Oxidative Fragmentations and Skeletal Rearrangements of Oxindole Derivatives

Article abstract of DOI:10.1021/acs.orglett.6b03789

An oxidative sequence for the conversion of oxindoles to structurally distinct heterocyclic scaffolds and aniline derivatives is disclosed by the combination of a copper-catalyzed C-H peroxidation and subsequent base-mediated fragmentation reaction. In contrast to classic enzymatic (i.e., kynurenine pathway) and biomimetic methods (i.e., Witkop-Winterfeldt oxidation) for oxidative indole cleavage, this protocol allows for the incorporation of external nucleophiles. The new transformation displays broad functional group tolerance and is applicable to tryptophan derivatives, opening potential new avenues for postsynthetic modification of polypeptides, bioconjugation, and unnatural amino acid synthesis.

Full text of DOI:10.1021/acs.orglett.6b03789

Letter
pubs.acs.org/OrgLett
Oxidative Fragmentations and Skeletal Rearrangements of Oxindole
Derivatives
Hendrik F. T. Klare, Alexander F. G. Goldberg, Douglas C. Duquette, and Brian M. Stoltz*
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
ABSTRACT: An oxidative sequence for the conversion of oxindoles to
structurally distinct heterocyclic scaffolds and aniline derivatives is
disclosed by the combination of a copper-catalyzed C−H peroxidation
and subsequent base-mediated fragmentation reaction. In contrast to
classic enzymatic (i.e., kynurenine pathway) and biomimetic methods
(i.e., Witkop−Winterfeldt oxidation) for oxidative indole cleavage, this
protocol allows for the incorporation of external nucleophiles. The new transformation displays broad functional group tolerance
and is applicable to tryptophan derivatives, opening potential new avenues for postsynthetic modification of polypeptides,
bioconjugation, and unnatural amino acid synthesis.
and is one of the few methods available for the conversion of
indoles to structurally distinct scaffolds (Scheme 1B).6
he chemistry of indoles and their derivatives is diverse and
Twell-studied owing to their ubiquity in natural products,
pharmaceuticals, agrochemicals, fragrances, and organic dyes and
pigments.1 Importantly, indole serves as part of the side-chain of
tryptophan, an essential amino acid and a precursor to an array of
bioactive small molecules and complex natural products. For
instance, dietary tryptophan that is not incorporated into
proteins is predominately metabolized along the kynurenine
pathway to several nonindole, bioactive metabolites (Scheme
1A).2 Similarly, complex indole-containing natural products are
often observed alongside oxidized derivatives.3 The biomimetic
variant of this transformation, known as the Witkop−Winterfeldt
oxidation,4 has been accomplished under a variety of conditions5
The discovery of new indole fragmentation and ring-expansion
methods is particularly appealing given the numerous methods
for the preparation7 and functionalization8 of indoles. The utility
of methods for indole synthesis could be broadened by
considering them not only as synthetic targets, but as
intermediates toward other heterocycles as well. Furthermore,
mild and selective transformations of indoles may be applied to
tryptophan fragments in applications such as bioconjugation.9,10
As part of our research on new indole-related methodologies11
and on indole-containing natural products,12 we have discovered
a mechanistically different sequence for oxidative fragmentation
of indole and oxindole derivatives that is complementary to the
prevailing synthetic and enzymatic pathways (Scheme 1C). This
method facilitates C2−C3 bond cleavage of the oxindole ring
with concomitant reaction with a nucleophile, thereby offering
access to diverse heterocycles and aniline derivatives, which are
unattainable by conventional biomimetic oxidations.
a
Scheme 1. Oxidative Fragmentations of the Indole Core
In the course of our studies on oxidative transformations of
oxindoles, we observed that 3-methyloxindole (1a) undergoes a
Kharasch−Sosnovsky-type C−H peroxidation13 by tert-butyl
hydroperoxide (t-BuOOH) in the presence of numerous metal
salts (Scheme 2).14 Notably, Cheng, Liu, and co-workers
independently reported that the same reaction is also catalyzed
by cobalt(II) salen complexes in aqueous solution, requiring
slightly elevated temperatures of 55 °C for efficient turnover.15
While the Schiff base ligand proved to be crucial in their protocol,
we found that catalytic amounts of simple base metal salts alone
promote the C−H peroxidation of oxindoles already at room
temperature in various organic solvents such as CH2Cl2,
CH3CN, or MeOH (see Tables S1−S3 in the Supporting
a
IDO = indoleamine 2,3-dioxygenase; TDO = tryptophan 2,3-
Received: December 20, 2016
dioxygenase.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03789
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Scheme 2. C−H Peroxidation of 3-Substituted Oxindoles
Scheme 3. Competing Pathways for Base-Mediated
Peroxyoxindole Fragmentation
To confirm this mechanistic hypothesis, we designed several
control experiments with alternative nucleophiles and substrates
(Scheme 4). First, phenyl-substituted peroxyoxindole 2b was
Information). Copper(I) chloride provided optimal results, and
peroxidation proceeded exclusively at the benzylic position of the
oxindole core; the structure of 3-peroxyoxindole 2a was
unambiguously confirmed by single-crystal X-ray diffraction
analysis. The reaction also performed well in the presence of
water, thereby allowing the use of aqueous solutions of t-
BuOOH. However, no desired reaction was observed with any
other peroxide besides t-BuOOH. While exploring the substrate
scope, we found that this selective peroxidation reaction tolerates
a variety of functional groups, including alcohols (2d), carboxylic
acids (2e), amides (2f), and protected amines (2g and 2h).
Although a number of approaches to access various organic
peroxides have been developed,16 methods to prepare peroxides
bearing an oxindolyl functionality are still scarce.17 The catalytic
direct C−H peroxidation provides straightforward access to N-
unsubstituted 3-peroxyoxindoles,15 which represent an unusual
class of previously unexplored oxindole derivatives.18 We
therefore set out to study the reactivity profile of these
compounds in the context of new reaction discovery.
Scheme 4. Mechanistic Control Experiments
Aside from well-established reductive O−O bond cleavage of
the peroxide, we reasoned that the tert-butylperoxy substituent
could serve as a leaving group for the purpose of oxindole
alkylation. Akin to our previous studies on this topic,11c−e we
considered that basic elimination of t-BuOOH from oxindole 2a
would lead to reactive o-azaxylylene intermediate 3a. This species
could then react with a malonate nucleophile to afford C3
alkylated product 4a (Scheme 3, pathway A). In the event, we
observed only traces of the expected alkylated oxindole 4a, and
we were surprised to discover that quinolone 5a was formed as
the major product in 69% yield. We proposed that the
peroxyoxindole 2a reacts by a 4-oxa-Grob fragmentation,19
alternatively, this may be considered a homologous Kornblum−
DeLaMare rearrangement,20involving a C2−C3 bond cleavage
and elimination of tert-butyl alcohol (Scheme 3, pathway B).
This fragmentation would result in the simultaneous generation
of a benzylic ketone at C3 and an isocyanate moiety (cf. 6a),
which then suffers nucleophilic attack by dimethyl malonate.
Finally, the proposed intermediate 7a could convert to the
observed quinolone 5a by net condensative decarboxymethyla-
tion with the benzylic ketone, a process presumably driven by the
formation of extended conjugation.
treated under similar conditions, and we observed malonate
adduct 7b, analogous to the proposed intermediate 7a (Scheme
3, pathway B). Second, the presumed isocyanate intermediate
could be trapped by methanol to afford carbamate 8b. In this
example, both the peroxidation and the fragmentation were
performed in a single flask. Third, N-methylated analogue 9a
proved to be unreactive, regardless of whether a malonate
nucleophile was present or not, suggesting that deprotonation of
the oxindole nitrogen is critical for reactivity; this experiment
reasonably excludes the possibility of fragmentation occurring by
nucleophilic attack at the oxindole carbonyl. Fourth, in the
absence of an external nucleophile, 3-methyl-substituted
peroxyoxindole 2a undergoes intramolecular cyclization to
B
DOI: 10.1021/acs.orglett.6b03789
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form 4-hydroxyquinolinone 10a. Finally, hydrolysis occurs in the
presence of water to generate the corresponding aniline (e.g.,
11b). Overall, the peroxide fragmentation is rapid at ambient
temperature, and the starting materials are typically consumed
within seconds. The nascent 2-acylphenylisocyanate, which has
also been observed directly by in situ ReactIR spectroscopy (see
Figure S1), is then transformed into different heterocycles and
aniline derivatives by intra- or intermolecular nucleophilic attack.
The oxindole fragmentation reaction is noteworthy in the
context of the kynurenine pathway2 and the Witkop oxidation.4
In biological systems, catabolism of tryptophan is accomplished
primarily by two heme enzymes, indoleamine 2,3-dioxygenase
and tryptophan 2,3-dioxygenase (cf. Scheme 1A). The
mechanism of this enzymatic reaction is believed to proceed by
initial epoxidation of the indole, followed by ring opening and
oxidative cleavage by an iron oxo intermediate to afford N-
formylkynurenine, which decomposes under aqueous conditions
to the corresponding aniline, namely kynurenine.2 The
biomimetic Witkop oxidation can be performed under a variety
of conditions (cf. Scheme 1B), and may proceed by several
mechanisms.4,5 Notably, in all of these cases, the indole
substituents at C2 and C3 remain unchanged in the course of
the oxidative transformation. In contrast, we have demonstrated
a complementary oxidative sequence, which occurs by a distinct
mechanistic pathway, allowing for installation of new function-
ality in the oxidized derivative with oxygen-, carbon-, and
nitrogen-based nucleophiles.
Having developed a selective oxindole peroxidation/fragmen-
tation sequence, we envisioned the implementation of our
protocol on tryptophan derivatives, paving the way toward
relevant applications such as unnatural amino acid synthesis and
bioconjugation. In this context, it is relevant to note that methods
have been established for the incorporation of oxidized
tryptophan units on polypeptides and complex natural
products.21 We therefore prepared N-acetyl-L-tryptophan
methyl ester (12), as well as the two dipeptides 13 and 14, as
model substrates to this end. These tryptophan derivatives were
converted to the corresponding peroxyoxindoles 15, 16, and 17
using a two-step sequence combining the known acidic DMSO
oxidation to oxindolylalanine derivatives22 with our newly
developed peroxidation reaction (Scheme 5). The initial
DMSO oxidation was typically high yielding, although the C2-
chlorinated indole was routinely observed as a minor side
product. In all three cases, the peroxidation reaction proceeded
smoothly, despite the presence of several potential sites of
reactivity, including the benzylic center on phenylalanine, and
the α-carbon on each amino acid. Although this sequence is
unselective with regard to the stereochemistry at the indole 3-
position, this is inconsequential in the context of the
fragmentation reaction since that center is planarized in the
final products.
The reactivity of the tryptophan-derived peroxide 15 was akin
to that observed with simpler substrates, affording skeletally
rearranged kynurenine derivatives, including valine-derived urea
19 and methyl carbamate 20 (Scheme 6). Interestingly, N-
Scheme 6. Tryptophan-Derived Peroxide Fragmentation
acetylkynurenine methyl carbamate 20 was obtained in
diminished enantiomeric excess. While the two-step oxidation
sequence furnished peroxyoxindole 15 as an enantiomerically
pure mixture of diastereomers, treatment with cesium carbonate
in methanol led to partial racemization. Attempts to optimize the
methanolysis reaction using a wide array of organic and inorganic
bases, cosolvents, and reduced temperatures did not assist in
preserving enantiomeric excess. Consequently, we synthesized
the N-Boc protected peroxyoxindole 18. Gratifyingly, this
substrate furnished the corresponding N-Boc-kynurenine methyl
carbamate 21 in excellent yield with perfect stereochemical
fidelity when treated with sodium carbonate in methanol.
Preliminary findings have also shown that these peroxides react
selectively with amines in DMSO/H2O mixtures at pH ≥ 9 to
afford coupled derivatives. These experiments suggest that the
oxindole fragmentation reaction may potentially be applied in
the context of bioconjugation and unnatural amino acid
synthesis.
In summary, we have discovered a mild, selective, and
biocomplementary sequence for oxidative indole fragmentation
that hinges on a copper-catalyzed C−H peroxidation of
oxindoles followed by a base-mediated rearrangement. In
contrast to known biomimetic indole oxidations, this method
provides access to diverse heterocycles and aniline derivatives
from a single precursor and constitutes an exquisite opportunity
for tryptophan modification. Applications of this method toward
bioconjugation, unnatural amino acid synthesis, and postsyn-
thetic peptide modification are the subject of ongoing
investigations in our laboratory.
Scheme 5. C−H Peroxidation of Tryptophan Derivatives
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03789.
X-ray data for 2a (CIF)
Experimental procedures, characterization, optimization,
and crystallographic data as well as NMR and IR spectra
(PDF)
C
DOI: 10.1021/acs.orglett.6b03789
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Letter
(e) Krall, N.; da Cruz, F. P.; Boutureira, O.; Bernardes, G. J. L. Nat.
Chem. 2016, 8, 103−113.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: stoltz@caltech.edu.
ORCID
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Francis, M. B. J. Am. Chem. Soc. 2004, 126, 10256−10257.
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(d) Ruiz-Rodríguez, J.; Albericio, F.; Lavilla, R. Chem. - Eur. J. 2010, 16,
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M. J. Am. Chem. Soc. 2016, 138, 10798−10801.
Hendrik F. T. Klare: 0000-0003-3748-6609
Brian M. Stoltz: 0000-0001-9837-1528
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NSF under the CCI Center for
Selective C−H Functionalization (CHE-1205646). We thank
DAAD (postdoctoral fellowship to H.F.T.K.), NSERC (graduate
scholarship to A.F.G.G.), NSF (predoctoral research fellowship
to D.C.D., No. DGE-1144469), the Gordon and Betty Moore
Foundation, Amgen, Abbott, Boehringer Ingelheim, and Caltech
for financial support. Larry Henling (Caltech) is acknowledged
for X-ray analysis, and Dr. Robert Craig and Dr. Guillaume
Lapointe (both Caltech) are thanked for helpful discussions.
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