Magnesium(ii)-catalyzed asymmetric hetero-Diels-Alder reaction of Brassard's dienes with isatins

Article abstract of DOI:10.1039/c3cc47800a

The first catalytic asymmetric hetero-Diels-Alder reaction of Brassard's dienes with isatins was realized using Mg(ii)/N,N′-dioxide complexes as catalysts, affording the corresponding chiral spirolactones bearing tetrasubstituted centers in up to 99% yield with up to 99% ee and >99:1 dr within 3 hours. In the mechanism, based on the operando IR experiments, a predominant Diels-Alder pathway was found in the reaction. A possible transition state model was also proposed. This journal is

Full text of DOI:10.1039/c3cc47800a

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Magnesium(II)-catalyzed asymmetric hetero-Diels–
Alder reaction of Brassard’s dienes with isatins†
Cite this: Chem. Commun., 2014,
50, 994
Jianfeng Zheng, Lili Lin, Yulong Kuang, Jiannan Zhao, Xiaohua Liu and
Xiaoming Feng*
Received 10th October 2013,
Accepted 16th November 2013
DOI: 10.1039/c3cc47800a
www.rsc.org/chemcomm
The first catalytic asymmetric hetero-Diels–Alder reaction of Brassard’s
The HDA reaction of Brassard type diene 1 with isatin 3e was
dienes with isatins was realized using Mg(II)/N,N0-dioxide complexes as selected as the model reaction because of the easy separation of
catalysts, affording the corresponding chiral spirolactones bearing four isomers of the corresponding spirolactone 4e in chiral
tetrasubstituted centers in up to 99% yield with up to 99% ee and HPLC. Firstly, various metal salts coordinated in situ with
>99 : 1 dr within 3 hours. In the mechanism, based on the operando N,N0-dioxide L1 derived from L-pipecolic acid were examined
IR experiments, a predominant Diels–Alder pathway was found in the in CH2Cl2 at 35 1C. As shown in Table 1, Sc(OTf)3, In(OTf)3, and
reaction. A possible transition state model was also proposed.
Cu(OTf)2, that once showed good efficiency in HDA reaction,
gave very poor results (Table 1 entries 1–3). To our delight, the
The enantioselective hetero-Diels–Alder (HDA) reaction1 of Brassard’s L1–Mg(OTf)2 complex promoted the reaction much better,
dienes2 with carbonyl compounds is a classic approach to access giving the desired spirolactone 4e in 50% yield, 95% ee and
optically active six-membered d-lactones,3 which are widely found 93 : 7 dr (Table 1, entry 4). The yield could be slightly improved
in bioactive natural products and have been frequently used as to 56% by using Mg(ClO4)2 instead of Mg(OTf)2 as the metal salt
versatile intermediates for further manipulations.4 Compared (Table 1, entry 5). The abundance and low toxicity of magnesium
with Danishefsky’s dienes, the terminal twofold substitutions of make the chiral magnesium(II) complexes more attractive.11
Brassard’s dienes enhanced the difficulty of controlling the Encouraged by these results, various chiral N,N0-dioxide ligands
enantioselectivity of the HDA reaction.5 Still, several catalytic
systems, including chiral TADDOL,6a Ti or Cu/Schiff base,6b,c
Table 1 Optimization of the reaction conditions
Ti/BINOL6d and In/N,N0-dioxide,6e have been developed for highly
enantioselective HDA reaction of Brassard’s dienes with aldehydes.
Meanwhile, chiral phosphoric acid7a and Yb/N,N0-dioxide7b have
also been applied to catalyze the asymmetric HDA reaction of
Brassard’s dienes with imines. However, there is still no report on
catalytic asymmetric HDA reaction between Brassard’s dienes and
any kind of ketones up to now. Recently, isatins have emerged as
one of the most promising new classes of carbonyl compounds.8,9
The HDA reaction of Brassard’s dienes with isatins can construct
bio-potential chiral spirolactone frameworks straightforwardly.
As part of our efforts in developing highly enantioselective HDA
reaction with ketones, we herein report our achievements in the
catalytic asymmetric HDA reaction of Brassard’s dienes with
isatins under mild reaction conditions using metal/N,N0-dioxide
complexes as catalysts developed by our group.10
Entrya
Ligand
Metal
Yieldb (%)
drc
eec (%)
1
2
3
4
5
6
7
8
9d
L1
L1
L1
L1
L1
L2
L3
L4
L4
Sc(OTf)3
In(OTf)3
0
26
23
50
56
53
68
70
93
—
—
7
36 : 64
55 : 45
93 : 7
95 : 5
76 : 24
96 : 4
95 : 5
95 : 5
Cu(OTf)2
Mg(OTf)2
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
11
95
96
50
95
96
96
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
† Electronic supplementary information (ESI) available: Additional experimental
and spectroscopic data. CCDC 959984. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c3cc47800a
a
Unless specified, all reactions were performed using L–metal (10 mol%,
b
1 : 1), 1 (0.15 mmol), 3e (0.10 mmol) at 35 1C for 1 hour. Isolated yield.
c
d
Determined by HPLC analysis (Chiralcel IB). TFA (30 mL) was added
after the reaction. TFA = Trifluoro acetic acid.
994 | Chem. Commun., 2014, 50, 994--996
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were synthesized and coordinated with Mg(ClO4)2 to promote
the reaction. The results showed that the steric hindrance of
ortho-substituents on the aniline ring of the N,N0-dioxide played
a crucial role in the selectivity of the reaction (Table 1, entries 6
and 7). When L2 with a small methyl group was used, the ee
and dr values were decreased dramatically to 50% and 76 : 24,
respectively. Meanwhile, upon changing the steric isopropyl to
the ethyl substituent (L3), no obvious effect was found. When
ligand L4 containing the 2,6-diethyl-4-methylaniline moiety was
used, 4e was obtained in 70% yield with 96% ee and 95 : 5 dr
(Table 1, entry 8). In the above cases, besides the cycloaddition
adduct, a small amount of Mukaiyama aldol product with the
same ee value as 4e can also be isolated. But not all of the aldol
product could be transformed to the cycloadduct 4e in the
optimized L4–Mg(ClO4)2 catalytic system. The yield of the
desired spirolactone 4e could be improved to 93% by treatment
of the reaction mixture with TFA, which could accelerate the
transformation of the aldol product to 4e (Table 1, entry 9).
With the optimized reaction conditions in hand, the scope of the
HDA reaction of 1 with various isatins 3 was explored. As summari-
zed in Table 2, neither electron-donating nor electron-withdrawing
substituted groups on the aromatic ring of isatins had obvious
impact on the outcomes of the reaction. The desired chiral spiro-
lactones were isolated in excellent yields (90–99%) with excellent
diastereo- and enantioselectivities (92 : 8–99 : 1 dr) (Table 2,
entries 1–11). In addition, isatin 3n containing a fused saturated
ring was also tolerated in the reaction, giving the corresponding
spirolactone 4n in 99% yield with 96% ee and 96 : 4 dr (Table 2,
entry 12). The absolute configuration of 4e was determined by
X-ray crystallography to be (20R,30R), while the absolute configu-
ration of 4b–4d and 4f–4m was also determined to be (20R,30R) by
comparing their circular-dichroism spectra with that of 4e.
Scheme 1 Substrate scope of the HDA reaction of Brassard’s diene 2 with
isatins 3.
We also examined the HDA reaction of Brassard’s diene 2
with isatins in the presence of Mg(II)/N,N0-dioxide complexes
(Scheme 1). After surveying the effect of the magnesium counter-
anion using the reaction of Brassard’s diene 2 with isatin 3a as
model reaction, the desired chiral spirolactone 5a was isolated in
82% yield and 93% ee in the presence of a 1 : 1.1 molar ratio of
L4 to Mg(OTf)2. Under the optimized reaction conditions, various
isatins 3 were tested. As shown in Scheme 1, for both electron-
donating and electron-withdrawing substituted isatins, the
desired spirolactones were obtained in moderate to good yields
(73–92%) and excellent enantioselectivites (90–99% ee). N-Methyl
protected isatin 3o also gave the corresponding d-lactone 5o in
60% yield and 91% ee.
To show the prospect of the methodology in synthesis, a gram-
scale synthesis of 4e was carried out. By treatment of 2 mmol of
3e in the L4–Mg(ClO4)2 catalytic system, 4e was obtained in 89%
yield (0.76 g) with 89 : 11 dr and 95% ee (Scheme 2).
When Lewis acid catalyzed HDA reactions are considered, two
pathways known as the Mukaiyama Aldol pathway12 and the Diels–
Alder pathway13 have generally been taken into account. In order
to probe the pathway proceeding in the Mg(II)/N,N0-dioxide-
catalyzed HDA reaction, operando IR experiments of 1 with
isatin 3e were carried out. It can be seen from Scheme 3 that
both a great amount of cycloaddition product 4e and a small
amount of Mukaiyama aldol product 6 are formed at the
beginning of the reaction. And, the amount of 4e increased
sharply while that of 6 decreased slightly with the reaction
proceeding. These were matched with the reaction phenomena
that cycloaddition product 4e and the Mukaiyama aldol product 6
can both be isolated before treatment with TFA; and the isolated
6 can be partly cyclized to the corresponding cycloadduct 4e
under the optimized catalytic conditions. These observations
indicate that Diels–Alder and stepwise Mukaiyama aldol path-
ways both existed in the magnesium(II)-catalyzed HDA reaction of
Brassard type diene 1 with isatins but the Diels–Alder pathway is
found to be the predominant one.
Table 2 Substrate scope of the HDA reaction of Brassard type diene
1 with isatins 3
Entrya
R1
Yieldb (%)
drc
eec (%)
1
2
3
4
5
6
7
8
5-F
5-Cl
4-Br
5-Br
6-Br
5-I
5-Me
7-Me
5,7-Me2
5-MeO
7-CF3
99 (4b)
96 (4c)
98 (4d)
93 (4e)
90 (4f)
90 (4h)
99 (4i)
99 (4j)
90 (4k)
99 (4l)
99 (4m)
95 : 5
96 : 4
99 : 1
95 : 5
94 : 6
92 : 8
96 : 4
98 : 2
98 : 2
97 : 3
92 : 8
96 (R,R)
98 (R,R)
99 (R,R)
96 (R,R)
98 (R,R)
96 (R,R)
98 (R,R)
99 (R,R)
98 (R,R)
99 (R,R)
98 (R,R)
On the basis of the absolute configuration of product 4e and
our previous reports,10 a possible transition state was proposed
9
10
11
12
99 (4n)
96 : 4
96
a
All reactions were carried out using 10 mol% L4–Mg(ClO4)2 (1 : 1) as
catalyst at 35 1C for 1 h. After reaction, TFA was added and the mixture
b
c
was continuously stirred at rt for 2 h. Isolated yield. Determined by
HPLC analysis.
Scheme 2 Gram-scaled version of the reaction.
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We appreciate the National Basic Research Program of China
(973 Program: No. 2011CB808600), the National Natural Science
Foundation of China (No. 21321061, 21290182, and 21172151)
and the Ministry of Education (No. 20110181130014) for financial
support.
Notes and references
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Scheme 3 The 3D ATR-FTIR profile and the reaction pathway of the HDA
reaction of Brassard type diene 1 with isatin 3e.
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Fig. 1 Proposed transition state model and the absolute configuration of 4e.
to illustrate the origin of the asymmetric induction. Both
oxygen atoms of the amide and N-oxide were coordinated with
the central metal in the complex. The isatin coordinates to the
Mg(II) in a bidentate fashion with its dicarbonyl groups. The
Re face of the isatin is shielded by the neighboring 2,6-diethyl-
4-methylphenyl group of the ligand, therefore, the diene 1 attacks
from the Si face to afford (20R,30R)-4e (Fig. 1).
In summary, we have developed a highly enantioselective
HDA reaction of Brassard’s dienes 1 and 2 with isatins catalyzed
by chiral Mg(II)/N,N0-dioxide complexes. The reaction could pro-
ceed smoothly in less than 3 hours, affording the corresponding
chiral spirolactones in up to 99% yield, 99% ee and >99 : 1 dr.
In terms of the mechanism of the reaction, both the Diels–Alder
pathway and the stepwise Mukaiyama aldol pathway were
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And a possible transition state model was also proposed. Further
investigation of the HDA reaction of Brassard’s dienes with
simple ketones is underway in our group.
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996 | Chem. Commun., 2014, 50, 994--996
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