The asymmetric Cu(ii)-indolinylmethanol complex catalyzed Diels-Alder reaction of 2-vinylindoles with β,γ-unsaturated α-ketoesters: An efficient route to functionalized tetrahydrocarbazoles

Article abstract of DOI:10.1039/c4ob00196f

An efficient asymmetric Diels-Alder reaction of 2-vinylindoles with β,γ-unsaturated α-ketoesters has been developed for the construction of functionalized tetrahydrocarbazoles. The products were obtained in high yields (up to 96%) with good stereoselectiv

Full text of DOI:10.1039/c4ob00196f

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The asymmetric Cu(II)–indolinylmethanol complex
catalyzed Diels–Alder reaction of 2-vinylindoles
with β,γ-unsaturated α-ketoesters: an efficient
route to functionalized tetrahydrocarbazoles†
Cite this: Org. Biomol. Chem., 2014,
12, 4172
Banlai Ouyang,a Tingting Yu,a Renshi Luoa and Gui Lu*a,b
Received 25th January 2014,
Accepted 4th April 2014
An efficient asymmetric Diels–Alder reaction of 2-vinylindoles with β,γ-unsaturated α-ketoesters has been
developed for the construction of functionalized tetrahydrocarbazoles. The products were obtained in
high yields (up to 96%) with good stereoselectivities (ee up to 95%, dr up to >99 : 1).
DOI: 10.1039/c4ob00196f
www.rsc.org/obc
Introduction
The tetrahydrocarbazole scaffold is present in many naturally
occurring and artificial biologically active compounds.1
Although many asymmetric methods have been developed to
access these chiral cyclic architectures,2 the catalytic stereo-
selective Diels–Alder reaction is synthetically more efficient.
When using 2-vinylindoles or 3-vinylindoles as diene counter-
parts, various dienophiles (maleimides, methyleneindol-
inones, nitroolefins or α,β-unsaturated aldehydes etc.) can be
used to construct the tetrahydrocarbazole scaffold, and up to
four stereogenic centers can be established simultaneously
(Scheme 1).3 For example, Ricci et al. developed a catalytic
asymmetric Diels–Alder reaction of 3-vinylindoles with male-
imides and quinones, and achieved high yields and excellent
enantioselectivities in the presence of a bifunctional acid–base
organocatalyst.3b Later Barbas’s group described a highly
efficient organocatalytic Diels–Alder reaction of 3-vinylindoles
with methyleneindolinones for the direct synthesis of carbazo-
lespirooxindole derivatives in almost quantitative yields with
excellent stereoselectivities.3c Zhao et al. have realized enantio-
and diastereoselective Diels–Alder reactions between 2-vinyl-
indoles and α,β-unsaturated aldehydes.3d Xiao and coworkers
provided an efficient access to a variety of multisubstituted
Scheme 1 Diels–Alder reactions of 2 or 3-vinylindoles.
Recently, Melchiorre et al. developed a highly stereo- and
tetrahydrocarbazoles with high stereoselectivities via the regioselective vinylogous Diels–Alder reaction of 2-vinylindoles
reaction of 2-propenylindoles with nitroolefins.3e
with cyclic dienones for the synthesis of structurally diverse
tetrahydrocarbazoles.3f MacMillan’s group described the
tandem Diels–Alder reactions of 2-vinyltryptamines, which
were successfully applied in the total synthesis of some
naturally occurring biologically active compounds such as
(+)-Minfiensine, (−)-Vincorine and (−)-Minovincine, respect-
ively.3g–i Despite these contributions, the development of the
direct Diels–Alder reaction of 2-vinylindoles or 3-vinylindoles
with β,γ-unsaturated α-ketoester dienophiles is still a challen-
ging frontier in the field of asymmetric catalysis.
aInstitute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen
University, Guangzhou 510006, P. R. China
bInstitute of Human Virology, Sun Yat-sen University, Guangzhou 510080,
P. R. China. E-mail: lugui@mail.sysu.edu.cn
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, analytical and spectroscopic data for synthetic compounds, copies of
NMR spectra and HPLC chromatograms. CCDC 978574. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c4ob00196f
4172 | Org. Biomol. Chem., 2014, 12, 4172–4176
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Chiral indole derivatives have recently been successfully uti- provided poor asymmetric inductions (Table 1, entries
lized in a variety of asymmetric reactions, such as nucleophilic 7–9, 11).
addition of diethylzinc to aldehydes, ketone reduction, aldol
Subsequently, various chiral ligands were evaluated. Chiral
reactions and so on.4 Our group has also developed some indolinylmethanol ligands L1–L6 exhibited moderate to good
novel dihydroindole and perhydroindole derivatives for the levels of asymmetric inductions, depending on the steric
asymmetric Michael reaction of aldehydes to nitroalkenes4a nature of substituents on the indolinylmethanols. For
and Reformatsky reactions.4h Compared with their parent pyr- example, ligand L1 with a phenyl substituent furnished the
rolidine analogs, indole derivatives possessing an additional product with good diastereoselectivity but poor enantio-
cyclohexane or phenyl rings in the molecular skeletons, may selectivity (Table 1, entry 12).
exert stronger influences on the orientation of substrates,
hence improving the stereoselectivity for the asymmetric benzylic substituents gave 3a in good yields and high ee values
reaction. (Table 1, entries 5 and 13–14), and L2 was the best ligand.
Indolinylmethanols L2–L4 with benzylic or substituted
We were interested in accessing new structurally diverse Further increasing the length of the carbon chain of the sub-
tetrahydrocarbazole systems as drug candidates. Herein we stituents on the indolinylmethanols led to worse results
have developed a catalytic asymmetric Diels–Alder reaction of (Table 1, entries 15–16). N-protected indolinylmethanol L7,
2-vinylindoles with β,γ-unsaturated α-ketoesters, which has not perhydroindole derivatives L8 and L9, proline-derived amino
been previously reported in the literature (Scheme 1e). Using alcohol L10 proved to be completely unselective (Table 1,
chiral Cu(II)–indolinylmethanol complex as catalyst, the corres- entries 17–20). Although chiral bisoxazoline L11 has been
ponding cycloadducts were obtained in high yields (up to widely used in many catalytic asymmetric reactions,5c,6 it only
96%) with good stereoselectivities (ee up to 95%, dr up to provided poor enantioselectivity in this Diels–Alder reaction
>99 : 1).
(Table 1, entry 21). A survey of reaction media revealed that
CH2Cl2 was the optimal solvent (Table 1, entry 5 vs. entries
22–24). Interestingly, the content of H2O in CH2Cl2 was quite
important for good stereoselectivity, the existence of 0.1 mmol
H2O in the catalytic system led to improved diastereoselectivity
and enantioselectivity (92 : 8 dr and 95% ee), while H2O-satu-
Results and discussion
Chiral copper salts possess proper Lewis acidities and electro- rated CH2Cl2 as solvent furnished the cycloadduct in 76%
philic activities, and have been successfully utilized in many yield with 75% ee (Table 1, entry 5 and entries 25–26). Redu-
enantioselective Diels–Alder reactions.5 So we chose chiral cing the loading of Cu(OTf)2–L2 to 5 mol% caused significant
copper salts as Lewis acids for the cycloaddition reaction. loss in ee and yield (Table 1, entry 27).
β,γ-Unsaturated α-ketoester 1a and 2-vinylindole 2a were used
With the established conditions in hand, we next examined
as dienophile and diene, respectively. The ketoester moiety of the scope and limitations of both β,γ-unsaturated α-ketoester
1a was anticipated to have strong chelation with chiral copper and 2-vinylindole substrates. The results are summarized in
catalyst, hence inducing good stereoselectivities (both ee and Table 2. Changing the ester moiety of β,γ-unsaturated α-keto-
dr) for the model reaction.
esters 1 from COOMe to the more hindered COOEt or COOiPr
In the absence of any copper catalyst, the reaction between did not affect the reactivity and diastereoselectivity, but the ee
1a and 2a at room temperature afforded both [4 + 2] adduct 3a values dramatically decreased to 53% and 34%, respectively
and Friedel–Crafts alkylation product 4a in 76% and 11% (Table 2, entries 1–3). A variety of aromatic β,γ-unsaturated
yield, respectively (Table 1, entry 1). But in the presence of Cu- α-ketoesters could be used in this reaction, giving the corres-
(OTf)2, the Friedel–Crafts alkylation was totally inhibited; only ponding products 3 in good yields with high dr values and
cycloadduct 3a could be isolated in 88% yield and 92 : 8 dr moderate to high ee values (Table 2, entries 4–15). The steric
(Table 1, entry 2). The combination of Cu(OTf)2 and chiral hindrance of R1 substituent on 1 showed significant influences
indolinylmethanol L2 gave the desired cycloadduct in high on the enantioselectivities, when R1 was an ortho-substituted
yield with good enantioselectivity (82% ee, Table 1, entry 4). phenyl group, higher ees were achieved (Table 2, entry 4 vs.
Encouraged by these preliminary results, we further examined entries 5 and 6, entry 12 vs. entries 13 and 14). The smaller
the effects of temperatures, Lewis acids, chiral ligands and sol- 2-fluorophenyl substituted 1 afforded product 3d in 96% yield
vents on both the yields and the stereoselectivities.
with 93% ee (Table 2, entry 4), while the larger 2-bromophenyl
The reaction temperatures showed slight influences on the substituted 1 provided 3i in 80% yield with 71% ee (Table 2,
reaction selectivity, although 30 °C resulted in higher ee entry 9). We attributed this to the smaller steric hindrance of
(Table 1, entry 5). Higher or lower temperatures than 30 °C 2-fluoro substituent. The reaction was also sensitive to the elec-
caused decreases in enantioselectivities (Table 1, entries 3–6). tronic properties of the β,γ-unsaturated α-ketoester. 4-Methoxy-
Various Lewis acids were screened and Cu(OTf)2 was found to phenyl substituted substrate 1 yielded the corresponding product
be the optimal choice for the Diels–Alder reaction. Zn(OTf)2 in good enantioselectivity (Table 2, entry 14), while 4-fluoro-
led to similar yield and diastereoselectivity, but significantly phenyl substituted β,γ-unsaturated α-ketoester gave the cyclo-
lower ee values than Cu(OTf)2 (Table 1, entry 10). Other Lewis adduct with only 52% ee (Table 2, entry 6). Heteroaryl
acids as Sc(OTf)3, Yb(OTf)3, In(OTf)3 and Cu(OAc)2·H2O all substituted 1 was also suitable for this cycloaddition reaction.
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Table 1 Optimization of the reaction conditionsa
Entry
T (°C)
L
Lewis acid
Solvent
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
rt
rt
0
rt
—
—
—
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Toluene
DCE
76
88
84
91
90
82
86
76
53
91
40
71
92
97
87
75
60
50
86
48
69
88
95
95
90
76
77
79 : 21
92 : 8
0
0
74
82
90
86
1
8
6
51
5
48
82
90
70
55
0
1
0
0
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Sc(OTf)3
Yb(OTf)3
In(OTf)3
Zn(OTf)2
Cu(OAc)2·H2O
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L1
L3
L4
L5
L6
L7
L8
L9
L10
L11
L2
L2
L2
L2
L2
L2
79 : 21
87 : 13
86 : 14
84 : 16
69 : 31
73 : 27
81 : 19
82 : 18
73 : 29
93 : 7
86 : 14
85 : 15
86 : 14
88 : 12
85 : 15
90 : 10
87 : 13
89 : 11
79 : 21
79 : 21
85 : 15
80 : 20
92 : 8
30
40
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27g
10
84
77
80
95
75
75
CHCl3
DCMe
DCMf
DCM
85 : 15
84 : 16
a Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), Lewis acid (10 mol%), ligand (10 mol%), 1.5 mL solvent. b Isolated yield of 3a. c Determined
by chiral HPLC analysis and NMR spectroscopic analysis. d Determined by chiral HPLC analysis. e 0.1 mmol H2O was added to 1.5 mL DCM.
f DCM was saturated with H2O. g 5 mol% Cu(OTf)2 and 5 mol% L2 were used.
The desired product 3p can be isolated in good yield and high posed to account for the stereoselectivity of this Diels–Alder
diastereoselectivity, although its enantioselectivity was moder- reaction (Fig. 2). The 2-vinylindole attacked the β,γ-unsaturated
ate (Table 2, entry 16).
α-ketoester preferably from the underside via an endo-
We also expanded our catalytic system to other 2-vinyl- approach, leading to the formation of the predominant
indoles. Preliminary studies showed that good yields, high dr (2R,3R,4R)-product. The benzylic chain of the ligand induced a
values and moderate to high ee values were generally obtained better selectivity for it might cover partial face of the ketoester.
for the desired products 3 (Table 2, entries 17–22). The absol- Water is crucial for high ee, and we attributed this to its
ute configuration of 3a was unambiguously determined to be coordination with copper,7 which might modify the geometry
(2R,3R,4R) by X-ray crystallographic analysis (Fig. 1). The con- of copper centre and enhance the stereofacial selection.
figurations of other products were determined by analogy
to 3a.
Based on previous studies5,7 and the crystal structure of
Conclusions
product 3a, we speculated that a concerted mechanism was
more convincing. A possible transition-state stereomodel with
a distorted octahedral geometry at the copper centre was pro-
In conclusion, we have developed an efficient asymmetric
Diels–Alder reaction of 2-vinylindoles with β,γ-unsaturated
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Table 2 Scope of the reactiona
Entry
R1
R2
R3
3
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Me
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
90
89
95
96
94
86
91
84
80
77
68
80
84
86
84
92 : 8
87 : 13
91 : 9
>99 : 1
84 : 16
94 : 6
89 : 11
99 : 1
93 : 7
94 : 6
95 : 5
94 : 6
88 : 12
90 : 10
93 : 7
95
53
34
93
50
52
67
56
71
59
57
87
58
78
91
i-Pr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
o-F-C6H4
m-F-C6H4
p-F-C6H4
o-Cl-C6H4
p-Cl-C6H4
o-Br-C6H4
p-Me-C6H4
p-Ph-Ph
o-MeO-Ph
m-MeO-Ph
p-MeO-Ph
2,5-(MeO)2-C6H3
9
10
11
12
13
14
15
16
Me
Ph
3p
86
98 : 2
42
17
18
19
20
21
22
Ph
Me
Me
Me
Me
Me
Me
p-Br-C6H4
p-Br-C6H4
p-Br-C6H4
p-Br-C6H4
p-Me-C6H4
p-Me-C6H4
3q
3r
3s
3t
3u
3v
82
79
82
69
73
91
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
96 : 4
59
56
68
90
56
50
o-F-C6H4
2,5-(MeO)2-C6H3
o-MeO-C6H4
Ph
o-MeO-C6H4
a Reaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), Cu(OTf)2 (10 mol%), L2 (10 mol%), DCM (1.5 mL), H2O (0.1 mmol), 30 °C. b Isolated yield.
c Determined by chiral HPLC analysis and NMR spectroscopic analysis. d Determined by chiral HPLC analysis.
α-ketoesters. With chiral Cu(OTf)2–indolinylmethanol complex
as catalyst, highly functionalized tetrahydrocarbazoles can be
achieved in high yields (up to 96%) with moderate to good
stereoselectivities (up to >99 : 1 dr, up to 95% ee). Further
application of this method for the synthesis of structurally
diverse tetrahydrocarbazole system as drug candidates is cur-
rently underway in our laboratory.
Fig. 1 The X-ray crystal structure of enantiomerically pure 3a.
Acknowledgements
This work was financially supported by the National High-tech
R&D Program of China (863 Program, no. 2013AA092903)
and Guangdong Innovative Research Team Program (no.
2009010058).
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