Dearomatization of Indoles via a Phenol-Directed Vanadium- Catalyzed Asymmetric Epoxidation and Ring-Opening Cascade

Article abstract of DOI:10.1002/adsc.201500557

An enantioselective dearomatization of indole derivatives was realized by the complexes derived from the vanadium complex VO(acac)₂ and C₂-symmetric bis-hydroxamic acid (BHA) ligands. The reaction proceeded via asymmetric epoxidation

Full text of DOI:10.1002/adsc.201500557

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DOI: 10.1002/adsc.201500557
Dearomatization of Indoles via a Phenol-Directed Vanadium-
Catalyzed Asymmetric Epoxidation and Ring-Opening Cascade
Long Han,a,b Wei Zhang,a Xiao-Xin Shi,b and Shu-Li Youa,b,*
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, Peopleꢀs Republic of China
Fax: (+86)-21-5492-5087; e-mail: slyou@sioc.ac.cn
School of Pharmacy, East China University of Science and Technology, 130 Mei-Long Road, Shanghai 200237, Peopleꢀs
b
Republic of China
Received: June 9, 2015; Revised: August 1, 2015; Published online: October 13, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500557.
Abstract: An enantioselective dearomatization of
indole derivatives was realized by the complexes
derived from the vanadium complex VO(acac)2 and
C2-symmetric bis-hydroxamic acid (BHA) ligands.
The reaction proceeded via asymmetric epoxidation
and ring-opening by the linked phenol cascade,
Epoxides exist as key moieties in numerous natural
products and biologically active molecules, and also
serve as important synthetic intermediates associated
with versatile sequential ring opening processes.[1]
Since more than one stereogenic center could be
launched in a single step, asymmetric epoxidation re-
actions have received broad research interest and wit-
nessed dramatic growth during the past decades.[2]
Enantiomerically enriched epoxides derived from un-
functionalized olefins,[3] electron-deficient olefins[4]
and (homo)allylic alcohols[5] have been achieved by
well-developed chiral catalytic systems including
either transition metal catalysts or organocatalysts.
Meanwhile, catalytic asymmetric dearomatization
affording
5a,6,10b,11-tetrahydrochromeno[2,3-b]-
indol-10b-ol derivatives in up to 83% yield and
98% ee under mild reaction conditions.
Keywords: asymmetric catalysis; dearomatization;
epoxidation; indoles; vanadium
Scheme 1. Enantioselective epoxidative dearomatization reaction.
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Dearomatization of Indoles
(CADA) reactions have recently witnessed rapid de- duced by Yamamoto and co-workers.[5,10,11] Interest-
velopment due to their advantage in constructing ingly, our recent studies led to successful asymmetric
complex molecules from relatively simple starting ma- epoxidation of alkenylphenol substrates, which has
terials.[6] Particularly, oxidative dearomatization reac- not been documented before.[12] Herein, we report the
tions of various electron-rich aromatic rings have CADA reaction of indole derivatives via vanadium-
a great potential in the total synthesis of natural prod- catalyzed asymmetric epoxidation and subsequent
ucts.[7,8] However, the enantioselective oxidative dear- phenol ring-opening reaction sequence (Scheme 1).
omatization reactions are far from being fully ex-
Firstly, variation of the BHA ligand structure was
plored, and the dearomatization reactions via asym- performed on model substrate 1a. Ligand 3a with bi-
metric epoxidation approaches are rare. In 2000, phenyl moieties was utilized in the asymmetric epoxi-
¯
Omura, Smith and their co-workers reported the dative dearomatization reaction, and the desired
enantioselective synthesis of 3a-hydroxyfuroindolines product 2a was afforded in 33% yield and 49% ee
from tryptophols using Sharpless asymmetric epoxida- (entry 1, Table 1). Slight elevation of the enantioselec-
tion conditions.[9] Recently, we realized the catalytic tivity was achieved with ligands 3b and 3c embedded
asymmetric epoxidation of tryptophol derivatives with with relatively more flexible moieties than biphenyl
the chiral vanadium complexes derived from the C2 groups (60% ee and 66% ee, respectively; entries 2
symmetric bis-hydroxamic acid (BHA) ligands intro- and 3). To our great delight, excellent enantioselective
control was realized when ligand 3d was utilized
(91% ee, entry 4). However, ligands 3e and 3f, de-
signed based on 3d with modified trityl groups, could
not provide 2a with better results (81% ee and 78%
ee, respectively; entries 5 and 6).
Table 1. Vanadium-catalyzed asymmetric epoxidation and
ring-opening – ligand screening.[a]
With the optimal ligand in hand, the reaction pa-
rameters were then further optimized. As shown in
Table 2, several oxidants were tested with toluene as
the solvent, and t-BuOOH was chosen as the best one
(entries 1–4, Table 2). Cumene hydroperoxide (CHP),
slightly bulkier than t-BuOOH, provided similar re-
sults (entries 1 and 2). Further examination of the sol-
Table 2. Vanadium-catalyzed asymmetric epoxidation and
ring-opening – reaction parameters.[a]
Entry Oxidant
Solvent
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
t-BuOOH
CHP[d]
m-CPBA
toluene
toluene
toluene
46
49
91
89
–
–
95
–
low conversion
low conversion
58
low conversion
low conversion
30% H2O2 toluene
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
CH2Cl2
THF
MeOH
o-xylene 46
CHCl3
Entry
Ligand
Time [h]
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
72
72
72
72
72
72
33
34
34
46
40
53
49
60
66
91
81
78
–
92
91
94
9
42
46
10[e]
CH2Cl2
[a]
Reaction conditions: 0.25 mmol 1a, 4.0 mol% VO(acac)2,
4.8 mol% ligand 3 and 0.375 mmol oxidant in solvent
(1.0 mL) at 08C.
[a]
Reaction conditions: 0.25 mmol 1a, 4.0 mol% VO(acac)2,
4.8 mol% ligand 3 and 0.375 mmol t-BuOOH (70% wt
aqueous solution) in toluene (1.0 mL) at 08C.
Isolated yield.
[b]
[c]
[d]
[e]
Isolated yield.
Determined by HPLC analysis.
CHP=cumene hydroperoxide.
Room temperature, 4 h.
[b]
[c]
Determined by HPLC analysis.
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Long Han et al.
vent disclosed that reaction in CH2Cl2 delivered the
best results (58% yield, 95% ee, entries 5–9). Further
increasing the catalyst loading to 10 mol% led to
slightly higher yield (62%) without affecting the ee.
Finally, the reaction temperature was increased to fa-
cilitate the reaction rate. Unfortunately, a lower yield
resulted due to the decomposition of the product at
room temperature (46% yield, 94% ee, entry 10).
Prolonged reaction time (120 h) led to a slightly
lower yield (50%) due to the decomposition of 2a
(entry 1, Table 3). Therefore, several N-protecting
groups were investigated to offset the instability of
À
the products caused by the free N H of indoles. With
a methyl group installed, the reaction occurred in
a higher yield albeit with lower enantiomeric excess
(62% yield, 86% ee, entry 2). When a Bn group was
introduced, a significant improvement of yield was
observed although the enantioselective control de-
clined slightly (89% yield, 90% ee, entry 3). Other
electron-donating groups such as p-MeO-C6H4 and 1-
naphthyl led to similar results with higher yields but
lower ee values (entries 4 and 5, Table 3). Finally, no
desired product was detected when the Boc group
was tested indicating that an electron-rich indole is
needed for the current reaction (entry 6, Table 3).
À
À
Various N H and N Bn indole derivatives were
then examined under the optimized reaction condi-
tions (entry 5, Table 2). The results are depicted in
Scheme 2. Excellent enantioselectivities and moderate
À
yields were obtained for most N H substrates with
varied substituents (5-Cl, 6-Cl, 6-F, 6-Br, 5-Br, 4-Br,
7-Br and 7-CH3) on the phenyl moiety of indoles (2g–
À
2n, Scheme 2). Two N Bn indole substrates were also
investigated. As shown in Scheme 2, the dearomatized
Table 3. Vanadium-catalyzed asymmetric epoxidation and
ring-opening – N-protecting groups.[a]
Scheme 2. Vanadium-catalyzed asymmetric epoxidation and
ring-opening – substrate scope.
Entry 1, R
Time [h] 2, Yield[b] [%] ee[c] [%]
1
2
3
4
5
6
1a, H
1b, Me
1c, Bn
1d, p-MeOC6H4 48
1e, 1-naphthyl
1f, Boc
72/120
72
48
2a, 58/50
2b, 62
2c, 89
2d, 64
2e, 71
95/95
86
90
88
92
products 2o and 2p were obtained in 83% and 77%
yields, respectively, and the enantioselective control
for these products was also satisfactory (2o and 2p,
Scheme 2).[13] Finally, a gram-scale reaction of 1l was
performed to evaluate the practicality of this asym-
metric dearomatization reaction, and the correspond-
ing product 2l was obtained in 63% yield and 98% ee
(Scheme 3). The absolute configuration was assigned
as (5aS,10bR) by a single crystal X-ray analysis of
enantiopure 2m.[14]
48
24
2f, N.R.
–
[a]
Reaction conditions: 0.25 mmol 1, 4.0 mol% VO(acac)2,
4.8 mol% ligand 3d and 0.375 mmol t-BuOOH (70% wt
aqueous solution) in CH2Cl2 (1.0 mL) at 08C.
Isolated yield.
[b]
[c]
The ee of 2 was determined by HPLC analysis.
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Dearomatization of Indoles
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dearomatization of indole derivatives via a vanadium-
catalyzed asymmetric epoxidation followed with an
intramolecular phenol-directed epoxide opening reac-
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Experimental Section
General Procedure for the Asymmetric
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To a solution of VO(acac)2 (0.02 mmol, 5.2 mg) in DCM
(2 mL) was added ligand 3 (0.024 mmol, 17.2 mg), and the
mixture was stirred for 1 h at room temperature. The above
mixture was stirred at 08C for 10 min, tert-butyl hydroperox-
ide (0.75 mmol, 104 mL, 70% aqueous solution) and sub-
strate 1 (0.5 mmol) were then added. After the reaction was
complete as monitored by TLC, aqueous saturated Na2SO3
(2 mL) was added. The organic layer was separated and the
aqueous layer was extracted with DCM (3”2 mL). The
combined organic layers were washed with brine (4 mL),
separated, dried over Na2SO4, filtered and concentrated
under reduced pressure. The crude product was purified by
column chromatography on silica gel (DCM/EtOAc=40/1,
v/v) to afford the desired product 2.
Acknowledgements
We thank the National Basic Research Program of China
(973 Program 2015CB856600) and National Natural Science
Foundation of China (21272252, 21332009, 21421091) for
generous financial support.
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