Copper-catalyzed highly enantioselective cyclopentannulation of indoles with donor-acceptor cyclopropanes

Article abstract of DOI:10.1021/ja4042127

A highly diastereo- and enantioselective BOX/Cu(II)-catalyzed C2,C3-cyclopentannulation of indoles with donor-acceptor cyclopropanes has been developed on the basis of asymmetric formal [3 + 2] cycloaddition of indoles. This reaction provides rapid and facile access to a series of enantioenriched cyclopenta-fused indoline products and can be further extended to the construction of tetracyclic pyrroloindolines. The synthetic potential of the reaction was demonstrated in a four-step synthesis of the core structure of borreverine.

Full text of DOI:10.1021/ja4042127

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Communication
Copper-Catalyzed Highly Enantioselective Cyclopentannulation
of Indoles with Donor-Acceptor Cyclopropanes
Hu Xiong, Hao Xu, Saihu Liao, Zuowei Xie, and Yong Tang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja4042127 • Publication Date (Web): 07 May 2013
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Copper-Catalyzed Highly Enantioselective Cyclopentannulation
of Indoles with Donor-Acceptor Cyclopropanes
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Hu Xiong,†,‡ Hao Xu,†, Saihu Liao, † Zuowei Xie,*,‡, § and Yong Tang*,†
†State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Scienc-
es, 345 Lingling Lu, Shanghai 200032, China
‡Shanghai-Hong Kong Joint Laboratory in Chemcial Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 345 Lingling Lu, Shanghai 200032, China
§Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
Asymmetric catalysis, [3+2] Annulation, Indoles, Cyclopropanes, Indolines
Supporting Information Placeholder
Figure 1. Cyclopenta-Fused Indolines in Natural Products.
ABSTRACT: A highly diastereo- and enantio-selective
BOX/Cu(II)-catalyzed C2,C3-cyclopentannulation of indoles
with donor-acceptor cyclopropanes is developed on the basis
of asymmetric formal [3+2] cycloaddition of indoles. This
reaction provides a rapid and facile access to a series of enan-
tioenriched cyclopenta-fused indoline products, and can be
further extended to the construction of tetracyclic pyrroloin-
dolines. The synthetic potential of the reaction was demon-
strated in a four-step synthesis of the core structure of borre-
verine.
C2,C3-fused indolines are widely present as core structures in
a large number of natural products and biologically active
molecules, and have been the focus of extensive synthetic
efforts for a long time.1 Recently, catalytic asymmetric trans-
We initiated our study with the ligand screening, using in-
dole 1a and cyclopropane 2a as the model substrates and
Cu(OTf)2 as the copper source. Tridentate ligands Ph-DBFOX
and -PyBOX which have shown good selectivity in the cy-
cloadditions of cyclopropanes with nitrones and aldehydes or
imines, 6a,6c,d did not show any activity in the current reaction
(entries 1 and 2). Indane-BOX ligand L4a gave the desired
cyclopenta-nnulation product 3a in 86% yield with a promis-
ing ee (55%, entry 3). To our delight, modification on the
bridging carbon by introducing a benzyl group not only in-
creased the catalytic activity but also significantly improved
the enantioselectivity to 80% ee (L4b, entry 4). However, a
coordinating oxazoline sidearm group8 retarded the reaction
rate and decreased the enantioselectivity by 12%, which may
result from the weakened Lewis acidity by the ligation of the
additional oxazoline to copper (entry 5). Further elaboration of
the ligands was thus focused on the benzyl sidearm group.
Unfortunately, both steric and electronic alternations on the
benzene ring failed to provide an obvious improvement in
enantioselectivity.9 Recently, we found that a type of cage-like
BOX ligands L5a-5b containing two aryl sidearm groups can
significantly improve the enantioselectivity in the cyclopropa-
nation reaction of alkenes, when comparing to the ligands with
only one aryl sidearm group or without this sidearm modifica-
tion.10 Though initial replacement of L4b with ligand L5a led
to a significant drop in selectivity (entry 6), introduction of a
tert-butyl group at the para or the two meta positions of the
formations of indoles has been emerging as a powerful enanti-
oselective strategy to synthesize these products, featuring the
rapid assembly of the multi-cyclic skeletons in a cascade fash-
ion and the readily available indole feedstocks.2-4 The key step
in this transformation is the generation of the chiral electro-
philic indoleniminium intermediate which is susceptible to the
intramolecular attack of a pendant group to close the ring.
Asymmetric organocatalytic Friedel-Crafts reaction is the
most studied approach to generate the chiral incipient indolen-
iminiums,3 while asymmetric metal-catalyzed reactions such
as palladium-catalyzed C3-allylation of indoles,4a copper-
catalyzed arylation,4e and the gold-catalyzed alkenylation4f
also proved to be effective. Recently, Barluenga and co-
workers4b reported the use of tungsten Fischer carbenes in the
asymmetric C2-C3 annulation reaction of indoles and Davies
et al.4c established a rhodium-catalyzed version with vinyldi-
azoacetates. The two works represent the few enantioselective
examples for the synthesis of cyclopenta-fused indoline which
is a common structure in many natural products1,7 such as kop-
sane, vindolinine, and dasyrachine (Figure 1). Within this sce-
nario, we wish to report here a new entry to this arsenal, a
highly diastereo- and enantio-selective Lewis acid-catalyzed
formal [3+2] cycloaddition5-6 of indoles with donor-acceptor
(D-A) cyclopropanes. In particular, pyrroloindoles can also
participate in this annulation reaction, which provides a core
structure in borreverines.7
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pendant phenyl group improved both the diastereo- and enan-
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tio-selectivity (entries 7 & 8), and the new ligand L5c was
identified as the best (the crystal structure of L5c /CuBr2 is
shown in Table 1).9 Varying the substrate ratio and lowering
the temperature to 0 °C further improved the stereoselectivity
to a decent level (20/1 dr and 91% ee, entry 9).
Table 1. Reaction Optimization.a
Entry Product
t
Yield drc
(%)b
ee
(%)d
8
9
10
11
12
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1
2
3
4
5
6
7
8
9
X = H (3aa)
5h
5h
95
95
20/1
19/1
91
90
5-Me (3ba)
5-Br (3ca)
5-Cl (3da)
5-OMe (3ea)
4-Me (3fa)
7-Me (3ga)
7-Br (3ha)
6-Me (3ia)
28h
25h
3h
96 >20/1 90
96 >20/1 91.5
96 >20/1 93
95 >50/1 95
94 >20/1 90
91 >30/1 94
95 >20/1 90
5h
5h
36h
5h
R1
PMP
CO2Me
CO2Me
N
Entry Ligand
t (h) Yield (%)b
drc
-
ee (%)d
-
H
Bn
R1 =
(3ja)
1
2
3
4
5
6
7
8
9e
24
24
24
2
NR
NR
86
93
76
88
94
93
95
Ph-DBFOX
Ph-PyBOX
L4a
10
11
5h
95
19/1
93
-
-
36h
85 >20/1 86
(3ka)
7.5/1
10/1
7/1
7/1
10/1
14/1
20/1
55
80
68
63
86
88
91
L4b
30
2
L4c
L5a
2
L5b
12
13
14
X = H (3la)
5-Me (3ma)
30h
24h
8h
90 >20/1 95
97 >20/1 93
92 >30/1 95
2
L5c
5
L5c
5-OMe (3na)
a 1a/2a = 1.2/1, [2a] = 0.3 mmol in toluene (3 mL), N2. b Isolated
c
1
d
80
yield. Determined by H NMR analysis. Determined by chiral
HPLC. e 1a/2a = 1/1.5, [2a] = 0.3 mmol in toluene (3 mL), at 0℃.
e
15
16
5h
98
3.3/1
/94
Under the optimized conditions, reaction scope was exam-
ined and the results were tabulated in Table 2. The reaction
worked well with a range of indoles. Comparing with 5-
methyl substituted indole 1b, the reactions of 5-Br and 5-Cl
indole (1c and 1d) were slower, but the electronic effect on the
enantioselectivity is negligible (entries 2,5 vs. 3,4). 4-Methyl
substituted indoles were converted with a slightly higher dia-
stereo- and enantio-selectivity (>50/1 dr and 95% ee, entry 6)
than other substitution patterns (5-, 6-, 7-, entries 2, 7 and 9).
It is noteworthy that indole C3-substituents rather than me-
thyl4b,c are also compatible in the current reaction and addi-
tional functionalities like hydroxy, amino, allyl groups can be
introduced into the final products (entries 10-14). In the case
of 1k, the pendant carbamate group may also act as a compet-
ing nucleophile to
(3oa)
PMP
42h
77 >50/1 96f
CO2Me
CO2Me
N
Bn
(3pa)
17
R3
=
4-(TBSO)-C6H4
36h
88 >30/1 94
(3nb)
18
19
20
2-furyl (3nc)
2-thienyl (3nd)
3,4,5-
8h
12h
7d
94
94
12/1
20/1
86
92
Table 2. Reaction Scope.a
83 >20/1 89
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Figure 2. Proposed work model for the stereoselection.
(MeO)3C6H2(3ne)
CH=CHPh (3nf)
1
2
21
12h
72h
83
12/1
90
tBu
tBu
tBu
tBu
3
4
5
O
N
O
-
O
N
H
H
O
O
N
6
7
N
Cu
Cu
H
H
H
O
-
22g
R3 = vinyl (3ag)
Ph (3ah)
45
3.5/1
10/1
9/1
84
89
86
O
O
MeO
MeO
OMe
tBu
tBu
23h,i
24h,j
168h 88
106h 90
OMe
tBu
8
9
tBu
R
H
+
4-I-C6H4 (3ai)
+
S
R
Si
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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R
Re
disfavored
a
MeO
OMe
1 (0.2 mmol), 2 (0.3 mmol), Cu(OTf)2 (0.02 mmol), L5c (0.022
N
b
c
1
N
Bn
mmol) in toluene (3 mL). Isolated yield. Determined by H
favored
Bn
d
NMR analysis. Determined by HPLC using a chiral stationary
phase. e With 2.0 equiv of 2a, at -30 °C. f With 3.5 equiv of 2a, at
-30 °C. g At 40 °C, 3.0 equiv of 2g. h Kinetic resolution, at 40 °C,
with 2.0 equiv of cyclopropane. i 49% conv., recovered (S)-2h: 90%
ee, S = 94. j 51% conv., recovered (S)-2i: 89% ee, S =38.
PMP
PMP
R
R
CO2Me
CO2Me
CO2Me
CO2Me
N
N
H
H
Bn
Bn
give pyrroloindoline as a side product, but it was not observed
by proton NMR analysis of the crude product (entry 11). Re-
markably, the reaction of penta-fused indole 1o also proceeded
smoothly under this condition, delivering the [3,3,3,0]-
tetracyclic indoline 3oa which contains two quaternary bridg-
ing carbons in high yield and good stereoselectivities (entry
15). And the reaction of 2,3-dimethyindole 1p also proceeded
Inspired by the beneficial electronic effect of the electron-
donating groups and good enantioselectivity in the reaction of
penta-fused indole 1o, a synthetic route for the synthesis of the
tricyclic core of borreverine7e was designed based on the cy-
clopentannulation of pyrroloindole 9 (Scheme 1). Gratifyingly,
the [3+2] annulation of 9 with 10 can even be carried out at -
40 ºC, and only a single diastereoisomer was observed with
high enantioselectivity (95% ee). The four-step synthesis start-
ing from tryptamine 6 gave the desired product 11 in 23%
overall yield. The success with the pyrroloindole-type sub-
strates provides a novel and rapid access to the tetracyclic
pyrroloindoline structures.
well at -30 °C (96% ee, entry 16). It is worth mentioning that
indoles without a C3 substituent normally only gave the C3-
Friedel-Crafts alkylation product with high ee rather than the
[3+2] annulation product.11 On the other hand, heteroaryls
such as 2-furyl and 2-thienyl substituted as well as alkenyl
substituted cyclopropanes all participated in the annulation
reaction with high enantioselectivity (entries 18-19 and 21).
To our delight, vinyl cyclopropane 3g also reacted well with a
good enantioselectivity, affording a vinyl group for further
modifications (entry 22), while alkyl cyclopropanes (R3 = H or
Me) are inert under the current reaction conditions and no
product formed even at 50 °C after two days. In general, ex-
cept for 1o and 2g, all reactions proceeded with excellent dia-
stereocontrol (from 12/1 to >50/1 dr). The absolute configura-
tion of 3ha was assigned by X-ray crystallography,12 while the
configurations of other products were assigned by analogy.
For less reactive cyclopropanes, the present reactions could
proceed with a concurrent kinetic resolution of the cyclopro-
panes, though the reactions are normally slower. At ca. 50%
conversion, both the [3+2] annulation products and the recov-
ered (S)-cyclopropanes 2h-i can be obtained in high yields
with high enantioselectivities (entries 23 & 24).
Scheme 1. Synthesis of the Core of Borreverine.
In summary, a highly diastereo- and enantio-selective cy-
clopenta-annulation reaction of indoles with cyclopropanes
has been successfully developed. The reaction performed well
over a series of indoles and D-A cyclopropanes under mild
conditions, giving penta-fused indoline products in excellent
diastereoselectivities (up to >50/1 dr) and enantioselectivities
(up to 95% ee). The application of this reaction to pyrroloin-
doles established an unprecedented approach to tetracyclic
pyrroloindoline compounds. The synthetic potential of the
current reaction was demonstrated in a four-step synthesis of
the core structure of borreverine.
On the basis of crystal structure of L5c/CuBr2 complex, the
square planar geometry of Box/Cu2+/dicarbonyl complexes,13
together with the step-wise annulation mechanism5, a work
model (Figure 2) was tentatively proposed to reason the enan-
tioselection in the present reaction. Considering the steric de-
mand in the nucleophilic attack of C3-substituted indoles to a
sp3 carbon and the donor group stabilization effect, the C2
carbon in cyclopropanes must have a significant carbenium
ion character.6a,14 The approach of the Si face of indole to the
transient (R)-cyclopropane (left) should be more favored,
which experiences less steric interactions with the ligand inda-
nyl substituent. The preference for (R)-cyclopropane is in line
with the kinetic resolution results (entries 23 & 24, Table 2),
in which (S)-configured cyclopropanes were recovered.
ASSOCIATED CONTENT
Supporting Information.
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Page 4 of 6
amples, see: (d) Bajtos, B.; Yu, M.; Zhao, H.; Pagenkopf, B. L.
Experimental procedures, characterizations and analytical data of
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L5c/CuBr2. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
J. Am. Chem. Soc. 2007, 129, 9631-9634. (e) Abd Rabo Mousta-
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AUTHOR INFORMATION
Corresponding Author
zxie@cuhk.edu.hk; tangy@mail.sioc.ac.cn
Note
9
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
We are grateful for the financial support from the National Natu-
ral Sciences Foundation of China (No. 20932008 and 21121062),
the Major State Basic Research Development Program (Grant No.
2009CB825300), NSFC/RGC Joint Research Scheme (Grant No.
21061160493 to TY and N_CUHK470/10 to ZX) and the Chinese
Academy of Sciences. H. Xiong and H. Xu contributed equally to
this work.
(8) For reviews on the sidearm strategy, see: (a) Zhou, J.; Tang, Y.;
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Zhou, Y.-Y.; Wang, L.-J.; Li, J.; Sun, X.-L.; Tang, Y. J. Am.
Chem. Soc. 2012, 134, 9066-9069.
(9) For more details, see the Supporting Information.
(10) Deng, C.; Wang, L.-J.; Zhu, J.; Tang, Y. Angew. Chem., Int. Ed.
2012, 51, 11620-11623.
(11) In the reactions of N-benzyl-2-methylindole, only Friedel-Crafts
alkylation products were isolated, and with 2.0 equiv of cyclo-
propane 2h, a good enantioselectivity (92% ee) can also be
achieved.
(12) For details, please see the surporting information.
(13) Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006, 106,
3561-3651.
(14) (a) Pohlhaus, P. D.; Sanders, S. D.; Parsons, A. T.; Li, W.; John-
son, J. S. J. Am. Chem. Soc.2008, 130, 8642-8650. (b) Campbell,
M. J.; Johnson, J. S.; Parsons, A. T.; Pohlhaus, P. D.; Sanders, S.
D. J. Org. Chem. 2010, 75, 6317-6325.
(5) Selected annulations of indoles with cyclopropanes, see: (a)
Harrington, P.; Kerr, M. A. Tetrahedron Lett. 1997, 38, 5949-
5952. (b) Kerr, M. A.; Keddy, R. G. Tetrahedron Lett. 1999, 40,
5671-5675. (c) England, D. B.; Kuss, T. D. O.; Keddy, R. G.;
Kerr, M. A. J. Org. Chem. 2001, 66, 4704-4709. For recent ex-
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