Enantioselective copper-catalyzed construction of aryl pyrroloindolines via an arylation-cyclization cascade

Article abstract of DOI:10.1021/ja305100g

An enantioselective arylation-cyclization cascade has been accomplished using a combination of diaryliodonium salts and asymmetric copper catalysis. These mild catalytic conditions provide a new strategy for the enantioselective construction of pyrroloindolines, an important alkaloid structural motif that is commonly found among biologically active natural products.

Full text of DOI:10.1021/ja305100g

Communication
pubs.acs.org/JACS
Enantioselective Copper-Catalyzed Construction of Aryl
Pyrroloindolines via an Arylation−Cyclization Cascade
Shaolin Zhu and David W. C. MacMillan*
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
S
* Supporting Information
ABSTRACT: An enantioselective arylation−cyclization
cascade has been accomplished using a combination of
diaryliodonium salts and asymmetric copper catalysis.
These mild catalytic conditions provide a new strategy for
the enantioselective construction of pyrroloindolines, an
important alkaloid structural motif that is commonly found
among biologically active natural products.
he pyrroloindolines and polypyrroloindolines represent a
diverse family of structurally complex polyindoline
T
alkaloids that have been isolated from a widespread series of
natural sources, including amphibians, plants, and marine algae.1
An important structural subclass, the C(3)-aryl pyrroloindoline
unit (Figure 1), is incorporated in a range of natural products that
have been shown to be cytotoxic against both lymphocytic
leukemia2a and lymphoblastoma2b cell lines. Moreover, the
structurally related pyrroloindoline−thiodiketopiperazine family
display nematicidal activity against pathogenic fungi such as
Pythium ultimum and Rhizoctonia solani,2c while the C(3)-aryl-
containing hodgkinsine (not shown) has been found to exhibit
antinociceptive properties that are similar to morphine.2d,3 The
structural complexity of the C(3)-aryl pyrroloindolines makes
them a particularly elusive and at the same time appealing target
for total synthetic efforts.4 In this context, both Overman and
Movassaghi have made seminal contributions in the design of
new reaction methods that allow for the rapid construction of
many of these complex alkaloids. The Overman group has
focused on the development of a Heck strategy for the
enantioselective construction of oxindoles that were elegantly
converted into quadrigemine C, psycholeine, asperazine, and
idiospermuline.4d−g In a complementary approach, the Movas-
saghi group has employed Friedel−Crafts additions to
enantiopure tryptophan derivatives in the synthesis of
naseseazines A and B.4a,b,5
Figure 1. Representative pyrroloindolines and arylation strategy.
Our design plan is outlined in Scheme 1. We proposed that
oxidative insertion of a ligand-bound Cu(I) complex into a
suitable diaryliodonium salt7,8 would result in a highly electro-
philic chiral Cu(III) species.9,10 Subsequent addition of the
indole nucleophile followed by reductive elimination and
amine−iminium cyclization would then yield the desired
enantioenriched pyrroloindoline product while reconstituting
the Cu(I) catalyst. As in our previous studies, we recognized that
substrate−catalyst bidentate coordination should be important
and thus sought to incorporate a pendant carbonyl on the
tryptamine nucleophile unit to facilitate the formation of a
square-pyramidal Cu(III) complex.11 Given the architectural
Recently our laboratory reported the enantioselective α-
arylation of carbonyls using copper bisoxazoline catalysis and
iodonium salts.6 As a thematic extension, we postulated that this
Cu(III)−aryl strategy could serve as a platform for pyrroloindo-
line construction via an enantioselective arylation−cyclization
cascade process using indole-based nucleophiles. Herein we
present the successful execution of these ideas and describe an
operationally trivial asymmetric catalytic approach that allows
the formation of a diverse range of C(3)-aryl pyrroloindoline
architectures in only one step. We expect this new
enantioselective catalysis method should be broadly applicable
to natural product and medicinal agent synthesis.
Received: May 25, 2012
Published: June 21, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
a b
,
Scheme 1. Mechanism of Asymmetric Arylation−Cyclization
Table 2. Scope of the Iodonium Aryl Coupling Component
Table 1. Evaluation of Cu−Box Catalysts and Iodonium
Counterions
T
yield
a
ee
a
b
Absolute configurations were assigned by chemical correlation or by
entry
catalyst
none
X
(°C)
A:B
(%)
(%)
b
analogy. Enantiomeric excesses were determined by chiral HPLC
1
2
3
4
5
6
7
8
OTf
OTf
OTf
OTf
OTf
PF6
23
23
−
29:1
0
69
20
71
90
99
99
96
−
−
8
c
analysis of the isolated products. Reaction performed at −15 °C.
(CuOTf)2·PhMe
d
e
Reaction performed at 0 °C. Symmetrical diaryliodonium salt was
1
2
3
3
3
23
4:1
f
g
used. Reaction performed at −5 °C. Using PF6 counterion.
23
3:1
61
h
i
Reaction performed at −10 °C. Reaction performed at room
20
1:10
1:16
1:17
1:40
98
temperature.
23
98
AsF6
AsF6
23
98
complete consumption of the iodonium was observed; however,
only the undesired product of C(2)-indole arylation was
observed (69% yield; entry 2). We next turned our attention
to ligated copper catalysts in the hope that this would allow the
Cu(III)−aryl species to participate more rapidly in the reductive
elimination step, thereby circumventing a deleterious C(3) to
C(2) migration step. Indeed, implementation of both the tert-
butyl- and isopropyl-substituted bisoxazoline (Box)12 ligands
with copper yielded an improved yield of the desired C(3)-aryl
adduct, albeit with modest enantiocontrol (8−61% ee; entries 3
and 4). Fortunately, when the phenyl-substituted bisoxazoline
ligand was employed, a dramatic increase in regio- and
enantioselectivity was observed (90% yield, 98% ee; entry 5).
Moreover, further optimization of temperature and the
3
−20
>99
a
b
Isolated yields. Determined by chiral HPLC analysis; the absolute
configuration was determined by chemical correlation or by analogy.
constraints of the ligand framework, this would impose a
significant bias for enantiofacial coordination at the indole Si face
(as shown), thereby enabling the required enantioselective
addition and cyclization steps.
The feasibility of the proposed arylation−cyclization cascade
was first examined using indole acetamide 4, diphenyliodonium
triflate, and a series of copper catalysts. As shown in Table 1, the
absence of catalyst resulted in no detectable product formation.
In contrast, when 5 mol % (CuOTf)2·PhMe was employed,
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Journal of the American Chemical Society
Communication
a b
,
5, 7, 8, 10, and 11). Notably, halogen-substituted aryl rings are
tolerated in this Cu(I)-catalyzed transformation, a critical
consideration for further elaboration of these pharmacophores
in medicinal chemistry or natural product studies (83% yield,
97% ee; entry 5).
Table 3. Scope of the Indole Acetamide Component
As revealed in Tables 3 and 4, this enantioselective arylation−
cyclization technology tolerates a wide range of substituents on
the indole component. Initial examination of the possible
substitution on the indolic nitrogen13 demonstrated that a range
of alkyl protecting groups are compatible; for example, N-
methyl-, N-benzyl-, and N-allyl-substituted indole acetamides
undergo addition−cyclization in >92% yield with nearly perfect
enantiocontrol (92−96% yield, 97−99% ee; Table 3, entries 1−3
and 8). Moreover, unsubstituted indolic nitrogens were tolerated
with little or no effect (80−98% yield, 90−95% ee; entries 4−6).
Examination of the substituent patterns on the nucleophile
framework revealed that this protocol is amenable to both
electron-rich (91−96% yield, 97−99% ee; Table 4, entries 3 and
5) and electron-poor indoles (80−93% yield, ≥99% ee; Table 4,
entries 1, 2, 4). As was the case for the aryl coupling partner, this
addition−cyclization sequence proceeds with perfect chemo-
selectivity for oxidative addition into the iodonium C−I bond in
the presence of halogens on the nucleophilic substrate (88%
yield, >99% ee; Table 4, entry 1). Finally, we were delighted to
find that this mechanism can be translated to the formation of six-
membered piperidinyl indolines with excellent enantiocontrol
using an indole propionamide substrate (67% yield, 97% ee;
Table 4, entry 6). This result suggests that a variety of alkaloid
pharmacophores might be readily generated using this new
asymmetric arylation strategy.
entry
R
PG
yield (%)
ee (%)
1
2
Me
Bn
allyl
H
Bn
Bn
Bn
Bn
Me
H
96
96
92
80
98
86
92
96
>99
>99
>99
90
c
3
4
5
6
7
8
H
93
H
95
Me
Me
H
>99
97
Me
a
Absolute configurations were assigned by chemical correlation or
analogy. Enantiomeric excesses were determined by chiral HPLC
analysis. Reaction performed at room temperature.
b
c
Table 4. Scope of the Indole Nucleophile Coupling
Component
ab
,
In conclusion, we have developed a new copper-catalyzed
cascade protocol that allows the rapid and enantioselective
construction of C(3)-aryl pyrroloindoline architectures. Further
investigations into the mechanistic details of this transformation,
including models for asymmetric induction, are currently
underway.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
dmacmill@princeton.edu
■
a
Absolute configurations were assigned by chemical correlation or
b
analogy. Enantiomeric excesses were determined by chiral HPLC
analysis. Using 30 mol % catalyst. Using PF6 counterion at 0 °C.
c
d
Notes
The authors declare no competing financial interest.
iodonium counterion afforded the desired C(3)-aryl pyrroloin-
doline in 96% yield and >99% ee as essentially a single
regioisomer (entries 6−8).
ACKNOWLEDGMENTS
■
Financial support was provided by the NIH NIGMS (R01
GM103558-01) and kind gifts from Merck, Amgen, and Abbott.
S.Z. thanks the Shanghai Institute of Organic Chemistry for a
postdoctoral fellowship.
With these optimized conditions in hand, we next turned our
attention to the scope of the aryl or heteroaryl coupling partner
in this new pyrroloindoline-forming reaction (Table 2). While
symmetrical diaryliodonium salts can be successfully employed
in this context, the approach pioneered by Gaunt in which aryl−
mesityl reagents are used to generate Ar−Cu(III) intermediates
is preferred for reasons of practicality.9b Importantly, both
electron-rich (82−92% yield, ≥98% ee; entries 1, 2, and 11) and
electron-deficient arenes (55−89% yield, 91−98% ee; entries 4−
8 and 10) were found to be suitable coupling partners in this new
protocol. Moreover, a broad range of ortho-, meta- and para-
substituted aryl rings with diverse steric and electronic properties
can be readily exploited (55−92% yield, 91−99% ee; entries 2, 4,
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