Direct asymmetric Michael addition of phthalide derivatives to chalcones

Article abstract of DOI:10.1016/j.tetlet.2013.07.108

The Michael addition of phthalides to chalcones employing a quinidine-derived thiourea catalyst Q-1 has been developed. The reported method led to the synthesis of 3,3-disubstituted phthalide derivatives in excellent yields, with excellent diastereo- and enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2013.07.108

Tetrahedron Letters 54 (2013) 5261–5265
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct asymmetric Michael addition of phthalide derivatives
to chalcones
Jie Luo a, Chunhui Jiang a, Haifei Wang b, Li-Wen Xu c, Yixin Lu a,
⇑
a Department of Chemistry and Medicinal Chemistry Program, Life Sciences Institute, National University of Singapore, 3 Science Drive 3, Singapore 117543, Republic of Singapore
b Hunan University of Technology, Hunan 412008, PR China
c Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University, Hangzhou 310012, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The Michael addition of phthalides to chalcones employing a quinidine-derived thiourea catalyst Q-1 has
been developed. The reported method led to the synthesis of 3,3-disubstituted phthalide derivatives in
excellent yields, with excellent diastereo- and enantioselectivities.
Received 4 June 2013
Revised 10 July 2013
Accepted 19 July 2013
Available online 27 July 2013
Ó 2013 Published by Elsevier Ltd.
Keywords:
Michael addition
Phthalide derivatives
Chalcones
Organocatalysis
Quinine thiourea catalyst
Conjugate addition reactions represent a very powerful tool for
the construction of carbon–carbon bonds in organic synthesis.1 In
1,3-dicarbonyl compounds,2 malononitrile,3 nitroalkanes,4
c-bute-
nolide,5 and
c
-butyrolactam6 have been explored extensively as
particular, the conjugate addition of carbon nucleophiles to
a,b-
donors in conjugate additions, among others.7 Phthalides, on the
other hand, are much less common donors in conjugate additions.
Phthalide derivatives bearing a quaternary stereocenter at the
3-position are important structural scaffolds and are present
unsaturated ketones is a very useful reaction, due to the ready
availability of the starting materials, and synthetic utility of the
conjugate addition products. A range of nucleophiles, including
O
O
O
O
O
+
R1
R2
R'
R
3,3-disubstituted
phthalides
CO2t-Bu
OH
Cl
O
O
O
O
O
O
N
O
OMe
OMe
Me
COOH
H
H
O
MeO
OH
NH2
O
Me
O
OH
O
OH
Altenuic acid II
O
O
O
(+)-Arnottin II
Isochlortetracycline
Scheme 1. Selected examples of 3,3-disubstituted phthalides and the designed Michael reaction.
⇑
Corresponding author. Tel.: +65 6516 1569; fax: +65 6779 1691.
E-mail address: chmlyx@nus.edu.sg (Y. Lu).
0040-4039/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.07.108

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J. Luo et al. / Tetrahedron Letters 54 (2013) 5261–5265
Table 1
Catalyst screening for the asymmetric Michael reaction of 1 and 2aa
O
O
cat (20 mol%)
Ph
+
Ph
O
O
CH2Cl2, RT, 30 h
Ph
N
O
t-BuO
CO2t-Bu
Ph
O
O
1
2a
3a
R
N
OMe
OMe
N
H
N
H
N
H
N
HN
H
H2N
HN
N
TsHN
HN
Ar
Ar
N
S
N
H
S
QD-1
Trp-1
QD-2
QD-3
: R = OMe
C-1: R = H
OMe
N
R
OMe
OMe
N
H
N
H
N
H
N
H
N
HN
H
H
N
NH
N
NH
NH
O
Ar
H
N
H
N
Ar
S
N
N
N
R
S
O
Ar
H
O
NH
Ar
S
Q-1
QD-4: R = t-Bu
: R = OMe
O
QD-5
CD-1: R = H
: R = 1H-indolyl-3-methyl
Q-2
Q-3
Ar = 3,5-CF3-Ph
Entry
Catalyst
Solvent
Conversionb
eec (%)
1
QD-1
QD-1
QD-1
Trp-1
QD-2
QD-3
C-1
Q-1
CD-1
Q-2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
>95%
<50%
<50%
>95%
<50%
>95%
>95%
>95%
>95%
>95%
>95%
>95%
>95%
>95%
>95%
>95%
>95%
>95%
0
60
53
80
—
ꢀ80
ꢀ80
88
86
82
2d
3e
4
5
6
7
8
9
10
11
12
13
14
15
16f
17g
18h
Q-3
67
QD-4
QD-5
Q-1
Q-1
Q-1
ꢀ23
ꢀ53
82
35
90
CH2Cl2
CH2Cl2
CH2Cl2
Q-1
Q-1
92
88
a
Reactions were carried out using 1 (0.05 mmol), 2a (0.06 mmol), catalyst (0.01 mmol), in CH2Cl2 (0.3 mL), room temperature. The diastereomeric ratios were determined
by 1H NMR analysis of the crude products, >19:1 for all the entries.
b
Yield of isolated product.
Determined by HPLC analysis on a chiral stationary phase.
20 mol % (+)-CAS was added.
20 mol % TFA was added.
3 Å molecular sieves were added.
4 Å molecular sieves were added.
5 Å molecular sieves were added.
c
d
e
f
g
h
widely in natural products and bioactive molecules.8 Our group has
keen interest in the synthesis of chiral phthalides, especially 3,3-
disubstituted phthalides containing a quaternary stereogenic cen-
ter.9 We previously demonstrated that installation of an ester
group at the 3-position of phthalides could impart them with en-
hanced reactivity. In this context, we developed direct asymmetric
Mannich reactions of phthalides,10 as well as enantioselective
regiodivergent allylic alkylations of phthalides with MoritaꢀBay-
lis–Hillman carbonates.11 Herein, we describe a highly diastereose-
lective and enantioselective conjugate addition of phthalide
derivatives to chalcones,12 leading to the formation of chiral phtha-
lides bearing vicinal quaternary and tertiary stereogenic centers
(Scheme 1).
investigated the catalytic effects of a wide range of bifunctional
amine catalysts (Table 1). Catalyst QD-1 with a primary amine
group13 promoted the reaction, and the product was obtained in
quantitative yield. However, the reaction proceeded in a non-ster-
eoselective manner, affording a racemic mixture (entry 1). Intro-
duction of an acid additive to the reaction system induced
moderate enantiomeric excess, but with decreased chemical yields
(entries 2 and 3). We next turned our attention to tertiary amine-
containing bifunctional and multifunctional catalysts. When L-
tryptophan-derived thiourea Trp-1 was employed, the desired
conjugate addition product was obtained quantitatively, with very
high diastereoselectivity and 80% ee (entry 4). Quinidine-derived
sulfonamide catalyst QD-2 failed to catalyze the reaction (entry
5). Among a number of cinchona alkaloid-derived thiourea and
squaramide catalysts (entries 6–10), quinine-derived Q-1 was
We selected the conjugate addition of phthalide derivative 1 to
a,b-unsaturated ketone 2a in CH2Cl2 as a model reaction, and

J. Luo et al. / Tetrahedron Letters 54 (2013) 5261–5265
5263
Table 2
Table 2 (continued)
Reaction scopea
Entry
Product
Yieldb (%)
eec (%)
O
O
O
O
O
Q-1 (20 mol%)
O
O
+
R1
R2
R2
40 h, r.t.
t-BuO
CO2t-Bu
t-BuO
3b to 3m
R1
O
O
O
8
93
92
O
2b to 2m
1
3i
Entry
Product
Yieldb (%)
eec (%)
NO2
O
O
O
Br
O
1
t-BuO
87
92
85
86
88
87
91
88
9
85
86
89
81
90
81
87
t-BuO
O
O
O
O
3b
O
NO2
O
O
S
O
O
t-BuO
2
3
4
5
6
7
86
97
93
90
91
85
10
11
12
t-BuO
O
O
O
3k
3c
O
O
Br
O
OMe
O
O
t-BuO
t-BuO
t-BuO
t-BuO
O
O
O
3d
3e
3l
O
O
F
O
O
90
t-BuO
O
O
O
O
3m
Reactions were0 carried out using
(0.01 mmol), and 4 ÅA MS in in CH2Cl2 (0.3 mL), room temperature. The diastereo-
meric ratios were determined by 1H NMR analysis of the crude products, >19:1 for
all the entries.
O
Cl
O
a
1
(0.05 mmol),
2
(0.06 mmol), Q-1
O
b
O
Yield of isolated product.
Determined by HPLC analysis on a chiral stationary phase.
c
3f
O
OMe
O
found to be the best, affording the desired product as essentially a
single diastereomer and with 88% ee (entry 8). Employment of
amino acid incorporating multifunctional catalysts did not offer
further improvement (entries 11–13). Other solvents did not turn
out to be beneficial (entries 14 and 15). Addition of 4 Å molecular
sieves in the presence of Q-1 in CH2Cl2 led to the completion of the
reaction within one day, and the desired conjugate addition prod-
uct was obtained as essentially a single diastereomer and with 92%
ee (entry 17).
We next examined the scope of the reaction (Table 2). In all the
examples, consistently high diastereoselectivities and enantiose-
lectivities were observed when a wide range of chalcones were
employed in the conjugate addition.
O
t-BuO
O
3g
3h
O
Cl
O
t-BuO
O
O
The practicability of our method was demonstrated by a scalea-
ble synthesis of 3a; the chemical yield, diastereoselectivity, and

5264
J. Luo et al. / Tetrahedron Letters 54 (2013) 5261–5265
O
O
O
Q-1 (10 mol%)
O
O
+
Ph
Ph
R2
CH2Cl2, 40 h, r.t.
CO2t-Bu
t-BuO
2a
(500 mg, 2.4 mmol)
R1
O
O
1 (468 mg, 2 mmol)
3a
(0.82 g, 93% yield,
>19:1 dr, 93% ee)
Scheme 2. Reaction scale-up.
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Figure 1. ORTEP structure of 3b.
enantioselectivity of the reaction were all well maintained
(Scheme 2). We were able to obtain the X-ray crystal structure of
the conjugate addition product 3b14 (Fig. 1), the absolute configu-
ration of which was determined to be (R,R). The absolute configu-
rations of the other conjugate addition products were assigned by
analogy.
In conclusion, we have developed the first asymmetric conju-
gate addition of 3-substituted phthalides to chalcones, catalyzed
by a quinine-derived thiourea catalyst. The conjugate addition
products were obtained in high yields, as essentially a single
diastereomer and with excellent enantioselectivities. The method
described here provides a convenient access to chiral 3,3-disubsti-
tuted phthalides. Biological evaluation of the phthalide derivatives
prepared is underway.
Acknowledgments
We thank the National University of Singapore(R-143-000-469-
112) and the Ministry of Education (MOE) of Singapore (R-143-
000-362-112), the Singapore-Peking-Oxford Research Enterprise
(COY-15-EWI-RCFSA/N197-1), and GSKꢀEDB (R-143-000-491-
592) for generous 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.tetlet.2013.07.
108.
References and notes
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