Chemoselective and enantioselective oxidation of indoles employing aspartyl peptide catalysts

Article abstract of DOI:10.1021/ja202706g

Catalytic enantioselective indole oxidation is a process of particular relevance to the chemistry of complex alkaloids, as it has been implicated in their biosynthesis. In the context of synthetic methodology, catalytic enantioselective indole oxidation allows a rapid and biomimetic entry into several classes of alkaloid natural products. Despite this potentially high utility in the total synthesis, reports of catalytic enantioselective indole oxidation remain sparse. Here we report a highly chemoselective catalytic system for the indole oxidation that delivers 3-hydroxy-indolenines with good chemical yields and moderate to high levels of enantio- and diastereoselectivity (up to 95:5 er and up to 92:8 dr). These results represent, to our knowledge, the most selective values yet reported in the literature for catalytic asymmetric indole oxidation. Furthermore, the utility of enantioenriched hydroxy-indolenines in stereospecific rearrangements is demonstrated.

Full text of DOI:10.1021/ja202706g

ARTICLE
pubs.acs.org/JACS
Chemoselective and Enantioselective Oxidation of Indoles
Employing Aspartyl Peptide Catalysts
Filip Kolundzic,† Mohammad N. Noshi,‡ Meiliana Tjandra,‡ Mohammad Movassaghi,*,‡ and Scott J. Miller*,†
†Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut 06520-8107, United States
‡Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307, United States
S Supporting Information
b
ABSTRACT: Catalytic enantioselective indole oxidation is a
process of particular relevance to the chemistry of complex
alkaloids, as it has been implicated in their biosynthesis. In the
context of synthetic methodology, catalytic enantioselective
indole oxidation allows a rapid and biomimetic entry into
several classes of alkaloid natural products. Despite this poten-
tially high utility in the total synthesis, reports of catalytic
enantioselective indole oxidation remain sparse. Here we report
a highly chemoselective catalytic system for the indole oxidation
that delivers 3-hydroxy-indolenines with good chemical yields
and moderate to high levels of enantio- and diastereoselectivity (up to 95:5 er and up to 92:8 dr). These results represent, to our
knowledge, the most selective values yet reported in the literature for catalytic asymmetric indole oxidation. Furthermore, the utility
of enantioenriched hydroxy-indolenines in stereospecific rearrangements is demonstrated.
’ INTRODUCTION
In contrast, classical peracid-mediated oxidation of indoles provides
an opportunity to assess alternative approaches to the chemo- and
enantioselective oxidation of indoles. Indeed, the classical and highly
general oxidation potential of m-chloroperbenzoic acid (MCPBA)
recently inspired the development of a catalytic cycle for asymmetric
epoxidation based on the transient generation of aspartic peracids in
peptide-based catalysts (Figure 2a).10 For example, it is now known
that the aspartic acid residue (e.g., 7) can function as a catalyst
following carboxyl activation with carbodiimide reagents. In the
presence of hydrogen peroxide, the putative peracid 8 is formed,
which then delivers an O-atom to an olefin to form an epoxide,
regenerating the free acid. Mechanistic studies have documented
aspects of this catalytic cycle, including the observation of off-cycle
intermediates such as 9.11,12 Nonetheless, these may reinsert into
the catalytic cycle under the aegis of nucleophilic catalysts such a
N,N-dimethylaminopyridine (DMAP), or the corresponding N-oxide
(10). Moreover, as shown in Figure 2b, this approach was rendered
enantioselective for the epoxidation of substrates like 11, which could
be converted to epoxide 12 in up to 96:4 enantiomeric ratio (er;
92% ee), with application of as little as 5 mol % of catalyst 13. Given
the generality of MCPBA in the effective oxidation of a wide range of
olefinic compounds, we wished to explore whether or not the aspartyl
peptide-based oxidation catalysts might be appropriate for the
effective oxidation of indolic compounds of relevance to natural
product synthesis. We report herein our studies, which allow us to
conclude that this approach is indeed appropriate for the efficient
The catalytic enantioselective oxidation of indoles is a significant
challenge and one of particular relevance to the total synthesis of
complex, naturally occurring alkaloids.1 At the same time, enzymatic
oxidation of indoles is well-recognized as a key step in indole alkaloid
biosynthesis,2 rendering oxidation approaches to their chemical
synthesis inherently biomimetic.3 Chemically, tryptamine deriva-
tives such as 1 may be chemoselectively oxidized to afford hydroxy-
indolenines (3), which derive from the intermediate indole oxides
(2) (Figure 1). These compounds, in turn, may be subjected to
highly stereoselective rearrangements. Notably, in a condition-
dependent fashion, hydroxy-indolenines of type 3 may be converted
to either the 3-oxindole regioisomer 4 or the 2-oxindole regioisomer
5.4ꢀ6 These oxidative isomerizations have played a critical role in a
number of elegant natural product syntheses for introduction of
challenging stereochemical arrays.4
Selective indole oxidation presents a myriad of challenges to
the goal of developing catalytic enantioselective approaches.
Presently, asymmetric catalytic approaches to the preparation
of optically enriched 3-hydroxy-indolenines (3), from achiral
starting materials, are quite limited. Application of the venerable
extant asymmetric epoxidation catalysts7 to these highly elec-
tron-rich heterocycles has been reported, but with only limited
success.8 Among the challenges, in addition to stereocontrol, is
the issue of chemoselectivity. Reactivity may be diverted from the
desired formation of 3 to the observation of N-hydroxy-indoles
(6) and indole-ring hydroxylation.9 Thus, complications are
often encountered with a variety of metal-catalyzed, dioxirane-
or oxaziridine-mediated approaches.
Received: March 25, 2011
Published: May 03, 2011
r
2011 American Chemical Society
9104
dx.doi.org/10.1021/ja202706g J. Am. Chem. Soc. 2011, 133, 9104–9111
|

Journal of the American Chemical Society
ARTICLE
Figure 1. Oxidation of indoles and rearrangements.
Scheme 1. Two Synthetic Strategies Used for Preparation of
Substrates in This Study from Simple Tryptaminesa
a Route a, conditions: (a) I2 (1.1 equiv), AgOTf (1.1 equiv), THF,
ꢀ78 f 23 °C, 15 min, 96%. (b) Pd2(dba)3 (2.5 mol%), XPhos (10 mol %)
K3PO4 (2.0 equiv), toluene, water, 110 °C, 2 h, PhB(OH)2 (1.5 equiv), 75%.
Route b, conditions: (c) [Ir(OMe)(COD)]2(3 mol %), dtbpy (6 mol %),
(Bpin)2 (2.0 equiv), CH2Cl2, 65 °C, 3 h, 78%. (d) Pd2(dba)3 (2.5 mol %),
XPhos (10 mol %), K3PO4 (2.0 equiv), toluene, water, 110 °C, 2 h, PhI
(1.0 equiv) 82%. dtbpy =4,40-di-tert-butyl-2,20-bipyridine.
Figure 2. Aspartyl peptide-based catalytic enantioselective oxidation.
(a) Development of a peracid-based catalytic cycle. (b) Development of
enantioselective variants of the process. DMAP = N,N-dimethyl-4-
aminopyridine, DIC = diisopropylcarbodiimide.
chemoselective oxidation of many indoles to the corresponding
hydroxy-indolenines. Moreover, we describe our studies of stereo-
selective indole oxidation, including the first reports of significant
levels of enantioselectivity and indeed diastereoselectivity in catalytic
asymmetric indole oxidation reactions.
two concise and equally versatile synthetic routes as illustrated in
Scheme 1. The first route involves C2-halogenation of tryptamine
derivatives such as 15, followed by Suzuki-Miyaura coupling with aryl
boronates to afford 2-aryltryptamines (Scheme 1, Route a). An
alternative route utilizes iridium-catalyzed13 C2-borylation of trypt-
amines, followed by palladium-catalyzed cross-coupling with aryl
halides (Scheme 1, Route b).14,15
We then turned our attention to the oxidation chemistry, employ-
ing the simple aspartic acid derivative 16 (eq 1) as a catalyst. As out-
lined in eq 1, performing the oxidation at 25 °C, the indole substruc-
ture of 14 was oxidized to the corresponding 3-hydroxy-indolenine
derivative 17, isolated in 55% yield. In addition to 17, approximately
’ RESULTS AND DISCUSSION
Our studies began with tryptamine 14 (Scheme 1) as a superb
substrate for development of the chemistry aimed at a variety
of complex indole alkaloids containing cyclotryptamine and cyclo-
tryptophan substructures. Substrates such as 14 may be prepared by
9105
dx.doi.org/10.1021/ja202706g |J. Am. Chem. Soc. 2011, 133, 9104–9111

Journal of the American Chemical Society
ARTICLE
15% of an alternative oxidation product 18 had formed, and this side
product could be removed by column chromatography.16 In terms of
enantioselectivity, we noted minimal enantioselectivity when the
simple catalyst 16 was employed. However, employing catalyst 13
(Figure 2), discovered during the original aspartyl-peptide epoxida-
tion study,10 we were pleased to observe that 17 could be formed in
64% yield, with an er of 56:44 under analogous conditions (10 mol %,
25 °C; eq 2). A preliminary screen of reaction conditions revealed that
maintaining the temperature at 0 °C is beneficial for selectivity, and
that at this temperature 3-hydroxy-indolenine 17 is formed with 60:40
er (70% yield). These effects are amplified with the 2-naphthyl-
substituted indole 19 (eq 3). At 25 °C, indole 19 is converted to 20
with a 67:33 er. At 0 °C, hydroxyindolenine 20 is formed with an
encouraging er of 84:16 (70% yield). Notably, under these conditions
the formation of the byproduct is also suppressed. We attributed this
behavior to the presence of an alternative and nonselective oxidation
pathway at higher temperatures, perhaps via DICꢀH2O2 adduct,17
which seems to be mostly suppressed at 0 °C. In terms of reaction
efficiency, and in line with earlier results,10 a strong dependence of the
conversion on the presence of nucleophilic cocatalyst N,N-dimethyl-
4-aminopyridine is observed.
With encouraging levels of chemoselectivity and a preliminary
observation of enantioselectivity in the aspartyl peptide-catalyzed
oxidation of indoles, we then turned our attention to the issue of
stereoselectivity. We describe here our initial efforts in the area of
diastereoselective oxidation of indoles. We chose to study this
type of stereoselective process for several reasons. First, the
notion of using chiral catalysts as tools for the selective modifica-
tion of complex architectures is a challenging frontier for the field
of asymmetric catalysis.18 Such approaches are also of potential
value in the total synthesis of stereochemically complex mole-
cules, including complex indole alkaloids.4 In addition, the study
of double diastereodifferentiating reactions often provides valu-
able data of a fundamental nature in the development of
asymmetric processes.19 Thus, we began with an examination
of chiral aspartyl peptides that might affect selective oxidation of
tryptophan derivatives such as 21 (Figure 3). In order to proceed
with an appropriate catalyst, it was important to benchmark its
inherent selectivity with an achiral substrate. Thus, we examined
a library of peptides based on a historically valuable β-turn
scaffold20 that incorporated a catalytic Asp residue as the N-
terminal residue (see Supporting Information for more details).
This study was initially conducted with substrate 19, an achiral
analogue that was thought to mimic more elaborated bis(indolyl)
substrates of interest (to be discussed below). Through this
process, peptide 22 emerged as a promising catalyst for oxidation
of simple indoles such as 19 (94:6 er; 57% yield; eq 4).
With catalyst 22 in hand, we turned our attention to oxidation
of chiral substrates derived from tryptophan, such as compound
21. It is well precedented that the presence of a chiral center in
the indole side chain renders the oxidation diastereoselective.6,21
Thus, unsurprisingly, use of octanoic acid as an achiral catalyst for
the oxidation of 21 we observed formation of diastereomers 23
and 24 in the diastereomeric ratio of 69:31 (59% combined yield;
Figure 3, eq 5). A similar diastereomeric ratio (dr) value is
observed in the oxidation of 21 using stoichiometric quantities of
DMDO.6 On the other hand, a significant amplification of
diastereoselectivity of the reaction is observed when peptide 22
is used as a catalyst. In this case, a striking “matched” case of
double asymmetric induction is observed, with the formation of
23 and 24 as a 92:8 mixture of diastereomers (75% combined
yield; Figure 3, eq 6).22 Significantly, use of the enantiomer of
peptide-catalyst 22 led to a nonselective, “mismatched” case, and
a 49:51 mixture of diastereomers 23 and 24 was observed (69%
combined yield; Figure 3, eq 7). We note parenthetically that
9106
dx.doi.org/10.1021/ja202706g |J. Am. Chem. Soc. 2011, 133, 9104–9111

Journal of the American Chemical Society
ARTICLE
Figure 3. Studies of double asymmetric induction in the chemoselective catalytic oxidation of 21.
major compound 23 possesses the correct stereochemical array
relative to many naturally occurring cyclotryptamines.6
We then wished to assess the viability of aspartyl peptide-
based oxidation catalysis in increasingly complex settings. Thus,
we wished to examine the challenge of chemoselective oxidation
in the face of substrates that present two indolyl NꢀH groups,
each a potential culprit in terms of undesired NꢀH oxidation
side reactions. Notably, substrate 25 also possesses an acetamide,
with an additional potentially vulnerable NꢀH function. Given
the presence of a second highly electron rich aromatic system,
one can envision formation of multiple regioisomeric indole
oxidation products emanating from 25 (e.g., hydroxy-indole-
nines 26 and 27; hydroxy-indole tautomers 28ꢀ30; distinct
NꢀOH indoles 31 and 32; N-hydroxy-acetamide 33; and distal
indole ring oxidation products such as 34; Figure 4), as well as
other oxidation products.
In addition to these chemoselectivity challenges, we wished to
assess whether catalyst 22 was portable to this new substrate class
in terms of affording comparable levels of diastereoselectivity in
the specific formation of 26 and 27. Thus, the bis(indole)
compound 25 became our next focus for study. Remarkably, as
shown in Figure 5, we found that substrate 25 was an excellent
substrate for chemoselective oxidation to the corresponding
hydroxy-indolenines 26 and 27. Indeed, these compounds could
be isolated in 72ꢀ83% chemical yield under the catalytic
Figure 4. Various hypothetical oxidation products derived from 25.
conditions. Competing NꢀH oxidation reactions were not signi-
ficant side reactions. Moreover, only the desired tryptaminyl in-
dole oxidation products were isolated, with no perturbation of the
second indole moiety detected. The inherent diastereoselectivity
of bis(indole) 25 was defined as a 64:36 ratio, employing
octanoic acid as the catalyst (72% yield; Figure 5, eq 8). The
results in terms of peptide-based control of stereochemistry were
also encouraging. As shown in Figure 5, diastereomers 26 and 27
were obtained in an 88:12 diastereomeric ratio when catalyst 22
was employed (10 mol %), a manifestation of a “matched” case of
double asymmetric induction (83% yield; Figure 5, eq 9).23
Moreover, hydroxy-indolenines 26 and 27 are readily separated
by flash column chromatography. In the mismatched case, the
enantiomer of catalyst 22 delivered 26/27 as a 42:58 diastere-
omeric mixture (78% isolated yield; Figure 5, eq 10). Of note, the
reversal of diastereoselectivity reveals that the catalyst overrides,
albeit modestly, the inherent stereoselectivity preference of the
substrate.
Most notably, under the present conditions, none of the
products arising from the oxidation of the second indole moiety
or from the indole N-oxidation could be detected, thus obviating
the necessity for the introduction of protecting groups into the
synthetic schemes. The higher reactivity of the double bond of
the more substituted indole may be correlated to the correspond-
ing higher HOMO energy resulting from a partial orbital overlap
with the aromatic system of the second indole.24 Compound 25
is readily accessible in two steps (Scheme 2) from a commercially
available tryptophan derivative, consistent with the conditions
9107
dx.doi.org/10.1021/ja202706g |J. Am. Chem. Soc. 2011, 133, 9104–9111

Journal of the American Chemical Society
ARTICLE
Figure 5. Studies of double asymmetric induction in the chemoselective catalytic oxidation of 25.
Scheme 2. Preparation of the Chiral Bis(indole) 25 via
Table 1. Oxidation of Simple 2-Arylindoles with Peptide 22
as a Catalyst
Indole Borylation/SuzukiꢀMiyaura Coupling Protocola
a pin = pinacol, dtbpy =4,40-di-tert-butyl-2,20-bipyridine, XPhos =2-
dicyclohexylphosphino-20,40,60-triisopropylbiphenyl.
discussed in Scheme 1, and therefore these results represent a
step efficient entry into optically pure tryptophan-based 3-hydro-
xy-indolenines.13,14
Having defined a highly chemoselective indole oxidation
process employing a mild and catalytic process, we next wished
to determine if these diastereoselective reactions might be
extendable to enantioselective processes. Since catalytic enantio-
selective reactions that convert indoles to the corresponding
hydroxy-idolenines are so rare, we wished to document the scope
of catalyst 22 for the highly challenging arena of enantioselective,
electon rich heterocycle oxidation. Thus, our studies began by
examining a range of different tryptamine derivatives with mono-
cyclic aryl substitution at the indolic 2-position (Table 1). As noted
above (eq 2), the parent compound 14 undergoes a smooth
chemoselective oxidation with peptide 13 employed as the catalyst
(60:40 er; 65% yield). Employing catalyst 22, the er is enhanced to
77:23 (entry 1). Moreover, we found that substrates containing
ortho substituents on the 2-aryl substructure were subject to quite
selective reactions with catalyst 22. Thus, o-CF3 compound 36a
undergoes catalytic enantioselective oxidation to give 37a with a
a Reaction conditions for indole oxidation: indole (1.0 equiv), peptide
(10 mol %), and DMAP (5 mol %) in CHCl3 (0.1 M) at 0 °C, then add
aqueous H2O2 (1.2 equiv), and DIC (1.2 equiv). b Concentration of
indole in these reactions was increased to 0.5 M. c Concentration of
indole in this reaction was increased to 0.2 M. DMAP = N,N-dimethyl-4-
aminopyridine, DIC = diisopropylcarbodiimide, Phth = phthaloyl. d A
sluggish reaction and complex mixture of products is observed.
94:6 er (93% isolated yield; entry 2). The o-NO2-substituted
compound 36b is also a good substrate for catalyst 22, although
9108
dx.doi.org/10.1021/ja202706g |J. Am. Chem. Soc. 2011, 133, 9104–9111

Journal of the American Chemical Society
ARTICLE
Table 2. Oxidation of Indoles Incorporating an Elaborate
Arene with Peptide 22 as a Catalyst
Table 3. Oxidation of Simple Bis(indoles) with Peptide 22 as
a Catalyst
a Reaction conditions for indole oxidation: indole (1.0 equiv), peptide
(10 mol %), and DMAP (5 mol %) in CHCl3 (0.1 M) at 0 °C, then add
aqueous H2O2 (1.2 equiv), and DIC (1.2 equiv). b Recrystallized to 95:5
er from 95/5 2-propanol/ethanol mixture (yield after recrystallization
47%). DMAP = N,N-dimethyl-4-aminopyridine, DIC = diisopropylcar-
bodiimide, Phth = phthaloyl, SES = 2-(trimethylsilyl)ethylsulfonyl.
a Reaction conditions for indole oxidation: indole (1.0 equiv), peptide
(10 mol %), and DMAP (5 mol %) in CHCl3 (0.1 M) at 0 °C, then add
aqueous H2O2 (1.2 equiv), and DIC (1.2 equiv). b Recrystallized to
>98:2 er from 95/5 2 propanol/ethanol mixture (yield after recrystalli-
zation 45%). Recrystallized to >99:1 er from dichloromethane (yield
after recrystallization 71%). DMAP = N,N-dimethyl-4-aminopyridine,
compound 38a performed similarly, with 39a obtained as a 95:5
er (88% isolated yield, entry 2). In the case of both products 20
and 39a, recrystallization afforded material that was essentially
enantiopure (er >98:2). On the other hand, the alternative sub-
stitution pattern of the athracenyl moiety (9- versus 1-position)
defines substrate 38b as a less optimal case for catalyst 22, with
39b obtained with an 84:16 er, but in only 7% isolated yield
(entry 3). It appears that a compound possessing aryl rings fused
on both sides of the 2-phenyl substituent engenders unfavorable
interactions with the catalyst, thus preventing its efficient proces-
sing. Alleviating these interactions, as in the remotely substituted
naphthalene derivative 38c allows reaction to occur (39c is
obtained in 74% yield), although this ortho-unsubstituted com-
pound exhibits modest enantioselectivity (67:33 er, entry 4).
In addition, we wished to study the enantioselective indole
oxidation substrate scope in structural arenas that would allow for
an increasingly demanding assessment of chemoselectivity.
Thus, we explored a class of compounds containing a second
indole moiety, as well as additional oxidation-sensitive NꢀH
functional groups. Bis(indole) substrates 40aꢀc (Table 3) were
generally25 prepared by a SuzukiꢀMiyaura coupling of the
2-borylated tryptamines with the corresponding aryl halides as
alluded to in Scheme 1.6 As discussed earlier, oxidation products
derived from these compounds (41aꢀc) could find a direct
application in the synthesis of complex alkaloids, and similar
intermediates are often invoked in the biosynthesis of these
natural products.2 At the onset of our investigations, we con-
firmed that 2-(7-indolyl)tryptamines (40aꢀc) undergo highly
c
DIC = diisopropylcarbodiimide, Phth = phthaloyl.
the er and yield are slightly attenuated for product 37b (89:11 er,
78% yield, entry 3). A substrate-bearing o-CH3 group (36c)
performs similarly (37c: 88:12 er, 76% yield, entry 4). On the other
hand, for reasons that are at present unclear, the o-MeO-containing
compound 36d is resistant to efficient oxidation (entry 5). The
para-substitued compounds 36e and 36f are oxidized with reason-
able yields (37e and 37f, 64% and 69%, respectively) but exhibit
modest er (∼3:1, entries 6 and 7). Thus, we found that 2-phenyl
substituents bearing an electron-withdrawing or an electron-neutral
substituent ortho relative to the indole attachment site (e.g.,
substrates 36aꢀc) resulted in the formation of products (37aꢀc)
with the highest er values. The high er’s and yields obtained with
these compounds additionally attest to their position as good
substrates for peptide catalyst 22, and they also represent perhaps
the highest enantioselectivities yet reported for the nonenzymatic
catalytic enantioslective oxidation of indolic compounds.
The presence of an ortho substituent stimulated an examina-
tion of additional substrates that possessed analogous substitu-
tion, including elaborated arene substitution. As shown in
Table 2, compounds 19 and 38aꢀc proved interesting in this
regard. In particular, the 2-napthyl-substituted tryptamine 19
proved to be a good substrate for catalyst 22, with 20 delivered
with an er of 94:6 (57% isolated yield, entry 1). The anthracenyl
9109
dx.doi.org/10.1021/ja202706g |J. Am. Chem. Soc. 2011, 133, 9104–9111

Journal of the American Chemical Society
ARTICLE
ratio. We project that this transformation, in conjunction with
the catalytic enantioselective indole oxidation, will find applica-
tions in synthesis of complex, naturally occurring alkaloids.
Figure 6. Determination of absolute stereochemistry through X-ray
diffraction analysis.
chemoselective oxidation with oxygen delivery at the site of the
1,2-disubstituted indole, rather than to the competing functional
groups. Notably, in all cases (Table 3), chemoselectivity proved
very high, as is reflected in the isolated chemical yields. In cases
such as 40a,b, selective indole oxidation occurs in the presence of
two indoles, as well as additional amide functionality. For the
former case, sulfonamide 41a is obtained as an 86:14 er, in 77%
isolated yield (entry 1), while the latter pivaloyl amide 41b is
obtained in 87% yield, with a 83:17 er (entry 2). These are in
comparison to the parent bis(indole) 40c, which is converted to
41c with an 82:18 er, isolated in 89% yield (entry 3). While the
phthalate compound 41c had formed with slightly lower er value
as compared to the other analogues tested, this oxidation product
was readily recrystallized to the enantiomeric ratio of 95:5, and
the single crystals thus obtained allowed us to unambiguously
assign the sense of the asymmetric induction through X-ray
diffraction analysis (vide infra). In all cases, the observed chemo-
selectivity is exceptionally high.
For purposes of comparison to the results obtained with
bis(indoles) with both indolyl-N atoms unprotected, we also
elected to examine the enantioselective oxidation of SES-pro-
tected indole 42. Interestingly, catalyst 22 mediates formation of
43 in 70% isolated yield, with a 93:7 er (Table 3, entry 9). This
result suggests that enantioselectivities may be enhanced, at least
in some cases, through the use of protecting groups or the
incorporation of bulky substituents. Moreover, we suspect that
studies of catalyst optimization could well lead to higher inherent
enantioselectivities for the unprotected bis(indoles) found in
Table 3 (e.g., 40aꢀc). On the other hand, preliminary investiga-
tions of compounds that bear 2,3-dialkyl substitution afford the
product of over-oxidation as the dominant product.26 The
current catalyst and conditions are thus well tuned for selective
oxidation of 2-aryl-/indolyl-3-alkyl substrates, substrates of great
interest in the context of the assembly of oligocyclotryptamine
natural products.
’ CONCLUSIONS
We have described a highly chemoselective and mild catalytic
system for the asymmetric oxidation of 2-aryltryptamine deriva-
tives. Noteworthy features of this chemistry include broad
substrate scope and functional group tolerance and a highly
versatile catalyst design that allows for adjustment and optimiza-
tion for key substrate classes of interest. While a single catalyst,
optimized for substrate 14, was used in this study for uniformity
and direct comparison, the practical nature of catalyst tuning
combined with the overall high level of stereoinduction in all
cases holds great promise for application in complex setting. For
example, as illustrated in Figures 3 and 5, catalyst 22, optimized
for substrate 14, demonstrated an outstanding level of diastereo-
selection in the oxidation of substrates 21 and 25 in matched
cases while still reversing the inherent substrate selectivity in the
corresponding mismatched cases. Moreover, this unique catalyst
was found to afford high er’s for several substrates of interest.
Application of this catalyst system to oxidation of highly func-
tional tryptamine and tryptophan derivatives in more challenging
settings in the context of asymmetric synthesis of complex
natural products is ongoing and will be the subject of upcoming
reports.
’ EXPERIMENTAL SECTION
General Indole Oxidation Protocol. The oxidation of indoles
was carried out in a reaction flask mounted to a cryogenic cooler with
temperature control of (0.1 °C. Reactions were set up on the benchtop
without exclusion of air or moisture. In a typical experiment, indole
(0.1 mmol) was dissolved in 890 μL of chloroform (for deviations from
the standard concentration see Tables 1ꢀ3), and peptide 22 was
added as a chloroform solution (typically 100 μL of 0.1 M solution,
0.01 mmol). To this solution was added a chloroform solution of N,N-
dimethyl-4-aminopyridine (typically 10 μL of 0.5 M solution, 5 μmol),
followed by 12.2 μL of aqueous 30% hydrogen peroxide (0.12 mmol).
The biphasic mixture was stirred at 0 °C for 5 min, and the reaction
was initiated by the addition 18.6 μL of diisopropylcarbodiimide
(0.12 mmol). After 20 h, the reaction mixture was diluted with 2.0 mL
of chloroform and directly purified by flash chromatography or
preparative TLC.
As noted above, several of the indole oxidation products were
highly crystalline. A representative of the bis(indole) product
class, compound 41c was subjected to X-ray diffraction analysis
and the stereochemistry of the C-3 alcohol was assigned the R
absolute configuration, as depicted in Figure 6. The assignment
was confirmed through additional diffraction analyses, as well as
through comparison with a literature data pertaining to a related
system.6
Full details may be found in the Supporting Information.
Finally, the application of catalytic asymmetric indole oxida-
tion creates important opportunities for manipulation of the
products to elaborated, enantioenriched materials. In this vein,6
we have demonstrated that hydroxy-indolenines such as 23 and
24 may be rearranged with a high level of stereoselectivity. As
shown in eq 11, we now report that compounds 39a and 39c may
be rearranged with complete preservation of the enantiomeric
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
compound characterization. This material is available free of
charge via the Internet at http://pubs.acs.org.
9110
dx.doi.org/10.1021/ja202706g |J. Am. Chem. Soc. 2011, 133, 9104–9111

Journal of the American Chemical Society
ARTICLE
’ AUTHOR INFORMATION
(6) Movassaghi, M.; Schmidt, M. A.; Ashenhurst, J. A. Org. Lett.
2008, 10, 4009–4012.
Corresponding Author
movassag@mit.edu; scott.miller@yale.edu
(7) For selected reviews and recent advances, see:(a) Johnson, R. A.;
Sharpless, K. B. In Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon: New York, 1991; Vol. 7, p 389. (b) Jacobsen, E. N.; Wu, M. H. In
Comprehensive Asymmetric Catalysis II; Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer-Verlag: Berlin, 1999; p 649. (c) Aggarwal, V. K.; Winn,
C. L. Acc. Chem. Res. 2004, 37, 611–620. (d)Xia, Q. H.;Ge, H. Q.;Liu, Z. M.;
Su, K. X. Chem. Rev. 2005, 105, 1603–1662. (e) Kelly, D. R.; Roberts, S. M.
Biopolymers 2006, 84, 74–89. (f) Berkessel, A.; Koch, B.; Toniolo, C.;
Rainaldi, M.; Broxterman, Q. B.; Kaptein, B. Biopolymers 2006, 84, 90–96.
(g) Wong, O. A.; Shi, Y. Chem. Rev. 2008, 108, 3958–3987. (h) Li, Z.; Zhang,
W.; Yamamoto, H. Angew. Chem., Int. Ed. 2008, 47, 7520–7522.
(8) For an interesting and promising example, see ref 4q.
(9) (a) Taniguchi, M.; Anjiki, T.; Nakagawa, M.; Hino, T. Chem.
Pharm. Bull. 1984, 32, 2544–2554. (b) Berrier, C.; Jacquesy, J. C.;
Jouannetaud, M. P.; Renoux, A. New J. Chem. 1987, 11, 611–615. (c)
Duflos, A.; Redoules, F.; Fahy, J.; Jacquesy, J.; Jouannetaud, M. J. Nat.
Prod. 2001, 64, 193–195. (d) Lakatosh, S. A.; Balzarini, J.; Andrei, G.;
Snoeck, R.; De Clercq, E.; Preobrazhenskaya, M. N. J. Antibiot. 2002,
55, 768–773. (e) Beyer, M.; Fritscher, J.; Feresin, E.; Schiemann, O.
J. Org. Chem. 2003, 68, 2209–2215.
’ ACKNOWLEDGMENT
This work is supported by National Institutes of Health,
National Institute of General Medical Sciences (GM096403 to
S.J.M. and GM089732 to M.M.). M.M. also thanks Amgen and
DuPont for additional financial support. M.M., M.N.N., and
M.T. thank Dr. Cristina M. Nieto-Oberhuber and Ms. Yuki
Nakamura in the Movassaghi group for helpful discussions.
’ REFERENCES
(1) (a) Williams, R. M.; Kwast, E.; Coffman, H.; Glinka, T. J. Am.
Chem. Soc. 1989, 111, 3064–3065. (b) Sanz-Cervera, J. F.; Glinka, T.;
Williams, R. M. Tetrahedron 1993, 49, 8471–8482. (c) Schmidt, M. A.;
Movassaghi, M. Synlett 2008, 3, 313–324.
(2) Williams, R. M.; Stocking, E. M.; Sanz-Cervera, J. F. In Biosynth-
esis: Aromatic Polyketides, Isoprenoids, Alkaloids; Topics in Current
Chemistry; Leeper, F. J., Vederas, J. C., Eds.; Springer: Berlin, 2000.
(3) (a) Schkeryantz, J. M.; Woo, J. C. G.; Siliphaivanh, P.; Depew,
K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11964–11975. (b)
Wang, H.; Ganesan, A. J. Org. Chem. 2000, 65, 4685–4693. (c) Baran,
P. S.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 7904–7905. (d) Marti, C.;
Carreira, E. M. Eur. J. Org. Chem. 2003, 12, 2209–2219. (e) Williams,
R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36, 127–139.
(10) Peris, G.; Jakobsche, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007,
129, 8710–8711.
(11) (a) Greene, F. D.; Kazan, J. J. Org. Chem. 1963, 28, 2168–2171.
(b) Rebek, J.; McCready, R.; Wolf, S.; Mossman, A. J. Org. Chem. 1979,
44, 1485–1493. (c) Spantulescu, M. D.; Jain, R. P.; Derksen, D. J.;
Vederas, J. C. Org. Lett. 2003, 5, 2963–2965.
(12) Jakobsche, C. E.; Peris, G.; Miller, S. J. Angew. Chem., Int. Ed.
2008, 47, 6707–6711.
(4) For representative examples of the utility of hydroxyindolenine
intermediates in complex synthesis, see:(a) Finch, N.; Taylor, W. I.
J. Am. Chem. Soc. 1962, 84, 3871. (b) Finch, N.; Gemenden, C. W.; Hsu,
I. H.; Kerr, A.; Sim, G. A.; Taylor, W. I. J. Am. Chem. Soc. 1965,
87, 2229–2235. (c) Hutchison, A. J.; Kishi, Y. J. Am. Chem. Soc. 1979,
101, 6786–6788. (d) Williams, R. M.; Glinka, T.; Kwast, E.; Coffman,
H.; Stille, J. K. J. Am. Chem. Soc. 1990, 112, 808–821. (e) Jossang, A.;
Jossand, P.; Hadi, H. A.; Sevenet, T.; Bodo, B. J. Org. Chem. 1991,
56, 6527–6530. (f) Gueller, R.; Borschberg, H. Helv. Chim. Acta 1993,
76, 1847–1862. (g) Stoermer, D.; Heathcock, C. H. J. Org. Chem. 1993,
58, 564–568. (h) Gueller, R.; Borschberg, H. Tetrahedron Lett. 1994,
35, 865–868. (i) Cushing, T. D.; Sanz-Cervera, J. F.; Williams, R. M.
J. Am. Chem. Soc. 1996, 118, 557–579. (j) Takayama, H.; Kurihara, M.;
Subhadhirasakul, S.; Kitajima, M.; Aimi, N.; Sakai, S. Heterocycles 1996,
42, 87–92. (k) Ito, M.; Clark, C. W.; Mortimore, M.; Goh, J. B.; Martin,
S. F. J. Am. Chem. Soc. 2001, 123, 8003. (l) Baran, P. S.; Corey, E. J. J. Am.
Chem. Soc. 2002, 124, 7904–7905. (m) Williams, R. M.; Cox, R. J. Acc.
Chem. Res. 2003, 36, 127and references cited therein. (n) Liu, Y.;
McWhorter, W. W., Jr.; Hadden, C. E. Org. Lett. 2003, 5, 333–335.
(o) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005, 127,
15394–15396. (p) Poriel, C.; Lachia, M.; Wilson, C.; Davies, J. R.;
Moody, C. J. J. Org. Chem. 2007, 72, 2978–2987. (q) Pettersson, M.;
Knueppel, D.; Martin, S. F. Org. Lett. 2007, 9, 4623–4626. (r) Miller,
K. A.; Tsukamoto, S.; Williams, R. M. Nature Chem. 2009, 1, 63–68.
(5) For examples of aryl migration, see:(a) Witkop, B.; Ek, A. J. Am.
Chem. Soc. 1951, 73, 5664–5669. (b) Evans, F. J.; Lyle, G. G.; Watkins, J.;
Lyle, R. E. J. Org. Chem. 1962, 27, 1553–1557. (c) Hishmat, O. H.;
Abd-El Rahman, A. H.; El-Ebrashi, N. M. A.; Ishmail, M. M. F. Chem. Ind.
1986, 4, 142–143. (d) Liu, Y.; McWhorter, W. W., Jr. J. Org. Chem. 2003,
68, 2618–2622. For key related studies, see:(e) Witkop, B.; Patrick, J. B.
J. Am. Chem. Soc. 1951, 2188–2195. (f) Acheson, R. M.; Snaith, R. W.;
Vernon, J. M. J. Chem. Soc. 1964, 3229–3223. (g) Walser, A.; Blount,
J. F.; Fryer, R. I. J. Org. Chem. 1973, 38, 3077–3084. (h) Wenkert, E.; Shi,
Y. Synth. Commun. 1989, 19, 1071–1079. (i) Zhang, X.; Foote, C. S.
J. Am. Chem. Soc. 1993, 115, 8867–8868. (j) Tany, M.; Matsumoto, S.;
Aida, Y.; Arikawa, S.; Nakane, A.; Yokoyama, Y.; Murakami, Y. Chem.
Pharm. Bull. 1994, 42, 443–453. (k) Lachia, M.; Poriel, C.; Slawin,
A. M. Z.; Moody, C. J. Chem. Commun. 2007, 286–288. (l) Lindel, T.;
Br€auchle, L.; Golz, G.; B€ohrer, P. Org. Lett. 2007, 9, 283–286.
(13) (a) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura, N.
Tetrahedron Lett. 2002, 43, 5649–5651. (b) Ishiyama, T.; Takagi, J.;
Nobuta, Y.; Miyaura, N. Org. Synth. 2005, 82, 126–131.
(14) (a) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007,
129, 3358–3366.(b) See also ref 6.
(15) Synthesis details may be found in the Supporting Information.
(16) Astolphi, P.; Greci, L.; Rizzoli, C.; Sgarabotto, P.; Marrosu, G.
J. Chem. Soc. Perkin Trans. 2, 2001, 1634–1640.
(17) (a) Majetich, G.; Hicks, R. Synlett 1996, 649–651. (b) Murray,
R. W.; Iyanar, K. J. Org. Chem. 1998, 63, 1730–1731. (c) Majetich, G.;
Hicks, R.; Sun, G.; McGill, P. J. Org. Chem. 1998, 63, 2564–2573.
(18) (a) Lewis, C. A.; Miller, S. J. Angew. Chem., Int. Ed. 2006, 45, 5616–
5619. (b) Balskus, E. P.; Jacobsen, E. N. Science 2007, 317, 1736–1740.
(19) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. 1985, 24, 1–76.
(20) (a) Rose, G. D.; Gierasch, L. M.; Smith, J. A. Adv. Protein Chem.
1985, 37, 1–109. (b) Haque, T. S.; Little, J. C.; Gellman, S. H. J. Am. Chem.
Soc. 1996, 118, 6975–6985. (c) Miller, S. J. Acc. Chem. Res. 2004, 37, 601–610.
(21) (a) Kametani, T.; Kanaya, N.; Ihara, M. J. Am. Chem. Soc. 1980,
102, 3974–3975. (b) Plate, R.; Akkerman, M. A. J.; Ottenheijm, H. C. J.
J. Chem. Soc., Perkin Trans. 1 1987, 2481–2490. (c) Sanz-Cervera, J. F.;
Glinka, T.; Williams, R. M. Tetrahedron 1993, 49, 8471–8482. (d)
Schkeryantz, J. M.; Woo, J. C. G.; Siliphaivanh, P.; Depew, K. M.;
Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11964–11975.
(22) The stereochemical assignments for the products are discussed
below and in the Supporting Information.
(23) Catalytic reactions involving substrate 25 have been performed
on up to 770 mg (2 mmol) of the substrate with excellent consistency
and reproducibility.
(24) Calculations at the B3LYP/6-31G(d) suggests the HOMO
of (N-phthalimido)-2-phenyltryptamine is higher than that of
(N-phthalimido)-tryptamine by 2.9 kcal/mol.
(25) Substrates 40a,b were prepared by deprotection of compound
40c followed by amine acylation or sulfonylation.
(26) Oxidation of 2,3-dimethylindole and 3-(2-N,N-phthaloyl-
aminoethyl)-2-(3-oxobutyl)-1H-indole under the standard conditions deli-
vers the corresponding over-oxidation products. See Supporting Information.
9111
dx.doi.org/10.1021/ja202706g |J. Am. Chem. Soc. 2011, 133, 9104–9111