Reversal of enantioselectivity induced by the achiral part of an organocatalyst in a Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetasy.2016.01.002

A new series of chiral organocatalysts was developed by attaching achiral heterocyclic units via a methylene group to (S)-2-hydroxyethylbenzimidazole for the asymmetric Diels-Alder reaction between anthrone enolate and maleimides. While organocatalysts wi

Full text of DOI:10.1016/j.tetasy.2016.01.002

Tetrahedron: Asymmetry 27 (2016) 130–135
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Reversal of enantioselectivity induced by the achiral part of an
organocatalyst in a Diels–Alder reaction
⇑
Trupti S. Tawde, Swapnil J. Wagh, Jai V. Sapre, Vaibhav N. Khose, Purav M. Badani, Anil V. Karnik
Department of Chemistry, University of Mumbai, Mumbai 400 098, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of chiral organocatalysts was developed by attaching achiral heterocyclic units via a methy-
lene group to (S)-2-hydroxyethylbenzimidazole for the asymmetric Diels–Alder reaction between
anthrone enolate and maleimides. While organocatalysts with pyridine, quinoline, and 1,3,4-oxadiazole
achiral heterocyclic subunits gave Diels–Alder adducts with an (S,S)-configuration, the organocatalyst
with a benzotriazole subunit caused formation of the (R,R)-configuration for the Diels–Alder adducts
Ó 2016 Elsevier Ltd. All rights reserved.
Received 16 December 2015
Accepted 4 January 2016
Available online 12 January 2016
1. Introduction
states via hydrogen bond interactions and enhanced basic nature.
In the past few years this structural motif has been successfully
The Diels–Alder reaction is one of the most prominent C–C bond
forming reactions. While Lewis acid catalyzed asymmetric Diels–
Alder reactions have seen phenomenal growth in terms of effi-
ciency and enantioselectivity;1 reasonable levels of enantioselec-
tivities2 have also been observed in chiral base induced
generation of diene components undergoing cycloadditions with
dienophiles. Generation of the enolate of anthrone by use of a chi-
ral base for asymmetric Diels–Alder reactions with maleimides is a
representative example of this class of Diels–Alder reactions.
Prominent contributions to this reaction have come from Kagan,3
Yamamoto,4 Wong,2b Gobel,2c and others.2d–f
Chiral organocatalysis induced asymmetric synthesis is a very
delicate phenomenon. The stereochemical outcome is the result
of difference in the geometries of the competing diastereomeric
transition states. To have better control over the stereochemical
outcome of these reactions, all the parameters contributing to
the transition state must be fully understood. Typically
asymmetric synthesis relies upon several parameters, which
include the type of chiral influence, its proximity to the reaction
site, availability of additional binding sites, etc. For example,
many catalysts have exhibited marked improvement in enantio-
selectivity simply by attachment of an achiral unit such as a
thiourea.5
explored for the development of organocatalysts for a variety of
asymmetric transformations such as Michael reactions,8 Aldol
reactions,9 Diels–Alder reactions10 and in kinetic resolutions.11
Due to the significant role that these chiral heterocycle tweezers
can play in numerous applications, the asymmetric synthesis of
enantiopure heterocycles using chiral heterocyclic tweezers con-
tinues to be a highly active field of research.
2. Results and discussion
Recently we reported2a the use of (S)-2-hydroxyethyl-
benzimidazole [HEB 1] for the Diels–Alder reaction between the
enolate from anthrone 3 and maleimides 4 with low to moderate
enantioselectivity. Obviously the chiral catalyst employed was
not providing sufficiently effective diastereomeric transition
states to afford satisfactory levels of enantioselection.
Then having realized that HEB 1 is not an optimum catalyst for
the reaction between anthrone enolate 3 and maleimide 4,2a we
decided to structurally modify the HEB 1 by attaching a nitrogen
containing heteroaryl ring to the HEB 1 by a flexible arm. It has
been expected that the conjugate acid of the heteroaryl moiety,
after abstracting the proton from the anthrone, would remain in
the close-proximity to the benzimidazole ring and the hydroxyl
group would then have hydrogen bonding interaction with the
maleimide part resulting in good levels of enantioselection.
Based on this premise, chiral tweezers 2a–d (Fig. 1) were
developed by a simple synthetic protocol shown in Scheme 1.
A literature search reveals that in the recent years, chiral mole-
cules with two heterocyclic rings6 have become functional alterna-
tives to thioureas5 and guanidine7 based organocatalysts, due to
formation of distinctly different rigid diastereomeric transition
All the tweezers, namely, (S)-(ꢀ)-N-(methyl-20-pyridyl)-2-(
a-
hydroxyethyl)benzimidazole [Pyr-HEB] 2a, (S)-(ꢀ)-N-(methyl-
⇑
Corresponding author. Tel.: +91 022 26526091; fax: +91 022 26528547.
E-mail address: avkarnik@chem.mu.ac.in (A.V. Karnik).
20-quinolyl)-2-(
a-hydroxyethyl)benzimidazole [Qn-HEB] 2b,
http://dx.doi.org/10.1016/j.tetasy.2016.01.002
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.

T. S. Tawde et al. / Tetrahedron: Asymmetry 27 (2016) 130–135
131
H
N
This serendipitous finding was then further investigated. All the
chiral tweezers employed by us have been developed from a com-
mon synthon, (S)-2-hydroxyethylbenzimidazole [HEB 1], naturally,
2a–2d, have the same stereogenic center with the same configura-
tion, that is (S). We were anticipating enhanced enantioselectivi-
ties with 2a–2d, in relation to 1,2a due to the additional nitrogen
containing heterocycle, however we unexpectedly stumbled upon
reversal of enantioselectivity for the Diels–Alder adduct 5a–g
when 2d was used as the chiral organocatalyst. The answer to
this puzzling observation apparently lies in the nature of
interactions between the protonated heteroaryl rings and
benzimidazole moiety, which are proposed to be different for
transition states involving 2a–2c and 2d.
Unusual reversal of enantioselectivity has been reported by
many groups in a variety of reactions,12 for reactions employing
chiral metal-based catalysts,13 and with a few organocatalysts.14
The chiral chemists would expect to see the opposite effect of
the chiral metal-based catalysts/chiral organocatalysts with oppo-
site configuration affording mirror image enantioselectivity, as in
the case of Sharpless epoxidation.15 However, there are examples
where the chiral influence was the same and the difference in achi-
ral reaction parameters such as pressure,16 temperature,17 sol-
vent,18 achiral additives, and19 type of Lewis acids20 employed
have influenced the reversal of enantioselectivity. Interesting
examples have also been found where the absolute configuration
in the chiral catalyst is the same and only a slight difference in
the catalyst structure resulted in complete opposite enantiofacial
selectivity.21
While organocatalytic asymmetric Diels–Alder reaction
between the enolate of anthrone 3 and maleimide 4 has been
reported2–4 by many groups, to the best of our knowledge, reversal
of enantioselectivity while employing catalysts with same absolute
configuration has not been reported previously for this reaction.
The mechanism proposed by Yamammoto4a and others2b,3 to
account for the stereochemical outcome in this reaction appears
satisfactory. On these lines in our case we propose that, the
acidic proton of the anthrone 3 was abstracted by the chiral
catalysts 2a–d, converting anthrone 3 into its enolate form with
a protonated amine as its counterion. The chiral catalyst with a
hydroxyl group present at the stereogenic center then formed an
H-bond with the maleimide. Thus the chiral amine was partially
bonded to the diene part and the dienophile part to induce
stereoselectivity. In the case of approach of the maleimide 4 from
the right hand side, an (S,S)-configuration was expected, on the
other hand in the case of the approach of the maleimide 4 from
the left hand side, a (R,R) configuration could be expected.
To account for the stereochemical outcome of the asymmetric
Diels–Alder reaction using the chiral organocatalyst 1 to 2a–d; var-
ious possibilities were considered. Possibility number one was
obviously the protonation of the most basic benzimidazole nitro-
gen, the unsubstituted nitrogen in the benzimidazole ring, the con-
jugate acid thus formed, would remain close to the anion of
anthrone and the hydroxyl group would then have a hydrogen
bonding interaction with the maleimide part resulting in the 11
member cyclic transition state Figure 2A. In such a scenario all the
catalysts 2a–2c would have resulted in Diels–Alder adducts with
the same configuration, for example, (S,S); as the additional hetero-
cyclic ring arm would have been largely ineffective in influencing
the stereochemical outcome of the reaction. Since a different config-
urational isomer of the Diels–Alder adduct was obtained in the case
of 2d, we had to look for some other possibility.
H
N
H
CH3
OH
N
CH3
CH3
N
OH
N
OH
N
H
H2C
H2C
N
N
1
(S)-(-)-HEB
2a
2b
(S)-(-)-Qn-HEB
(S)-(-)-Pyr-HEB
H
N
H
N
CH3
CH3
N
OH
N
OH
H2C
H2C
N
O
N
N
N
N
(S)-(-)-Oxd-HEB 2c
2d
(S)-(-)-Btz-HEB
Figure 1. Proposed chiral tweezers 1, 2a–d.
H
CH3
OH
N
N
RnCH2Cl, K2CO3
DMF, rt
CH2
Rn
H
CH3
OH
N
(S)-(-)-Oxd-HEB 2c
or
N
H
2d
(S)-(-)-Btz-HEB
(S)-(-)-HEB 1
H
CH3
OH
N
N
.
RnCH2ClHCl, NaOH
acetone: water (8:2)
reflux
CH2
Rn
2a
(S)-(-)-Pyr-HEB
or
(S)-(-)-Qn-HEB 2b
Scheme 1. Synthetic pathway for preparation of chiral base tweezers 2a–d.
(S)-(ꢀ)-N-[methyl-20-50(phenyl-10,30,40-oxadiazolyl)]-2-(
a-hydroxyethyl)
benzimidazole [Oxd-HEB 2c], (S)-(ꢀ)-N-(methyl-10-benzotria-
zolyl)-2-(
a
hydroxyethyl)benzimidazole [Btz-HEB 2d] were
obtained in good yields and with excellent enantiopurities. A nota-
ble feature of 1H NMR spectra of these compounds is the appear-
ance of two doublets for the linker ‘CH2’ group, which clearly
indicated diastereotopic nature of the ‘CH2’ protons in these com-
pounds and interestingly indicated that these compounds exhibit
some levels of conformational preferences even in free form.
When we carried out the initial experiments of the Diels–Alder
reaction between anthrone enolate 3, generated by chiral tweezers
2a–d and maleimide 4a–g, mixed results were obtained; all the
tweezers were not found to be uniformly efficient and tweezers
2a–c gave the major stereoisomer of the Diels–Alder adduct 5a–g
as (S,S), while the tweezer 2d gave (R,R) as the major stereoisomer
of 5a–g (Scheme 2).
O
O
N
Rn
Pyr-HEB 2a, DCE, -10oC
O
N
Rn
or
Btz-HEB 2d, CHCl , rt
3
O
HO
O
Possibility number two could be protonation of the nitrogen on
the heteroaryl ring attached to the benzimidazole. The conjugate
acid thus formed then would remain partially bonded to the oxy-
gen anion of the anthrone enolate. Again the hydroxyl group of
the benzimidazole ring could be expected to hydrogen bond with
4a-g
5a-g
3
Scheme 2. Substrate scopes of anthrone 3 and maleimide 4 for asymmetric Diels–
Alder reaction.

132
T. S. Tawde et al. / Tetrahedron: Asymmetry 27 (2016) 130–135
O
approach from the left hand side (Fig. 2C) and consequently the
predominant stereoisomer would be (R,R).
O
O
Rn
N
While the best results, in terms of the extent of enantioselectiv-
ity, were obtained in case of tweezer Pyr-HEB 2a. Tweezers Pyr-
HEB 2a and Btz-HEB 2d were evaluated for the optimal conditions
by investigating the effect of solvents and the effect of tempera-
ture. Lowering the temperature of the reaction using Pyr-HEB 2a
from room temperature to ꢀ10 °C, extended the reaction time
yet furnished better enantioselectivities, up to 88% ee. On further
lowering the temperature, the cycloaddition was retarded. While
no reaction progress was observed for the reaction using Btz-HEB
2d at lower temperature.
Rn
N
Rn
N
O-
O
O-
N
O
O-
O
H
H
H
N
H
H
H
O
H
N
N
O
H
H3C
O
CH3
CH3
H
N
N
N
N
N
N
N
Under the optimized conditions, we explored the scope of the
asymmetric Diels–Alder reaction and the results are summarized
in Table 1. A notable feature being while tweezer 2a gave better
enantioselectivities for N-alkyl maleimides, tweezer 2d was found
to afford better enantioselectivity with N-phenyl maleimide.
Table 1 presents the results under optimal conditions.
C
A
B
Figure 2. Transition state model of approach of maleimide 4 toward anthrone
enolate with (A) catalyst Pyr-HEB 2a involving protonated benzimidazole nitrogen,
(B) catalyst Pyr-HEB 2a involving protonated pyridine nitrogen (C) catalyst Btz-HEB
2d involving protonated benzotriazole nitrogen.
3. Conclusion
the maleimide part. This could result in a large sized 14 or 15
membered transition state; this naturally would be less crowded
than the medium sized 11 membered transition state. This is illus-
trated in Figure 2B and C.
In conclusion, we have come across a serendipitous finding that
a change in the achiral part of chiral organocatalysts caused rever-
sal in enantioselectivity of the Diels–Alder adducts, even though
the stereogenic center in these organocatalysts had the same con-
figuration. The possible reason to this observation could be due to
the repulsive interaction between the benzimidazole part and the
protonated benzotriazole part in 2d, unlike in other organocata-
lysts 2a–2c, where attractive interactions appear to be dominant.
These results can have useful applications in understanding the
parameters responsible for enantioselectivities and contribute to
the development of other organocatalysts.
Based on this possibility we propose that though the nitrogen
atom on the benzimidazole ring was expected to be the site for
protonation, the actual protonation could be taking place on the
nitrogen atom of the heteroaryl nitrogen atom due to formation
of larger, less crowded 14/15 membered transition state complex.
This protonated base then would remain bonded to the enolate of
anthrone 3. The benzimidazole part could possibly have an attrac-
tive interaction with the protonated flexible arm heterocycle and
would remain in the close proximity to the benzimidazole ring.
The side arm of the benzimidazole ring with a stereogenic center
and hydroxyl group would be partially bonded via a hydrogen
bond with the maleimide part. This would make the approach of
the maleimide facile from the right hand side, and the predomi-
nant stereoisomer obtained would be (S,S). This accounts for the
stereochemical outcome as (S,S), when 2a–2c were employed as
the organocatalysts (Fig. 2B).
When benzotriazolyl side arm 2d with three nitrogen atoms
and a fused ring was employed, the benzotriazole ring after proto-
nation at N-3, possibly could not remain in the same plane and in
close proximity to the benzimidazole ring due to repulsion
between nitrogen atoms on benzotriazole and nitrogen atoms on
benzimidazole and also due to the bulk of the benzotriazole. The
two benzo-fused azoles rings would be forced as far away as pos-
sible. This would make the approach of the maleimide 4 difficult
from the right hand side, thus the maleimide part was forced to
4. Experimental
4.1. General
1H NMR, 13C NMR, COSY, DEPT-135, HSQC spectrums were
recorded in CDCl3 and DMSO-d6 using spectrometer operating at
300 MHz (13C NMR, DEPT-135 are recorded at 75 MHz) with TMS
as an internal standard Multiplicities are indicated as s (singlet),
d (doublet), t (triplet), q (quintet), and m (multiplet), and coupling
constants (J) are reported in Hertz. Splitting patterns that could not
be easily interpreted are designated as multiplet (m). IR spectra
were recorded on FT-IR instrument. Enantiomeric excesses were
determined by chiral HPLC analysis. The absolute configurations
of the known products were assigned by chiral HPLC and specific
rotation comparisons with the reported data.2–4 Melting points
Table 1
Substratea scope of anthrone 3 and maleimide 4a–g for asymmetric Diels–Alder reactions
Entry
N-Substitute maleimide 4, Rn=
Adduct 5
With Pyr-HEB 2a
With Btz-HEB 2d
Yieldb (%)
eec (%)
Configurationd
Yieldb (%)
eec (%)
Configurationd
1
2
3
4
5
6
7
CH3
C2H5
C3H7
tert-Bu
Bn
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
94
90
90
87
75
65
60
63
88
14
48
78
17
16
(S,S)
(S,S)
(S,S)
(S,S)
(S,S)
(S,S)
(S,S)
85
75
88
79
86
91
82
12
23
22
30
24
73
23
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
Ph
p-CH3OC6H4
4g
5g
a
All reactions were carried out using N-substituted maleimide 4 (0.5 mmol), anthrone 3 (0.5 mmol) in 5 ml of solvent with 10 mol % of catalyst 2a/2d at the specified
temperature.
b
Isolated yield after column chromatography.
c
The enantiomeric excess was determined by Chiral HPLC using Chiralcel AD column of Diacel.
d
Configuration was determined by comparison of the specific rotation reported in the literature.2–4

T. S. Tawde et al. / Tetrahedron: Asymmetry 27 (2016) 130–135
133
were recorded and uncorrected. The progress of the reaction was
monitored by thin-layer chromatography (TLC) using silica gel.
All reagents and solvents were commercially available with analyt-
ical grade and used as received.
Found: C, 75.14; H, 5.72, N, 13.91; Chiral HPLC: Chiralpak IB col-
umn of diacel, i-PrOH/Hexane 10:90, Flow rate 0.6 mL/min,
kmax = 254 nm, tmajor = 12.61 min, tminor = 17.32 min, 87% ee.
4.2.2.3. (S)-(ꢀ)-N-[Methyl-20-50(phenyl-10,30,40-oxadiazolyl)]-2-
(a-hydroxyethyl)benzimidazole Oxd-HEB 2c.
Compound
4.2. Synthesis and characterization of compounds 2a–d
2c was prepared by procedure B; Colorless solid, 1.71 g, 97% yield;
melting point: 145 °C; Specific rotation: [
a
]
25 = ꢀ47 (c 1, CHCl3); IR
D
4.2.1. Procedure A: preparation of chiral tweezer 2a and 2b
(KBr, cmꢀ1):
mmax 3473, 3142, 2980, 1609, 1527, 1449, 1321, 1161,
To the solution of sodium hydroxide (0.37 g, 9.25 mmol) in
1096, 767; 1H NMR (300 MHz, DMSO-d6): d 7.93–7.90 (m, 2H),
7.67–7.52 (m, 5H), 7.31–7.20 (m, 2H), 6.04 (unresolved singlet,
2H), 5.82 (d, 1H, J = 6.2 Hz –OH), 5.16 (t, 1H, J = 6.6 Hz), 1.64 (d,
3H, J = 6.6 Hz); 13C NMR (75 MHz, DMSO-d6): d 164.42, 162.40,
156.11, 141.52, 135.43, 131.94, 129.22, 126.39, 123.0, 122.60,
121.92, 119.12, 110.09, 62.45, 38.27, 21.56; DEPT-135 (75 MHz,
DMSO-d6): one negative peak at d 38.26 for one ‘CH2’ group; COSY
(300 MHz, DMSO-d6): Signal indicating coupling between H of CH3
(d 1.64) and H of CH (d 5.16). The signal indicating coupling
between H of CH (d 5.16) and H of OH (d 5.82); ESI MS: m/z (M+)
value at 320.04; Anal. Calcd for C18H16N4O2: C, 67.49; H, 5.03; N,
17.49. Found: C, 67.55; H, 5.14; N, 17.44; Chiral HPLC: Chiralpak
IB column of diacel, i-PrOH/Hexane 15:85, Flow rate 0.6 mL/min,
kmax = 254 nm, tmajor = 17.69 min, tminor = 12.61, 93% ee.
10 ml of Acetone/water (8:2), (S)-(ꢀ)-2-(
a
-hydroxyethyl)benzimi-
(1 g, 6.17 mmol), 2-(chloromethyl)pyridine
(1 g, 6.17 mmol)/2-(chloromethyl)quinoline
dazole (HEB)
hydrochloride
1
hydrochloride (1.32 g, 6.17 mmol) were added. The reaction mix-
ture was refluxed for 8 h. The reaction was monitored for complete
consumption of HEB 1 by TLC. After completion of reaction acetone
was removed by distillation. The remaining residue was diluted
with water and stirred at room temperature. The solid obtained
was filtered and dried.
4.2.2. Procedure B: preparation of chiral tweezer 2c and 2d
To the solution of (S)-(ꢀ)-2-(a-hydroxyethyl)-benzimidazole
HEB 1 (1 g, 6.17 mmol) and K2CO3 (1.27 g, 9.25 mmol) in DMF
(50 mL) 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole (1.20 g, 6.17 mmol)/
1-(chloromethyl)-1H-benzotriazole (1.04 g, 6.17 mmol) was
added. The reaction mixture was stirred at room temperature for
7 h. The reaction was monitored for complete consumption of
HEB 1 by TLC. After completion of reaction mixture was poured
into crushed ice. The solid obtained was filtered and dried.
4.2.2.4. (S)-(ꢀ)-N-(Methyl-10-benzotriazolyl)-2-(
a-hydroxyethyl)
Compound 2d was prepared by
benzimidazole Btz-HEB 2d.
procedure B; colorless solid, 1.77 g, 98% yield; melting point:
135 °C; [
a
]
25 = ꢀ45 (c 1, CHCl3); IR (KBr, cmꢀ1): mmax 3300, 3094,
D
1449, 1244, 1011, 745; 1H NMR (300 MHz, DMSO-d6): d 8.09–
7.74 (m, 4H), 7.66–7.59 (m, 2H), 7.46–7.42 (m, 2H), 7.30–7.20
(m, 2H), 6.03 (d, 1H, J = 6.6 Hz, -OH), 5.39 (t, 1H, J = 6.6 Hz), 1.65
4.2.2.1. (S)-(ꢀ)-N-(Methyl-20-pyridyl)-2-(
a-hydroxyethyl)benz-
(d, 3H, J = 6.3 Hz.); 13C NMR (75 MHz, DMSO-d6):
d 156.31,
imidazole Pyr-HEB 2a.
Compound 2a was prepared by proce-
dure A; colorless solid, 1.55 g, 99% yield, melting point: 95 °C;
145.01, 141.58, 134.88, 132.40, 128.48, 128.14, 124.44, 123.03,
122.38, 119.39, 119.35, 110.60, 62.08, 54.50, 21.00; DEPT-135
(75 MHz, DMSO-d6): one negative peak at d 54.50 for one ‘CH2’
group; COSY (300 MHz, DMSO-d6): Signal indicating coupling
between H of CH3(d 1.65)and H of CH(d 5.39). The signal indicating
coupling between H of CH (d 5.39) and H of OH (d 6.032); ESI MS:
m/z (M+) value at 293.54; Anal. Calcd for C16H15N5O: C, 65.52; H,
5.15; N, 23.88. Found: C, 65.55; H, 5.08; N, 23.95; Chiral HPLC:
Chiralpak IB column of diacel, DCM (20% ethanol)/Hexane
30:70, Flow rate = 0.8 mL/min, kmax = 254 nm, tmajor = 16.18 min,
tminor = 13.30 min, 98% ee.
[
a
]
25 = ꢀ39 (c 1, CHCl3); IR (KBr, cmꢀ1): mmax 3212, 2926, 1594,
D
1434, 1318, 732; 1H NMR (300 MHz, CDCl3): d 8.42–8.41 (m, Ar-
H, 1H), 7.74–7.58 (m, Ar-H, 2H), 7.26–7.14 (m, Ar-H, 5H), 6.33 (s,
1H, OH), 5.55 (two doublets, J = 16.2 Hz, J = 15.9 Hz, 2H), 5.30 (q,
1H), 1.79 (d, 3H, J = 6.6 Hz); 13C NMR (75 MHz, CDCl3): d 156.58,
154.78, 149.48, 142.04, 137.65, 135.14, 123.25, 122.88, 122.37,
122.15, 120.00, 109.43, 62.57, 48.71, 21.41; DEPT-135 (75 MHz,
CDCl3): One negative peak at d 48.71 for one ‘CH2’ group; COSY
(300 MHz, CDCl3): Signal indicating coupling between ‘H’ of CH
(d 5.30) and ‘H’ of CH3 (d 1.79). Also signal at d 5.50 ppm is corre-
lated to the signal at d 5.47 ppm, indicating coupling between pro-
tons of CH2 group; ESI MS: m/z (M+) value at 254.13; Anal. Calcd for
4.3. Asymmetric Diels–Alder reaction of anthrone 3 and various
N-substituted maleimides 4a–g
C15H15N3O: C, 71.13; H, 5.97; N, 16.59. Found: C, 71.02; H, 5.91; N,
16.52. Chiral HPLC: Chiralpak IB column of diacel, i-PrOH/Hexane
10:90, Flow rate 0.6 mL/min, kmax = 254 nm, tmajor = 83.73 min,
tminor = 75.53 min, 100% ee.
4.3.1. Representative experimental procedure for the Diels–Alder
reaction
4.3.1.1. For chiral Tweezer Pyr-HEB 2a.
To a 50 mL round
4.2.2.2. (S)-(ꢀ)-N-(Methyl-20-quinolyl)-2-(
a-hydroxyethyl)benz-
Compound 2b was prepared by proce-
bottom flask (RBF) containing Pyr-HEB 2a (10 mol %) and a stirring
bar, anhydrous 1,2-dichloroethane at ꢀ10 °C, anthrone 3 (97 mg,
0.5 mmol) and N-substituted maleimide 4a–g (0.5 mmol) were
added in this sequence. The reaction was carried out under dry
condition and monitored with TLC. After stirring at ꢀ10 °C for 8–
12 h, on completion, the reaction mixture was acidified with dilute
hydrochloric acid and extracted with chloroform. The organic
extracts were washed with brine, dried over sodium sulfate and fil-
tered. The solvent was removed in vacuum, purified by using Silica
column chromatography (gradient elution with chloroform/pet.
ether mixtures; 80:20).
imidazole Qn-HEB 2b.
dure A; colorless solid, 1.81 g, 97% yield; melting point: 105 °C;
[
a
]
25 = ꢀ17 (c 1, CHCl3); IR (KBr, cmꢀ1): mmax 3221, 2927, 2866,
D
1593, 1458, 1089, 735; 1H NMR (300 MHz, CDCl3): d 8.22–7.24
(m, Ar-H, 10H and s, OH, 1H), 5.84 (two doublets, J = 15.9 Hz,
J = 16.2 Hz, 2H), 5.48 (q, 1H), 1.88 (d, 3H, J = 6.6 Hz); 13C NMR
(75 MHz, CDCl3):
d 156.63, 155.19, 147.28, 142.10, 138.14,
135.26, 130.51, 128.46, 127.60, 127.47, 127.17, 122.98, 122.49,
120.10, 119.64, 109.41, 62.66, 49.24, 21.46; DEPT-135 (75 MHz,
CDCl3): One negative peak at d 49.23 for one ‘CH2’ group; COSY
(300 MHz, CDCl3): Signal indicating coupling between ‘H’ of CH
(d 5.48 ppm) and ‘H’ of CH3 (d 1.88 ppm). Also the signal at d
5.78 ppm is correlated to the signal at d 5.76 ppm, indicating cou-
pling between protons of CH2 group; ESI MS: m/z (M+) value at
304.19; Anal. Calcd for C19H17N3O: C, 75.23; H, 5.65; N, 13.85.
4.3.1.2. For chiral Tweezer Btz-HEB 2d.
To a 50 mL RBF con-
taining Btz-HEB 2d (10 mol %) and a stirring bar, anhydrous Chlo-
roform at room temperature, anthrone 3 (97 mg, 0.5 mmol) and
N-substituted maleimide 4a–g (0.5 mmol) were added in this

134
T. S. Tawde et al. / Tetrahedron: Asymmetry 27 (2016) 130–135
sequence. The reaction was carried out under dry condition and
monitored with TLC. After stirring at room temperature for 12 h,
on completion, the reaction mixture was acidified with dilute
hydrochloric acid and extracted with chloroform. The organic
extracts were washed with brine, dried over sodium sulfate, and
filtered. The solvent was removed in vacuum, purified by using sil-
ica column chromatography (gradient elution with chloroform/pet.
ether mixtures; 80:20).
(m, 1H), 7.21–7.03 (m, 8H), 6.32 (m, 2H), 4.71 (d, 1H, J = 3.3 Hz),
4.56 (s, 1H), 4.25 (s, 2H), 3.40 (dd, 1H, J = 3.3 Hz, J = 8.1 Hz), 3.23
(d, 1H, J = 8.7 Hz); ESI MS: (C25H19NO3) m/z (M+) value at 380.86.
Chiral HPLC: Chiralpak IB column of diacel, i-PrOH/Hexane 20:80,
Flow
tminor = 25.72 min, 78% ee; {[a]
25 = +36.5 (c 1, CHCl3)} with
D
rate
0.6 mL/min,
kmax = 230 nm,
tmajor = 21.16 min,
catalyst 2a, 24% ee {[
a
]
25 = ꢀ13.6 (c 1, CHCl3)} with catalyst 2d.
D
4.3.1.8. 4-Hydroxy-2-phenyl-3a,4,9,9a-tetrahydro-4,9[10,20]-ben-
zeno-1H-benz[f]isoindole-1,3(2H)-dione 5f. Colorless solid,
4.3.1.3.
benzeno-1H-benz[f]isoindole-1,3(2H)-dione 5a.
4-Hydroxy-2-methyl-3a,4,9,9a-tetrahydro-4,9[10,20]-
Colorless
119.3 mg, 65% yield with catalyst 2a, 167 mg, 91% yield with cata-
lyst 2d; melting point: 204–205 (Lit. 208–209 °C);4a 1H NMR
solid, 143.4 mg, 94% yield with catalyst 2a, 129.7 mg, 85% yield
with catalyst 2d; melting point: 184–186 (Lit. 189–190 °C);4a 1H
NMR (300 MHz, CDCl3): d 7.69 (m, 1H), 7.48 (m, 1H), 7.36 (m,
1H), 7.34–7.10 (m, 5H), 4.72 (d, 1H, J = 3.3 Hz), 4.42 (s, 1H), 3.32
(dd, 1H, J = 3.6 Hz, J = 8.5 Hz), 3.11 (d, 1H, J = 8.4 Hz), 2.49 (s, 3H);
ESI MS: (C19H15NO3) m/z (M+) value at 304.95; Chiral HPLC:
Chiralpak IB column of diacel, i-PrOH/Hexane 10:90, Flow rate
0.6 mL/min, kmax = 230 nm, tmajor = 23.33 min, tminor = 19.64 min,
(300 MHz, CDCl3):
d 7.73 (d, 1H, J = 7.2 Hz), 7.56 (d, 1H,
J = 7.2 Hz),7.41 (d, 1H, J = 6.9 Hz),7.36–7.21 (m, 8H), 6.51–6.47
(m, 2H), 4.84 (d, 1H, J = 3.3 Hz), 4.57 (s, 1H, OH),3.47 (dd, 1H,
J = 3.6 Hz, J = 8.7 Hz), 3.26 (d, 1H, J = 8.7 Hz); ESI MS: (C24H17NO3)
m/z (M+) value at 366.80. Chiral HPLC: Chiralpak IB column of
diacel,
i-PrOH/Hexane
20:80,
Flow
rate
0.6 mL/min,
kmax = 230 nm, tmajor = 27.24 min, tminor = 34.56 min, 17% ee;
25 = +44.1 (c 1, CHCl3)} with catalyst 2a, 12% ee
{[
(c 1, CHCl3)} with catalyst 2d.
a] a]
25 = +9.8 (c 1, CHCl3)} with catalyst 2a, 73% ee {[
D
25 = ꢀ38.7
63% ee; {[a]
D
D
{[a]
25 = ꢀ8.6 (c 1, CHCl3)} with catalyst 2d.
D
4.3.1.4. 4-Hydroxy-2-ethyl-3a,4,9,9a-tetrahydro-4,9[10,20]-ben-
zeno-1H-benz[f]isoindole-1,3(2H)-dione 5b. Colorless solid,
4.3.1.9. 4-Hydroxy-2-(4-methoxyphenyl)-3a,4,9,9a-tetrahydro-4,9
[10,20]-benzeno-1H-benz[f]isoindole-1,3(2H)-dione 5g.
Colorless
143.5 mg, 90% yield with catalyst 2a, 119.6 mg, 75% yield with cat-
alyst 2d; melting point: 210–212 (Lit. 213–215 °C);2a 1H NMR
(300 MHz, CDCl3): d 7.69 (m, 1H), 7.50 (m, 1H), 7.36 (m, 1H),
7.27–7.13 (m, 5H), 4.73 (d, 1H, J = 3.6 Hz), 4.53 (s, 1H), 3.29 (dd,
1H, J = 3.6 Hz, J = 8. Hz), 3.14 (q, 2H), 3.07 (d, 1H, J = 8.7 Hz), 0.40
(t, 3H, J = 7.2 Hz); ESI MS: (C20H17NO3) m/z (M+) value at 318.96;
Chiral HPLC: Chiralpak AD column of diacel, i-PrOH/Hexane
10:90, Flow rate 0.6 mL/min, kmax = 230 nm, tmajor = 26.97 min,
solid, 119.1 mg, 60% yield with catalyst 2a, 162.7 mg, 82% yield with
catalyst 2d; melting point: 203–205 (Lit. 206–207 °C);4a 1H NMR
(300 MHz, CDCl3): d 7.40 (m, 3H), 7.33–7.23 (m, 5H), 6.79 (d, 2H,
J = 9.0 Hz), 6.37 (d, 2H, J = 8.7 Hz), 4.83 (d, 1H, J = 3.6 Hz), 4.50
(s, 1H, OH), 3.76 (s, 3H), 3.45 (dd, 1H, J = 3.6 Hz, J = 8.7 Hz),3.24
(d, 1H, J = 8.7 Hz); ESI MS: (C25H19NO4) m/z (M+) value at 396.81.
Chiral HPLC: Chiralpak IB column of diacel, i-PrOH/Hexane
20:80, Flow rate 0.6 mL/min, kmax = 230 nm, tmajor = 29.15 min,
tminor = 24.27 min, 88% ee; {[a]
25 = +33.7 (c 1, CHCl3)} with
D
tminor = 31.57 min, 16% ee; {[a]D
25 = +4.2 (c 1, CHCl3)} with catalyst
catalyst 2a, 23% ee; {[a]
25 = ꢀ9.1 (c 1, CHCl3)} with catalyst 2d.
D
2a, 23% ee; {[a D
]
25 = ꢀ5.7 (c 1, CHCl3)} with catalyst 2d.
4.3.1.5. 4-Hydroxy-2-propyl-3a,4,9,9a-tetrahydro-4,9[10,20]-ben-
zeno-1H-benz[f]isoindole-1,3(2H)-dione 5c. Colorless solid,
Acknowledgment
149.8 mg, 90% yield with catalyst 2a, 146.5 mg, 88% yield with cat-
alyst 2d; melting point: 218–220 °C; 1H NMR (300 MHz, CDCl3): d
7.69 (m, 1H), 7.50 (m, 1H), 7.34 (m, 1H), 7.27–7.13 (m, 5H), 4.72 (d,
1H, J = 3.6 Hz), 4.52 (s, 1H), 3.29 (dd, 1H, J = 3.6 Hz, J = 8.5 Hz), 3.08
(q, 2H), 3.01 (d, 1H), 0.79 (m, 2H), 0.54 (t, 3H, J = 7.5 Hz); ESI MS:
(C21H19NO3); m/z (M+) value at 333.02; Chiral HPLC: Chiralpak IB
column of diacel, i-PrOH/Hexane 10:90, Flow rate 0.6 mL/min,
kmax = 230 nm, tmajor = 19.87 min, tminor = 15.55 min, 14% ee;
Authors are thankful to UGC-BSR, India, for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.01.
002.
{[a]
25 = +5.7 (c 1, CHCl3)} with catalyst 2a, 22% ee; {[
a]
25 = ꢀ8.5
D
D
(c 1, CHCl3)} with catalyst 2d.
References
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