A Pd(0)-mediated indole (macro)cyclization reaction

Article abstract of DOI:10.1021/ja3121394

Herein we report a systematic study of the Larock indole annulation designed to explore the scope and define the generality of its use in macrocyclization reactions, its use in directly accessing the chloropeptin I versus II DEF ring system as well as key

Full text of DOI:10.1021/ja3121394

Article
pubs.acs.org/JACS
A Pd(0)-Mediated Indole (Macro)cyclization Reaction
Steven P. Breazzano, Yam B. Poudel, and Dale L. Boger*
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: Herein we report a systematic study of the
Larock indole annulation designed to explore the scope and
define the generality of its use in macrocyclization reactions, its
use in directly accessing the chloropeptin I versus II DEF ring
system as well as key unnatural isomers, its utility for both
peptide-derived and more conventional carbon-chain based
macrocycles, and its extension to intramolecular cyclizations
with formation of common ring sizes. The studies define a
powerful method complementary to the Stille or Suzuki cross-coupling reactions for the synthesis of cyclic or macrocyclic ring
systems containing an embedded indole, tolerating numerous functional groups and incorporating various (up to 28-membered)
ring sizes. As a result of the efforts to expand the usefulness and scope of the reaction, we also disclose a catalytic variant of the
reaction, along with a powerful Pd2(dba)3-derived catalyst system, and an examination of the factors impacting reactivity and
catalysis.
INTRODUCTION
■
Embedded macrocyclic indoles and their oxidized variants are a
recurring structural motif present in many natural products.1
To the best of our knowledge, no one had previously reported
the use of a Pd(0)-mediated Larock indole annulation reaction2
to furnish both the macrocycle and the indole in a single
transformation. Confronted with the challenges posed by the
natural products chloropeptin I and II,1b−j structures rivaling
those of the glycopeptide antibiotics3 in complexity, our initial
attempts to achieve cyclization of the macrocycle containing the
tryptophan-derived moiety were unsuccessful using a range of
cyclization strategies including free radical cyclization reactions4
and peptide coupling reactions.5 As a result, we examined
modifications of a Larock annulation protocol permitting the
use of aryl bromides originally developed by Farina and co-
workers6 to achieve the key macrocyclization concurrent with
introduction of the indole en route to a total synthesis of these
natural products.5 This key reaction provided the fully
functionalized DEF ring system of chloropeptin II in superb
conversion (89%) and good atropdiastereoselectivity (4:1 R:S,
R = Ac, Figure 1). Moreover, we found that increasing the size
of the substrate aniline amide improved the modest
atropdiastereoselectivity, providing the macrocycle 2 in good
yield (70%) with complete control of the atropselectivity
Figure 1. First-generation Pd(0)-mediated macrocyclization.
(>20:1 R:S, R = benzoyl, Figure 1). The use of further modified
reaction conditions, enlisting a soluble tertiary amine base (vs
NaHCO3) avoided competitive dechlorination and epimeriza-
tion. The use of nonpolar aprotic solvents increased both the
rate and conversions of the macrocyclization, permitting the use
of lower reaction temperatures (110 °C), and the incorporation
sented the first reported examples of what we believe to be a
powerful macrocyclization strategy rivaling the more conven-
tional Stille8 and Suzuki9 cross-coupling reactions.
In a second-generation approach to the chloropeptins in
which the western macrocycle was already in place, the key
of a large removable terminal alkyne substituent (−SiEt3) as
first disclosed by Larock and co-workers2,7 was used to control
Received: December 12, 2012
Published: January 8, 2013
the indole cyclization regioselectivity. These studies repre-
© 2013 American Chemical Society
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macrocyclization was conducted with substrate 3, containing
four phenols, five secondary amides, a carbamate, and six labile
aryl chlorides, and provided the product 4 (56%) exclusively as
a single atropisomer (>20:1, detection limits) possessing the
natural (R)-configuration (Figure 2).5a In this instance, the
with use of 2-bromo-6-iodoaniline would be expected to furnish
the chloropeptin I ring system directly following macro-
cyclization. Thus, the requisite precursor 6 was prepared,
following the approach developed for the synthesis of 1 with
the exception that 2-bromo-6-iodoaniline versus 2-bromo-5-
iodoaniline was used in the early-stage Suzuki−Miyaura
coupling (Supporting Information). Exposure of the precursor
6 to the reaction conditions used in the first-generation
synthesis of 2 [Pd(OAc)2, DtBPF, Et3N in toluene/acetonitrile,
0.002 M, 110 °C, 1 h] provided the desired macrocycle 7 in
good yield (66%). Much to our satisfaction, only a single
atropisomer corresponding to the natural atropisomer config-
uration was observed (>20:1, detection limits) (Figure 3).
Figure 2. Second-generation macrocyclization.
increased complexity of the substrate and the reverse
macrocyclization order did not diminish the atropdiastereose-
lectivity. Rather, it provided an improvement over the 4:1
selectivity that was observed with the analogous N-acetyl
substrate 2 and the reaction exhibited superb functional-group
tolerance. In a deliberate approach and by virtue of a single-step
acid-catalyzed conversion of chloropeptin II to chloropeptin I,10
only cyclization to provide the more strained and challenging
indole C6 versus C7-linked biaryl DEF ring system found in
chloropeptin II was examined. Herein, we report a systematic
study designed to explore the scope and define the generality of
this new macrocyclization reaction, its use in also directly
accessing the chloropeptin I versus II DEF ring system as well
as key isomers, its utility for both peptide-derived and more
conventional carbon-chain-based macrocycles, its extension to
intramolecular cyclizations with formation of more common
ring sizes, and the factors impacting reactivity and catalysis.
RESULTS AND DISCUSSION
■
Macrocyclic Peptides. Chief among our initial studies was
the extension of the cyclization reaction to the direct
preparation of the indole C7-linked DEF ring system of
chloropeptin I and its possible use in accessing the unnatural
C5-linked isomer. Although previous work demonstrated that
the 16−17-membered macrocycle present in chloropeptin II
(complestatin) rearranges to the less strained DEF ring system
of chloropeptin I upon exposure to acid, providing access to
both natural products by a single route,5 we were especially
interested in establishing whether the macrocyclization method
could be extended to direct construction of the chloropeptin I
DEF ring system. Modification of the aniline component of the
substrate introduced by way of a Suzuki−Miyaura11 coupling
Figure 3. Additional isomeric macrocyclization substrates.
Inspection of the chemical shifts of key 1H NMR signals12,13 of
7 indicate that the indole is in the same spatial orientation as
that found in the natural product. The deshielded chemical
shifts of D6H and EαH and especially the pronounced shielded
chemical shift of FαH are diagnostic of the natural (R)-
atropisomer stereochemistry (Figure 4). Similarly, the distinct
chemical shifts and diagnostic coupling of the two hydrogens of
F
βH of 7 are characteristic of the natural (R)-atropisomer. This
stereochemistry was further established by observation of
diagnostic NOEs between D6H/F5H, D6H/F6H, D6H/EαH, and
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“natural” configuration for this presently unnatural C5-linkage
(Figure 4).
In addition to probing the site of biaryl linkage to the indole,
the examination of a series of systematically altered peptide-
derived substrates further revealed the generality of the
observations, established the scope of ring sizes accessible on
complex substrates, shed further light on the structural features
contributing to the success of the macrocyclization of 2, and
allowed us to probe the impact of ring size on the unique
chemical and conformational properties of the chloropeptin
DEF ring systems. Simplification of the peptide backbone with
incorporation of commercially available, unsubstituted amino
acids for the chlorinated arylglycine E-subunit provided ample
opportunity for this exploration. In particular, and by increasing
the backbone by a single methylene unit at a time, the resulting
modified skeletons allowed us to probe the presence and
interconversion of atropisomers as well as their propensity for
participation in the unusual acid-catalyzed ring expansion
rearrangement responsible for the direct conversion of
chloropeptin II to chloropeptin I. The syntheses of the
cyclization substrates 10−15 are provided in the Supporting
Information, and the results of their examination are
summarized in Figure 5. Most notably, when glycine was
1
Figure 4. Diagnostic H NMR chemical shifts and NOEs for indole
macrocycles (CDCl3).
D6H/DαH. Significantly, the Pd(0)-mediated macrocyclization
reaction was extended to directly provide the chloropeptin I
DEF ring system in good yield (66%) and with complete
atropdiastereoselectivity (>20:1).
The provocative suggestion from modeling studies con-
ducted by others14 had suggested that a C5-linked indole might
well account for the spectroscopic properties attributed to the
natural chloropeptin II DEF ring system bearing a C6-linked
indole. Although synthetic studies have confirmed the structure
(C6-linked indole) and stereochemistry (R-atropisomer) of the
chloropeptin II DEF ring system, the behavior and properties of
this isomeric C5-linked indole macrocyclic ring system
remained of interest to us. The requisite precursor 8 for
macrocyclization was prepared following the approach
developed for 1, enlisting 2-bromo-4-iodoaniline in the early-
stage Suzuki−Miyaura coupling reaction (Supporting Informa-
tion). Exposure of this substrate to the macrocyclization
conditions furnished the new C5-linked macrocycle 9 as a single
atropisomer in excellent yield (71%) without reoptimization of
the reaction parameters (Figure 3). Importantly, the chemical
shifts of the key diagnostic hydrogens of 9 are significantly
different and easily distinguishable from those of either
atropisomer of 2 and 6. Comprehensive NMR studies,
including correlation spectroscopy (COSY) and nuclear
Overhauser enhancement (NOE), confirmed the structural
and atropisomer stereochemical assignment of 9, adopting a
Figure 5. Cyclic peptide macrocyclizations.
incorporated in place of the chlorinated arylglycine E subunit,
the macrocyclization yield providing 16 (n = 1) was
substantially reduced, and the macrocyclic product bears only
the natural (R)-configuration. Since 16 (n = 1) and 2 are
macrocycles of the same ring size and indole linkage site, the
reduced yield for the closure of 10 versus 1 suggests the 3,5-
dichloro-4-hydroxyphenylglycine side chain of 1 may help
preorganize the substrate in a compact conformation favorable
to cyclization to provide 2. When the glycine unit was extended
by one carbon (β-alanine), the macrocyclization yield
substantially improved without additional optimization, and
interestingly, a 1:1 atropisomer ratio was observed. While the
individual atropisomers of 17 (n = 2) were easily separated by
silica gel chromatography, they were found to slowly
interconvert at room temperature, and after 8 h at 50 °C, a
1:1 thermodynamic mixture was reestablished. Given that the
atropisomers of the natural products chloropeptin I and II or
their individual DEF ring systems do not interconvert even at
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temperatures as high as 180 °C,5a,12a it is remarkable that this
insertion of one additional methylene unit (now a 17−18-
membered vs 16−17-membered macrocycle) allows slow
room-temperature atropisomer interconversion. Performing
the annulation on substrates with increasingly longer linker
lengths of n = 3, 4, and 7 provided the macrocyclic indoles in
good yields without further optimization and with no
observance of atropisomers. Increasing the linker length by
an additional four methylene units (n = 11) to form a 28-
membered macrocycle resulted in slightly lower yield; however,
the reaction only needed to be warmed for an additional 3 h,
and no additional dilution was required. Notably, no
intermolecular reaction was detected under any reaction
conditions.
Thus, peptide macrocyclization by a Larock indole
annulation proved general, rivaling the power of the more
conventional Suzuki or Stille cross-coupling protocols. It is of
special note that it surpassed the effectiveness of either the
Suzuki or Stille coupling macrocyclizations enlisted in the
synthesis of chloropeptin II or I DEF ring systems,12,15
providing high yields and complete control of the atropisomer
stereochemistry.5 However, and like the observations made also
with the chloropeptin Stille or Suzuki macrocyclizations,12,15
effective ring closure was observed only with use of
stoichiometric palladium reagent, presumably due to macro-
cycle sequestration of the transition metal. As detailed in the
next section, reactions requiring catalytic palladium reagent
were found to be effective with more conventional macro-
cyclization substrates.
With a variety of new macrocyclic scaffolds assembled
bearing the embedded macrocyclic indole, studies designed to
probe the unusual acid-catalyzed ring rearrangement of
chloropeptin II to chloropeptin I were conducted. Mindful
that strain release in going from the 16−17-membered
macrocycle in chloropeptin II to the macrocycle featured in
chloropeptin I drives the reaction, we conducted systematic
studies with the macrocycles bearing larger ring sizes as well as
the unnatural C5-linked isomer of the chloropeptin DEF ring
system. In previous work, we demonstrated that indole free NH
(vs N-acetyl) is necessary for the reaction and that the N-acetyl
protecting group used during the course of the synthesis of
chloropeptin II tamed the inherent reactivity (Figure 6).5
Further, the rearrangement proceeds smoothly on the isolated
DEF ring system where the substrate contains the indole free
NH and an unprotected D-ring C4 phenol.12a On the DEF
chloropeptin II macrocyclic ring system bearing phenol methyl
ethers, the requisite rearrangement precursors were prepared
from the macrocyclization products by removing the indole N-
acetyl and triethylsilyl groups and by protecting primary amine
as its N-acetyl derivative. Both the natural and unnatural
atropisomers rearrange to the corresponding ring-expanded
macrocycle with retention of stereochemistry, further illustrat-
ing that the D-ring C4 free phenol is not required for
observation of the rearrangement. With the ring-expanded
macrocycles derived from 17 and 19 (n = 2 and n = 4), no
rearranged product was detected upon their exposure to neat
trifluoroacetic acid (TFA) at 50 °C for 15 min or to TFA at
room temperature for 16 h, conditions known to promote the
rearrangement (Figure 6). Rather, only recovered starting
material was observed and eventually complex mixtures of
unidentified compounds were observed upon extended
exposure to the more forceful reaction conditions. These
results suggest that these ring systems do not possess sufficient
Figure 6. Acid-catalyzed rearrangement studies.
or the same inherent strain found in the chloropeptin II system
to drive the rearrangement reaction. In the case of the
unnatural C5-linked isomer, treatment with neat TFA did not
affect a clean rearrangement. Only recovered starting material
was observed at room temperature (16 h), and complex
mixtures devoid of detectable rearranged product were
observed at elevated temperatures (50 °C, 5−20 min).
Carbon-Chain-Based Macrocycles. Extension of the
reaction to the synthesis of macrocycles lacking the repetitive
amide bonds of peptides and the development of a catalytic
variant of the reaction were first explored with substrate 22.
Investigations of the catalytic indole macrocyclization com-
menced with the catalyst system that was employed stoichio-
metrically in our total synthesis of the chloropeptins.5 The
stoichiometric reaction provided an excellent yield (82%) of the
desired macrocycle 23 under these conditions, performing even
better than the peptide-derived substrates (Figure 7, entry 1).
Moreover, the reaction provided good yields of the product
when 10 mol % Pd(OAc)2 was used (Figure 7, entry 2).
Optimization efforts exploring various solvents [N-methyl-2-
pyrrolidone (NMP, 56%), dimethyl sulfoxide (DMSO, 52%),
MeCN (61%), toluene (53%), and N,N-dimethylformamide
(DMF, 67%)], added base (vs Et3N), ligands, or temperatures
further improved the yield of the reaction and indicated that
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Figure 7. Optimization of catalytic Pd(0)-mediated macrocyclization.
macrocyclization of such substrates, even when conducted with
catalytic palladium, is much less sensitive to the reaction
conditions. However, recovery of the starting material without
reduction of the aryl bromide prompted us to examine other
catalyst systems known to facilitate Pd-catalyzed trans-
formations.16 Additives, such as silver nitrate or silver
carbonate, known to enhance the rate and yield of the cross-
coupling of organic halides with some organometallic reagents,
simply led to decomposition of the starting material.17
Although the substrate was inert toward many candidate
palladium catalysts including PdCl2, PdCl2(PhCN)2, and
PdCl2(PPh3)2, other readily accessible catalysts including
PdCl2(PPh3)2, Pd(PPh3)4, and Pd2(dba)3 supported the
macrocyclization reaction effectively (Figure 7). However, we
were most pleased to find improved results using a Pd2(dba)3
catalyst system that was also remarkably successful in a
challenging Suzuki coupling reaction in our vancomycin
synthetic studies (Figure 7, entry 9), arising from its unusually
rapid oxidative addition to a hindered and electron-rich aryl
bromide.3c,d Further optimization of this catalyst system
revealed that 1,1'-bis(di-tert-butylphosphino)ferrocene
(DtBPF) was the best ligand of those examined and that
DMF was the most effective solvent examined, although others
were also effective. Use of K2CO3 often provided the products
in unreliable yields, partially due to hydrolysis of the ester and
indole acetamide. Organic bases such as Et3N that are soluble
under these reaction conditions typically provided the desired
product in improved yields. With the use of 15 mol % catalyst
with the DtBPF ligand in DMF (0.02 M) at 130 °C for 3 h, the
reaction provided the desired indole macrocycle in 72% yield
(Figure 7, entry 10). Notably, and as detailed later, the
improved catalyst system worked effectively with hindered
substrates for which the original Pd(OAc)2 catalyst was
ineffective.
Figure 8. Scope of catalytic macrocyclization and cyclization reaction.
found to be compatible with a variety of ring sizes and with a
range of tethers linked by an ester, ether, or amide. Exemplified
are substrates in which the bromide and the tethering groups
are in the meta positions to provide the 16- and 12-membered
macrocycles in good yield (Figure 8, examples 23−27 and 30).
Even substrates bearing hindered, electron-rich ortho-disub-
stituted aryl bromides were effective participants in the
macrocyclization reaction with the reactive Pd2(dba)3-derived
catalyst, providing the products in good yields (Figure 8,
examples 28 and 29). The use of a substrate bearing a free
aniline or its acetamide derivative did not meaningfully impact
or alter the success of the macrocyclization reaction (Figure 8,
23 vs 24).
In addition to macrocyclization, the catalytic indole
annulation was also extended to an intramolecular cyclization
reaction. Despite the synthetic potential of such reactions, we
were not able to locate an example and found only a single
report of an intramolecular Larock-inspired indole annulation
in which a mechanistically distinct alkyne amidopalladation was
observed with alkynes tethered by N-acylation of a 2-
chloroaniline.18 Thus, a variety of aryl bromide substrates
leading to six- and seven-membered ring fused indole
derivatives were also examined and provided the cyclized
products in excellent yields (Figure 8, examples 31−34). The
substrates chosen represent significant challenges for imple-
Without individual optimization, the scope of catalytic
macrocyclization reaction was examined with the preparation
of a variety of macrocyclic indoles from their corresponding 2-
bromoanilines or acetamides (Figure 8). The reaction was
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mentation because of the hindered, electron-rich character of
the starting aryl bromide. Despite the potential of slow
oxidative addition to the electron-rich ortho-disubstituted aryl
bromides and like the macrocyclization observations, no
detrimental effect was observed during the cyclization of
these compounds. Presumably, this may be attributed to a
combination of the unique Pd2(dba)3-derived catalyst reac-
tivity3d and its coordination to the proximal polar amine or
amide of the substrates. In this respect, it is noteworthy that the
use of even stoichiometric Pd(OAc)2 instead of the more
reactive and catalytic Pd2(dba)3 for preparation of the ether-
linked tricycles 31 and 32 did not provide the desired
cyclization products.
peptide-derived substrates, its superb functional-group toler-
ance, it use in directly accessing the chloropeptin I as well as
chloropeptin II DEF ring system and key isomers, its utility for
macrocyclization of more conventional carbon-chain-based
macrocycles, its extension to the intramolecular cyclization of
more common ring sizes, and factors impacting reactivity and
catalysis. Combined, the studies define a powerful method
complementary to the Stille or Suzuki cross-coupling reaction
for cyclization or macrocyclization reactions.23
ASSOCIATED CONTENT
* Supporting Information
■
S
Additional text and two schemes with full experimental details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Fused indoles substituted at the 3- and 4-positions comprise
a large family of biologically active natural and unnatural
products and can potentially be accessed via the current
strategy (Figure 9).19 For example, tricyclic indole 34 serves as
AUTHOR INFORMATION
Corresponding Author
boger@scripps.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support of the National
Institutes of Health (CA041101), the Skaggs Institute for
Chemical Biology, and fellowship support from the National
Science Foundation (S.P.B., 2008−2011).
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CONCLUSIONS
■
Recently, we reported the total synthesis of the chloropeptin
family of natural products, including chloropeptin II (comple-
statin),5 chloropeptin I,5 amd complestatin A and complestatin
B (neuroprotectin A and B),13b bicyclic peptides bearing a
tryptophan-derived indole embedded in the macrocycle.
Central to the design of the approach, a Pd(0)-mediated
intramolecular Larock indole annulation reaction was devel-
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system in both first- and second-generation total syntheses. The
key macrocyclization reactions proceeded in superb yields with
excellent atropselectivity, demonstrating exceptional functional-
group tolerance. Herein, we disclose a systematic study of this
Pd(0)-mediated Larock indole annulation for macrocyclization
that defines the scope and generality of the reaction for
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