, colorless solid;
mp 211–213 ЊC; [α]D20 ϩ34.8 (c 0.7, CHCl3); δH (CDCl3) 3.11 (d,
J 8.9, 1H, HOCCH), 3.31 (dd, J 3.5, 8.9, 1H, CHCHCH), 4.26
(s, NCH2), 4.42 (s, 1H, OH), 4.70 (d, J 3.2, 1H, CHCH), 6.70
(d, J 5.9, 2H, Ph), 7.0–7.4 (m, 10H, Ph), 7.66 (d, J 7.3, 1H, Ph);
δC (CDCl3) 42.2, 44.4, 47.5, 50.6, 120.7, 123.6, 124.4, 127.2,
134.5, 136.4, 139.3, 140.6, 142.7, 176.0, 177.5; IR (Nujol) 3359,
1767, 1680; Anal. Calcd for C25H19NO: C, 78.72; H, 5.02; N,
3.67; Found C, 78.77; H, 4.99; N, 3.67%. HPLC (S,S)-isomer
19.6 min (major), (R,R)-isomer 21.5 min (minor).
4-Hydroxy-2-(2,4-dibromophenyl)-3a,4,9,9a-tetrahydro-4,9-
[1Ј,2Ј]benzeno-1H-benz[ f ]isoindole-1,3(2H)-dione 5h. 63% ee;
colorless solid; mp 206–207 ЊC; [α]D20 ϩ21.0 (c 0.5, CHCl3);
δH (CDCl3) 3.34 (d, J 8.1, 1H, HOCHCH), 3.55 (dd, J 3.2, 8.8,
1H, CHCHCH), 4.36 and 4.47 (s, 1H, OH), 4.82 (d, J 3.2,
1H, CHCH), 7.2–7.5 (m, 11H, Ph); δC (CDCl3) 44.7, 48.0, 51.1,
121.0, 121.2, 122.7, 123.8, 124.2, 124.8, 127.0, 127.2, 127.3,
129.8, 130.6, 131.1, 131.8, 135.7, 136.8, 138.5, 141.1, 142.0,
174.3, 175.9; IR (Nujol) 3440, 1770, 1700; HRMS (Mϩ) Calcd
for C24H15Br2NO3: 526.9379; Found 526.9419; HPLC (S,S)-
isomer 18.2 min (major), (R,R)-isomer 23.6 min (minor).
4-Hydroxy-2-phenyl-3a,4,9,9a-tetrahydro-4,9-[1Ј,2Ј]benzeno-
1H-benz[ f ]isoindole-1,3(2H)-dione 5c. 61% ee; colorless solid;
mp 208–209 ЊC; [α]D20 ϩ37.0 (c 0.5 in CHCl3); δH (CDCl3) 3.25 (d,
J 8.6, 1H, HOCHCH), 3.46 (dd, J 3.5, 8.6, 1H, CHCHCH),
4.56 (s, 1H, OH), 4.83 (d, J 3.2, 1H, CHCH), 6.4–6.5 (m, 2H,
Ph), 7.2–7.3 (m, 8H, Ph), 7.40 (d, J 7.3, 1H, Ph), 7.55 (d, J 7.7,
1H, Ph), 7.73 (d, J 7.3, 1H, Ph); δC (CDCl3) 44.8, 47.7, 50.8,
120.9, 121.1, 123.8, 124.7, 126.3, 126.8, 126.9, 127.2, 127.3,
129.0, 129.1, 130.8, 136.6, 138.8, 140.9, 142.3, 175.6, 177.1;
IR (Nujol) 3420, 1773, 1700; HRMS (Mϩ) Calcd for C24H17-
NO3: 367.1207; Found 367.1197; HPLC (S,S)-isomer 30.5 min
(major), (R,R)-isomer 33.6 min (minor).
4-Hydroxy-2-(2,6-dimethyl)-3a,4,9,9a-tetrahydro-4,9-[1Ј,2Ј]-
benzeno-1H-benz[ f ]isoindole-1,3(2H)-dione 5i. 50% ee; color-
less solid; mp 211–213 ЊC; [α]D20 ϩ20.6 (c 0.5, CHCl3); δH (CDCl3)
0.94 (s, 3H, CH3), 1.98 (s, 3H, CH3), 3.37 (d, J 3.2, 9.2, 1H,
HOCHCH), 3.55 (dd, J 3.2, 9.2, 1H, CHCHCH), 4.50 (s, 1H,
OH), 4.86 (d, J 3.5, 1H, CHCH), 6.9–7.3 (m, 6H, Ph), 7.3–7.4
(m, 3H, Ph), 7.59 (d, J 7.3, 1H, Ph), 7.69 (d, J 7.3, 1H, Ph);
δC (CDCl3) 16.1, 17.7, 17.9, 44.3, 47.6, 50.6, 54.3, 120.6, 121.6,
123.6, 125.1, 126.6, 126.7, 126.8, 127.5, 127.6, 127.9, 128.2,
128.4, 128.5, 129.5, 132.2, 133.7, 134.3, 134.7, 136.2, 137.2,
138.5, 139.8, 141.5, 143.0, 175.2, 176.8; IR (Nujol) 3420, 1770,
1700; HRMS (Mϩ) Calcd for C26H21NO3: 395.152; Found
395.1517; HPLC (S,S)-isomer 19.3 min (major), (R,R)-isomer
23.5 min (minor).
4-Hydroxy-2-(4-trifluoromethylphenyl)-3a,4,9,9a-tetrahydro-
4,9-[1Ј,2Ј]benzeno-1H-benz[ f ]isoindole-1,3(2H)-dione 5d. 50%
ee; colorless solid; mp 219–220 ЊC; [α]D20 ϩ20.0 (c 0.5, CHCl3);
δH (CDCl3) 3.30 (d, J 8.9, 1H, HOCHCH), 3.51 (dd, J 3.5, 8.6,
1H, CHCHCH), 4.47 (s, 1H, OH), 4.84 (d, J 3.5, 1H, CHCH),
6.67 (d, J 8.4, 2H, Ph), 7.2–7.3 (m, 5H, Ph), 7.42 (d, J 7.0, 1H,
Ph), 7.57 (d, J 8.4, 3H, Ph), 7.74 (d, J 7.3, 1H, Ph); δC (CDCl3)
44.8, 47.7, 50.9, 120.9, 121.1, 123.8, 124.7, 126.1, 126.2, 126.3,
126.6, 126.7, 126.9, 127.3, 127.4, 134.0, 136.6, 138.7, 140.8,
142.1, 145.1, 176.6; IR (Nujol) 3505, 1780, 1706, 1323; HRMS
(Mϩ) Calcd for C25H16F3NO3: 435.1081; Found 435.1064;
HPLC (S,S)-isomer 18.6 min (major), (R,R)-isomer 20.3 min
(minor).
4-Hydroxy-2–(2-tert-butylphenyl)-3a,4,9,9a-tetrahydro-4,9-
[1Ј,2Ј]benzeno-1H-benz[ f ]isoindole-1,3(2H)-dione 5j. 87% ee;
colorless solid; mp 192–193 ЊC; [α]D20 ϩ34.8 (c 0.5, CHCl3);
δH (CDCl3) 1.21 (s, 9H, 3 × CCH3), 3.30 (d, J 8.9, 1H, HOCH-
CH), 3.52 (dd, J 3.5, 8.6, 1H, CHCHCH), 4.66 (s, 1H, OH),
4-Hydroxy-2-(4-fluorophenyl)-3a,4,9,9a-tetrahydro-4,9-[1Ј,2Ј]-
benzeno-1H-benz[ f ]isoindole-1,3(2H)-dione 5e. 57% ee; color-
less solid; mp 191–192 ЊC; [α]D20 ϩ28.4 (c 0.5, CHCl3); δH (CDCl3)
3.25 (d, J 8.6, 1H, HOCHCH), 3.47 (dd, J 3.5, 8.6, 1H,
J. Chem. Soc., Perkin Trans. 1, 2001, 1002–1006
1005

View Article Online
4.84 (d, J 3.5, 1H, CHCH), 6.97 (t, J 6.8, 1H, Ph), 7.2–7.5 (m,
9H, Ph), 7.58 (d, J 7.0, 1H, Ph), 7.72 (d, J 6.8, 1H, Ph);
δC (CDCl3) 31.6, 35.5, 44.6, 48.0, 51.0, 121.0, 121.4, 123.9,
125.0, 126.9, 127.0, 127.3, 127.4, 128.4, 129.6, 129.8, 130.1,
137.2, 139.0, 141.5, 142.5, 147.7, 176.8, 178.6; IR (Nujol) 3480,
1770, 1700; HRMS (Mϩ) Calcd for C28H25NO3: 423.1833;
Found 423.1861; HPLC (S,S)-isomer 12.1 min (major), (R,R)-
isomer 14.4 min (minor).
1713; HRFABMS (M ϩ H)ϩ Calcd for C28H26NO3: 424.1914;
Found 424.1937.
Acknowledgements
We thank Dr T. Okajima at Saga University for helpful dis-
cussions about molecular orbital calculations.
(10S)-10-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)anthracen-9(10H)-
one (S)-6c—typical procedure for conversion of adduct 5 to
ketone 6
References
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To a solution of ent-5c (75 mg, 0.18 mmol) in CH3OH (4 cm3),
triethylamine (2 drops) was added, and the mixture was stirred
at room temperature for 1 day. After evaporation, the residue
was purified with flash column chromatography (silica gel, 15%
EtOAc in hexane) to give 6c (26 mg, 35% yield); colorless solid;
[α]D20 Ϫ140.2 (c 1.0, CH3OH); δH (CDCl3) 2.07 (dd, J 5.1, 19.4,
1H, CHCH2), 2.41 (dd, J 9.5, 19.4, 1H, CHCH2), 3.5–3.7 (m,
1H, CH2CH), 5.26 (d, J 3.24, 1H, Ph-CH), 7.0–7.2 (m, 2H, Ph),
7.4–7.7 (m, 9H, Ph), 8.1–8.2 (m, 2H, Ph); δC (CDCl3) 29.3, 29.8,
42.0, 49.9, 126.2, 127.8, 128.0, 128.1, 128.1, 128.6, 128.7, 128.8,
129.1, 131.4, 132.4, 133.2, 133.5, 133.7, 138.1, 142.2, 173.8,
176.8, 183.6; HRFABMS (M ϩ H)ϩ Calcd for C24H18NO3:
368.1285; Found 368.1258.
(10S)-10-[2,5-Dioxo-1-(2-tert-butylphenyl)pyrrolidin-3-yl]-
anthracen-9(10H)-one (S)-6j. 35% yield; yellow oil; [α]D20 Ϫ69.3
(c 1.0, CH3OH); δH (CDCl3) 1.27 (s, 9H, 3 × CCH3), 2.09 (dd,
J 5.4, 18.8, 1H, CHCH2), 2.42 (dd, J 9.5, 18.6, 1H, CHCH2),
3.6–3.7 (m, 1H, CH2CH), 5.31 (d, J 3.0, 1H, Ph-CH), 6.3–6.4
(m, 2H, Ph), 7.2–7.3 (m, 2H, Ph), 7.4–7.5 (m, 2H, Ph), 7.5–7.7
(m, 4H, Ph), 8.3–8.4 (m, 2H, Ph); δC (CDCl3) 29.4, 31.6, 31.7,
35.7, 41.5, 50.3, 121.0, 127.3, 127.8, 127.9, 128.1, 128.4, 128.7,
128.9, 129.8, 130.2, 132.4, 133.2, 133.6, 133.7, 138.4, 142.3,
147.8, 174.9, 178.0, 183.6; IR (neat) 1184, 1251, 1661, 1668,
1006
J. Chem. Soc., Perkin Trans. 1, 2001, 1002–1006