Enantioselective organocatalytic Michael-hemiketalization catalyzed by a trans-bifunctional indane thiourea catalyst

Article abstract of DOI:10.1039/c1ob05404j

An efficient, convenient and enantioselective Michael-hemiketalization reaction has been developed for the synthesis of naphthoquinones. In this work, a novel trans-bifunctional indane thiourea catalyst has been reported to promote this process to afford

Full text of DOI:10.1039/c1ob05404j

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PAPER
Enantioselective organocatalytic Michael-hemiketalization catalyzed by a
trans-bifunctional indane thiourea catalyst†
Yaojun Gao, Qiao Ren, Swee-Meng Ang and Jian Wang*
Received 15th March 2011, Accepted 23rd March 2011
DOI: 10.1039/c1ob05404j
An efficient, convenient and enantioselective Michael-hemiketalization reaction has been developed for
the synthesis of naphthoquinones. In this work, a novel trans-bifunctional indane thiourea catalyst has
been reported to promote this process to afford high yields (up to 99%) and high to excellent
enantiomeric excesses (90–98% ee).
Introduction
Naphthoquinones occur in various families of plants, fungi,
bacteria and insects linking the electron transport chains in
the metabolic pathway with the oxidative processes.1 Many of
these naturally occurring naphthoquinones and their synthetic
analogues are important precursors for the synthesis of natural
products and pharmaceuticals.2 Therefore, naphthoquinones have
been broadly explored for their anti-inflammatory,3 antifungal,4
trypanocida,5 molluscicidal,6 leishmanicidal7 and antitumor bio-
logical activities.4,8
Lapachol 1 (Fig. 1) is a natural naphthoquinone that occurs
Fig. 1 Examples of naphthoquinones as pharmaceutical drugs.
naturally in the grain of many wooden trees and is widely applied
in American folk medicine.9 It is because lapachol 1 and its
derivatives (for example, antitumor agent 3 and kalafungin 4,
Fig. 1) were found to exhibit a wide spectrum of biological
activities, such as anticancer, antimicrobial and anti-inflammatory
functions.10 Recent progress has shown that the biological activi-
ties of lapachol and derivatives are associated with their promising
structure and ability to induce oxidative stress at the level of
the enzyme P450 reductase.11 In this regard, an exploration of
potential anti-malarial agents was carried out. Gratifyingly, this
discovery resulted in a highly lipophilic drug, Atovaquone 2 that
closely resembles the structure of an ubiquinone.12 Currently, a
combination of atovaquone and makarone is being used to treat
malaria, and also is useful for the treatment of illnesses caused by
Pneumocystis carinii.13
pure naphthoquinone via an organocatalytic asymmetric manner
are still extremely rare. In 2008, Rueping et al. first reported
the example of diaryl-prolinol ether organocatalyst promoted
asymmetric Michael reaction of 2-hydroxy-1,4-naphthoquinone
and a-unsaturated aldehydes (Scheme 1).15 In brief, this strategy
employed iminium ion catalysis process to promote the key C–C
bond-forming. Recently, H-bonding mediated catalysis for C–C
bond formation has been discovered as a new powerful tool and
mild synthetic method for the efficient construction of molecular
architectures.16 Especially, there was a remarkable development
and application on chiral bifunctional thiourea catalysis.16 The
utilization of inexpensive and readily synthesized chiral thiourea
catalysts attracted considerable interest and proved to be effective
In view of the significance of the framework, efficient syntheses
of naphthoquinones are of great interest. Although asymmetric
organocatalysis as a powerful tool in particular has proven itself
to be a valuable instrument in the preparation of enantiomeri-
cally enriched compounds,14 the examples that generated optical
Department of Chemistry, National University of Singapore, 3 Science Drive
3, Singapore, 117543. E-mail: chmwangj@nus.edu.sg; Fax: (+)65-6516-
1691
† Electronic supplementary information (ESI) available: CCDC reference
number 800850. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1ob05404j
Scheme 1 Organocatalyst promoted Michael addition of 2-hydroxy-
1,4-naphthoquinone to unsaturated system.
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Table 1 Evaluation of chiral thiourea catalystsa
in several asymmetric transformations. Herein, we wish to report
a novel strategy for the preparation of chiral naphthoquinones
through H-bonding mediated enantioselective Michael addition
reaction and a novel chiral trans-indane thiouea catalyst (Scheme
2). Surprisingly this catalyst has a trans-configuration, in contrast
to the successful indane thiourea catalysts developed by our
group.17 Moreover, this strategy allowed a quick construction
of diversely functionalized naphthoquinones under mild reaction
conditions and achieved high to excellent enantioselectivities (90–
98% ee) and excellent yields (94–99%).
Entry
Cat.
t (h)
Yield (%)b
ee (%)c
11
22
33
44
55
66
I
2
2
2
2
2
2
97
96
96
98
97
96
74
55
64
87
71
9
II-a
II-b
II-c
III
IV
a Reaction was conducted on 0.1 mmol scale in CH2Cl2 (0.5 mL) at r.t. for
2 h, and the ratio of 6a/5 is 1 : 1.1. b Yield of isolated product aftercolumn
chromatography. c Enantiomeric excess (ee) was determined by HPLC.
activity to offer a 97% yield in 2 h. However, only a moderate
enantioselectivity (74% ee) was achieved. Therefore, development
of a novel and active chiral catalyst which can promote a reaction
with a result of both high efficiency and excellent stereo-control is
our current main focus. In planning our catalyst investigation,
we decided to firstly examine the indane bifunctional amine-
thiourea catalytic system developed and reported by our group.
This kind of system has demonstrated some unique aspects, such
as higher activity, excellent stereo-control, and flexible skeleton.
Based on our previous experience, catalyst III and IV (Fig. 2)
both exhibited high stereo-control in Michael reaction related
cascade processes. We assumed that they might also promote this
reaction and generate some surprising results. Unfortunately, the
promising catalyst III just provided a very general result (Table
1, 97%, 71% ee). Catalyst IV, the similar analogue of catalyst III
with a switch of amine and thiourea functional groups, totally
lost the stereo-control for this reaction (Table 1, 96%, 9% ee).
Meanwhile, our previous experience in using indane thiourea
catalyst told us that the dihedral angle is one of the critical
factors for stereochemistry control. In view of the structures of
catalyst III and IV, we found that amine and thiourea groups
are in the syn position. We then suspected if the syn position
of two functional groups had an influence on stereoselectivity
improvement. Consequently, catalysts II (Fig. 2) were synthesized
evaluated. In contrast to catalyst IV¢s structure, catalysts II just
have a chiral inversion on the amine part while maintaining all the
other features. Gratifyingly, catalyst II-c demonstrated a superior
stereo-control in enantioselectivity (Table 1, 98%, 87% ee). These
results fully proved our catalyst design is on the right track.
Obviously, the ring size played an important role in improving
enantioselectivity. The most bulky six member ring based amine is
the most favored in comparison with three and five member rings.
For further optimization, solvent, as well as reaction temper-
ature, was examined (Table 2). These experiments revealed that
the best results with regards to reactivity and enantioselectivity
were obtained with Cl(CH2)2Cl at -20 ◦C (Table 2, entry 6). The
process was completed within 24 h and afforded naphthoquinone
derivative 7a (compound 7a was coexisted with anomer 8a in
CDCl3, see ESI† for details) in 97% yield and with an excellent
enantioselectivity (96% ee). In varying reaction temperature, the
enantioselectivity can be dramatically enhanced by an appropriate
reduction on temperature. Most importantly, there is not any yield
Scheme 2 Strategy for enantioselective synthesis of naphthoquinones.
Results and discussion
Recently, we uncovered an interesting indane thiourea cat-
alytic system which sufficiently promoted several asymmetric
transformations.17 Having established the capacity of chiral indane
thioureas to catalyze asymmetric cascade processes by using varied
nucleophiles and electrophiles for new bond formation, we sought
to utilize this indane catalytic system for the construction of novel
and useful complexes.
To probe the feasibility of the proposed reaction, 2-hydroxy-
1,4-naphthoquinone 5 was treated with b–unsaturated a–keto
ester 6a in the presence of catalyst I (Fig. 2), developed by
Soo´s18 and Dixon19 and Connon20 groups respectively (Table 1).
As shown in Table 1, catalyst I exhibited an excellent catalytic
Fig. 2 Evaluated chiral thiourea catalysts.
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Table 2 Optimization of reaction conditionsa
Table 3 Substrate scopea
T/◦C
t (h)
Yield (%)b
ee (%)c
Entry
R1
R2
t (h)
Yield (%)b
ee (%)c
Entry
Solvent
1
2
3
4
5
6
7
8
Ph (7a)
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
24
24
24
24
36
36
36
36
36
36
36
36
36
24
36
24
97
99
99
98
95
95
98
98
97
97
96
97
95
96
94
97
96
96
97
97
95
94
90
93
90
90
96
94
91
95
98
96
1
2
3
4
5
6
7
8
9
10
11
DMSO
CH2Cl2
CHCl3
Cl(CH2)2Cl
Cl(CH2)2Cl
Cl(CH2)2Cl
Et2O
Anisole
Toluene
Xylene
r.t.
r.t.
r.t.
r.t.
2
2
2
2
5
24
2
2
2
2
2
92
98
97
98
98
97
96
96
96
97
96
45
87
80
89
94
96
87
83
82
83
85
4-FC6H4 (7b)
4-ClC6H4 (7c)
3-ClC6H4 (7d)
2-ClC6H4 (7e)
2-BrC6H4 (7f)
4-MeOC6H4 (7g)
4-MeSC6H4 (7h)
4-AllyloxyC6H4 (7i)
4-BnOC6H4 (7j)
3-PhOC6H4 (7k)
4-iPrC6H4 (7l)
1-Naphthyl (7m)
2-Thiophene (7n)
Et (7o)
0 ◦
C
-20 ◦
r.t.
r.t.
r.t.
r.t.
C
9
10
11
12
13
14
15
16
PhCF3
r.t.
a Unless specified, see the Experimental section for reaction conditions.
b Yield of isolated product. c Enantiomeric excess (ee) was determined by
HPLC analysis.
Ph (7p)
a Unless specified, see the Experimental section for reaction conditions.
b Yield of isolated product. c Enantiomeric excess (ee) was determined by
HPLC analysis.
loss penalty in the process (Table 2, entries 4–6, 2 to 24 h, 97% to
98% yield, 89% to 96% ee). Furthermore, less polar solvents are
fundamental for obtaining relatively higher enantioselectivities at
room temperature (Table 2, entries 2–4 and 7–11, 80–89% ee). For
high polar solvent, a relatively low enantioselectivity was observed
by potentially destroying the H-bonding interaction (Table 2, entry
1, 45% ee).
Under the optimized reaction conditions, the generality of our
process was tested by using various b–unsaturated a–keto esters
6 (Table 3). Aromatic b–unsaturated a–keto esters having both
neutral (Table 3, entry 1), electron-withdrawing (Table 3, entries
2–6) and electron-donating substituents (Table 3, entries 7–12)
can effectively be applied to this transformation; the substitution
pattern of the arene had limited influence on the enantioselectivity
of the reaction (Table 3, entries 2–13, 90–97% ee). In addition, it
was possible to use both heteroaromatic (Table 3, entry 14) and
aliphatic b–unsaturated a–keto ester (Table 3, entry 15) in this
reaction. Meanwhile, the ester modification (Me replaced Et) also
had no obvious effect on the enantioselectivity (Table 3, entry 16).
The ability permitted the assembly of a diverse of functionalized
naphthoquinone complexes in excellent yields (Table 3, 94–99%)
and with high to excellent enantioselectivities (Table 3, 90–98%
ee). The absolute configuration of the product 7f was determined
by single-crystal X-ray analysis (See ESI†).
Scheme 3 Structure elaboration of 7a.
Conclusions
Furthermore, the highly enantiomerically enriched naphtho-
quinone complexes obtained by this method can be easily con-
verted into dihydropyridine naphthoquinones. As an example,
7a was converted to dihydropyridine naphthoquinone 9 in 42%
yield and 75% ee by a simple one-step treatment (Scheme 3).
Surprisingly, there is a reduction of the ee value within this
conversion process. In addition, naphthoquinone complex 7a also
can react with methanesulfonyl chloride to afford complex 10
under the condition of triethyl amine (Scheme 3, 40% and 94%
ee). In this case, a halogen, chloride, was introduced to replace
hydroxyl group. More importantly, ee value was remained in this
process.
In summary, we have developed an efficient and convenient enan-
tioselective Michael-hemiketalization reaction for the synthesis of
naphthoquinone complexes with excellent yields (94–99%) and
high to excellent enantioselectivities (90–98% ee). This protocol
proceeded through a new and simple trans–amine–thiourea indane
catalyst promoted conjugated addition strategy. We hope that the
catalytic system and strategy demonstrated here could be applied
to other asymmetric transformations to efficiently assemble chiral
materials with complex structures. Further elaboration of the
products to other types of biologically active compounds and the
potential application of the catalytic system are now ongoing in
our group.
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(4R)-Ethyl 4-(4-fluorophenyl)-2-hydroxy-5,10-dioxo-3,4,5,10-
tetrahydro-2H-benzo[g]chromene -2-carboxylate (7b). (Table 3,
entry 2). 1H NMR (500 MHz, CDCl3) d 8.00 (d, J = 94.9 Hz, 2H),
7.69 (d, J = 22.1 Hz, 2H), 7.44 (bs, 0.67 H), 7.24 (d, J = 23.6 Hz,
1.21 H), 6.98 (bs, 2H), 4.92 (d, J = 49.2 Hz, 0.73 H), 4.69 (bs, 0.19
H), 4.32 (t, J = 25.7 Hz, 2.63 H), 4.11–4.07 (m, 0.36 H), 3.67 (d,
J = 14.8 Hz, 0.33 H), 2.72 (bs, 0.19 H), 2.38 (bs, 1 H), 1.34 (t,
J = 7.1 Hz, 3 H); 13C NMR (125 MHz, CDCl3) d 183.15, 183.13,
181.41, 179.21, 168.11, 162.52, 160.75, 160.70, 160.57, 153.06,
138.47, 135.18, 134.24, 133.25, 132.07, 130.85, 129.77, 129.18,
128.74, 126.39, 126.25, 115.74, 115.57, 115.27, 95.21, 63.62,
62.53, 42.31, 37.82, 35.07, 34.09, 29.67, 13.93; HRMS (ESI) calcd
for C22H17FNaO6 (M + Na+) 419.0907, found 419.0895; HPLC
(Chiralpak IC, i-propanol/hexane = 20/80, flow rate 1.0 mL
min-1, l = 254 nm): tmajor = 10.88 min, tminor = 15.99 min, ee = 96%;
[a]2D5 = +27.7 (c = 1.37 in CHCl3).
Experimental
General methods
Chemicals and solvents were purchased from commercial sup-
pliers and used as received. 1H and 13C NMR spectra were
recorded on a Bruker ACF300 (300 MHz) or AMX500 (500 MHz)
spectrometer. Chemical shifts were reported in parts per million
(ppm), and the residual solvent peak was used as an internal
reference: proton (chloroform d 7.26), carbon (chloroform d
77.0) or tetramethylsilane (TMS d 0.00) was used as a reference.
Multiplicity was indicated as follows: s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), dd (doublet of doublet), bs
(broad singlet). Coupling constants were reported in Hertz (Hz).
Low resolution mass spectra were obtained on a Finnigan/MAT
LCQ spectrometer in ESI mode, and a Finnigan/MAT 95XL-T
mass spectrometer in EI mode. All high resolution mass spectra
were obtained on a Finnigan/MAT 95XL-T mass spectrometer.
For thin layer chromatography (TLC), Merck pre-coated TLC
plates (Merck 60 F254) were used, and compounds were visualized
with a UV light at 254 nm. Further visualization was achieved
by staining with KMnO4 solution, or ninhydrin followed by
heating using a heat gun. Flash chromatography separations were
performed on Merck 60 (0.040–0.063 mm) mesh silica gel. The
enantiomeric excesses of products were determined by chiral phase
HPLC analysis. Optical rotations were recorded on Jasco DIP-
1000 polarimeter.
(4R)-Ethyl 4-(4-chlorophenyl)-2-hydroxy-5,10-dioxo-3,4,5,10-
tetrahydro-2H-benzo[g]chromene-2-carboxylate (7c). (Table 3,
1
entry 3). H NMR (500 MHz, CDCl3) d 8.15–8.01 (m, 1.5 H),
7.92–7.90 (m, 0.48 H), 7.75–7.67 (m, 2 H), 7.40 (t, J = 8.2 Hz,
0.69 H), 7.24 (ddd, J = 29.3, 18.3, 8.0 Hz, 3.58 H), 4.86 (d,
J = 109.7 Hz, 1 H), 4.40–4.24 (m, 2.74 H), 4.07 (dd, J = 19.5,
9.5 Hz, 0.32 H), 3.68 (dd, J = 18.9, 5.7 Hz, 0.31 H), 2.72 (dd, J =
14.0, 7.7 Hz, 0.22 H), 2.42–2.30 (m, 1.22 H), 1.34 (t, J = 7.1 Hz,
3 H); 13C NMR (75 MHz, CDCl3) d 183.37, 179.74, 153.11,
140.67, 134.58, 133.28, 132.49, 132.19, 130.37, 129.01, 128.77,
126.64, 126.30, 123.78, 63.31, 34.29, 13.92; HRMS (ESI) calcd
for C22H17ClNaO6 (M + Na+) 435.0611, found 435.0598; HPLC
(Chiralpak IC, i-propanol/hexane = 20/80, flow rate 1.0 mL
min-1, l = 254 nm): tmajor = 10.77 min, tminor = 15.66 min, ee = 97%;
[a]2D5 = +18.7 (c = 1.37 in CHCl3).
General procedure
To a solution of 2-hydroxynaphthalene-1,4-dione 5 (17.5 mg,
0.1 mmol) in 0.45 mL of DCE was added (E)-Ethyl 2-oxo-4-
phenylbut-3-enoate 6a (23 mg, 0.11 mmol) at -20 ◦C, followed
by adding of 50 mL of pre-cooled catalyst II-c solution (4.2 mg in
50 mL of DCE, 0.01 mmol). The mixture was stirred at -20 ◦C for
24 h. The crude product was purified by column chromatography
on silica gel, eluted by hexane–EtOAc = 2 : 1 to afford 36.7 mg
(97% yield) of the desired product 7a as yellow solid.
(4R)-Ethyl 4-(3-chlorophenyl)-2-hydroxy-5,10-dioxo-3,4,5,10-
tetrahydro-2H-benzo[g]chromene-2-carboxylate (7d). (Table 3,
entry 3).1H NMR (500 MHz, CDCl3) d 8.14–7.91 (m, 2 H), 7.70
(d, J = 23.3 Hz, 2 H), 7.40 (d, J = 51.7 Hz, 0.68 H), 7.22–7.14 (m,
3.22 H), 4.99 (d, J = 20.5 Hz, 0.77 H), 4.79 (s, 0.18 H), 4.40–4.23
(m, 2.69 H), 4.13–4.05 (m, 0.35 H), 3.67 (d, J = 14.5 Hz, 0.31H),
2.71 (d, J = 6.9 Hz, 0.19 H), 2.37 (dt, J = 25.9, 10.2 Hz, 1.16 H),
1.34 (t, J = 7.1 Hz, 3 H);13C NMR (125 MHz, CDCl3) d 192.28,
182.98, 179.11, 168.02, 153.24, 144.93, 135.19, 134.23, 133.29,
131.99, 130.84, 130.00, 128.28, 127.28, 127.13, 126.95, 126.43,
126.29, 125.61, 124.28, 95.19, 63.62, 62.55, 41.95, 37.60, 35.43,
35.41, 34.90, 34.56, 13.91; HRMS (ESI) calcd for C22H17ClNaO6
(M + Na+) 435.0611, found 435.0601; HPLC (Chiralpak IC,
i-propanol/hexane = 20/80, flow rate 1.0 mL min-1, l = 254 nm):
tmajor = 11.07 min, tminor = 13.40 min, ee = 97%; [a]2D5 = +7.1 (c =
1.47 in CHCl3).
(4R)-Ethyl 2-hydroxy-5,10-dioxo-4-phenyl-3,4,5,10-tetrahydro-
2H-benzo[g]chromene-2-carboxylate (7a). (Table 3, entry 1). H
1
NMR (500 MHz, CDCl3) d 8.15–8.08 (m, 1H), 8.03–8.0 (m, 0.44
H), 7.90 (dt, J = 6.6, 3.0 Hz, 0.48 H), 7.75–7.63 (m, 2.3H), 7.47
(d, J = 7.3 Hz, 0.6 H), 7.33–7.18 (m, 4.4 H), 5.01–4.95 (m, 0.74
H), 4.72 (s, 0.16 H), 4.45 (dd, J = 7.6, 3.5 Hz, 0.19 H), 4.38–4.25
(m, 2.5 H), 4.15 (dd, J = 19.2, 9.8 Hz, 0.32 H), 3.67 (dd, J = 19.2,
5.7 Hz, 0.30 H), 2.74 (dd, J = 14.3, 7.7 Hz, 0.19 H), 2.46–2.36 (m,
1.27 H), 1.32 (dd, J = 9.0, 5.5 Hz, 3 H); 13C NMR (125 MHz,
CDCl3) d 192.66, 183.97, 183.24, 183.12, 181.50, 179.30, 178.98,
168.19, 160.68, 153.56, 153.06, 152.57, 142.84, 141.94, 140.99,
135.11, 134.22, 134.15, 133.34, 133.17, 132.96, 132.76, 132.07,
131.89, 130.94, 130.83, 129.07, 128.76, 128.57, 128.33, 128.16,
127.57, 127.22, 127.07, 126.93, 126.68, 126.58, 126.49, 126.43,
126.39, 126.21, 126.05, 125.10, 123.73, 122.98, 95.96, 95.23, 63.54,
63.44, 62.48, 42.24, 37.83, 35.74, 35.28, 34.74, 33.54, 13.93, 13.89;
HRMS (ESI) calcd for C22H18NaO6 (M + Na+) 401.1001, found
401.0999; HPLC (Chiralpak IC, i-propanol/hexane = 20/80, flow
rate 1.0 mL min-1, l = 254 nm): tmajor = 15.37 min, tminor = 20.34
min, ee = 96%; [a]D25 = +26.7 (c = 1.13 in CHCl3).
(4S)-Ethyl 4-(2-chlorophenyl)-2-hydroxy-5,10-dioxo-3,4,5,10-
tetrahydro-2H-benzo[g]chromene-2-carboxylate (7e). (Table 3,
entry 3).1H NMR (500 MHz, CDCl3) d 8.11–7.92 (m, 2 H),
7.68 (s, 2 H), 7.40 (d, J = 6.0 Hz, 1 H), 7.13 (d, J = 32.8 Hz,
3 H), 4.94–4.74 (m, 2 H), 4.36–4.33 (m, 2 H), 2.69 (s, 0.35 H),
2.42 (d, J = 65.3 Hz, 1.39 H), 1.34 (t, J = 6.6 Hz, 3 H); 13C
NMR (75 MHz, CDCl3) d 182.89, 179.14, 168.07, 154.00, 153.33,
140.21, 138.83, 134.23, 133.27, 131.89, 130.90, 129.90, 129.60,
127.96, 127.25, 126.44, 126.32, 124.75, 95.91, 95.31, 63.58, 35.11,
32.50, 30.86, 29.66, 13.92; HRMS (ESI) calcd for C22H17ClNaO6
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(M + Na+) 435.0611, found 435.0611; HPLC (Chiralpak IC,
i-propanol/hexane = 20/80, flow rate 1.0 mL min-1, l = 254 nm):
tmajor = 13.36 min, tminor = 16.31 min, ee = 95%; [a]2D5 = +29.6 (c =
1.33 in CHCl3).
6.0 Hz, 0.35 H), 2.38 (d, J = 9.5 Hz, 1 H), 1.34 (t, J = 7.1 Hz, 3
H);13C NMR (75 MHz, CDCl3) d 192.79, 184.06, 183.24, 181.60,
179.36, 168.27, 157.55, 157.35, 152.89, 152.35, 135.11, 134.91,
134.15, 133.36, 133.28, 133.17, 132.98, 132.16, 131.72, 130.87,
130.70, 129.25, 128.63, 128.24, 127.09, 126.40, 126.23, 126.06,
125.40, 124.06, 118.04, 117.62, 115.01, 114.79, 114.58, 114.45,
95.91, 95.25, 68.81, 63.60, 63.48, 62.47, 42.47, 37.89, 35.20, 35.03,
33.94, 32.69, 29.68, 13.95; HRMS (ESI) calcd for C25H22NaO7
(M + Na+) 457.1263, found 457.1251; HPLC (Chiralpak IC, i-
propanol/hexane = 20/80, flow rate 1.0 mL min-1, l = 254 nm):
tmajor = 20.60 min, tminor = 39.69 min, ee = 90%; [a]2D5 = +53.9 (c = 1.5
in CHCl3).
(4S)-Ethyl 4-(2-bromophenyl)-2-hydroxy-5,10-dioxo-3,4,5,10-
tetrahydro-2H-benzo[g]chromene-2-carboxylate (7f). (Table 3,
entry 6).1H NMR (500 MHz, CDCl3) d 8.04 (dd, J = 85.6, 26.6 Hz,
2 H), 7.70–7.58 (m, 3 H), 7.19–7.07 (m, 3 H), 4.87–4.72 (m, 2H),
4.34 (dd, J = 15.9, 7.4 Hz, 2 H), 2.55 (dt, J = 212.8, 59.1 Hz, 2
H), 1.34 (t, J = 6.3 Hz, 3 H); 13C NMR (125 MHz, CDCl3) d
182.81, 179.10, 168.03, 154.00, 140.46, 134.19, 133.40, 133.26,
132.91, 131.95, 130.91, 129.72, 128.26, 128.18, 127.92, 126.97,
126.43, 126.30, 124.86, 123.79, 122.63, 95.96, 95.31, 63.61, 60.37,
33.46, 32.76, 21.00, 13.93; HRMS (ESI) calcd for C22H17BrNaO6
(M + Na+) 479.0106, found 479.0101; HPLC (Chiralpak IC,
i-propanol/hexane = 20/80, flow rate 1.0 mL min-1, l = 254 nm):
tmajor = 14.23 min, tminor = 16.53 min, ee = 94%; [a]2D5 = +13.3 (c =
0.87 in CHCl3).
(4R)-Ethyl 4-(4-(benzyloxy)phenyl)-2-hydroxy-5,10-dioxo-3,4,
5,10-tetrahydro-2H-benzo[g]chromene-2-carboxylate (7j). (Table
3, entry 10).1H NMR (500 MHz, CDCl3) d 8.15–7.90 (m, 2 H),
7.74–7.63 (m, 2.59 H), 7.43–7.28 (m, 6.20 H), 7.17–7.15 (m, 1.62
H), 6.93–6.88 (m, 2 H), 5.02–4.93 (m, 3 H), 4.41–4.23 (m, 2.76 H),
4.10 (dd, J = 19.1, 9.6 Hz, 0.35 H), 3.64 (dd, J = 19.2, 6.0 Hz,
0.32 H), 2.73–2.68 (m, 0.19 H), 2.43–2.37 (m, 1 H), 1.35–1.31(m, 3
H);13C NMR (125 MHz, CDCl3) d 192.78, 184.04, 183.22, 181.57,
179.32, 168.23, 160.77, 157.76, 157.56, 152.91, 152.39, 137.05,
135.07, 135.02, 134.19, 134.12, 133.35, 133.31, 133.14, 132.94,
132.83, 132.16, 130.87, 129.28, 129.12, 128.90, 128.66, 128.54,
128.52, 128.38, 128.27, 128.11, 127.92, 127.88, 127.48, 127.40,
127.24, 127.06, 126.49, 126.38, 126.20, 126.03, 125.32, 124.01,
115.09, 114.90, 114.67, 95.98, 95.31, 70.01, 63.51, 63.42, 62.43,
42.46, 37.91, 35.29, 35.04, 33.95, 32.78, 13.93, 13.91; HRMS (ESI)
calcd for C29H24NaO7 (M + Na+) 507.1420, found 507.1414; HPLC
(Chiralpak IC, i-propanol/hexane = 20/80, flow rate 1.0 mL min-1,
(4R)-Ethyl 2-hydroxy-4-(4-methoxyphenyl)-5,10-dioxo-3,4,5,10-
tetrahydro-2H-benzo[g]chromene-2-carboxylate (7g). (Table 3,
entry 7).1H NMR (500 MHz, CDCl3) d 8.14–7.90 (m, 2 H), 7.68
(d, J = 24.9 Hz, 2 H), 7.39 (d, J = 7.6 Hz, 0.69 H), 7.16 (d, J =
7.9 Hz, 1.26 H), 6.85–6.82 (m, 2 H), 4.86 (d, J = 88.3 Hz, 0.85 H),
4.39–4.23 (m, 2.59 H), 4.09 (dd, J = 18.8, 9.3 Hz, 0.35 H), 3.76 (d,
J = 10.7 Hz, 3 H), 3.65 (d, J = 19.2 Hz, 0.41 H), 2.69 (d, J = 7.3 Hz,
0.18 H), 2.39 (d, J = 7.9 Hz, 1 H), 1.33 (t, J = 6.9 Hz, 3 H);13C
NMR (125 MHz, CDCl3) d 192.78, 184.03, 183.21, 181.56, 179.33,
168.21, 160.77, 158.47, 158.23, 152.89, 152.40, 135.05, 134.72,
134.10, 133.29, 133.11, 132.92, 132.80, 132.14, 130.85, 129.22,
128.61, 128.22, 127.03, 126.36, 126.17, 126.00, 125.32, 124.03,
123.27, 114.19, 113.95, 113.79, 96.02, 95.34, 63.45, 63.37, 62.42,
55.16, 42.44, 37.92, 35.37, 35.00, 33.92, 32.81, 13.91; HRMS (ESI)
calcd for C23H20NaO7 (M + Na+) 431.1107, found 431.1101; HPLC
(Chiralpak IC, i-propanol/hexane = 20/80, flow rate 1.0 mL min-1,
l = 254 nm): tmajor = 24.43 min, tminor = 41.02 min, ee = 90%; [a]D25
+42.2 (c = 1.53 in CHCl3).
=
(4R)-Ethyl 2-hydroxy-5,10-dioxo-4-(3-phenoxyphenyl)-3,4,5,10-
tetrahydro-2H-benzo[g]chromene-2-carboxylate (7k). (Table 3,
1
entry 11). H NMR (500 MHz, CDCl3) d 8.01 (ddd, J = 47.3,
l = 254 nm): tmajor = 23.49 min, tminor = 44.30 min, ee = 90%; [a]D25
+58.7 (c = 1.37 in CHCl3).
=
11.5, 7.4 Hz, 2 H), 7.73–7.66 (m, 2 H), 7.31–7.18 (m, 3.55 H),
7.08–6.80 (m, 5.3 H), 4.96 (t, J = 64.9 Hz, 1 H), 4.41–4.07 (m,
2.7 H), 4.10 (dd, J = 18.8, 9.3 Hz, 0.28 H), 3.66 (dd, J = 19.2,
5.0 Hz, 0.27 H), 2.72 (dd, J = 13.9, 7.6 Hz, 0.19 H), 2.45–2.33
(m, 1.26 H), 1.33 (t, J = 7.1 Hz, 3 H);13C NMR (125 MHz,
CDCl3) d 183.19, 179.16, 168.10, 157.01, 153.01, 144.89, 134.16,
133.15, 129.63, 126.22, 123.16, 118.75, 116.90, 95.24, 63.45, 42.08,
37.67, 34.63, 29.64, 13.90; HRMS (ESI) calcd for C28H22NaO7
(M + Na+) 493.1263, found 493.1258; HPLC (Chiralpak IC, i-
propanol/hexane = 20/80, flow rate 1.0 mL min-1, l = 254 nm):
tmajor = 14.18 min, tminor = 17.62 min, ee = 96%; [a]2D5 = +11.7 (c =
1.73 in CHCl3).
(4R)-Ethyl 2-hydroxy-4-(4-(methylthio)phenyl)-5,10-dioxo-3,4,
5,10-tetrahydro-2H-benzo[g]chromene -2-carboxylate (7h). (Ta-
1
ble 3, entry 8). H NMR (500 MHz, CDCl3) d 8.03 (dd, J =
74.2, 37.4 Hz, 2 H), 7.68 (d, J = 23.0 Hz, 2 H), 7.39–7.17 (m, 4 H),
5.04 (d, J = 83.9 Hz, 1 H), 4.38–4.09 (m, 3 H), 3.67 (d, J = 17.0 Hz,
0.27 H), 2.71 (bs, 0.19 H), 2.45–2.36 (m, 4 H), 1.32 (bs, 3 H). 13
C
NMR (125 MHz, CDCl3) d 183.11, 179.26, 168.09, 153.04, 139.68,
136.51, 134.19, 133.15, 130.79, 127.74, 127.05, 126.35, 126.17,
124.89, 95.26, 63.47, 42.07, 37.73, 35.14, 34.21, 15.85, 13.88;
HRMS (ESI) calcd for C23H20NaO6S (M + Na+) 447.0878, found
447.0873; HPLC (Chiralpak IC, i-propanol/hexane = 20/80, flow
rate 1.0 mL min-1, l = 254 nm): tmajor = 19.14 min, tminor = 31.89
min, ee = 93%; [a]D25 = +52.9 (c = 1.43 in CHCl3).
(4R)-Ethyl 2-hydroxy-4-(4-isopropylphenyl)-5,10-dioxo-3,4,5,
10-tetrahydro-2H-benzo[g]chromene-2-carboxylate (7l). (Table
3, entry 12).1H NMR (500 MHz, CDCl3) d 8.09–7.91 (m, 2 H),
7.68 (d, J = 20.8 Hz, 2 H), 7.38 (s, 1 H), 7.15 (bs, 3 H), 4.81 (d,
J = 154.8 Hz, 1 H), 4.42–4.14 (m, 2.89 H), 3.64 (d, J = 15.8 Hz,
0.31 H), 2.78 (d, J = 72.2 Hz, 1 H), 2.40 (d, J = 8.2 Hz, 1 H),
1.32 (bs, 3 H), 1.22 (bs, 6 H);13C NMR (125 MHz, CDCl3) d
192.81, 184.01, 183.14, 181.59, 179.35, 168.25, 160.76, 152.98,
147.47, 147.00, 139.96, 138.28, 135.05, 134.09, 133.11, 132.91,
132.17, 130.89, 129.13, 128.08, 127.40, 127.11, 126.79, 126.62,
126.40, 126.19, 126.02, 125.35, 123.95, 104.97, 95.34, 63.46, 62.42,
(4R)-Ethyl 4-(4-(allyloxy)phenyl)-2-hydroxy-5,10-dioxo-3,4,5,
10-tetrahydro-2H-benzo[g]chromene-2-carboxylate (7i). (Table
1
3, entry 9). H NMR (500 MHz, CDCl3) d 8.16–7.90 (m, 1.66
H), 7.92–7.91 (m, 0.42 H), 7.75–7.58 (m, 2.34 H), 7.38 (d, J =
8.5 Hz, 0.73 H), 7.16 (d, J = 8.2 Hz, 1 H), 6.87–6.82 (m, 2 H), 6.03
(dt, J = 24.3, 9.6 Hz, 1 H), 5.32 (ddd, J = 27.4, 24.3, 10.7 Hz, 2
H), 4.94 (dd, J = 9.6, 5.8 Hz, 0.29 H), 4.74 (s, 0.35 H), 4.45–4.22
(m, 4.56 H), 4.10 (dd, J = 19.1, 9.6 Hz, 0.34 H), 3.64 (dd, J = 19.2,
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42.41, 37.94, 35.44, 34.32, 33.61, 23.87, 13.91; HRMS (ESI) calcd
for C25H24NaO6 (M + Na+) 443.1471, found 443.1465; HPLC
(Chiralpak IC, i-propanol/hexane = 20/80, flow rate 1.0 mL min-1,
rate 1.0 mL min-1, l = 254 nm): tmajor = 10.50 min, tminor = 12.10
min, ee = 98%; [a]D25 = +18.5 (c = 1.17 in CHCl3).
l = 254 nm): tmajor = 14.02 min, tminor = 18.78 min, ee = 94%; [a]D25
+39.6 (c = 1.0 in CHCl3).
=
(4R)-Methyl 2-hydroxy-5,10-dioxo-4-phenyl-3,4,5,10-tetra-
hydro-2H-benzo[g]chromene-2-carboxylate (7p). (Table 3, entry
16).1H NMR (500 MHz, CDCl3) d 8.03 (dd, J = 77.6, 37.5 Hz,
2 H), 7.68 (d, J = 23.6 Hz, 2 H), 7.46 (bs, 0.67 H), 7.30–7.22
(m, 4.4 H), 4.89 (d, J = 117.6 Hz, 1 H), 4.43–4.11 (m, 1 H), 3.86
(d, J = 15.1 Hz, 3 H), 3.67 (d, J = 16.4 Hz, 0.28 H), 2.72 (bs,
0.18 H), 2.46–2.37 (m, 1.22 H); 13C NMR (75 MHz, CDCl3) d
192.20, 183.98, 183.09, 181.46, 179.31, 168.60, 152.94, 142.65,
140.95, 135.09, 134.17, 133.33, 133.16, 132.95, 132.73, 132.05,
130.78, 129.05, 128.72, 128.56, 128.34, 128.12, 127.53, 127.20,
127.05, 126.91, 126.67, 126.39, 126.21, 126.04, 125.02, 123.65,
95.39, 53.79, 52.94, 42.32, 37.86, 35.69, 35.46, 34.64, 33.58, 29.62;
HRMS (ESI) calcd for C21H16NaO6 (M + Na+) 387.0845, found
387.0839; HPLC (Chiralpak IC, i-propanol/hexane = 20/80, flow
rate 1.0 mL min-1, l = 254 nm): tmajor = 12.76 min, tminor = 18.37
min, ee = 96%; [a]D25 = +28.7 (c = 1.17 in CHCl3).
(4R)-Ethyl 2-hydroxy-4-(naphthalen-1-yl)-5,10-dioxo-3,4,5,10-
tetrahydro-2H-benzo[g]chromene-2-carboxylate (7m). (Table 3,
entry 13). 1H NMR (500 MHz, CDCl3) d 8.28–7.07 (m, 11 H), 5.71
(s, 0.13 H), 5.02 (d, J = 96.2 Hz, 1 H), 4.54 (bs, 0.20 H), 4.23–4.13
(m, 2 H), 3.63 (d, J = 16.7 Hz, 0.14 H), 2.80 (dd, J = 13.7, 8.0 Hz,
0.23 H), 2.53–2.39 (m, 1 H), 1.21 (ddd, J = 14.5, 10.6, 6.3 Hz, 3
H). 13C NMR (125 MHz, CDCl3) d 192.63, 183.10, 183.00, 179.25,
178.94, 168.15, 154.00, 139.31, 136.93, 135.14, 134.23, 134.15,
133.36, 133.21, 132.97, 132.08, 131.95, 131.00, 130.92, 130.53,
129.41, 129.13, 127.72, 127.53, 127.22, 126.47, 126.42, 126.29,
126.09, 125.73, 125.52, 125.42, 125.28, 125.07, 123.40, 122.58,
95.96, 95.53, 63.44, 62.49, 60.38, 42.95, 36.94, 33.40, 31.95, 29.65,
21.00, 14.15, 13.92, 13.80; HRMS (ESI) calcd for C26H20NaO6
(M + Na+) 451.1158, found 451.1152; HPLC (Chiralpak IC, i-
propanol/hexane = 20/80, flow rate 1.0 mL min-1, l = 254 nm):
tmajor = 21.03 min, tminor = 29.86 min, ee = 91%; [a]2D5 = +45.2 (c = 1.5
in CHCl3).
(R)-Ethyl 5,10-dioxo-4-phenyl-1,4,5,10-tetrahydrobenzo[g]-
quinoline-2-carboxylate (9). A solution of 7a (38 mg, 0.1 mmol)
and ammonium acetate (77 mg, 1.0 mmol) in ethanol (0.5 mL)
was heated at 70 ◦C for 30 min. The solvent was evaporated and
the mixture was purified by column chromatography on silica gel,
eluted by hexane–EtOAc = 10 : 1 to provide 9 as a red solid (15
mg, 42% yield). 1H NMR (500 MHz, CDCl3) d 8.07 (dd, J = 7.6,
0.9 Hz, 1 H), 8.00 (dd, J = 7.7, 1.1 Hz, 1 H), 7.70–7.61 (m, 3 H),
7.36 (dd, J = 8.2, 0.9 Hz, 2 H), 7.31 (dd, J = 10.4, 5.0 Hz, 2 H), 7.21
(dd, J = 10.2, 4.3 Hz, 1 H), 6.18 (dd, J = 5.4, 1.9 Hz, 1 H), 5.05
(d, J = 5.4 Hz, 1 H), 4.38–4.27 (m, 2 H), 1.34 (t, J = 7.1 Hz,
3 H);13C NMR (125 MHz, CDCl3) d 182.48, 180.11, 162.13,
144.91, 138.86, 134.69, 132.96, 132.49, 130.36, 128.77, 128.25,
127.22, 126.49, 126.30, 126.10, 115.44, 113.69, 62.04, 38.50, 14.13;
HRMS (ESI) calcd for C22H17NNaO4 (M + Na+) 382.1055, found
382.1050; HPLC (Chiralpak IC, i-propanol/hexane = 20/80, flow
rate 1.0 mL min-1, l = 254 nm): tminor = 20.62 min, tmajor = 26.70
min, ee = 75%; [a]D25 = +180.7 (c = 0.27 in CHCl3).
(4S)-Ethyl 2-hydroxy-5,10-dioxo-4-(thiophen-2-yl)-3,4,5,10-
tetrahydro-2H-benzo[g]chromene-2-carboxylate (7n). (Table 3,
entry 14). 1H NMR (500 MHz, CDCl3) d 8.18–8.04 (m, 1.62 H),
7.97–7.95 (m, 0.27 H), 7.71 (ddd, J = 29.0, 15.3, 6.9 Hz, 2.42 H),
7.14 (d, J = 5.0 Hz, 0.81 H), 7.06 (d, J = 3.5 Hz, 0.53 H), 6.94–
6.88 (m, 1.25 H), 5.29 (dd, J = 9.5, 6.0 Hz, 0.46 H), 4.86–4.62
(m, 0.77 H), 4.33 (ddd, J = 21.4, 10.6, 5.2 Hz, 2 H), 4.12 (dd,
J = 19.1, 9.3 Hz, 0.55 H), 3.77 (dd, J = 19.2, 6.0 Hz, 0.51 H),
2.73 (dd, J = 14.5, 7.3 Hz, 0.16 H), 2.59–2.48 (m, 0.73 H), 1.34 (t,
J = 7.1 Hz, 3 H); 13C NMR (75 MHz, CDCl3) d 192.16, 183.61,
183.08, 181.45, 160.53, 152.46, 143.49, 135.22, 134.25, 133.43,
133.23, 133.07, 132.73, 130.79, 129.12, 128.77, 127.15, 126.81,
126.64, 126.56, 126.43, 126.28, 126.16, 125.40, 125.14, 124.89,
124.46, 124.25, 123.78, 123.54, 122.97, 95.64, 95.26, 63.64, 62.56,
43.43, 38.24, 34.94, 30.94, 29.88, 28.36, 13.93; HRMS (ESI) calcd
for C20H16NaO6S (M + Na+) 407.0565, found 407.0560; HPLC
(Chiralpak IC, i-propanol/hexane = 20/80, flow rate 1.0 mL min-1,
l = 254 nm): tmajor = 19.84 min, tminor = 26.87 min, ee = 95%; [a]D25
+52.6 (c = 1.17 in CHCl3).
=
(2R,4R)-Ethyl 2-chloro-5,10-dioxo-4-phenyl-3,4,5,10-tetra-
hydro-2H-benzo[g]chromene-2-carboxylate (10). To a solution of
7a (76 mg, 0.2 mmol) in DCM (1 mL) were added triethylamine
(0.1 mL) and methanesulfonyl chloride (0.05 mL) at room
temperature. After 12 h, the mixture was purified by column
chromatography on silica gel, eluted by hexane–EtOAc = 7 : 1 to
provide 10 as yellow oil (32 mg, 40% yield). 1H NMR (500 MHz,
CDCl3) d 8.20–8.18 (m, 1 H), 7.80–7.98 (m, 1 H), 7.76–7.70 (m,
2 H), 7.31–7.28 (m, 2 H), 7.23 (dd, J = 7.1, 5.2 Hz, 3 H), 4.38–
4.30 (m, 3 H), 3.00 (dd, J = 14.7, 7.7 Hz, 1 H), 2.83 (dd, J = 14.7,
6.1 Hz, 1 H), 1.34 (t, J = 7.3 Hz, 3 H);13C NMR (126 MHz, CDCl3)
d 182.91, 177.67, 165.40, 153.12, 141.28, 134.37, 133.69, 131.84,
130.85, 128.65, 127.51, 126.92, 126.64, 126.62, 123.77, 91.46,
63.62, 40.77, 34.96, 13.89; HRMS (ESI) calcd for C22H17ClNaO5
(M + Na+) 419.0662, found 419.0659; HPLC (Chiralpak IC, i-
propanol/hexane = 20/80, flow rate 1.0 mL min-1, l = 254 nm):
tminor = 32.20 min, tmajor = 37.06 min, ee = 94%; [a]2D5 = +149.7 (c =
0.33 in CHCl3).
(4S)-Ethyl 4-ethyl-2-hydroxy-5,10-dioxo-3,4,5,10-tetrahydro-
2H-benzo[g]chromene-2-carboxylate (7o). (Table 3, entry 15). 1H
NMR (500 MHz, CDCl3) d 8.09 (dd, J = 20.8, 9.8 Hz, 2 H), 7.76–
7.66 (m, 2 H), 4.68 (d, J = 84.2 Hz, 0.55 H), 4.40–4.26 (m, 2H),
3.63 (bs, 0.47 H), 3.50 (dd, J = 18.0, 8.8 Hz, 0.49 H), 3.30 (dd,
J = 18.1, 5.5 Hz, 0.50 H), 3.10–2.98 (m, 0.57 H), 2.33–2.15 (m,
1.39 H), 1.90–1.61 (m, 4.47 H), 1.35 (ddd, J = 46.0, 25.4, 18.3 Hz,
3.83 H), 1.05 (t, J = 7.4 Hz, 1.17 H), 0.96–0.84 (m, 2.52 H);13C
NMR (75 MHz, CDCl3) d 193.49, 184.26, 183.85, 181.27, 179.19,
169.00, 160.91, 153.19, 151.68, 135.03, 134.02, 133.18, 133.09,
132.90, 132.08, 130.91, 129.23, 127.03, 126.57, 126.29, 126.23,
126.07, 125.74, 124.34, 95.96, 63.47, 62.38, 42.30, 32.97, 32.21,
29.21, 28.79, 27.73, 25.79, 25.23, 24.97, 13.94, 12.13, 11.94, 10.65;
HRMS (ESI) calcd for C18H18NaO6 (M + Na+) 353.1001, found
353.0996; HPLC (Chiralpak IC, i-propanol/hexane = 20/80, flow
3696 | Org. Biomol. Chem., 2011, 9, 3691–3697
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Acknowledgements
We gratefully acknowledge the National University of Singapore
for financial support of this work (Academic Research Grant:
R143000408133, R143000408733 and R143000443112).
Notes and references
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