Enantioselective synthesis of dihydrocoumarin derivatives by chiral scandium(iii)-complex catalyzed inverse-electron-demand hetero-Diels-Alder reaction

Article abstract of DOI:10.1039/c4cc10343b

An asymmetric inverse-electron-demand hetero-Diels-Alder reaction between o-quinone methides and azlactones to generate potentially pharmacological active dihydrocoumarins has been achieved efficiently by using a chiral N,N′-dioxide-Sc(iii) complex as the catalyst. The desired products were obtained in high yields with excellent enantioselectivities and diastereoselectivities (up to 94% yield, 96% ee and >19:1 dr) under mild reaction conditions. A concerted reaction pathway was confirmed by Operando IR and control experiments.

Full text of DOI:10.1039/c4cc10343b

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Enantioselective synthesis of dihydrocoumarin
derivatives by chiral scandium(III)-complex
catalyzed inverse-electron-demand
hetero-Diels–Alder reaction†
Cite this:DOI: 10.1039/c4cc10343b
Received 27th December 2014,
Accepted 27th January 2015
Haipeng Hu,a Yangbin Liu,a Jing Guo,a Lili Lin,a Yali Xu,a Xiaohua Liua and
DOI: 10.1039/c4cc10343b
Xiaoming Feng*ab
www.rsc.org/chemcomm
An asymmetric inverse-electron-demand hetero-Diels–Alder reac- and a nitrogen atom substituted quaternary stereocenters also
tion between o-quinone methides and azlactones to generate exhibit charming biological activities.7 Herein, we demonstrate a
potentially pharmacological active dihydrocoumarins has been highly efficient IEDDA reaction of QMs with azlactones catalyzed
achieved efficiently by using a chiral N,N0-dioxide–Sc(III) complex by a chiral N,N0-dioxide–scandium(III) complex, generating amino
as the catalyst. The desired products were obtained in high yields substituted 3,4-dihydrocoumarins.
with excellent enantioselectivities and diastereoselectivities (up to
Initially, QM (1a) and azlactone (2a) were employed as the
94% yield, 96% ee and 419 : 1 dr) under mild reaction conditions. model substrates, and the reaction was investigated at 35 1C in
A concerted reaction pathway was confirmed by Operando IR and
control experiments.
Table 1 Optimization of the reaction conditions
Chiral dihydrocoumarin derivatives have attracted much atten-
tion due to their pharmacological and physiological activities
such as anti-inflammatory, HIV replication inhibition and anti-
oxidant.1 Consequently, significant efforts have been devoted to
the asymmetric synthesis of these fascinating molecules and
many methods have been reported in recent years.2 Among
them, the [4+2] cycloaddition of ortho-quinone methides (QMs)
with enolates was found to be an efficient way for the synthesis
of chiral dihydrocoumarin with continuous stereocenters. In
2008, Lectka reported the [4+2] cycloaddition of QMs with silyl
ketene acetals catalyzed by chiral ammonium fluoride, and a
stepwise reaction pathway was proposed.3 Later, Ye’s group
reported chiral N-heterocyclic carbenes to catalyze the formal
[4+2] cycloaddition reaction of QMs and ketenes, affording chiral
3,3,4-trialkyl substituted 3,4-dihydrocoumarins.4 On the other
hand, azlactones involving the nucleophilic C4 and electrophilic
C5 could serve as electron-rich dienophiles via enolization.5
However, they have not been employed in the inverse-electron-
demand hetero-Diels–Alder (IEDDA)6 reaction with QMs. What’s
more, the corresponding products containing a tertiary carbon
Entrya Ligand
Metal
Additive
Yieldb (%) eec (%)
1
2
3
4
L-PrMe2
L-PrMe2
L-PrMe2
L-PrPr2
Ni(OTf)2
Yb(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
—
—
—
—
—
—
—
60
54
38
12
o5
11
14
41
38
50
67
90
19
24
74
25
80
77
80
46
67
88
91
91
5
6
L-PrMe2Bu
L-PiMe2Bu
7
8
9
10
11
12d
L-RaMe2Bu Sc(OTf)3
L-RaMe2Bu Sc(OTf)3
L-RaMe2Bu Sc(OTf)3
L-RaMe2Bu Sc(OTf)3
L-RaMe2Bu Sc(OTf)3
L-RaMe2Bu Sc(OTf)3
Na2CO3
DABCO
DMAP
Imidazole
Imidazole
a Key Laboratory of Green Chemistry & Technology, Ministry of Education, College
of Chemistry, Sichuan University, Chengdu 610064, P. R. China.
E-mail: xmfeng@scu.edu.cn; Fax: +86 28 85418249; Tel: +86 28 85418249
b Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),
P. R. China
a
Unless otherwise noted, the reactions were performed with metal/ligand
(1 : 1, 10 mol%), 1a (0.10 mmol), 2a (0.10 mmol) and additive (0.10 eq.) in
b
c
THF (1.0 mL) at 35 1C for 72 h. Isolated yield. Determined by chiral
d
HPLC analysis. The reaction was performed with 1a (0.12 mmol), metal–
† Electronic supplementary information (ESI) available: Additional experimental
and spectroscopic data. CCDC 1039793. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c4cc10343b
ligand (1 : 1.05, 10 mol%), 2a (0.10 mmol) and additive (0.15 eq.) in THF
(1.0 mL) at 35 1C for 72 h. The dr were all over 19 : 1 detected by 1H NMR
spectra. PMP = p-methoxyphenyl, Bn = benzyl.
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Table 2 Substrate scope of the asymmetric IEDDA reaction
THF. Various metal salts complexing with chiral L-proline-derived
N,N0-dioxide L-PrMe2 were investigated (Table 1, entries 1–3). The
target product 3a was obtained in 60% yield with only 19% ee
when Ni(OTf)2 was applied as the metal (Table 1, entry 1), mean-
while, the Michael addition product was isolated unexpectedly.
However, when other metals were employed in the reaction, the
Michael addition product was not detected. The complex of
Yb(OTf)3 also gave a moderate result (Table 1, entry 2). Inspiringly,
Sc(OTf)3 was able to improve the ee to 74% sharply albeit with a
decreased yield (Table 1, entry 3). Subsequently, various ligands
were evaluated (Table 1, entries 4–7). It was found that the steric
hindrance at the amide moiety of the N,N0-dioxide ligands
affected the enantioselectivity of the reaction apparently. Upon
improving the steric hindrance from the 2,6-dimethyl to 2,6-
diisopropyl group, the ee was decreased sharply from 74% to
25% (Table 1, entries 3 and 4). L-PrMe2Bu with an additional
tertiary butyl substitution on the para-position of the phenyl ring
compared to L-PrMe2 increased the ee to 80%, however, decreased
the yield to less than 5% (Table 1, entry 5). L-Pipecolic acid derived
L-PiMe2Bu and L-ramipril derived ligand L-RaMe2Bu could
improve the yield a little, and the latter could also give 80% ee.
In order to improve the reactivity of the reaction, basic additives were
designedly added in the catalytic system to facilitate the enolization
of azlactones. As expected, both inorganic and organic bases
improved the reactivity (Table 1, entries 8–12), and the latter were
more beneficial for the enantioselectivity. Imidazole as the additive
could not only increase the yield to 67% but also promote the ee to
91%. Finally, by adjusting the metal to ligand ratio to 1 : 1.05 and the
proportion of 1a to 2a to 1.2 : 1.0, 3,4-dihydrocoumarin 3a was
obtained in 90% yield with 91% ee (Table 1, entry 12). In all cases,
the diastereoselectivity of the reaction was over 19 : 1.
Entrya
R1
R2
Yieldb (%)
eec, f (%)
1
2
3
4
5
6
7
8
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
90 (3a)
84 (3b)
89 (3c)
90 (3d)
64 (3e)
68 (3f)
90 (3g)
87 (3h)
85 (3i)
94 (3j)
88 (3k)
85 (3l)
80 (3m)
94 (3n)
63 (3o)
42 (3p)
70 (3q)
91 (3r)
75 (3s)
71 (3t)
70 (3u)
91(7R,8R)
92(7R,8R)
94(7R,8R)
91(7R,8R)
94(7R,8R)
92(7R,8R)
93(7R,8R)
92(7R,8R)
90(7R,8R)
96
91(7R,8R)
91
92(7R,8R)
93
4-FC6H4
4-ClC6H4
4-BrC6H4
4-NCC6H4
4-F3CC6H4
4-MeC6H4
4-EtC6H4
4-MeOC6H4
4-O2NC6H4
3-ClC6H4
2-ClC6H4
3,5-Me2C6H3
3,5-(O2N)2C6H3
Bn
Ph
Ph
Ph
Ph
Ph
Ph
9
10
11
12
13d
14
15
16
17
18
19
20
21e
94(7R,8R)
91(7R,8R)
92(7R,8R)
91(7R,8R)
82(7R,8R)
77(7R,8R)
91(7R,8R)
4-FC6H4CH2
4-ClC6H4CH2
4-BrC6H4CH2
CH3SCH2CH2
Me
f
H
a
Unless otherwise noted, the reactions were performed with L-RaMe2Bu-
Sc(OTf)3 (1: 1.05, 10 mol%), 1a (0.12 mmol), 2 (0.1 mmol) and imidazole
b
c
(0.15 eq.) in THF (1.0 mL) at 35 1C for 72 h. Isolated yield. Determined
d
by HPLC analysis. The reaction was performed with imidazole (0.3 eq.)
e
f
at 35 1C for 96 h. In the reaction 1a was changed to 1b. The absolute
configuration of 3d was determined to be (7R,8R) by X-ray crystallo-
graphic analysis, others were confirmed by comparison with the CD
1
spectra. The dr were all over 19:1 detected by H NMR spectra.
Under the optimized reaction conditions (Table 1, entry 12),
a wide range of azlactones 2 were investigated. As shown in
Table 2, azlactones with either electron-withdrawing or electron-
donating substituents on the phenyl ring in the R1 group could be
smoothly converted to the corresponding products in high yields,
good enantioselectivities and excellent diastereoselectivities (up to
94% yield, 96% ee, 419 : 1 dr) (Table 2, entries 1–14). In addition,
azlactone 2o with two benzyl groups was well tolerated in the
reaction, giving 63% yield and 94% ee (Table 2, entry 15). When
Scheme 1 The gram-scale synthesis of 3a.
substituent R2 was examined, both benzyl and alkyl groups QM 1a and 2.60 mmol (0.65 g) azlactone 2a reacted well to
were compatible. Substituents on the benzyl group exhibited an afford the desired adduct 3a in 67% yield (0.89 g) with 91% ee
obvious electronic effect. The yield increased correspondingly and 419 : 1 dr (Scheme 1).
with the electron-withdrawing decreased (Table 2, entries 16–18).
In order to investigate the reaction pathway, the Operando IR
For alkyl substituted 2s and 2t, high ee values (82% ee, 77% ee) and control experiments were carried out (Fig. 1). In the Operando
and moderate yields (75% yield, 71% yield) were obtained IR experiments, it was clearly demonstrated that the amount of
(Table 2, entries 19 and 20). Moreover, the reaction proceeded product 3a increased with the consumption of QM 1a and azlactone
well with substrate 1b, which contained a slightly steric hindrance 2a. Additionally, the signal of the Michael-addition product 3aa was
change (Table 2, entry 21). The absolute configuration of product not detected. On the other hand, when 3aa was exposed to the
3d was determined to be (7R,8R) by X-ray crystallography analysis, standard reaction system, no dihydrocoumarin 3a was obtained. All
the others were confirmed in comparison with the Cotton effect in the experiments indicate that the reaction undergoes the concerted
the CD spectra (see the ESI† for details).
pathway rather than the stepwise pathway.
Considering the potential biological activities of dihydro-
On the basis of the experimental results, our previous work8 and
coumarins and in order to show the synthetic utility of the the absolute configuration of the products, a possible transition-
catalyst system, the gram-scale synthesis of 3a was performed. state model was proposed. As shown in Fig. 2, the tetradentate
Under the optimized reaction conditions, 3.12 mmol (0.80 g) N,N0-dioxide L-RaMe2Bu and monodentate QM9,10 1a coordinate to
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Notes and references
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Fig. 2 Proposed transition state and the absolute configuration of 3d.
scandium(III) to form a rigid octahedral complex. The group under-
neath the ligand shields the Si face of the QM. Therefore, azlactone
2d attacks predominantly from the Re face to give the product 3d in
an exclusively endo fashion and with a (7R,8R)-configuration.11
In conclusion, we have developed an efficient method for the
asymmetric synthesis of dihydrocoumarins with nitrogen atom
substituents in high yields with excellent enantioselectivities and
diastereoselectivities firstly by using the inverse-electron-demand
hetero-Diels–Alder reaction of QMs and azlactones. Operational
simplicity and mild reaction conditions were attributed to the
efficiency of the chiral N,N0-dioxide–Sc(III) complex. Further appli-
cation of these kinds of catalysts to other reactions is underway.
We appreciate the National Basic Research Program of China
(973 Program: No. 2011CB808600) and the National Natural Science
Foundation of China (No. 21372162, 21290182, and 21172151) for
financial support.
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11 CCDC 1039793 (3d) for more data see ESI†.
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