Organocatalytic Michael addition of naphthoquinone with α,β-unsaturated ketones: Primary amine catalyzed asymmetric synthesis of lapachol analogues

Article abstract of DOI:10.1002/ejoc.201001570

A highly efficient organocatalytic synthesis of lapachol analogues from the Michael addition of naphthoquinone to various α,β-unsaturated ketones catalyzed by primary amines is presented. Good to high yields (up to 93 %) and high to excellent enantioselec

Full text of DOI:10.1002/ejoc.201001570

FULL PAPER
DOI: 10.1002/ejoc.201001570
Organocatalytic Michael Addition of Naphthoquinone with α,β-Unsaturated
Ketones: Primary Amine Catalyzed Asymmetric Synthesis of Lapachol
Analogues
Guangcun Zhang,[a] Yifeng Wang,[a] Wei Zhang,[a] Xiangsheng Xu,[a] Aiguo Zhong,[b] and
Danqian Xu*[a]
Keywords: Amines / Michael addition / Asymmetric synthesis / Organocatalysis / Natural products
A highly efficient organocatalytic synthesis of lapachol ana-
cellent enantioselectivities (up to 98%ee) were obtained for
logues from the Michael addition of naphthoquinone to vari- the target compounds. MS (ESI) provided evidence for the
ous α,β-unsaturated ketones catalyzed by primary amines is
key intermediates in the proposed mechanism.
presented. Good to high yields (up to 93%) and high to ex-
Quinones and their derivatives are used on a large scale
as dye reagents, and they often possess biological activities;
for example, lapachol and α- and β-lapachone (Scheme 1)
are important components of antibacterial, fungicidal, anti-
malarial, trypanocidal, antiparasitic, and antitumoral
agents.[5] Their trypanocidal activity could be to help cure
Chagas disease, one of the most important endemic diseases
caused by Trypanosoma cruzi, which affects 16–18 million
people in large areas of Latin America and Africa.[6]
Furthermore, lapachone analogues may present potential
inhibitive ability of DNA topoisomerase II, and by this way,
they have great cancer-preventing potential.[7] Conse-
quently, the development of an efficient synthesis to obtain
these valuable compounds has attracted great interest, and
recently, enantioselective organocatalytic reactions of
naphthoquinone to electron-withdrawing olefins have been
reported.[8] Based on these previous strategies, we intro-
duced a new asymmetric procedure involving primary
amine organocatalysts for the synthesis of various lapachol
analogues starting from readily available α,β-unsaturated
ketones and naphthoquinone.
Introduction
Organocatalysis has been one of the focal points of
chemical research. The process has been developed to pos-
sess special features, and it is atom economic, environmen-
tally benign, and operationally convenient.[1] Many organo-
catalysts have been applied in a variety of asymmetric reac-
tions; chiral secondary amines, in particular, are extremely
powerful reagents and dominated the field of amino cataly-
sis early on.[2] Meanwhile, chiral primary amines have also
been demonstrated to be effective catalysts in a wide range
of enantioselective organic reactions.[3] Compared to sec-
ondary amine-mediated transformations, the use of primary
amine organocatalysts has often been shown to be comple-
mentary or superior.
The Michael addition to α,β-unsaturated systems is an
important carbon–carbon bond-forming reaction in or-
ganic synthesis, and the development of enantioselective
catalytic protocols for this reaction could be an efficient
route for the synthesis of drugs or drug-like bioactive small
molecules, which have been the research focus of medicinal
or bioorganic chemists and chemical biologists.[4] Further
development of new asymmetric reactions with the use of
easily available organocatalysts and the discovery of a more
practical catalytic asymmetric process to afford novel chiral
bioactive compounds are research areas that require atten-
tion.
[a] State Key Laboratory Breeding Base of Green Chemistry-
Synthesis Technology, Zhejiang University of Technology
Hangzhou 310014, China
Scheme 1. Structures of lapachol and lapachones.
Fax: +86-571-88320609
E-mail: chrc@zjut.edu.cn
[b] Department of Pharmaceutical and Chemical Engineering,
Taizhou College,
Results and Discussion
Linhai Zhejiang 317000, China
To start, we chose benzalacetone (1a) to react with
naphthoquinone 2 as the model reaction in the presence of
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001570.
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Primary Amine Catalyzed Asymmetric Synthesis of Lapachol Analogues
primary amine catalysts (Scheme 2), and the representative table effect on organocatalytic reactions; therefore, we ex-
results are summarized in Table 1.
amined the reaction media and co-catalysts for this reac-
tion. Reactions in polar solvents, such as MeOH and iP-
rOH, provided low yields and ee values (Table 1, Entries 8
and 9), and in DMF a trace amount of the product was
found (Table 1, Entry 10). When the reaction was per-
formed in less polar solvents, such as THF, (iPr)2O, and
PhCH3, high yields and ee values were afforded (Table 1,
Entries 11–13). Having screened various acids, optimum
conditions for the Michael reaction (88% yield, 93%ee)
were discovered when TFA was used as the co-catalyst and
THF as the solvent (Table 1, Entry 18). A supplementary
screening for solvents was put to trial (Table 1, Entries 19
and 20), but the outcome was inferior to our previous re-
sults (Table 1, Entry 18).
On the basis of the above results, further investigations
were warranted to examine the capability of the catalysis
system to catalyze the asymmetric Michael addition of vari-
ous α,β-unsaturated ketones with naphthoquinone under
the optimized experimental conditions.
Scheme 2. Primary amine catalysts screened for the reaction.
All the amine catalysts tested performed well in the
model reaction (Table 1, Entries 1–6), but the use of a pri-
As seen from Table 2, a wide array of α,β-unsaturated
mary amine thiourea provided disappointing results ketones, which bear electron-donating, electron-neutral, or
(Table 1, Entry 7). We were pleased to find Ib (20 mol-%) electron-withdrawing groups at the phenyl group, reacted
derived from cinchonidine in combination with PhCOOH smoothly with naphthoquinone to afford corresponding
(40 mol-%) exhibited high catalytic activity for the asym- products 3a–h in good to high yields (65–93%) and with
metric Michael addition (78% yield, 92%ee; Table 1, En- high levels of enantioselectivity (91–98%ee). Generally,
try 2). As is known, solvents and acid additives have a no- electron-withdrawing groups at the ortho-, meta- or para-
Table 1. Screening studies of the organocatalytic asymmetric Michael addition reaction of 1a to 2.[a]
Entry
Cat.
Acid
Solvent
Time [h]
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Ia
Ib
IIa
IIb
III
IV
V
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
4-MeC6H4COOH
salicylic acid
4-NO2C6H4COOH
CF3SO3H
TFA
DCM
DCM
DCM
DCM
DCM
DCM
DCM
MeOH
iPrOH
DMF
THF
(iPr)2O
PhCH3
THF
THF
THF
60
60
60
60
60
60
60
72
48
72
72
48
48
40
48
48
72
48
48
48
72
78
59
70
55
70
trace
38
50
trace
86
75
75
80
80
70
30
88
75
87
92
–82[d]
–84[d]
80
75
n.d.[e]
60
37
n.d.
93
66
72
80
86
85
75
93
83
78
THF
THF
DCM
DCE
TFA
TFA
60
[a] All reactions were carried out with 1a (0.15 mmol) and 2 (0.10 mmol) in the presence of the catalyst (20 mol-%) and co-catalyst acid
(40 mol-%) in solvent (1.0 mL) at room temperature. [b] Isolated yield after column chromatography. [c] Determined by chiral HPLC.
[d] A minus sign before the ee value signifies the enantiomer opposite to that obtained in all other entries in this table. [e] Not detected.
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G. Zhang, Y. Wang, W. Zhang, X. Xu, A. Zhong, D. Xu
FULL PAPER
position of the phenyl group were well tolerated and high (Table 2, Entries 2–7). A moderate yield and ee value arose
yields and excellent enantioselectivities were observed when a methoxy group on the phenyl moiety was present
or when furfuralacetone was employed to react with 2
Table 2. Michael addition reactions of α,β-unsaturated ketones
(Table 2, Entries 8 and 9). Reactions of 2 with cycloalk-
enones were also investigated, which revealed good results
with yields exceeding 92% with enantioselectivities
Ն92%ee (Table 2, Entries 10 and 11). All the above proves
that catalyst Ib can be perfectly applied to the asymmetric
Michael reaction of α,β-unsaturated ketones with 2-hy-
droxy-1,4-naphthalenedione for the synthesis of lapachol
analogues.
with naphthoquinone promoted by catalyst Ib.[a]
To determine the absolute configurations of the final ad-
ducts, a useful technique by comparing the electronic circu-
lar dichroism (ECD) spectra of the chiral product with cal-
culated time-dependent density functional theory
(TDDFT) results was adopted.[9] We investigated Michael
Entry
R
n
Time
[h]
Adduct
Yield[b]
[%]
ee[c]
[%]
1
2
Ph
4-BrC6H4
–
–
48
48
3a
3b
82
93
94
93.5/
Ͼ99[d]
91
3
4
5
3-BrC6H4
2-ClC6H4
4-ClC6H4
–
–
–
48
72
48
3c
3d
3e
88
75
87
92
91.5/
Ͼ99[d]
96
98
95
84
92
94
6
7
8
9
10
11
2,4-Cl2C6H3
4-NO2C6H4
3-MeOC6H4
2-furan
–
–
–
–
–
1
2
72
52
96
72
8
3f
3g
3h
3i
3j
3k
78
85
65
67
93
92
–
12
[a] All reactions were carried out with 1 (0.15 mmol) and 2
(0.10 mmol) in the presence of Ib (20 mol-%) and TFA (40 mol-%)
in THF (1.0 mL) at room temperature. [b] Isolated yield after col-
umn chromatography. [c] Determined by chiral HPLC. [d] After
recrystallization from dichloromethane/petroleum ether (1:3).
Figure 1. Theoretical ECD spectrum (dotted line) for product 3b
simulated by the TD-DFT/6-311+G*//DFT/6-311+G*method,
compared with the experimental spectrum (solid line).
Figure 2. Proposed catalytic mechanism for primary amine catalysis.
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Eur. J. Org. Chem. 2011, 2142–2147

Primary Amine Catalyzed Asymmetric Synthesis of Lapachol Analogues
adduct 3b for its absolute stereochemistry (Figure 1), and
Conclusions
the experimental ECD spectrum matched the theoretical
data of the S configuration (Figure 1); they both showed a
negative cotton effect around 240 nm. The absolute config-
uration of the products implies that naphthoquinone should
favor attack from the Re face of the α,β-unsaturated
ketones (Figure 2).
In summary, we have developed a highly efficient asym-
metric organocatalytic Michael addition reaction of
naphthoquinones to a diverse array of α,β-unsaturated
ketones in good to high yields and with excellent enantio-
selectivities. The useful ECD-TDDFT technique was
adopted to determine the absolute configuration of the final
product. MS (ESI) confirmed the intermediates of the reac-
tion to prove the proposed reaction mechanism. This repre-
sents a novel asymmetric synthesis of lapachol analogues,
and the corresponding products obtained could be further
derivatized for additional applications, which is currently
under investigation in our laboratory.
Based on the absolute configuration of the final product
and the previous reports of primary amine catalysis,[3]
a
catalytic mechanism for the reaction is proposed (Figure 2).
Firstly, under the catalysis of a protonic acid, the catalytic
cycle is initiated by nucleophilic attack of the primary
amine to the carbonyl group of substrate 1. Resultant inter-
mediate A then undergoes dehydration to form iminium
cation B, which furnishes a preorganized structure and con-
trols the enantioselectivity of the reaction. In the cycle,
naphthoquinone is assumed to interact with the tertiary
amine group of Ib through H-bonding, enhancing the nu-
cleophilic character of the reacting carbon center to attack
the activated ketones and inducing the Michael addition
from the Re face of the α,β-unsaturated ketones. That al-
lows the Michael addition of 1 and 2 to take place, provid-
ing corresponding iminium intermediate D. Ultimately,
through hydrolysis, the procedure provides the product and
regenerates catalyst Ib.
To prove the rationality of the proposed mechanism, we
studied the reaction by MS (ESI),[10] which enabled us to
identify all critical intermediates in the reaction mixture,
especially during dehydration and hydrolysis of the interme-
diates of the iminium ion (Figure 3). The spectrum of the
sample obtained from the reaction mixture of Ib (20 mol-
%), TFA (40 mol-%), 1a (0.15 mmol), and 2 (0.1 mmol) af-
ter stirring for 2 h revealed ions at m/z = 294.32, 422.40,
440.22, 596.32, and 614.10, corresponding to the signals for
the catalyst ([Ib + H]+), iminium intermediate B, dehy-
dration intermediate A ([B + H2O]+), adduct D, and hydrol-
ysis adduct E ([D + H2O]+), respectively.
Experimental Section
General Methods: Unless otherwise mentioned, all reagents and sol-
vents were obtained from commercial suppliers and used without
further purification. Flash chromatography (FC) was carried out
using silica gel (200–300 mesh). Monitoring of reactions was per-
formed by TLC on silica gel precoated on glass plates, and spots
1
were visualized with UV light at 254 nm. H and 13C NMR were
recorded in CDCl3 with a Bruker Avance III (500 MHz for 1H
NMR and 125 MHz for 13C NMR) at 25 °C. TMS served as in-
1
ternal standard (δ = 0 ppm) for H NMR and CDCl3 was used as
1
internal standard (δ = 77.0 ppm) for 13C NMR. H NMR spectro-
scopic data are reported as follows: chemical shift, multiplicity (s
= singlet, d = doublet, t = triplet, m = multiplet), coupling con-
stants [Hz], and integration. MS (ESI) spectra were determined
with a Thermo LCQ fleet instrument and controlled by Xcalibur
software. HRMS spectra were determined with an Agilent 6210
TOF LC–MS. HPLC experiments were carried out using a JASCO
LC-2000 Plus system with MD-2010 HPLC diode array detector.
CD spectra were measured with a JASCO J-815 CD spectrometer
in 0.5 gL–1 iPrOH.
General Procedure for the Michael Reactions: All reactions were
carried out with
a mixture of α,β-unsaturated ketones 1
(0.15 mmol), naphthoquinone 2 (0.10 mmol), Ib (20 mol-%), and
additive TFA (40 mol-%) stirred at room temperature for the corre-
sponding time (TLC; hexane/ethyl acetate, 1:1). The flash column
chromatography was carried out over silica gel (petroleum ether/
ethyl acetate, 3:1). Enantiomeric excess values of the products were
determined by chiral HPLC using a Chiralpak AS-H or OD-H
column.
2-Hydroxy-3-(3-oxo-1-phenylbutyl)naphthalene-1,4-dione
(3a):
Yield: 26.8 mg (82%); yellow solid; m.p. 143–145 °C; [α] = –38.2 (c
= 0.10, MeOH). HPLC (Chiralpak OD-H column, hexane/iPrOH
= 85:15, 1.0 mL/min): tR = 16.4 (minor), 17.8 (major) min; 94%ee.
1H NMR: δ = 2.2 (s, 3 H), 3.3 (dd, J = 17.9, 6.0 Hz, 1 H), 3.8 (dd,
J = 17.8, 9.7 Hz, 1 H), 5.0 (dd, J = 9.7, 6.0 Hz, 1 H), 7.2 (t, J =
7.37 Hz, 1 H), 7.2–7.3 (m, 2 H), 7.4–7.5 (m, 2 H), 7.7 (t, J = 8.1 Hz,
1 H), 7.7 (t, J = 7.6 Hz, 1 H), 8.0 (d, J = 7.8 Hz, 1 H), 8.1 (d, J =
8.0 Hz, 1 H) ppm. 13C NMR: δ = 29.9, 35.9, 46.4, 124.4, 124.8,
126.0, 126.7, 127.0, 127.8, 128.1 (2 C), 129.2 (2 C), 132.9, 135.0,
141.1, 152.6, 181.7, 184.3, 207.5 ppm. MS (ESI–): m/z = 319.2 [M –
H]–. HRMS: calcd. for C20H15O4 319.0973; found 319.0959.
2-[1-(4-Bromophenyl)-3-oxobutyl]-3-hydroxynaphthalene-1,4-dione
(3b): Yield: 37.1 mg (93%); yellow solid; m.p. 162–164 °C; [α] =
–36.4 (c = 0.10, MeOH). HPLC (Chiralpak AS-H column, hexane/
iPrOH = 97:3, 1.0 mL/min); tR = 70.3 (major), 96.9 (minor) min;
Figure 3. Mass spectrum (ESI) of the reaction 2 h after its start.
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G. Zhang, Y. Wang, W. Zhang, X. Xu, A. Zhong, D. Xu
FULL PAPER
93.5%ee (Ͼ99% after recrystallization). 1H NMR: δ = 2.2 (s, 3 H),
3.3 (dd, J = 18.0, 6.3 Hz, 1 H), 3.7 (dd, J = 18.0, 9.3 Hz, 1 H), 4.9
(dd, J = 9.3, 6.3 Hz, 1 H), 7.3–7.4 (m, 2 H), 7.4–7.5 (m, 2 H), 7.7
(d, J = 7.6 Hz, 1 H), 7.7 (d, J = 7.8 Hz, 1 H), 8.0 (d, J = 7.7 Hz,
1 H), 8.1 (d, J = 7.7 Hz, 1 H) ppm. 13C NMR: δ = 29.0, 35.5, 45.8,
2-Hydroxy-3-[1-(4-nitrophenyl)-3-oxobutyl]naphthalene-1,4-dione
(3 g): Yield: 31.2 mg (85%); yellow solid; m.p. 172–174 °C; [α] =
–46.3 (c = 0.10, MeOH). HPLC (Chiralpak AD-H column, hexane/
iPrOH = 90:10, 1.0 mL/min): tR = 92.0 (major), 64.2 (minor) min;
1
98%ee. H NMR: δ = 2.2 (s, 3 H), 3.4 (dd, J = 18.1, 6.6 Hz, 1 H),
123.9, 125.9, 126.7, 127.2, 129.0, 129.9 (2 C), 131.3 (2C), 132.5, 3.7 (dd, J = 18.4, 8.9 Hz, 1 H), 5.1 (dd, J = 8.2, 7.1 Hz, 1 H), 7.6
132.8, 134.8, 140.6, 153.0, 181.3, 184.04, 206.8 ppm. MS (ESI–): (d, J = 8.7 Hz, 2 H), 7.7–7.8 (m, 2 H), 8.0–8.1 (m, 2 H), 8.3 (d, J
m/z = 397.1 [M – H]–, 399.3 [M – H]–. HRMS: calcd. for
C20H14BrO4 397.0075; found 399.0084.
= 8.7 Hz, 2 H) ppm. 13C NMR: δ = 29.8, 36.2, 45.6, 123.8 (2 C),
124.3, 126.3, 126.4, 127.2, 129.2 (2 C), 133.2, 133.3, 135.3, 146.8,
149.2, 152.9, 181.3, 183.9, 205.7 ppm. MS (ESI–): m/z = 364.1 [M –
H]–. HRMS: calcd. for C20H14NO6 364.0821; found 364.0812.
2-[1-(3-Bromophenyl)-3-oxobutyl]-3-hydroxynaphthalene-1,4-dione
(3c): Yield: 35.2 mg (88%); yellow solid; m.p. 151–154 °C; [α] =
–39.5 (c = 0.10, MeOH). HPLC (Chiralpak OD-H column, hexane/
iPrOH = 97:3, 1.0 mL/min): tR = 18.2 (major), 21.2 (minor) min;
2-Hydroxy-3-[1-(3-methoxyphenyl)-3-oxobutyl]naphthalene-1,4-
dione (3h): Yield: 22.8 mg (65%); yellow solid; m.p. 148–150 °C; [α]
= –45.2 (c = 0.10, MeOH). HPLC (Chiralpak OD-H column, hex-
1
91%ee. H NMR: δ = 2.2 (s, 3 H), 3.3 (dd, J = 18.0, 6.1 Hz, 1 H),
3.7 (dd, J = 18.0, 9.5 Hz, 1 H), 4.9 (dd, J = 9.4, 6.2 Hz, 1 H), 7.2
(dd, J = 16.5, 8.5 Hz, 1 H), 7.3–7.4 (m, 2 H), 7.6 (d, J = 7.6 Hz, 1
H), 7.6 (t, J = 7.6, 7.6 Hz, 1 H), 7.7 (dd, J = 5.2, 3.9 Hz, 1 H), 8.0
(d, J = 6.6 Hz, 1 H), 8.1 (d, J = 7.7 Hz, 1 H) ppm. 13C NMR: δ =
29.9, 36.0, 46.0, 122.5, 123.9, 126.1, 127.0, 127.2, 129.2, 129.9,
130.1, 131.2, 132.8, 133.1, 135.2, 144.0, 152.7, 181.6, 184.1,
206.4 ppm. MS (ESI–): m/z = 397.0 [M – H]–, 399.4 [M – H]–.
HRMS: calcd. for C20H14BrO4 397.0075; found 397.0059.
ane/iPrOH
= 97:3, 1.0 mL/min): tR = 21.3 (major), 19.9
1
(minor) min; 95%ee. H NMR: δ = 2.2 (s, 3 H), 3.2 (dd, J = 17.9,
6.0 Hz, 1 H), 3.7 (dd, J = 18.0, 9.9 Hz, 1 H), 3.8 (s, 3 H), 4.9 (dd,
J = 9.7, 6.0 Hz, 1 H), 6.7 (dd, J = 7.9, 2.4 Hz, 1 H), 7.0–7.1 (m, 2
H), 7.2 (t, J = 7.9, 7.9 Hz, 1 H), 7.7 (d, J = 8.7 Hz, 1 H), 7.8 (d, J
= 7.6 Hz, 1 H), 8.0 (d, J = 7.5 Hz, 1 H), 8.1 (d, J = 7.7 Hz, 1
H) ppm. 13C NMR: δ = 29.9, 36.4, 46.3, 55.2, 111.9, 114.3, 120.6,
124.5, 126.0, 127.1, 129.2, 129.5, 132.9,132.9, 135.0, 143.3, 152.7,
159.7, 181.7, 184.2, 207.0 ppm. MS (ESI–): m/z = 349.2 [M – H]–.
HRMS: calcd. for C21H17O5 349.1076; found 349.1061.
2-[1-(2-Chlorophenyl)-3-oxobutyl]-3-hydroxynaphthalene-1,4-dione
(3d): Yield: 26.7 mg (75%); yellow solid; m.p. 147–150 °C; [α] =
–38.0 (c = 0.10, MeOH). HPLC (Chiralpak OD-H column, hexane/
iPrOH = 97:3, 1.0 mL/min): tR = 21.2 (major), 16.8 (minor) min;
2-[1-(Furan-2-yl)-3-oxobutyl]-3-hydroxynaphthalene-1,4-dione (3i):
Yield: 20.8 mg (67%); yellow solid; m.p. 131–133 °C; [α] = –27.3 (c
= 0.10, MeOH). HPLC (Chiralpak OD-H column, hexane/iPrOH
= 90:10, 1.0 mL/min): tR = 25.1 (major), 28.3 (minor) min; 84%ee.
1H NMR: δ = 2.2 (s, 3 H), 3.3 (dd, J = 17.8, 6.3 Hz, 1 H), 3.5 (dd,
J = 17.8, 8.9 Hz, 1 H), 5.1 (dd, J = 8.8, 6.4 Hz, 1 H), 6.1 (d, J =
3.2 Hz, 1 H), 6.3 (dd, J = 3.1, 1.9 Hz, 1 H), 7.5 (dd, J = 5.7, 3.3 Hz,
1 H), 7.7–7.8 (m, 2 H), 8.1 (d, J = 7.4 Hz, 1 H), 8.2 (d, J = 7.8 Hz,
1 H) ppm. 13C NMR: δ = 29.8, 30.1, 44.6, 105.8, 110.4, 122.0,
126.2, 126.4, 127.2, 129.3, 133.0, 135.2, 141.3, 153.1, 154.2, 181.5,
183.7, 206.2 ppm. MS (ESI–): m/z = 308.9 [M – H]–. HRMS: calcd.
for C18H13O5 309.0763; found 309.0773.
1
92%ee. H NMR: δ = 2.2 (s, 3 H), 3.2 (dd, J = 17.9, 6.3 Hz, 1 H),
3.7 (dd, J = 17.5, 9.0 Hz, 1 H), 4.9 (dd, J = 9.0, 6.6 Hz, 1 H), 7.0–
7.1 (m, 2 H), 7.2 (t, J = 1.8, 1.8 Hz, 1 H),7.4 (d, J = 7.9 Hz, 1 H),
7.6 (d, J = 7.6 Hz, 1 H), 7.7 (dd, J = 5.2, 3.9 Hz, 1 H), 8.0 (dd, J
= 7.8, 0.7 Hz, 1 H), 8.1 (d, J = 4.5 Hz, 1 H) ppm. 13C NMR: δ =
30.0, 35.9, 46.3, 124.7, 125.9, 126.6, 127.0, 127.8, 128.0, 129.1,
129.2, 129.5, 132.8, 134.9, 136.3, 138.6, 152.6, 181.6, 184.3,
207.4 ppm. MS (ESI–): m/z = 353.2 [M – H]–, 355.2 [M – H]–.
HRMS: calcd. for C20H14ClO4 353.0581; found 353.0595.
2-[1-(4-Chlorophenyl)-3-oxobutyl]-3-hydroxynaphthalene-1,4-dione
(3e): Yield: 31.0 mg (87%); yellow solid; m.p. 158–159 °C; [α] =
–42.5 (c = 0.10, MeOH). HPLC (Chiralpak AS-H column, hexane/
iPrOH = 97:3, 1.0 mL/min): tR = 52.4 (major), 70.6 (minor) min;
91.5%ee (Ͼ99% after recrystallization). 1H NMR: δ = 2.2 (s, 3 H),
3.3 (dd, J = 18.0, 6.3 Hz, 1 H), 3.7 (dd, J = 17.9, 9.3 Hz, 1 H), 4.9
(dd, J = 8.9, 6.6 Hz, 1 H), 7.2–7.3 (m, 2 H), 7.4–7.5 (m, 2 H), 7.7
(d, J = 7.6 Hz, 1 H), 7.8 (d, J = 7.8 Hz, 1 H), 8.0 (d, J = 7.7 Hz,
1 H), 8.1 (d, J = 7.7 Hz, 1 H) ppm. 13C NMR: δ = 29.0, 35.5, 45.8,
123.9, 125.9, 126.8, 127.2, 128.7, 129.0, 129.9 (2 C), 131.3 (2 C),
132.8, 134.9, 140.6, 153.0, 181.3, 184.1, 206.9 ppm. MS (ESI–): m/z
= 353.2 [M – H]–. HRMS: calcd. for C20H14ClO4 353.0581; found
353.0593.
2-Hydroxy-3-(3-oxocyclopentyl)naphthalene-1,4-dione (3j): Yield:
23.6 mg (92%); yellow solid; m.p. 168–169 °C; [α] = –49.2 (c = 0.10,
MeOH). HPLC (Chiralpak AS-H column, hexane/iPrOH = 97:3,
1.0 mL/min): tR = 50.3 (major), 46.7 (minor) min; 92%ee. 1H
NMR: δ = 2.2–2.6 (m, 5 H), 2.9 (dd, J = 18.3, 10.6 Hz, 1 H), 3.9
(dd, J = 16.9, 8.6 Hz, 1 H), 7.7 (t, J = 7.6, 7.6 Hz, 1 H), 7.8 (t, J
= 7.6, 7.6 Hz, 1 H), 8.1 (d, J = 7.6 Hz, 1 H), 8.2 (d, J = 7.7 Hz, 1
H) ppm. 13C NMR: δ = 27.0, 32.0, 38.5, 41.6, 123.9, 126.2, 127.0,
129.2, 132.9, 133.1, 135.2, 153.3, 181.2, 184.3, 218.9 ppm. MS
(ESI–): m/z = 255.2 [M – H]–. HRMS: calcd. for C15H11O4
255.0657; found 255.0666.
2-Hydroxy-3-(3-oxocyclohexyl)naphthalene-1,4-dione (3k): Yield:
25.2 mg (93%); yellow solid; m.p. 181–183 °C; [α] = –59.2 (c = 0.10,
MeOH). HPLC (Chiralpak OD-H column, hexane/iPrOH = 97:3,
1.0 mL/min): tR = 13.79 (major), 12.93 (minor) min; 94%ee. 1H
NMR: δ = 1.6–2.5 (m, 8 H), 3.5 (s, 1 H), 7.7 (dd, J = 13.0, 6.9 Hz,
1 H), 7.9 (t, J = 7.5, 7.5 Hz, 1 H), 8.1 (t, J = 14.5 Hz, 1 H), 8.2 (d,
J = 7.7 Hz, 1 H) ppm. 13C NMR: δ = 19.2, 25.7, 35.1, 39.3, 43.9,
123.3, 126.1, 126.4, 129.0, 133.0, 134.1, 135.2, 155.7, 181.3, 183.0,
210.8 ppm. MS (ESI–): m/z = 269.1 [M – H]–. HRMS: calcd. for
C16H13O4 269.0814; found 269.0814.
2-[1-(2,4-Dichlorophenyl)-3-oxobutyl]-3-hydroxynaphthalene-1,4-
dione (3f): Yield: 30.3 mg (78%); yellow solid; m.p. 151–154 °C; [α]
= –43.7 (c = 0.10, MeOH). HPLC (Chiralpak OD-H column, hex-
ane/iPrOH = 97:3, 1.0 mL/min): tR = 11.6 (minor), 13.0
1
(major) min; 96%ee. H NMR: δ = 2.2 (s, 3 H), 3.3 (dd, J = 17.9,
6.0 Hz, 1 H), 3.8 (dd, J = 17.8, 9.7 Hz, 1 H), 5.0 (dd, J = 9.7,
6.0 Hz, 1 H), 7.2 (t, J = 7.4, 7.4 Hz, 1 H), 7.3 (d, J = 7.5 Hz, 1 H),
7.5 (d, J = 7.6 Hz, 1 H), 7.7 (t, J = 7.6, 7.6 Hz, 1 H), 7.7 (t, J =
7.6, 7.6 Hz, 1 H), 8.0 (d, J = 7.8 Hz, 1 H), 8.1 (d, J = 8.0 Hz, 1
H) ppm. 13C NMR: δ = 29.6, 34.0, 45.9, 122.6, 126.2, 127.1, 127.6,
129.1, 129.5, 130.3, 132.9, 133.0, 133.1, 134.4, 135.3, 137.7, 153.4,
Supporting Information (see footnote on the first page of this arti-
181.4, 184.1, 206.2 ppm. MS (ESI–): m/z = 387.1 [M – H]–. HRMS: cle): Copies of the 1H NMR and 13C NMR data, mass spectra,
calcd. for C20H13Cl2O4 387.0191; found 387.0189.
and high-resolution mass spectra.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2142–2147

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Received: November 22, 2010
Published Online: March 1, 2011
Eur. J. Org. Chem. 2011, 2142–2147
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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