Regioselective cope rearrangement and prenyl transfers on indole scaffold mimicking fungal and bacterial dimethylallyltryptophan synthases

Article abstract of DOI:10.1021/jo501651z

Aromatic prenyltransferases are an actively mined enzymatic class whose biosynthetic repertoire is growing. Indole prenyltransferases catalyze the formation of a diverse set of prenylated tryptophan and diketopiperazines, leading to the formation of fungal toxins with prolific biological activities. At a fundamental level, the mechanism of C4-prenylation of l-tryptophan recently has surfaced to engage a debate between a "direct" electrophilic alkylation mechanism (for wt DMATS and FgaPT2) versus an indole C3-C4 "Cope" rearrangement followed by rearomatization (for mutant FgaPT2). Herein we provide the first series of regioselectively tunable conditions for a Cope rearrangement between C3 and C4 positions. Biomimetic conditions are reported that effect a [3,3]-sigmatropic shift whose two-step process is interrogated for intramolecularity and rate-limiting general base-promoted mechanism. Solvent polarity serves a crucial role in changing the regioselectivity, resulting in sole [1,3]-shifts under decalin. An intermolecular variant is also reported that effectively prenylates the C3 position of l-tryptophan, resulting in products that mimic the structures accessed by bacterial indole prenyltransferases. We report an elaborate investigation that includes screening various substituents and measuring steric and electronic effects and stereoselectivity with synthetically useful transformations.

Full text of DOI:10.1021/jo501651z

Article
pubs.acs.org/joc
Regioselective Cope Rearrangement and Prenyl Transfers on Indole
Scaffold Mimicking Fungal and Bacterial Dimethylallyltryptophan
†
Synthases
Karthikeyan Thandavamurthy,‡ Deepti Sharma, Suheel K. Porwal, Dale Ray, and Rajesh Viswanathan*
Department of Chemistry, Case Western Reserve University, Millis Science Center Room 214, 2074 Adelbert Road, Cleveland Ohio
44106-7078, United States
S
* Supporting Information
ABSTRACT: Aromatic prenyltransferases are an actively mined enzymatic class whose biosynthetic repertoire is growing. Indole
prenyltransferases catalyze the formation of a diverse set of prenylated tryptophan and diketopiperazines, leading to the
formation of fungal toxins with prolific biological activities. At a fundamental level, the mechanism of C4-prenylation of L-
tryptophan recently has surfaced to engage a debate between a “direct” electrophilic alkylation mechanism (for wt DMATS and
FgaPT2) versus an indole C3−C4 “Cope” rearrangement followed by rearomatization (for mutant FgaPT2). Herein we provide
the first series of regioselectively tunable conditions for a Cope rearrangement between C3 and C4 positions. Biomimetic
conditions are reported that effect a [3,3]-sigmatropic shift whose two-step process is interrogated for intramolecularity and rate-
limiting general base-promoted mechanism. Solvent polarity serves a crucial role in changing the regioselectivity, resulting in sole
[1,3]-shifts under decalin. An intermolecular variant is also reported that effectively prenylates the C3 position of L-tryptophan,
resulting in products that mimic the structures accessed by bacterial indole prenyltransferases. We report an elaborate
investigation that includes screening various substituents and measuring steric and electronic effects and stereoselectivity with
synthetically useful transformations.
from multiple genera of fungi1,9−30 and other microbial
INTRODUCTION
■
systems.31−36 The underlying mechanistic dichotomy between
Prenyltransferases are an extensive family of enzymes
a direct C4-prenylation on the indole nucleus (through an
responsible for activating and modifying isoprenoids (C5, C10,
electrophilic aromatic substitution3,37) and a C3-reverse
C15, C20, etc.) for the biosynthesis of diverse secondary
metabolites. Aromatic prenyltransferases are an actively mined
prenylation followed by a Cope rearrangement−tautomeriza-
tion sequence (recently brought to light by Tanner et
enzymatic class whose biosynthetic repertoire is growing.
al.27,28,38,39) still lingers, depending on the nature of the
Tryptophan-containing alkaloids and peptidyl natural products
enzyme one investigates. Proposed biosynthetic formalisms
are prenylated by a monophyletic subclass of aromatic
prenyltransferases in fungi, cyanobacteria, and a few plants.1
predated even the initial discovery and biochemical character-
ization of Claviceps purpurea DMATS gene.40,41 Mechanistic
Claviceps purpurea dimethylallyltryptophan synthase (DMATS)
speculations have spurred experimental research for over three
catalyzes the committed step toward formation of C4-
decades, with synthetic models originating from the labo-
dimethylallyltryptophan (1) from L-tryptophan (L-Trp) and
ratories of Arigoni,42 Wenkert,43 and Jackson,44−47 leading up
dimethylallyl diphosphate (DMAPP), as represented in Figure
1.2−5
to recent reports of elegant mechanistic probes developed by
Gaich and co-workers48,49 (Scheme 1A, B).
This step is a crucial biosynthetic event leading to the
formation of structurally diverse C4-prenylated alkaloid natural
products. Late-stage modifications on 1 lead to divergent
In the pregenomic era, the structure of echinulin, a fungal
prenylated tryptophan alkaloid, soon after its disclosure
generated active interest from synthetic chemists attempting
pathways toward ergot and clavine alkaloids, and their
specificity is organism-dependent.6−8 Evolutionarily related
DMATS species, also referred to as indole prenyl transferases
Received: July 21, 2014
(PTs), have been identified and biochemically characterized
Published: September 22, 2014
© 2014 American Chemical Society
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Figure 1. Enzymatic reaction catalyzed by C4-dimethylallyltryptophan synthase (4-DMATS) and its biosynthetic context toward clavine and
ergotamine alkaloid formation in multiple fungal organisms.
to offer a mechanistic rationale for its biosynthesis. The direct
C4 electrophilic alkylation mechanism originally proposed (and
experimentally verified) for the Claviceps 4-DMATS enzyme by
Poulter et al. recently has received a rejuvenated interest. The
position isotope exchange (PIX) experiments38,39 along with
the substitution studies on wild-type Claviceps 4-DMATS37
added further evidence for a direct C4 electrophilic alkylation
of L-Trp. The discovery of a C3-reverse prenylated pyrroloindo-
line product under a Lys174Ala mutant of FgaPT2 enzyme
raised the possibility of a potential C3- to C4-Cope
rearrangement as a mechanistic model.39 In the postgenomic
era, nearly 200 gene candidates that share significant sequence
similarity to DMATS are identifiable in publicly available
genomes. While the synthetic endeavors reported by Voute et
al.50 and Gaich et al.48,49 (as shown in Scheme 1B) provided
some insight into the feasibility of models proposed earlier by
Arigoni,42 Wenkert,43 and Jackson,44 these biosynthetic trans-
formations continue to present special challenges for synthetic
chemists attempting to mechanistically emulate their molecular
construction steps.
substituted indole C3-propionic acid carboxyethyl ester (16d)
and its methyl ketone version (16e), and a simpler C3-methyl
substitution (16f). The series of other substituted C3-reverse
prenylated oxindoles prepared for this study included examples
16g−k possessing a C6-carboxymethyl ester substitution and a
C6-fluoro-, C6-chloro-, C7-methyl-, and C5-methoxy-substi-
tuted oxindoles, respectively, all in moderate to high percent
isolated yields. Technically, any allylic alcohol could participate
in the one-step method involving activation with NCS as shown
in eq 1, and therefore a series of nonprenyl alcohols were
engaged to prepare oxindoles 16l−o, respectively. The
extended prenyl chain compounds geraniol and nerol gave
oxindoles 16p,q, respectively. Treatment of derivative 15r with
(E,E)-farnesol resulted in the formation of 16r.
Heat- and Microwave-Promoted [3,3]- and [1,3]-
Prenyl Transfer Rearrangements. Having synthesized
16a−r as precursors for testing the [3,3]-sigmatropic rearrange-
ment, we first attempted to identify the optimal set of solvent
and temperature conditions to effect this transformation. A
series of solvents ranging from those with very low dielectric
constants such as toluene and decalin to highly polar solvents
with very high dielectric constants such as dimethylacetamide
(DMAc) and water were screened (see Table S3 in the
Supporting Information). Bearing in mind that oxindole C3-
substitution drastically affects the conformational preferences
and populations with respect to reactivity at the C4 position,55
we chose to test the feasibility of the [3,3]-sigmatropic
rearrangement with a C3-methyl substituent for reasons of
least perturbation to the process of the two olefins engaging in
the rearrangement. Therefore, 16f was subjected to thermal
rearrangement conditions, it was observed that many solvents
were suboptimal in effecting any rearrangement, and we
recovered unreacted starting 16f. Upon employing DMAc
and decalin, two solvents with drastically different polarities, we
observed a dramatic shift in the regioselectivity of rearrange-
ment products, as illustrated in Scheme 2. When it was heated
to 160 °C in DMAc, oxindole 16f gave the Cope rearrangement
product 17f in 32% yield (see the Supporting Information for
additional details).
A direct Cope rearrangement51 on open-chain L-Trp to
access 1 is still missing. Herein we report, for the first time, a
detailed study of an efficient [3,3]-Cope rearrangement (from
C3 to C4), under biomimetic and environmentally friendly
conditions (Scheme 1C). Additionally, a regio- and stereo-
selective [1,3]-rearrangement and an intermolecular prenyl
transfer reaction resulting in pyrroloindolines (with C3-normal
prenyl substitution) are reported. These reactions are appealing
additions to the synthetic toolkit, considering the tediousness
that prefunctionalization of the C4 position of indole demands
for synthesizing complex, bioactive natural products.
RESULTS AND DISCUSSION
■
Access to Substrates for a [3,3]-Cope Rearrangement.
As shown in Table 1, in order to test the feasibility of a [3,3]-
sigmatropic rearrangement on the open-chain indole scaffold,
we prepared a variety of substrates using a Meerwein−
Eschenmoser−Claisen rearrangement52−54 on C3-substituted
indoles (15). Treatment of nitrile-containing C3-substituted
indole 15a with N-chlorosuccinimide (NCS) in the presence of
1,4-dimethylpiperazine, prenol (8), and trichloroacetic acid
resulted in a 61% yield of oxindole 16a. The series of reverse-
prenylated oxindoles synthesized included N-phthalyl-protected
tryptamine (16b), its N-Me-Tosyl protected variant (16c),
When decalin was employed as the solvent, under reflux
temperature, we observed smooth and near-quantitative
conversion to C3-dimethylallyl oxindole 18f, which contained
a normal prenyl substitution. A formal [1,3]-prenyl transfer
process at the C3 position of oxindole had occurred under
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Scheme 1. (A) Prior 4-DMATS Enzymatic Mimics That Failed, (B) C3−C4 Divinyl Cyclopropane Ring-Opening Cope
Rearrangement Reported by Schwarzer and Gaich,48 and (C) Description of Intra- and Intermolecular Prenyl Transfer
Reactions under Biomimetic Conditions Reported Herein
decalin as the nonpolar solvent. Thus, mechanistically divergent
pathways were found to be operative under the two solvent
conditions. Excited by the prospect of observing a [3,3]-
sigmatropic (reverse-prenyl to prenyl) rearrangement occurring
between the C3 and C4 positions of oxindole 16f, we next
tested a series of oxindoles for estimating the synthetic
efficiency of the Cope rearrangement. As shown in Table 2
(eq 2), various substitution patterns were studied, including
substituents at the C3, C5, C6, and C7 positions. Cyanoethyl-
containing 16a rearranged to give the [3,3]-product 17a in 31%
yield. The protected tryptamine 16b underwent a [3,3]-
sigmatropic shift to the C4 position in 74% yield. A range of
substitution patterns was tested, and uniformly, the efficiency of
the [3,3]-rearrangement was evaluated as given in Table 2.
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Table 1. Prenyl Transfer Reaction for Synthesis of Reverse-Prenylated Oxindoles
Minor amounts of [1,3]-rearrangement products were formed
in some cases. We probed the probable involvement of a
radical-mediated process during the formation of products
resulting from a [1,3]-prenyl rearrangement. On the basis of
similar studies performed by Harwood et al. on related Claisen
rearrangements,56−58 we wondered if the radical process
initiated by atmospheric oxygen could then be can inhibited
under presence of hydroquinone. Accordingly, when 16e,f were
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a
Scheme 2. Shift of Regioselectivity for Prenyl Transfer Reactions with Drastically Different Solvent Dielectric Constants
a
% yield refers to isolated yield after chromatography.
a
Table 2. Substrate Scope and Generality Given as a Function of R Group Variability at the C3 Position of Oxindoles
substituents
R1
yield (%)
[3,3]-17
substrate
R
R2
R3
time (h)
conversion (%)
[1,3]-18
16a
16b
16c
16dc
16e
16f
CH2CH2CN
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
20
17
18
48
43
50
17
15
15
18
22
40
15
nd
62
60
50
nd
nd
nd
ns
31
74
57
52
<5
4
CH2CH2NPhth
CH2CH2N(Tos)Me
CH2CH2COOEt
CH2CH2COCH3
Me
H
c
H
11
H
<5
b
c
H
43 (50 )
ca. 10
b
H
32 (36 )
16
<5
<5
<5
d
16g
CH2CH2COCH3
CH2CH2COCH3
CH2CH2COCH3
CH2CH2COCH3
CH2CH2COCH3
CH2CH(NPhth)COOMe
CH2CH2N(Nos)Me
H
COOMe
43
<5
<5
60
16h
16i
16j
16k
16s
16t
H
F
H
Cl
H
H
H
H
ns
c
H
45
nd
100
58
10
b
OMe
H
45 (50 )
<5
<5
61
50
c
H
11
a
b
Sterically larger R groups encouraged [3,3]-rearrangement. Abbreviations: nd, not determined; n, −not stable under the conditions tested. Isolated
c
d
yield based on recovered starting material. Calculated from1H NMR data. Unoptimized.
independently subjected to [1,3]-prenyl rearrangement con-
ditions in decalin, we observed complete recovery of starting
material, even after 72 h. However, the reaction proceeded well
when hydroquinone was eliminated, suggesting that the radical-
based mechanism was probable. Overall, in non-isatin-derived
substrates (16e,f) as well as in isatin-derived cases (21a−c; vide
infra), we observed a radical pathway to be operative under
[1,3]-rearrangement processes.
The synthetic utility of examples 16b, c, s, t is particularly
noteworthy, as many alkaloid natural products possess a
tryptamine or tryptophan side chain and their C4-prenylated
products are directly accessed through this [3,3]-rearrangement
process. Convinced that the strategy was working on oxindoles
with the tryptamine side chain, we studied the conditions to
improve reaction rates and yields. Multiple boron- and
aluminum-based Lewis acids failed to catalyze the Cope
rearrangement process. However, heating the oxindole in
aqueous phosphate buffer with microwave assistance dramat-
ically accelerated the rearrangement (Table 3).
For example, the cyanoethyl oxindole 16a, when subjected to
microwave irradiation at 150 W and 150 °C, in just 60 min (as
opposed to several hours under nonmicrowave heating
conditions) gave a 58% yield of the C4-prenylated 17a.
Phthalyl-protected tryptamine gave a 75% yield of the C4-
prenylated product 17b in 40 min. Substrates 16c−t all
underwent a [3,3]-Cope rearrangement in durations that
ranged between 40 and 90 min, at pH 8.8 in phosphate buffer.
Except in cases 16f, h, k all other substrates gave the [3,3]-
rearranged product 17 as the major product under these
conditions. The three exceptions produced minor amounts of
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a
Table 3. C4-Prenylation of Tryptophan Scaffold under Phosphate-Buffered Conditions
substituent
substrate
R
R1
R2
R3
temp (°C)
time (min)
yield [3,3]-product 17 (isolated) (%)
16a
16b
16c
16d
16e
16f
16g
16h
16i
CH2CH2CN
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
150
150
150
150
150
165
150
150
150
150
150
150
150
60
40
65
65
70
90
60
60
60
62
70
60
50
58
75
40
42
46
CH2CH2NPhth
CH2CH2N(Tos)Me
CH2CH2COOEt
CH2CH2COCH3
Me
H
H
H
H
b
H
16
CH2CH2COCH3
CH2CH2COCH3
CH2CH2COCH3
CH2CH2COCH3
CH2CH2COCH3
CH2 CH(NPhth)COOMe
CH2CH2N(Nos)Me
H
COOMe
40
d
H
F
40
H
Cl
H
H
H
H
45
50
16j
H
c
16k
16s
16t
OMe
H
48
54
ns
H
a
b
c
Abbreviations: ns, not stable under conditions tested. 42% of [1,3]-product was obtained 13% of [3,3]-product without an R group was obtained.
22% of [1,3]-product was obtained.
d
Scheme 3. (A) [3,3]-Prenyl Transfer reaction on L-Trp-Derived 16s, Starting with C3-Reverse Prenylation Followed by DMAc
or Phosphate-Buffer-Mediated Rearrangement To Yield 17s and (B) Chiral HPLC Analysis of a Single Diastereomer of 16s
Converting to a 3:1 Mixture of Diastereomers of 17s
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Scheme 4. [3,3]-Prenyl Transfer Reaction on α-Amino Acid, Starting with C3-Reverse Prenylation To Yield 16s after Protection
Followed by Heat- or Microwave-Mediated Rearrangement, (A) [3,3]-Cope Rearrangement of Geraniol-Derived 16p, (B) [3,3]-
Cope Rearrangement of Nerol-Derived 16q, and (C) [3,3] Cope Rearrangement of (E,E)-Farnesol-Derived 16r
either a [1,3]-prenyl rearrangement product (like in Table 2)
for 16f,k or showed loss of the C3-substituent altogether in the
case of 16h.
evaluated. Scheme 3B illustrates the results of such an
experiment. Upon chiral HPLC analysis of the product 17s,
we clearly observed a 3:1 ratio of products varying likely at the
C3 stereocenter. As the likelihood of epimerization at the α-
carbon of the α-amino acid chain is low, we attribute this result
to the presence of either antipode at the C3 center. Overall, this
Cope rearrangement proved to be stereoselective with respect
to the C3 oxindole center, and its stereochemical course could
also be translated to linear isoprenoid containing oxindoles.
As shown in Scheme 4, a chain-elongated version of the
prenyl transfer process was next tested on substrate 16p.
Similar to the case for 16s, oxindole 16p was accessed, as a
single diastereomer (in 58% yield), through a Meerwein−
Eschenmoser--Claisen rearrangement on N-phthalyl tryptamine
(Table 1). Subjecting 16p to a [3,3]-Cope rearrangement
process in DMAc solvent at 160 °C gave a 17:83 mixture (in
55% yield) of E and Z geometric isomers that differed in their
newly formed double-bond geometry. Similarly, when 16p was
subjected to microwave irradiation conditions, 17p was
obtained as a 23:77 mixture of E and Z isomers, as shown in
Scheme 4B. A Zimmerman−Traxler-like transition state
assembly, depicted by 19, probably rationalizes the observation
of formation of the Z isomer as the major product, keeping in
Realizing that a worthy test of a Cope rearrangement to
construct a C4-prenylated indole scaffold will be on a α-amino
acid scaffold of L-Trp, as shown in Scheme 3A, we attempted
sequential prenylation on the amino acid L-Trp upon protection
(as its methyl ester N-phthalyl counterpart) by subjecting it to a
Meerwein−Eschenmoser−Claisen rearrangement with prenol,
resulting in 16s in 80% yield. Thus, on subjecting 16s to either
the thermal rearrangement condition in DMAc or microwave
irradiation in phosphate buffer at pH 8.8, we were glad to
observe formation of 17s in 58−61% and 54% yields,
respectively. The product 17s was formed as a 1:1 mixture of
diastereomers (Scheme 3A).
This observation prompted that the Cope rearrangement/
tautomerization sequence of C3-reverse prenylation substrates
16 to products 17 is not necessarily stereospecific. In order to
further test the stereoselective nature of this transformation, we
sought to explore a control experiment wherein L-Trp-derived
16s, purified to a single diastereomeric composition (dr:
>99:1), could be subjected to the Cope rearrangement/
tautomerization sequence and the product stereochemistry be
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Scheme 5. (A) [1,3]-Prenyl Transfer Reaction for C3-Hydroxy-Substituted Oxindoles and (B) Proposed Pathway with Radical
Intermediate 23b Likely To Explain Regioselectivity Observed for Formation of 22 Based on Hydroquinone Inhibition Data in
A
mind that the participating atoms of the oxindole portion are
sp2 hybridized. The oxindole 16q, on the other hand, was
obtained as an 8:1 mixture of diastereomers (in 60% yield)
from the Meerwein−Eschenmoser−Claisen rearrangement on
N-phthalyl tryptamine and nerol as the allylic alcohol (Table 1).
When 16q was subjected to the Cope rearrangement process,
the C3 to C4 prenyl migration occurred smoothly, resulting in
17q, which possessed the E geometry across the newly formed
olefin in 46% and 62% yields, under DMAc or phosphate-
buffered conditions with microwave irradiation, respectively.
The product displayed the geometric ratio of E and Z isomers
reflective of a situation similar to 17p but opposite in
magnitude due to the nature of the diastereomeric composition
of 16q. Overall, we observed stereospecific C3 to C4 prenyl
transfer migration under Cope rearrangement conditions, with
respect to the olefinic portion of the isoprenoid chain, for
16p,q. Similarly, when oxindole 16r (previously synthesized
from (E,E)-farnesol in 48% yield) was subjected to Cope
rearrangement conditions, 17r was obtained in 52% yield as a
single isomer containing the Z,E double-bond geometry. Thus,
we see complete conservation of the double-bond geometry
related from farnesol substrate to product 17r after two
pericyclic rearrangements.
Mechanistic Evaluation of [3,3]-Cope Rearrangement.
Scheme 5 outlines the results we observed when C3-hydroxy
oxindoles 21a−c were subjected to the Cope rearrangement
conditions. Interestingly, as opposed to other examples where
anionic oxy-Cope rearrangements are known to occur in a
more accelerated manner, we observed no [3,3]-rearrangement
in any of these examples. Instead, every substrate underwent a
nearly exclusive [1,3]-prenyl rearrangement resulting in C3-
normal prenyl substitution in 22a−c. The synthetic efficiency of
these thermally activated [1,3]-prenyl migration processes was
reasonable, and 22a−c were obtained in 50%, 50%, and 41%
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Scheme 6. Mechanism of [3,3]-Prenyl Transfer Reaction: (A) Crossover Experiment; (B) Two-Step Mechanism; (C) pH
Dependence of (B); (D) Electrophilic Aromatic Substitution Model of 4-DMATS Involving Deprotonation of C4-Hydrogen
Similar to Intermediate 26
yields, respectively, with DMAc as the solvent. The
corresponding efficiency for [1,3]-prenyl transfer under micro-
wave-mediated conditions were considerably higher at 89%,
75%, and 87%, respectively, for 22a−c. While the [3,3]-Cope
rearrangement process was investigated mechanistically as
discussed below, the 3-hydroxy examples provided a reasonable
rationale, as represented in Scheme 5B, for their mechanism for
the [1,3]-prenyl migration event. Similar to the case for 16e,f,
the presence of 10 mol % hydroquinone during the [1,3]-prenyl
migration event entirely abrogated the formation of 22a−c. On
the basis of nature’s biosynthetic repertoire involving C5 (and
higher order) isoprenoid pyrophosphates (DMAPP, GPP, FPP,
etc.) in numerous examples of chain elongation and branching
events, it is reasonable to consider a prenyl cation involvement
(as shown in 23a) for the transformation of 21 to 22. However,
considering the fact that a radical inhibitor causes complete
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Scheme 7. Intermolecular Prenyl Transfer Reaction To Construct a Pyrroloindoline Skeleton under Biomimetic Conditions
shutdown of the conversion, we propose that a radical-based
pathway involving the tightly coupled radical pair 23b as the
likely intermediate toward 22. Wenkert and Sliwa, in their
reported study43 on 6-5-6 (or 6-5-5) pyrroloindolines that were
C3-reverse prenylated, observed this type of a [1,3]-prenyl shift
consistently for most examples they attempted under pyrolysis
conditions. The mechanistic explanation offered here also could
be applied to examples seen in their studies.
accelerate or decelerate the overall process, if this rear-
omatization event is rate-limiting. Therefore, we conducted
an investigation by estimating the percent conversion (and
corresponding percent yield) of the C4-prenylated product
(17b) formation, starting from 16b at various pHs in
phosphate-buffered solutions (Scheme 6C). Between pH 6
and 6.5, there was no 17b observed, indicating that the
deprotonation of the C4 proton to cause rearomatization was
shut down in even a slightly acidic medium. Drastic change
toward >60% conversion and yield was observed at pH ≥7.0.
The conversion and yield improved consistently with increase
in pH and were maximized close to pH 8.8. From a biomimetic
standpoint this result was a near replica of the enzyme active
site. The first step of the two-step process, a [3,3]-Cope
rearrangement, is not expected to involve polar or ionic
transition states (though this is not unprecedented) and
therefore is expected to be pH neutral. Though we treat this
Cope rearrangement as an equilibrium process, we do expect
the apparent equilibrium constant to be favoring 26,
considering steric congestion at C3 of the precursor oxindole
16. Therefore, the presence of a basic medium (at pH 8.8) is
seen to dramatically shift the overall efficiency toward 17b
through expediting the proton transfer event, resulting in a fully
aromatic and stabilized 17b. With 17b as a representative, we
anticipate most other substrates undergoing this prenyl transfer
process to conform to this biomimetic pH effect.
We next probed the [3,3]-Cope process for a mechanistic
understanding, specifically asking whether the process is strictly
intramolecular or if there was any intermolecularity involved
when the prenyl group migrates from the C3 to the C4 position
of the oxindole ring system. Therefore, as shown in Scheme 6A,
a competition experiment was conducted with 16f, q premixed
in an equimolar ratio and were subjected to phosphate-buffered
solution at pH 8.8 and microwave irradiation at 150 °C. At
complete conversion of the starting materials, we observed only
the formation of 17f,q. The product containing a prenyl (C5)
group on the C4 position of tryptamine scaffold represented by
24 and the product containing a geranyl (C10) unit at the C4
position of methyl-carrying oxindole represented by 25 were
1
not observed by H NMR. This observation confirmed that an
intermolecular scrambling of prenyl groups was not operative.
No prenyl-scrambled [1,3]-products were seen either, indicat-
ing overall that the Cope process is intramolecular under these
conditions.
Biochemical characterizations of DMATS and FgaPT2
revealed the presence of Lys174 and Glu89 as crucially
important and essential residues.3,37−39 Their roles were
clarified through mutation studies, which revealed that Glu89
was involved in activation of the indole nucleophile through
engagement in hydrogen bonding and ensuing removal of the
N1 hydrogen. Lys174, whose site-directed mutagenesis nearly
abolished the production of 1, served as the base responsible
for deprotonation and tautomerization of the intermediate
formed immediately after the C4-alkylation.
In our studies, as represented in Scheme 6B, considering that
a [3,3] rearrangement results in the nonaromatic intermediate
26 (equivalent to the biological case preceding formation of 1),
we wondered if this formal two-step process leading to C4-
prenylated 17b would be sensitive to varying pH. Due to the
fact that this “rearomatization” is essential for formation of the
eventual product 17, the influence of a basic or acidic medium
(mimicking the presence or absence of Lys174) is expected to
The Cope rearrangement was also found to be sensitive to
the ring substituent and the steric composition at the C3
position. As shown in Figure S1 (Supporting Information), the
duration of the thermal rearrangement for each substitution
pattern revealed the effect that the individual substitutions had
on the transformation. Electron-withdrawing substituents on
the aromatic ring of oxindole (16i, g, h) promoted the rate of
the prenyl transfer process to the C4 position. This correlated
with the expectation that the formal second step of the process
involving tautomerization of intermediate 26 is expected to be
promoted by electron-withdrawing substituents by virtue of
lowering the pKa of the proton at the C4 position of 26 (see the
blue highlight in Scheme 6B). Conversely, the presence of an
electron-donating methoxy substituent (16k) slowed down the
rearrangement process, again by virtue of increasing the pKa of
the proton at the C4 position of 26. The presence of
substituents on the C3 chain of the tryptamine or tryptophan
scaffold to a general extent had a positive effect on promoting
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Figure 2. Indole prenyltransferases and their regioselectivity of prenylation (blue) on L-Trp (red). Bold arrows reflect the fact that the indicated
enzyme has been biochemically characterized. Scaffolds presented in boxes represent examples for which biomimetic pathways are presented in this
report.
the rate of the rearrangement process. Steric effects were
manifested in two specific ways. The first type of steric effect
that was observed was on examples that carried a C3
substituent. Among a cyanoethyl group (16a), an ethyl methyl
ketone (16e), an ethyl carboxy ester (16d), and a protected
tryptophan (16s), we found that the rate was influenced by a
subtly balancing steric factor that tilted toward faster rearrange-
ment for substituents that were too bulky. Second, a possible
Thorpe−Ingold effect was apparent for substituents that forced
the reactive olefins to engage in the rearrangement process. An
extreme of this correlation can be seen in Gaich’s reports that
carry a cyclopropane to promote the rearrangement.48
Additionally, the absence of a Cope rearrangement on any of
the nonreverse prenyl oxindole examples (16l−o) corroborated
the apparent presence of the Thorpe−Ingold effect imposed by
the presence of the geminal dimethyl substitution of the
reverse-prenyl group. The relatively slow and sluggish rate
observed for C3-methyl substitution (16f) was attributable to a
similar effect.
Prenylating the C3 position of indoles directly with alkyl
electrophiles is a challenging process under aqueous conditions.
To address this challenge, an intermolecular prenyl transfer
reaction was attempted next, as outlined in Scheme 7. L-Trp
methyl ester (11) was subjected to prenylation at the C3
position in the presence of prenyl bromide in sodium acetate−
acetic acid buffer and pH 2.7 at room temperature and gave rise
to products 13 and 14 in a 4:1 ratio favoring the exo product.
The corresponding N1-methylated substrate (27) underwent
the C3-prenylation event with prenyl bromide and resulted in a
mixture of exo and endo diastereomers 28 and 29. The use of
prenyl bromide to activate the C3 position of the indole ring
system concomitantly resulted in formation of the pyrroloindo-
line ring system. Both in the case of nonmethylated 13 and in
the case of methylated 29,the products were characterized for
their relative stereochemistry through measurement of the
NOESY correlations around the protons of the pyrroloindoline
skeleton. The prenylation of indoles under aqueous conditions
is challenging. We derived our inspirations from the report of
Bocchi et al., though we fortuitously arrived at drastic
improvements over the percent yields of the pyrroloindoline
products.59 Additionally, the indole C3-prenylation conditions
we report herein results in approaches to natural product
biosynthetic studies of the nocardioazine alkaloids. A high
degree of biomimeticity is evident between our prenylation
strategy (11 to 13 + 14; and 27 to 28 + 29) and those of the
indole prenyltransferases observed in the literature leading to
multiple alkaloid pathways encoded by the Aspergillus sp.21 and
the Bacillus subtilis ComX pheromonone synthesizing ComQ
geranyl transferase enzyme.60,61
Tryptophan Prenylations in Biosynthesis. Tryptophan
prenylation (with C5 isoprenoid) is a well-documented
enzymatic phenomenon. Every possible site for enzymatic
prenylation on the indole scaffold (N1−C7) has been observed,
with the individual enzyme being functionally active on select
prenylation position(s) (Figure 2). Among the individual
pathways, indole prenyltransferases arguably are one of the
most intricate enzymes involved in the biosynthesis of complex
natural products. Fungal biosynthetic pathways leading to a
large collection of prenylated indole alkaloids (a few
representative examples are presented in Figure 2) have
spurred an extensive body of work on their structure
elucidation, asymmetric synthesis, medicinal chemistry, and
related studies. Gene clusters and their characterization have
evolved in the postgenomic era and have actively inspired
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further chemoenzymatic syntheses, mechanistic enzymol-
ogy,7,8,13,14,62 and structural biology of these unique bio-
catalysts.63 For example, aurantioclavines are representative of
the synthetic challenges that continue to spur newer method-
ologies to emerge.64,65 Well into the 21st century, the only
known L-Trp prenyltransferase was from Claviceps purpurea.
Genome sequencing projects on Aspergillus spurred the
identification of a series of indole prenyltransferases that were
found to prenylate a variety of substrates such as L-Trp,
diketopiperazines containing tryptophan units, and L-Trp-
conjugated benzodiazepines. As summarized in Figure 2, a
spectrum of prenylation patterns can now be observed.
Specifically, the work presented herein mimics the indole
prenyltransferases operative toward the biosynthesis of four
specific alkaloid classes. The C3-reverse prenylation reactions
used herein for the synthesis of a series of oxindoles 16 mimic
the products seen from AnaPT-catalyzed C3-reverse prenyla-
tion, leading to the formation of aszonalenin and CdpNPT-
catalyzed formation of roquefortines. The C3−C4 prenyl
migrating Cope rearrangement reported herein for the series of
compounds 16 transforming to 17 mimics the catalytic action
carried out by mutant FgaPT2. The product resulting from the
Cope rearrangement is identical with that formed from a direct
alkylation seen in Claviceps purpurea DMATS. The mimicry
shown by the intramolecular [1,3]-prenyl migration event (16
to 18 or 21 to 22) results in products that share structural
similarity to C3-normal prenylating enzymes. The intermolec-
ular prenylation reaction resulting in the C3-normal pattern
shown in Scheme 6 also mimics these indole prenyltransferases.
One such pathway leads to the formation of nocardioazines,
biosynthesized by Nocardiopsis sp. CMB M0232. Ongoing
activity in our laboratory is currently elucidating the enzyme
action of NozC, a bacterial homologue that prenylates C3
positions of L-Trp diketopiperazine substrates.
Interestingly, the catalysis affected by indole prenyltrans-
ferases is now beginning to be better understood through X-ray
crystallography. As represented in those with known three-
dimensional structures show remarkable similarity in their
biophysical folds leading to overlapping substrate−product
relationships with surprising levels of promiscuity. Overall, this
work is anticipated to enrich the synthetic toolkit63 and add
novel directions for future investigations in alkaloid total
synthesis and biosynthesis. Moreover, in conjunction with
earlier work published by Schwarzer et al.,48,49 these reactions
together offer feasibility for a Cope rearrangement mechanism,
at least under nonenzymatic conditions. In a related manner, a
possible extension of this work could be directly applicable to
the synthesis of compounds that may throw light on the
mechanisms of FgaPT2 and DMAW synthase enzymes from
Aspergillus and Claviceps, respectively.
tically, pH variations and the ensuing sensitivity revealed a
slower step involving tautomerization of the C4 proton to the
C3 position. In turn, this implied that the Cope rearrangement
itself could be the reversible faster step. Parallel to the Cope
rearrangement, we found that use of a nonpolar solvent such as
decalin promoted a regioselective [1,3]-prenyl transfer reaction
resulting in C3-normal prenyl substituted oxindoles. C3-
hydroxylation also enforced a stricter selectivity for the [1,3]-
prenyl transfer process. Direct prenylation of the L-Trp scaffold
was also effected under biomimetic conditions, resulting in
pyrroloindolines with C3-normal prenyl substitution. Overall,
these conditions are expected to find use in natural product
total synthesis, considering the urgent need for stereoselective
methods for complex alkaloid construction. The design and
synthesis of mechanistic probes for DMATS and related
enzymes may also be possible through these prenyl transfer
reactions. These results may prompt synthetic chemists in the
alkaloid field to explore additional methods of elaborating the
indole ring utilizing prenylations and sigmatropic rearrange-
ments.
EXPERIMENTAL SECTION
■
Representative Procedures. General Procedure A: Reverse
Prenylation of C3-Substituted Indoles. A two-neck round-bottomed
flask with a magnetic stir bar (capped with septa) was dried under
vacuum. Once cooled to ambient temperature under inert atmosphere,
the flask was charged with 3-cyanoethylindole (15a; 256 mg, 1.5
mmol) that was mixed with 5 mL of dry dichloromethane and stirred.
Freshly distilled 1,4-dimethylpiperazine (0.13 mL, 0.96 mmol) was
added, and the reaction flask was cooled to 0 °C on ice. Recrystallized
NCS (221 mg, 1.65 mmol) was added, and the stirring continued at
the same temperature for 2 h under nitrogen. In a separate round-
bottomed flask, CCl3COOH (60 mg, 0.36 mmol) and prenyl alcohol
(0.3 mL, 3.0 mmol) were mixed, diluted with dichloromethane (2
mL), and stirred at room temperature. After 2 min, this mixture was
cannulated into the reaction flask at 0 °C and the ensuing mixture was
gradually warmed to room temperature and stirred for 12 h. Wet
dichloromethane (3 mL with 5 drops of water) was added dropwise to
the mixture to quench the reaction. The reaction mixture was washed
with 0.5 M NaHCO3 (20 mL), 0.5 M HCl (20 mL), and brine (20
mL). The organic layers were dried with anhydrous Na2SO4 and
evaporated to yield the product mixture as a yellow oil. The mixture
was subjected to silica gel chromatography (18% ethyl acetate in
hexanes) to yield the purified product 16a (as a representative
example) in 61% isolated yield (236 mg, 0.93 mmol) as a pale oil that
solidified upon standing.
General Procedure B: Cope Rearrangement under Thermal
Conditions. The C3 reverse-prenylated oxindole 16s (1.0 g, 2.31
mmol) was taken in a vial and capped with a septum. Under nitrogen,
16s was dissolved in DMAc to form a 0.1 M solution. The solution
was transferred to a Schlenk tube using a syringe and capped under
nitrogen and heated in an oil bath at 155 °C for 40 h. The reaction
mixture was cooled to room temperature, and DMAc was removed in
vacuo. The reaction mixture was diluted with ethyl acetate (15 mL)
and washed with brine (15 mL × 3). The organic layer was dried with
anhydrous Na2SO4 and evaporated to give the crude product, which
was subjected to silica gel chromatography (refer to general
experimental details in the Supporting Information) with ca. 1/4 v/v
ethyl acetate/hexane as eluent, and the product oxindole 17s (as a
representative example) was isolated as a pale yellow solid in 61% yield
(610 mg, 1.41 mmol).
General Procedure C: Cope Rearrangement under Microwave
Irradiation. A 10 mM phosphate buffer (pH 8.8) was prepared by
dissolving 3 mg of monosodium phosphate hydrate and 262 mg of
disodium hydrogen phosphate in 100 mL of doubly deionized water.
C3-reverse prenylated oxindole (30 mg, 0.08 mmol) 16b was dissolved
in 0.75 mL of buffer in a microwave-compatible sealed tube and
subjected to irradiation of 150 W of 150 °C over 40 min. The reaction
CONCLUSION
■
L-Trp presents a dazzling array of nucleophilic positions that
enzymes take full advantage of by prenylating various positions
in natural product biosynthetic pathways. Synthetic mimicry of
these selective biocatalysts has been rare, primarily due to the
challenge in taming regio- and stereoselectivities of such
transformations. Herein we present a facile [3,3]-prenyl group
migrating Cope rearrangement that was evaluated for its
synthetic efficiency, substituent diversity, biomimeticity, and
possible mechanistic underpinnings. We find that the
phosphate-buffered microwave-mediated conditions uniformly
resulted in good yields of C4-prenylated products. Mechanis-
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mass was extracted with ethyl acetate (10 mL) and washed with brine
(10 mL). The organic layer was dried with anhydrous Na2SO4 and
evaporated to give the crude reaction mixture, which upon purification
by preparative TLC (refer to general experimental detailsin the
Supporting Information) gave the product 17b in 75% yield (22.5 mg,
0.06 mmol).
General Procedure D: [1,3]-Prenyl Group Rearrangement. The
C3 reverse-prenylated oxindole (50 mg, 0.13 mmol) 16b was
transferred to a Schlenk tube as a dichloromethane solution. The
solvent was removed by purging nitrogen followed by high vacuum to
remove the last traces of dichloromethane. The oxindole was added to
decalin to form a 0.1 M solution (turbidity observed). The Schlenk
tube was sealed and heated in an oil bath at 185 °C for 2 days. Decalin
was evaporated in vacuo. The crude sample was directly loaded into
the silica gel column using toluene as solvent. The product 18b was
obtained in 65% yield (32.5 mg, 0.087 mmol) after column
chromatography with 1/4 v/v ethyl acetate/hexane.
3H). 13C NMR (100 MHz, CDCl3): δ 181.1, 173.2, 143.2, 141.8,
130.1, 128.2, 125.9, 121.8, 114.0, 109.3, 60.5, 58.2, 42.0, 30.1, 26.5,
22.4, 21.9, 14.2. FT-IR (KBr, νmax): 3275, 2956, 1713, 1620, 1491,
1148 cm−1. HRMS (EI): calcd for C18H23NO3 [M]+ 301.1678, found
301.1677.
3-(2-Methylbut-3-en-2-yl)-3-(3-oxobutyl)indolin-2-one (16e). Fol-
lowing the general procedure A, treatment of 3-(2-oxobutyl)indole
(450 mg, 2.41 mmol) 15e gave product 16e as a semisolid (mp 98 °C)
1
in 50% yield (324 mg, 1.19 mmol). H NMR (400 MHz, CDCl3): δ
8.17 (br s, 1H), 7.21 (td, J = 7.6, 1.2 Hz, 1H), 7.15−7.12 (m, 1H),
6.99 (td, J = 7.6, 1.2 Hz, 1H), 6.89−6.85 (m, 1H), 6.03 (dd, J = 17.6,
10.8 Hz, 1H), 5.08 (dd, J = 10.8, 1.2 Hz, 1H), 4.99 (dd, J = 17.6, 1.2
Hz, 1H), 2.31−2.07 (m, 3H), 1.91 (s, 3H), 1.70−1.63 (m, 1H), 1.16
(s, 3H), 1.05 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 208.1, 181.6,
143.2, 141.8, 130.4, 128.1, 125.9, 121.9, 113.9, 109.6, 58.1, 41.9, 39.1,
30.1, 25.2, 22.5, 21.9. FT-IR (KBr, νmax): 2923, 1713, 1620, 1462,
1370, 752 cm−1. HRMS (EI): calcd for C17H21NO2 [M]+ 271.1572,
found 271.1580.
Methyl 3-(2-Methylbut-3-en-2-yl)-2-oxo-3-(3-oxobutyl)indoline-
6-carboxylate (16g). Following the general procedure A, treatment
of 6-carboxymethyl-3-(2-oxobutyl)indole (411 mg, 1.67 mmol) 15g
gave product 16g as a pale yellow oil in 74% yield (407 mg, 1.24
mmol). 1H NMR (400 MHz, CDCl3): δ 9.51 (br s, 1H), 7.68 (dd, J =
7.9, 1.5 Hz, 1H), 7.57 (d, J = 1.3 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H),
5.98 (dd, J = 17.4, 10.8 Hz, 1H), 5.05 (dd, J = 10.8, 0.8 Hz, 1H), 4.94
(dd, J = 17.4, 0.8 Hz, 1H), 3.89 (s, 3H), 2.37−2.02 (m, 3H), 1.89 (s,
3H), 1.71−1.54 (m, 1H), 1.15 (s, 3H), 1.01 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 207.7, 181.1, 166.7, 142.6, 142.2, 135.8, 130.2, 125.5,
123.4, 114.3, 110.2, 58.3, 52.4, 42.1, 38.9, 29.9, 25.0, 22.4, 21.8. FT-IR
(KBr, νmax): 3259, 2957, 1716, 1628, 1458, 1286 cm−1. HRMS (EI):
calcd for C19H23NO4 [M]+ 329.1627, found 329.1626.
6-Fluoro-3-(2-methylbut-3-en-2-yl)-3-(3-oxobutyl)indolin-2-one
(16h). Following the general procedure A, treatment of 6-
carboxymethyl-3-(2-oxobutyl)indole (453 mg, 2.20 mmol) 15h gave
product 16h as a pale yellow oil in 52% yield (331 mg, 1.15 mmol). 1H
NMR (400 MHz, CDCl3): δ 9.46 (br s, 1H), 7.10−6.98 (m, 1H),
6.71−6.60 (m, 2H), 5.99 (dd, J = 17.4, 10.8 Hz, 1H), 5.06 (dd, J =
10.8, 1.1 Hz, 1H), 4.96 (dd, J = 17.4, 1.1 Hz, 1H), 2.32−2.01 (m, 3H),
1.91 (s, 3H), 1.76−1.63 (m, 1H), 1.14 (s, 3H), 1.01 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 208.0, 182.0, 163.9, 161.5, 143.2, 142.9, 126.8,
125.6, 114.2, 108.3, 98.3, 57.8, 42.0, 39.0, 30.0, 25.2, 22.4. FT-IR (KBr,
νmax): 3262, 2968, 1709, 1600, 1488, 1206 cm−1. HRMS (EI): calcd for
C17H20FNO2 [M]+ 289.1478, found 289.1473.
General Procedure E: Intermolecular C3-Prenylation of Trypto-
phan. To a magnetically stirred solution of L-Trp methyl ester 11 (400
mg, 1.83 mmol) in sodium acetate/acetic acid buffer (pH 2.7, 30 mL)
was added prenyl bromide (635 μL, 5.50 mmol) over a period for 45−
50 min at room temperature. The resulting mixture was stirred at the
same temperature overnight. Evaporation of acetic acid under reduced
pressure resulted in a solid residue which was dissolved in ethyl
acetate. The solution was neutralized by addition of sodium carbonate
solution, and the ester was extracted three times with ethyl acetate.
The combined organic layers were dried over anhydrous Na2SO4 and
evaporated under reduced pressure, giving a diastereomeric mixture of
the cyclic products 13 and 14 (in a 4/1 ratio) in 67% overall yield
(358 mg, 1.25 mmol) (based on recovered starting material).
C3-Reverse Prenylated Oxindole Substrates. 3-(3-(2-Methylbut-3-
en-2-yl)-2-oxoindolin-3-yl) propanenitrile (16a). Following the
general procedure A, treatment of 3-cyanoethylindole 15a gave
product 16a (236 mg, 0.93 mmol) as a white solid (mp 86 °C) in 61%
1
yield. H NMR (400 MHz, CDCl3): δ 9.21 (br s, 1H), 7.25 (td, J =
7.6, 1.2 Hz, 1H), 7.16 (m, 1H), 7.03 (td, J = 7.6, 0.8 Hz, 1H), 6.93 (d,
J = 8.0 Hz, 1H), 6.03 (dd, J = 17.6, 10.8 Hz, 1H), 5.13 (dd, J = 10.8,
1.2 Hz, 1H), 5.02 (dd, J = 17.6, 1.2 Hz, 1H), 2.47 (ddd, J = 13.6, 11.2,
5.6 Hz, 1H), 2.17 (ddd, J = 13.6, 11.2, 4.8 Hz, 1H), 1.91 (ddd, J =
16.8, 11.2, 5.6 Hz, 1H), 1.71 (ddd, J = 16.4, 11.2, 4.8 Hz, 1H), 1.15 (s,
3H), 1.03 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 180.3, 142.6,
141.9, 128.8, 128.5, 125.6, 122.1, 119.1, 114.5, 110.1, 58.1, 42.1, 27.7,
22.1, 21.9, 13.4. FT-IR (KBr, νmax): 3275, 2923, 1737, 1620, 1491,
1370 cm−1. HRMS (EI): calcd for C16H18N2O [M]+ 254.1419, found
254.1415.
6-Chloro-3-(2-methylbut-3-en-2-yl)-3-(3-oxobutyl)indolin-2-one
(16i). Following the general procedure A, treatment of 6-chloro-3-(2-
oxobutyl)indole (291 mg, 1.31 mmol) 15i gave product 16i as a pale
N,4-Dimethyl-N-(2-(3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3-yl)-
ethyl)benzenesulfonamide (16c). Following the general procedure A,
treatment of N-Me-Tos-ethylindole (500 mg, 1.52 mmol) 15c gave
product 16c as a pale yellow solid (mp 104 °C), in 66% yield (414 mg,
1
yellow solid (mp 114 °C) in 40% yield (160 mg, 0.53 mmol). H
NMR (400 MHz, CDCl3): δ 9.30 (br s, 1H), 7.05 (dd, J = 8.3, 3.7 Hz,
1H), 7.00−6.88 (m, 2H), 5.99 (dd, J = 17.4, 10.8 Hz, 1H), 5.08 (dd, J
= 10.8, 1.0 Hz, 1H), 4.97 (dd, J = 17.4, 1.0 Hz, 1H), 2.34−2.02 (m,
3H), 1.93 (s, 3H), 1.75−1.63 (m, 1H), 1.16 (s, 3H), 1.02 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 207.9, 181.5, 142.9, 142.7, 133.8, 128.8,
126.6, 121.8, 114.4, 110.2, 57.9, 42.1, 39.0, 30.1, 25.1, 22.5, 21.9. FT-IR
(KBr, νmax): 3262, 2968, 1709, 1600, 1488, 1206 cm−1. HRMS (EI):
calcd for C17H20ClNO2 [M]+ 305.1183, found 305.1185.
1
1.01 mmol). H NMR (400 MHz, CDCl3): δ 7.78 (br s, 1H) 7.46−
7.41 (m, 2H), 7.26−7.18 (m, 4H), 7.05 (td, J = 7.6, 1.2 Hz, 1H),
6.85−6.82 (m, 1H), 6.01 (dd, J = 17.2, 10.8 Hz, 1H), 5.08 (dd, J =
10.8, 1.2 Hz, 1H), 4.96 (dd, J = 17.6, 1.2 Hz, 1H), 2.6 (s, 3H), 2.59−
2.51 (m, 1H), 2.43 (ddd, J = 13.4, 10.2, 5.2 Hz, 1H), 2.37 (s, 3H), 2.32
(ddd, J = 13.2, 10.3, 5.9 Hz, 1H), 2.06 (ddd, J = 13.4, 10.3, 4.8 Hz,
1H), 1.1 (s, 3H), 1.0 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 180.1,
143.2, 143.1, 141.5, 134.4, 129.7, 129.6 (2 × C), 128.2, 127.4 (2 × C),
126.0, 121.9, 114.0, 109.4, 56.7, 47.1, 42.1, 35.3, 29.5, 22.2, 21.8, 21.6.
FT-IR (KBr, νmax): 2923, 1737, 1620, 1491 cm−1. HRMS (EI): calcd
for C23H28N2O3S [M]+ 412.1821, found 412.1818.
7-Methyl-3-(2-methylbut-3-en-2-yl)-3-(3-oxobutyl) indolin-2-one
(16j). Following the general procedure A, treatment of 7-methyl-3-(2-
oxobutyl)indole (291 mg, 1.45 mmol) 15j gave product 16j as a pale
1
yellow oil in 63% yield (259 mg, 0.91 mmol). H NMR (400 MHz,
CDCl3): δ 9.96 (br s, 1H), 7.02 (m, 1H), 6.95 (d, J = 6.9 Hz, 1H),
6.92−6.83 (m, 1H), 6.02 (dd, J = 17.4, 10.8 Hz, 1H), 5.03 (dd, J =
10.8, 1.2 Hz, 1H), 4.96 (dd, J = 17.4, 1.2 Hz, 1H), 2.31 (s, 3H), 2.29−
2.23 (m, 1H), 2.21−2.02 (m, 2H), 1.88 (s, 3H), 1.69 (ddd, J = 15.6,
11.3, 3.4 Hz, 1H), 1.15 (s, 3H), 1.04 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 208.0, 182.3, 143.3, 140.7, 129.9, 129.4, 123.1, 121.7, 118.9,
113.7, 58.4, 41.8, 39.1, 30.0, 25.2, 22.5, 21.8, 16.6. FT-IR (KBr, νmax):
3262, 2968, 1709, 1713, 1600, 1488, 1206 cm−1. HRMS (EI): calcd for
C18H23NO2 [M]+ 285.1729, found 285.1722.
Ethyl 3-(3-(2-Methylbut-3-en-2-yl)-2-oxoindolin-3-yl)propanoate
(16d). Following the general procedure A, treatment of 3-ethyl-
carboxyethylindole (281 mg, 1.29 mmol) 15d gave product 16d as a
colorless oil, in 55% yield (214 mg, 0.71 mmol). 1H NMR (400 MHz,
CDCl3): δ 7.86 (br s, 1H), 7.23- 7.14 (m, 2H), 6.99 (td, J = 7.6, 1.2
Hz, 1H), 6.86−6.82(m, 1H), 6.05 (dd, J = 17.6, 10.8 Hz, 1H), 5.1 (dd,
J = 10.8, 1.2 Hz, 1H), 5.0 (dd, J = 17.6, 1.2 Hz, 1H), 3.98 (qq, J = 10.8,
7.2 Hz, 2H), 2.37 (ddd, J = 13.6, 11.1, 5.2 Hz, 1H), 2.2 (ddd, J = 13.6,
11.6, 4.8 Hz, 1H), 1.96 (ddd, J = 16.4, 11.6, 5.2 Hz, 1H), 1.62 (ddd, J
= 17.2, 11.6, 4.8 Hz, 1H), 1.17 (s, 3H), 1.14(t, J = 7.2 Hz, 3H), 1.06 (s,
5-Methoxy-3-(2-methylbut-3-en-2-yl)-3-(3-oxobutyl)indolin-2-
one (16k). Following the general procedure A, treatment of 5-
10061
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Article
methoxy-3-(2-oxobutyl)indole (455 mg, 2.09 mmol) 15k gave product
16k as a white solid (mp 136 °C) in 65% yield (410 mg, 1.36 mmol).
1H NMR (400 MHz, CDCl3): δ 9.11 (br s, 1H), 6.85−6.77 (m, 1H),
Hz, 1H), 7.03 (td, J = 8.0, 1.2 Hz, 1H), 6.86−6.76 (m, 2H), 5.82 (dd, J
= 17.5, 10.9 Hz, 1H), 5.24 (dd, J = 10.9 and 1.1 Hz, 1H), 5.01 (dd, J =
17.5, 1.1 Hz, 1H), 4.94−4.84 (m, 1H), 3.42−3.21 (m, 2H), 2.48−2.32
(m, 2H), 1.82−1.64 (m, 2H), 1.57 (s, 3H), 1.46 (s, 3H), 1.35 (ddd, J =
19.3, 12.9, 6.5 Hz, 1H), 1.27−1.16 (m, 4H). 13C NMR (100 MHz,
CDCl3): δ 180.0, 168.0 (2 × C), 141.7, 141.5, 133.8 (2 × C), 132.1 (2
× C), 131.4, 130.0, 127.9, 125.9, 124.6, 123.1 (2 × C), 121.7, 116.4,
109.7, 57.7, 45.8, 34.8, 34.4, 29.5, 25.8, 23.1, 17.7, 15.5. FT-IR (KBr,
νmax): 3319, 2923, 2253, 1773, 1712, 1620, 1475, 1402, 908, 733 cm−1.
HRMS (EI): calcd for C28H30N2O3 [M]+ 442.2256, found 442.2259.
2-(2-(3-(3,7-Dimethylocta-1,6-dien-3-yl)-2-oxoindolin-3-yl)ethyl)-
isoindoline-1,3-dione (16q). Following the general procedure A,
treatment of N-phthalyltryptamine (475 mg, 1.64 mmol) 15q gave
product 16q as a mixture of major and minor diastereomers (dr = 8:1)
as a pale yellow oil in 60% yield (434 mg, 0.98 mmol). Data for the
6.76−6.68 (m, 2H), 6.05 (dd, J = 17.4, 10.8 Hz, 1H), 5.07 (dd, J =
10.8, 1.2 Hz, 1H), 4.97 (dd, J = 17.4, 1.2 Hz, 1H), 3.75 (s, 3H), 2.31−
2.18 (m, 1H), 2.17−2.01 (m, 2H), 1.90 (s, 3H), 1.77−1.63 (m, 1H),
1.16 (s, 3H), 1.02 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 208.0,
181.4, 155.1, 143.1, 135.2, 131.9, 114.0, 113.1, 112.3, 109.7, 58.5, 55.7,
41.9, 39.1, 30.0, 25.2, 22.4, 21.8. FT-IR (KBr, νmax): 3262, 2968, 1709,
1713, 1600, 1488, 1206 cm−1. HRMS (EI): calcd for C18H23NO3 [M]+
301.1678, found 301.1674.
2-(2-(3-(But-3-en-2-yl)-2-oxoindolin-3-yl)ethyl)isoindoline-1,3-
dione (16l). Following the general procedure A, treatment of N-
phthalyltryptamine (400 mg, 1.38 mmol) 15l gave product 16l as a
mixture of major and minor diastereomers (dr = 5.6:1) as a pale yellow
oil in 32% yield (159 mg, 0.44 mmol) (alongside full recovery of
unreacted starting material). Data for the major diastereomer are as
1
major diastereomer are as follows. H NMR (400 MHz, CDCl3): δ
8.61 (br s, 1H), 7.71−7.64 (m, 2H), 7.63−7.56 (m, 2H), 7.18−7.13
(m, 1H), 6.98 (td, J = 7.7, 1.2 Hz, 1H), 6.85−6.79 (m, 1H), 6.75 (td, J
= 7.6, 1.1 Hz, 1H), 6.01 (dd, J = 17.5, 10.8 Hz, 1H), 5.27−5.14 (m,
1H), 5.01−4.90 (m, 2H), 3.46−3.22 (m, 2H), 2.52−2.34 (m, 2H),
1.75−1.62 (m, 2H), 1.57 (s, 3H), 1.51−1.41 (m, 5H), 1.06 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 180.6, 168.0 (2 × C), 142.0, 141.1,
133.7 (2 × C), 132.0 (2 × C), 131.3, 130.0, 127.9, 125.9, 124.7, 123.0
(2 × C), 121.5, 115.9, 109.8, 58.00, 46.0, 34.8, 34.0, 29.4, 25.8, 22.9,
17.7, 16.5. FT-IR (KBr, νmax): 3428, 2923, 2354, 1713, 1563, 1462,
1370 cm−1. HRMS (EI): calcd for C28H30N2O3 [M]+ 442.2256, found
442.2252.
1
follows. H NMR (400 MHz, CDCl3): δ 8.59 (br s, 1H), 7.71−7.66
(m, 2H), 7.64−7.58 (m, 2H), 7.11−7.05 (m, 1H), 7.01−6.98 (m, 1H),
6.87 6.74 (m, 2H), 5.83 (ddd, J = 16.9, 10.3, 9.0 Hz, 1H), 5.20−5.09
(m, 2H), 3.57−3.48 (m, 2H), 2.71 2.67 (m, 1H), 2.55−2.43 (m, 1H),
2.23 2.18 (m, 1H), 0.73 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 181.1, 168.0 (2 × C), 141.5, 138.0, 133.8 (2 × C), 132.0 (2
× C), 129.6, 127.9, 124.2, 123.0 (2 × C), 122.2, 117.6, 110.1, 54.9,
45.5, 34.4, 33.6, 14.8. FT-IR (KBr, νmax): 3257, 3065, 2972, 2927,
1772, 1707, 1619, 1469, 720 cm−1. HRMS (EI): calcd for C22H20N2O3
[M]+ 360.1474, found 360.1469.
(E)-2-(2-(2-oxo-3-(3,7,11-trimethyldodeca-1,6,10-trien-3-yl)-
indolin-3-yl)ethyl)isoindoline-1,3-dione (16r). Following the general
procedure A, treatment of N-phthalyltryptamine (900 mg, 3.10 mmol)
15r gave product 16r as a single diastereomer (dr > 19:1) as a pale
2-(2-(2-Oxo-3-(1-phenylallyl)indolin-3-yl)ethyl)isoindoline-1,3-
dione (16m). Following the general procedure A, treatment of N-
phthalyltryptamine (400 mg, 1.38 mmol) 15m gave product 16m as a
mixture of major and minor diastereomers (dr = 8:1) as a pale yellow
oil in 47% yield (274 mg, 0.65 mmol). Data for the major diastereomer
1
yellow oil in 48% yield (760 mg, 1.49 mmol). H NMR (400 MHz,
1
CDCl3): δ 8.28 (br s, 1H), 7.72−7.66 (m, 2H), 7.66−7.59 (m, 2H),
7.18 (d, J = 7.4 Hz, 1H), 7.03 (td, J = 7.7, 1.2 Hz, 1H), 6.88−6.76 (m,
2H), 5.84 (dd, J = 17.5, 10.9 Hz, 1H), 5.24 (dd, J = 10.9, 1.1 Hz, 1H),
5.05−4.97 (m, 2H), 4.91−4.87 (m, 1H), 3.46−3.21 (m, 2H), 2.50−
2.29 (m, 2H), 2.01−1.97 (m, 2H), 1.86−1.83 (m, 1H), 1.82−1.71 (m,
1H), 1.70−1.60 (m, 4H), 1.54 (s, 3H), 1.46 (s, 3H), 1.43−1.33 (m,
1H), 1.32−1.18 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 180.3,
168.0 (2 × C), 141.9, 141.5, 134.9, 133.8 (2 × C), 132.1 (2 × C),
131.4, 130.0, 127.9, 125.8, 124.5, 124.4, 123.1 (2 × C), 121.7, 116.4,
109.9, 57.7, 45.8, 39.7, 34.7, 34.4, 29.5, 26.7, 25.8, 23.0, 17.8, 16.1,
15.6. FT-IR (KBr, νmax): 3358, 2974, 2891, 2362, 1777, 1714, 1624,
1563, 1479, 1406, 1370, 1047 cm−1. HRMS (EI): calcd for
C33H38N2O3 [M]+ 510.2882, found 510.2880.
Methyl-2-(1,3-Dioxoisoindolin-2-yl)-3-(3-(2-methylbut-3-en-2-yl)-
2-oxoindolin-3-yl)propanoate (16s). Following the general procedure
A, treatment of N-phthalyl-L-tryptophan carboxymethyl ester (12.5 g,
0.035 mol) 15s gave product 16s as a pale yellow solid (mp 120 °C) in
80% yield (12.4 g, 0.029 mol) as a 1:1 mixture of two diastereomers.
1H NMR (400 MHz, CDCl3): δ 8.34 (br s, 1H), 7.85−7.79 (m, 2H),
7.72 (br s, 1H), 7.67−7.61 (m, 2H), 7.60−7.51 (m, 4H), 7.33−7.24
(m, 2H), 7.09 (td, J = 7.6, 1.2 Hz, 1H), 6.87 (dd, J = 16.5, 7.6 Hz, 2H),
6.48 (d, J = 4.0 Hz, 2H), 6.26 (dt, J = 7.4, 4.4 Hz, 1H), 6.07 (t, J = 11.2
Hz, 1H), 6.02 (t, J = 11.2 Hz, 1H), 5.13 (dd, J = 7.4, 1.1 Hz, 1H), 5.10
(dd, J = 7.4, 1.1 Hz, 1H), 5.03 (dd, J = 15.1, 1.1 Hz, 1H), 4.98 (dd, J =
15.1, 1.1 Hz, 1H), 4.79 (dd, J = 10.3, 4.6 Hz, 1H), 4.25 (dd, J = 11.1,
2.1 Hz, 1H), 3.68 (s, 3H), 3.63 (s, 3H), 3.21 (ABX, J = 14.8, 11.1 Hz,
1H), 3.05−2.95 (m, 2H), 2.90 (ABX, J = 14.8, 2.2 Hz, 1H), 1.15 (s,
3H), 1.12 (s, 3H), 1.03 (s, 3H), 0.99 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 179.9, 179.6, 169.8, 169.4, 167.4 (2 × C), 167.0 (2 × C),
142.9, 142.7, 142.1, 141.2, 134.1 (2 × C), 133.7 (2 × C), 131.8 (2 ×
C), 131.6 (2 × C), 130.1, 129.1, 128.7, 127.1, 125.9, 124.9, 123.6 (2 ×
C), 122.9 (2 × C), 122.0, 121.2, 114.4, 114.4, 110.0, 109.7, 56.9, 56.7,
53.1 (2 × C), 49.5, 49.1, 42.7, 42.4, 30.3, 28.9, 22.5, 22.1, 21.9, 21.5.
FT-IR (KBr, νmax): 2923, 1737, 1713, 1620, 1462, 1370 cm−1. HRMS
(EI): calcd for C25H24N2O5 [M]+ 432.1685, found 432.1666. HPLC:
tR for single diastereomer 10.8 min (Chiralpak AS column, 30%
iPrOH/Hex). The assignments for proton NMR data are provided in
Table S1 (Supporting Information).
are as follows. H NMR (400 MHz, CDCl3): δ 7.85 (br s, 1H), 7.72
7.56 (m, 4H), 7.30 (d, J = 7.4 Hz, 1H), 7.06 6.90 (m, 4H), 6.85 (t, J =
7.5 Hz, 1H), 6.67 (d, J = 7.2 Hz, 2H), 6.59 (d, J = 7.6 Hz, 1H), 6.25
(dt, J = 16.3, 10.3 Hz, 1H), 5.35−5.19 (m, 2H), 3.69 (d, J = 10.0 Hz,
1H), 3.48 (t, J = 6.6 Hz, 2H), 2.63 (dt, J = 14.6, 7.4 Hz, 1H), 2.38−
2.26 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 179.9, 168.0 (2 × C),
141.6, 138.4, 135.4, 133.8 (2 × C), 132.0 (2 × C), 129.1, 128.4 (2 ×
C), 128.3, 127.8 (2 × C), 127.0, 124.3, 123.1 (2 × C), 122.1, 119.2,
110.1, 58.0, 55.9, 34.4, 33.3. FT-IR (KBr, νmax): 3420, 2926, 2855,
1716, 1470, 1265 cm−1. HRMS (EI): calcd for C27H22N2O3 [M]+
422.1630, found 422.1626.
3-Allyl-3-methylindolin-2-one (16n). Following the general
procedure A, treatment of C3-methylindole (260 mg, 1.98 mmol)
15n gave product 16n as a pale yellow oil in 47% yield (174 mg, 0.93
1
mmol). H NMR (400 MHz, CDCl3): δ 8.88 (br s, 1H), 7.23−7.14
(m, 2H), 7.03 (td, J = 7.5, 1.0 Hz, 1H), 6.95−6.91 (m, 1H), 5.51 (ddt,
J = 17.1, 10.1, 7.3 Hz, 1H), 5.08−4.98 (m, 1H), 4.97 4.92 (m, 1H),
2.64−2.44 (m, 2H), 1.41 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
183.1, 140.5, 134.2, 132.6, 127.9, 123.3, 122.4, 118.9, 109.9, 48.9, 42.5,
22.9. FT-IR (KBr, νmax): 3371, 2253, 1709, 1470, 1160 cm−1. HRMS
(EI): calcd for C12H13NO [M]+ 187.0997, found 187.0998.
3-Methyl-3-(2-methylallyl)indolin-2-one (16o). Following the
general procedure A, treatment of C3-methylindole (500 mg, 3.82
mmol) 15o gave product 16o as a pale yellow oil in 53% yield (406
1
mg, 2.02 mmol). H NMR (400 MHz, CDCl3): δ 8.22 (br s, 1H),
7.23−7.16 (m, 2H), 7.07−7.00 (m, 1H), 6.92−6.84 (m, 1H), 4.61 4.59
(m, 1H), 4.56 4.53 (m, 1H), 2.73 (dd, J = 13.5, 0.8 Hz, 1H), 2.49 (d, J
= 13.5 Hz, 1H), 1.41 (s, 3H), 1.39 (dd, J = 1.4, 0.9 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 182.7, 141.3, 140.4, 134.3, 127.8, 123.7, 122.4,
114.5, 109.8, 49.3, 45.7, 25.1, 23.8. FT-IR (KBr, νmax): 3214, 2971,
2925, 1708, 1621, 1473, 1232 cm−1. HRMS (EI): calcd for C13H15NO
[M]+ 201.1154, found 201.1155.
2-(2-(3-(3,7-Dimethylocta-1,6-dien-3-yl)-2-oxoindolin-3-yl)ethyl)-
isoindoline-1,3-dione (16p). Following the general procedure A,
treatment of N-phthalyltryptamine (616 mg, 2.12 mmol) 15p gave
product 16p as a single diastereomer (dr > 19:1) as a pale yellow oil in
58% yield (544 mg, 1.23 mmol). 1H NMR (400 MHz, CDCl3): δ 7.98
(br s, 1H), 7.74−7.66 (m, 2H), 7.66−7.59 (m, 2H), 7.18 (d, J = 7.0
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Article
C4-Prenylated Products of Cope Rearrangement. 3-(4-(3-
Methylbut-2-en-1-yl)-2-oxoindolin-3-yl)propanenitrile (17a). Fol-
lowing general procedure B, under thermal rearrangement conditions,
C3-reverse prenyl oxindole (53 mg, 0.21 mmol) 16a gave product 17a
in 31% yield (16.4 mg, 0.06 mmol). Following general procedure C,
under microwave conditions, C3-reverse prenyl oxindole (7.5 mg,
0.029 mmol) 16a gave product 17a in 58% yield (4.4 mg, 0.017
mmol) as a colorless solid (mp 120 °C). 1H NMR (400 MHz,
CDCl3): δ 8.63 (br s, 1H), 7.20 (t, J = 7.8 Hz, 1H), 6.89 (d, J = 7.8 Hz,
1H), 6.77 (d, J = 7.3 Hz, 1H), 5.21 (dddd, J = 6.9, 5.5, 2.8, 1.4 Hz,
1H), 3.62 (dd, J = 8.2, 3.1 Hz, 1H), 3.42−3.23 (m, 2H), 2.59−2.43
(m, 2H), 2.41−2.31 (m, 1H), 2.25−2.14 (m, 1H), 1.77 (d, J = 1.3 Hz,
3H), 1.75 (d, J = 0.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 178.9,
141.6, 138.9, 134.1, 129.0, 124.8, 123.8, 121.4, 119.1, 108.1, 44.1, 31.5,
25.8, 25.6, 18.2, 13.4. FT-IR (KBr, νmax): 3275, 2956, 1620, 1563, 1458
cm−1. HRMS (EI): calcd for C16H18N2O [M]+ 254.1419, found
254.1419.
4-(3-Methylbut-2-en-1-yl)-3-(3-oxobutyl)indolin-2-one (17e). Fol-
lowing general procedure B, under thermal rearrangement conditions,
C3-reverse prenyl oxindole (92 mg, 0.34 mmol) 16e gave product 17e
in 43% yield (39.6 mg, 0.15 mmol). Following general procedure C,
under microwave conditions, C3-reverse prenyl oxindole (10 mg, 0.04
mmol) 16e gave product 17e in 46% yield (4.6 mg, 0.016 mmol) as a
colorless solid (mp 123 °C). 1H NMR (400 MHz, CDCl3): δ 8.52 (br
s, 1H), 7.16 (t, J = 7.8 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 6.72 (d, J =
7.8 Hz, 1H), 5.24−5.16 (m, 1H), 3.56 (dd, J = 7.6, 3.5 Hz, 1H), 3.35
(ddd, J = 24.0, 16.8 Hz, 2H), 2.61−2.48 (m, 1H), 2.46−2.26 (m, 2H),
2.23−2.12 (m, 1H), 2.06 (s, 3H), 1.73 (br s, 6H). 13C NMR (100
MHz, CDCl3): δ 207.9, 180.1, 141.6, 139.1, 133.6, 128.4, 126.5, 123.4,
121.7, 107.6, 44.5, 38.6, 31.3, 30.2, 25.9, 23.5, 18.1. FT-IR (KBr, νmax):
3275, 2956, 1713, 1620, 1563, 1458, 1148 cm−1. HRMS (EI): calcd for
C17H21NO2 [M]+ 271.1572, found 271.1571.
3-Methyl-4-(3-methylbut-2-en-1-yl)indolin-2-one (17f). C3-re-
verse-prenyl methyloxindole 16f was prepared according to published
methods.8 Following general procedure B, under thermal rearrange-
ment conditions, C3-reverse prenyl oxindole (56 mg, 0.26 mmol) 16f
gave product 17f in 32% yield (16.6 mg, 0.08 mmol).12 Following
general procedure C, under microwave conditions, C3-reverse prenyl
oxindole (7.0 mg, 0.023 mmol) 16f gave product 17f in 16% yield (1.1
2-(2-(4-(3-Methylbut-2-en-1-yl)-2-oxoindolin-3-yl)ethyl)-
isoindoline-1,3-dione (17b). Following general procedure B, under
thermal rearrangement conditions, C3-reverse prenyl oxindole (500
mg, 1.34 mmol) 16b gave product 17b in 74% yield (370 mg, 0.99
mmol) based on recovered starting material. Following general
procedure C, under microwave conditions, C3-reverse prenyl oxindole
(30 mg, 0.08 mmol) 16b gave product 17b in 75% yield (22.5 mg,
mg, 0.005 mmol)12 as a colorless solid (mp 124 °C). H NMR (400
1
MHz, CDCl3): δ 8.35 (br s, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.84 (d, J =
7.8 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 5.27 5.21 (m, 1H), 3.47 (q, J =
7.6 Hz, 1H), 3.40 (ABX, J = 16.0, 7.4 Hz, 1H), 3.30 (ABX, J = 16.0, 6.6
Hz, 1H), 1.74 (d, J = 1.2 Hz, 3H), 1.73 (br s, 3H), 1.53 (d, J = 7.6 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 181.2, 141.2, 138.6, 133.4,
129.0, 128.1, 123.2, 121.9, 107.6, 40.8, 31.3, 25.8, 18.1, 15.5. FT-IR
(KBr, νmax): 3162, 3028, 2984, 2915, 1717, 1684, 1620, 1455 cm−1.
HRMS (EI): calcd for C14H17NO [M]+ 215.1310, found 215.1314.
Methyl 4-(3-Methylbut-2-en-1-yl)-2-oxo-3-(3-oxobutyl)indoline-
6-carboxylate (17g). Following general procedure B, under thermal
rearrangement conditions, C3-reverse prenyl oxindole (94.0 mg, 0.29
mmol) 16g gave product 17g in 43% yield (40.4 mg, 0.12 mmol).
Following general procedure C, under microwave conditions, C3-
reverse prenyl oxindole (31 mg, 0.09 mmol) 16g gave product 17g in
40% yield (12.4 mg, 0.04 mmol) as a pale yellow solid (mp 90 °C). 1H
NMR (400 MHz, CDCl3): δ 8.34 (br s, 1H), 7.58 (d, J = 0.8 Hz, 1H),
7.39 (d, J = 1.4 Hz, 1H), 5.23−5.16 (m, 1H), 3.91 (s, 3H), 3.60 (dd, J
= 8.0, 3.7 Hz, 1H), 3.44 (ddd, J = 18.5, 15.8, 6.9 Hz, 1H), 2.60 (ddd, J
= 14.0, 9.8, 6.0 Hz, 1H), 2.50−2.38 (m, 1H), 2.38 2.28 (m, 1H), 2.20−
2.08 (m, 1H), 2.08 (s, 3H), 1.74 (d, J = 0.9 Hz, 6H). 13C NMR (100
MHz, CDCl3): δ 207.6, 179.4, 166.9, 141.8, 139.2, 134.3, 131.8, 130.5,
125.2, 121.1, 108.1, 52.4, 44.4, 38.5, 31.3, 30.2, 25.9, 23.4, 18.2; HRMS
(EI): calcd for C19H23NO4 [M]+ 329.1627, found 329.1622.
1
0.06 mmol) as a yellow solid (mp 184 °C). H NMR (400 MHz,
CDCl3): δ 8.97 (br s, 1H), 7.76−7.70 (m, 2H), 7.64−7.56 (m, 2H),
7.02 (t, J = 7.8 Hz, 1H), 6.7 (d, J = 8.1 Hz, 1H), 6.7 (d, J = 8.0 Hz,
1H), 5.21 (t, J = 7.0 Hz, 1H), 3.71 (ABX, J = 13.5, 6.7 Hz, 1H), 3.66
(ABX, J = 13.5, 7.0 Hz, 1H), 3.61 (t, J = 5.0 Hz, 1H), 3.41 (ABX, J =
16.0, 7.4 Hz, 1H), 3.29 (ABX, J = 16.0, 6.8 Hz, 1H), 2.55 (AB, J = 6.8
Hz, 1H), 2.51 (AB, J = 6.8 Hz, 1H), 1.72 (s, 3H), 1.71 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 179.6, 168.1 (2 × C), 142.0, 138.5, 133.8
(2 × C), 133.7, 132.1 (2 × C), 128.2, 125.7, 123.1 (3 × C), 121.5,
108.1, 44.0, 34.7, 31.4, 27.2, 25.8, 18.1. FT-IR (KBr, νmax): 3275, 2923,
1713, 1620, 1462, 1370, 752 cm−1. HRMS (EI): calcd for C23H22N2O3
[M]+ 374.1630, found 374.1633.
N,4-Dimethyl-N-(2-(4-(3-methylbut-2-en-1-yl)-2-oxoindolin-3-yl)-
ethyl)benzenesulfonamide (17c). Following general procedure B,
under thermal rearrangement conditions, C3-reverse prenyl oxindole
(100 mg, 0.24 mmol) 16c gave product 17c in 57% yield (57 mg, 0.14
mmol) based on recovered starting material. Following general
procedure C, under microwave conditions, C3-reverse prenyl oxindole
(7.0 mg, 0.017 mmol) 16c gave product 17c in 40% yield (2.8 mg,
0.007 mmol) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.94
(br s, 1H), 7.63−7.49 (m, 2H), 7.28 7.23 (m, 2H), 7.17 (t, J = 7.7 Hz,
1H), 6.88 (d, J = 7.5 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 5.29−5.21 (m,
1H), 3.59 (dd, J = 7.7, 3.2 Hz, 1H), 3.44 3.28 (m, 2H), 3.08−2.90 (m,
2H), 2.70 (s, 3H), 2.50−2.40 (m, 1H), 2.38 (s, 3H), 2.21−2.06 (m,
1H), 1.74 (d, J = 1.2 Hz, 3H), 1.73 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 179.3, 143.4, 141.6, 138.8, 134.4, 133.9, 129.7 (2 × C),
128.5, 127.6 (2 × C), 125.8, 123.4, 121.6, 107.6, 46.9, 43.3, 35.5, 31.4,
27.8, 25.9, 21.6, 18.2. FT-IR (KBr, νmax): 3275, 2923, 1713, 1620,
1462, 1370, 1148, 752 cm−1. HRMS (EI): calcd for C23H28N2O3S
[M]+ 412.1821, found 412.1826.
Ethyl 3-(4-(3-Methylbut-2-en-1-yl)-2-oxoindolin-3-yl)propanoate
(17d). Following general procedure B, under thermal rearrangement
conditions, C3-reverse prenyl oxindole (7.0 mg, 0.023 mmol) 16d
gave product 17d in 52% yield (3.6 mg, 0.012 mmol). Following
general procedure C, under microwave conditions, C3-reverse prenyl
oxindole (6.0 mg, 0.02 mmol) 16d gave product 17d in 42% yield (2.5
mg, 0.008 mmol) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ
8.52 (br s, 1H), 7.17−7.11 (m, 1H), 6.85 (d, J = 7.2 Hz, 1H), 6.74 (d,
J = 7.6 Hz, 1H), 5.22 (tdd, J = 5.7, 2.8, 1.4 Hz, 1H), 4.12−3.94 (m,
2H), 3.61 (dd, J = 6.8, 3.4 Hz, 1H), 3.36 (ddd, J = 23.6, 16.1, 7.1 Hz,
2H), 2.52−2.42 (m, 1H), 2.40−2.24 (m, 2H), 2.23−2.14 (m, 1H),
1.73 (d, J = 1.6 Hz, 6H), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 179.8, 173.0, 141.7, 138.9, 133.6, 128.5, 126.1, 123.8,
121.7, 107.6, 60.6, 44.7, 31.4, 29.6, 25.8, 24.6, 18.1, 14.3. FT-IR (KBr,
νmax): 3275, 2956, 2855, 1713, 1620, 1563, 1458, 1370 cm−1. HRMS
(EI): calcd for C18H23NO3 [M]+ 301.1678, found 301.1677.
6-Fluoro-4-(3-methylbut-2-en-1-yl)-3-(3-oxobutyl)indolin-2-one
(17h). Following general procedure C, under microwave conditions,
C3-reverse prenyl oxindole (22 mg, 0.076 mmol) 16h gave product
1
17h in 40% yield (8.8 mg, 0.03 mmol) as a pale oil. H NMR (400
MHz, CDCl3): δ 7.92 (br s, 1H), 6.56 (dd, J = 10.7, 2.3 Hz, 1H), 6.46
(dd, J = 8.3, 2.3 Hz, 1H), 5.26−5.12 (m, 1H), 3.54 3.48 (m, 1H),
3.40−3.25 (m, 2H), 2.63−2.52 (m, 1H), 2.45−2.28 (m, 2H), 2.17−
2.09 (m, 1H), 2.08 (s, 3H), 1.74 (d, J = 1.1 Hz, 3H), 1.71 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 207.8, 179.8, 164.3, 161.8, 142.3, 140.9,
134.5, 121.8, 120.9, 109.4, 96.2, 43.8, 38.5, 31.2, 25.9, 23.7, 18.1. FT-IR
(KBr, νmax): 3262, 2923, 2253, 1715, 1614, 1450, 1123 cm−1. HRMS
(EI): calcd for C17H20FNO2 [M]+ 289.1478, found 289.1478.
6-Chloro-4-(3-methylbut-2-en-1-yl)-3-(3-oxobutyl)indolin-2-one
(17i). Following general procedure C, under microwave conditions,
C3-reverse prenyl oxindole (83 mg, 0.27 mmol) 16i gave product 17i
1
in 45% yield (37.4 mg, 0.12 mmol) as a colorless oil. H NMR (400
MHz, CDCl3): δ 7.75 (br s, 1H), 6.84 (d, J = 1.8 Hz, 1H), 6.72 (d, J =
1.8 Hz, 1H), 5.17 (ddd, J = 7.1, 4.2, 1.5 Hz, 1H), 3.52 (dd, J = 7.9, 3.5
Hz, 1H), 3.4 3.24 (m, 2H), 2.64−2.53 (m, 1H), 2.46−2.28 (m, 2H),
2.16−2.06 (m, 4H), 1.74 (d, J = 1.3 Hz, 3H), 1.72 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 207.7, 179.3, 142.3, 140.6, 134.5, 133.9, 124.9,
123.2, 120.8, 108.0, 43.9, 38.5, 31.1, 30.2, 25.9, 23.6, 18.2. HRMS (EI):
calcd for C17H20ClNO2 [M]+ 305.1183, found 305.1182.
10063
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The Journal of Organic Chemistry
Article
7-Methyl-4-(3-methylbut-2-en-1-yl)-3-(3-oxobutyl)indolin-2-one
(17j). Following general procedure B, under thermal rearrangement
conditions, C3-reverse prenyl oxindole (100 mg, 0.35 mmol) 16j gave
product 17j in 60% yield (60 mg, 0.21 mmol). Following general
procedure C, under microwave conditions, C3-reverse prenyl oxindole
(8.0 mg, 0.028 mmol) 16j gave product 17j in 50% yield (4.0 mg,
0.014 mmol) as a pale oil. 1H NMR (400 MHz, CDCl3): δ 7.95 (br s,
1H), 6.98 (d, J = 7.9 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 5.24−5.14 (m,
1H), 3.57 (dd, J = 7.8, 3.4 Hz, 1H), 3.31 (ddd, J = 22.0, 15.9, 5.6 Hz,
2H), 2.60−2.50 (m, 1H), 2.37 (dddd, J = 30.0, 17.1, 9.5, 4.0 Hz, 2H),
2.22 (s, 3H), 2.20−2.10 (m, 1H), 2.06 (s, 3H), 1.72 (d, J = 1.3 Hz,
6H). 13C NMR (100 MHz, CDCl3): δ 207.9, 180.4, 140.3, 136.2,
133.4, 129.8, 126.1, 123.3, 122.0, 116.6, 44.8, 38.6, 31.1, 30.2, 25.9,
23.5, 18.1, 16.4. FT-IR (KBr, νmax): 3162, 3049, 2972, 2915, 2851,
1692, 1630, 1595, 1426 cm−1. HRMS (EI): calcd for C18H23NO2 [M]+
285.1729, found 285.1727.
procedure C, under microwave conditions, C3-reverse prenyl oxindole
(75 mg, 0.147 mmol) 16r gave product 17r in 52% yield (39 mg,
0.076 mmol) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.77−
7.70 (m, 3H), 7.65 7.62 (m, 2H), 7.00 (t, J = 7.8 Hz, 1H), 6.72−6.61
(m, 2H), 5.26 5.04 (m, 3H), 3.78−3.58 (m, 3H), 3.47−3.26 (m, 2H),
2.63−2.45 (m, 2H), 2.21−1.91 (m, 8H), 1.75−1.70 (m, 3H), 1.67 (s,
3H), 1.61−1.56 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 179.2,
168.0 (2 × C), 141.8, 138.7, 137.7, 135.6, 133.8 (2 × C), 132.1 (2 ×
C), 131.5, 128.3, 125.7, 124.5, 124.0, 123.3, 123.2 (2 × C), 121.9,
107.9, 43.9, 39.9, 34.7, 32.2, 31.0, 27.3, 26.9, 26.5, 25.9, 23.6, 17.9,
16.2. FT-IR (KBr, νmax): 3258, 2921, 2851, 1773, 1716, 1620, 1596,
1452, 1399, 1107, 718.8 cm−1. HRMS (EI): calcd for C33H38N2O3
[M]+ 510.2882, found 510.2885.
Methyl 2-(1,3-Dioxoisoindolin-2-yl)-3-(4-(3-methylbut-2-en-1-yl)-
2-oxoindolin-3-yl)propanoate (17s). Following general procedure B,
under thermal rearrangement conditions, C3-reverse prenyl oxindole
(1.0 g, 2.31 mmol) 16s gave product 17s in 61% yield (610 mg, 1.41
mmol). Following general procedure C, under microwave conditions,
C3-reverse prenyl oxindole (50.0 mg, 0.12 mmol) 16s gave product
17s in 54% yield (27.0 mg, 0.06 mmol) as a 1:1 mixture of
5-Methoxy-4-(3-methylbut-2-en-1-yl)-3-(3-oxobutyl)indolin-2-
one (17k). Following general procedure B, under thermal rearrange-
ment conditions, C3-reverse prenyl oxindole (62 mg, 0.21 mmol) 16k
gave product 17k in 45% yield (28 mg, 0.09 mmol). Following general
procedure C, under microwave conditions, C3-reverse prenyl oxindole
(15 mg, 0.05 mmol) 16k gave product 17k in 48% yield (7.2 mg, 0.023
1
diastereomers as a colorless solid (mp 220 °C). H NMR (400 MHz,
CDCl3): δ 8.89 (br s, 1H), 8.68 (br s, 1H), 7.72 (dd, J = 5.5, 3.0 Hz,
2H), 7.67−7.58 (m, 4H), 7.47 (dd, J = 5.5, 3.0 Hz, 2H), 7.20 (t, J = 7.7
Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.61 (t, J =
7.8 Hz, 1H), 6.41 (d, J = 7.7 Hz, 1H), 6.38 (d, J = 7.9 Hz, 1H), 5.24 (t,
J = 6.9 Hz, 1H), 5.12 (t, J = 6.9 Hz, 1H), 5.05 (dd, J = 9.4, 5.6 Hz,
1H), 4.79 (dd, J = 11.8, 2.5 Hz, 1H), 3.75−3.70 (m, 1H), 3.71 (s, 3H),
3.69−3.65 (m, 1H), 3.68 (s, 3H), 3.58 (dd, J = 7.6, 2.8 Hz, 1H), 3.43
(ABX, J = 15.7, 6.8 Hz, 1H), 3.39−3.27 (m, 4H), 3.22 (ABX, J = 16.0,
6.8 Hz, 2H), 1.74 (s, 6H), 1.73 (s, 6H). 13C NMR (100 MHz,
CDCl3): δ 179.3, 178.7, 169.5, 169.3 (2 × C), 167.2, 167.1 (2 × C),
142.1, 141.5, 138.8, 138.3, 134.0, 133.9 (2 × C), 133.8 (2 × C), 131.9
(2 × C), 131.7 (2 × C), 128.9, 127. 7 (2 × C), 125.7, 124.8, 123.5 (2
× C), 123.2, 123.2 (2 × C), 123.1, 121.4 (2 × C), 108.4, 108.0, 53.1,
53.0, 48.9, 48.7, 43.4, 43.3, 31.5, 31.2, 27.8, 27.5, 25.9, 25.8, 18.1, 18.1.
FT-IR (KBr, νmax): 3428, 2923, 1713, 1620, 1563, 1462, 1370, 752
cm−1. HRMS (EI): calcd for C25H24N2O5 [M]+ 432.1685, found
432.1684. HPLC: tR for each diastereomer 8.8 min (major) and 12.9
1
mmol) as a pale yellow solid (mp 140 °C). H NMR (400 MHz,
CDCl3): δ 7.99 (s, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 8.3 Hz,
1H), 5.10 5.02 (m, 1H), 3.79 (s, 3H), 3.57 (dd, J = 7.3, 3.5 Hz, 1H),
3.38 3.29 (m, 2H), 2.55−2.34 (m, 2H), 2.32−2.22 (m, 1H), 2.21−2.10
(m, 1H), 2.05 (s, 3H), 1.75 (s, 3H), 1.66 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 207.8, 179.6, 153.9, 134.8, 132.7, 128.7, 128.6, 121.7,
109.9, 107.2, 56.2, 44.9, 38.6, 30.1, 26.0, 25.9, 23.8, 18.1. FT-IR (KBr,
νmax): 3275, 2933, 1737, 1620, 1563, 1491, 1370, 1244 cm−1. HRMS
(EI): calcd for C18H23NO3 [M]+ 301.1678, found 301.1674.
(Z)-2-(2-(4-(3,7-Dimethylocta-2,6-dien-1-yl)-2-oxoindolin-3-yl)-
ethyl)isoindoline-1,3-dione (17p). Following general procedure B,
under thermal rearrangement conditions, C3-reverse prenyl oxindole
(60 mg, 0.27 mmol) 16p gave product 17p in 55% yield (33 mg, 0.075
mmol) as a mixture of E and Z isomers (E:Z = 17:83). Following
general procedure C, under microwave conditions, C3-reverse prenyl
oxindole (50 mg, 0.113 mmol) 16p gave product 17p in 50% yield (25
mg, 0.056 mmol) as a mixture of E and Z isomers (E:Z = 23:77) as a
i
min (minor) (Chiralpak AS column, 30% PrOH/Hex). A detailed
1
colorless oil. H NMR (400 MHz, CDCl3): δ 8.45 (br s, 1H), 7.78−
assignment of proton NMR signals is provided in Table S2
7.70 (m, 2H), 7.67−7.59 (m, 2H), 7.01 (t, J = 7.8 Hz, 1H), 6.74−6.63
(m, 2H), 5.26 5.20 (m, 1H), 5.16−5.02 (m, 1H), 3.76−3.58 (m, 3H),
3.47−3.26 (m, 2H), 2.61−2.45 (m, 2H), 2.20−1.98 (m, 4H), 1.72 (m,
3H), 1.67 (s, 3H), 1.59 (m, 3H). 13C NMR (100 MHz, CDCl3): δ
179.2, 168.1 (2 × C), 141.8, 138.7, 137.6, 133.8 (2 × C), 132.1 (2 ×
C), 131.9, 128.3, 125.7, 124.2, 123.3, 123.2 (2 × C), 121.9, 107.9, 43.9,
34.7, 32.1, 30.9, 27.3, 26.6, 25.9, 23.5, 17.8. FT-IR (KBr, νmax): 2919,
1769, 1716, 1616, 1450, 1398, 718 cm−1. HRMS (EI): calcd for
C28H30N2O3 [M]+ 442.2256, found 442.2258.
(Z)-2-(2-(4-(3,7-Dimethylocta-2,6-dien-1-yl)-2-oxoindolin-3-yl)-
ethyl)isoindoline-1,3-dione (17q). Following general procedure B,
under thermal rearrangement conditions, C3-reverse prenyl oxindole
(140 mg, 0.32 mmol) 16q gave product 17q in 46% yield (64.4 mg,
0.145 mmol) as a mixture of E and Z isomers (E:Z = 83:17).
Following general procedure C, under microwave conditions, C3-
reverse prenyl oxindole (24 mg, 0.054 mmol) 16q gave product 17q in
62% yield (14.9 mg. 0.034 mmol) as a mixture of E and Z isomers
(E:Z = 77:23) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.90
(br s, 1H), 7.76−7.70 (m, 2H), 7.64−7.57 (m, 2H), 7.01 (t, J = 7.8 Hz,
1H), 6.76−6.60 (m, 2H), 5.27−5.18 (m, 1H), 5.16−5.00 (m, 1H),
3.77−3.57 (m, 3H), 3.48−3.26 (m, 2H), 2.58−2.46 (m, 2H), 2.17−
1.99 (m, 4H), 1.74−1.69 (m, 3H), 1.66 (d, J = 1.0 Hz, 3H), 1.59 (m,
3H). 13C NMR (100 MHz, CDCl3): δ 179.6, 168.0 (2 × C), 141.9,
138.5, 137.4, 133.8 (2 × C), 132.1 (2 × C), 131.7, 128.2, 125.7, 124.2,
123.1 (2 × C), 121.4, 108.1, 44.0, 39.7, 34.7, 31.3, 27.1, 26.6, 25.8,
17.8, 16.4. FT-IR (KBr, νmax): 3246, 2968, 2923, 2851, 2366, 2334,
1773, 1733, 1705, 1616, 1596, 1453, 1400, 1113, 1018, 721 cm−1.
HRMS (EI): calcd for C28H30N2O3 [M]+ 442.2256, found 442.2251.
2-(2-(2-Oxo-4-((2Z,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)-
indolin-3-yl)ethyl)isoindoline-1,3-dione (17r). Following general
(Supporting Information).
N-Methyl-N-(2-(4-(3-Methylbut-2-en-1-yl)-2-oxoindolin-3-yl)-
ethyl)-4-nitrobenzenesulfonamide (17t). Following general proce-
dure B, under thermal rearrangement conditions, C3-reverse prenyl
oxindole (100 mg, 0.225 mmol) 16t gave product 17t in 50% yield (50
mg, 0.112 mmol)12 as a pale yellow oil. 1H NMR (400 MHz, CDCl3):
δ 8.38−8.28 (m, 2H), 7.94 (s, 1H), 7.90−7.84 (m, 2H), 7.18 (t, J = 7.8
Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.73 (d, J = 7.7 Hz, 1H), 5.29−5.21
(m, 1H), 3.60 (dd, J = 7.7, 3.2 Hz, 1H), 3.44 3.28 (m, 2H), 3.16−2.97
(m, 2H), 2.78 (s, 3H), 2.53−2.38 (m, 1H), 2.23−2.11 (m, 1H), 1.76
(d, J = 1.1 Hz, 3H), 1.74 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
179.02, 150.1, 143.5, 141.5, 138.9, 134.0, 128.7, 128.6 (2 × C), 125.5,
124.5 (2 × C), 123.6, 121.4, 107.8, 46.9, 43.2, 35.4, 31.4, 27.7, 25.9,
18.2. FT-IR (KBr, νmax): 3444, 2923, 1707, 1596, 1531, 1455, 1350,
1163, 738 cm−1. HRMS (EI): calcd for C22H25N3O5S [M]+ 443.1515,
found 443.1511.
C3-n-Prenylated Products of [1,3]-Prenyl Transfer Reaction. 2-(2-
(3-(3-Methylbut-2-en-1-yl)-2-oxoindolin-3-yl)ethyl)isoindoline-1,3-
dione (18b). Following general procedure D, under thermal
rearrangement conditions in decalin, C3-reverse prenyl oxindole (50
mg, 0.13 mmol) 16b gave product 18b in 65% yield (32.5 mg, 0.087
mmol) as a colorless solid (mp 167 °C). 1H NMR (400 MHz,
CDCl3): δ 7.72−7.66 (m, 2H), 7.65−7.59 (m, 2H), 7.54 (s, 1H),
7.11−7.05 (m, 1H), 6.98−6.91 (m, 1H), 6.79−6.71 (m, 2H), 4.88−
4.80 (m, 1H), 3.68−3.43 (m, 2H), 2.53−2.41 (m, 3H), 2.33−2.24 (m,
1H), 1.56 (s, 3H), 1.47 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
180.7, 168.0 (2 × C), 140.7, 136.0, 133.8 (2 × C), 132.1 (2 × C),
131.6, 127.7, 123.4, 123.1 (2 × C), 122.3, 117.1, 109.8, 52.0, 37.4, 34.5,
33.6, 26.0, 18.1. HRMS (EI): calcd for C23H22N2O3 [M]+ 374.1630,
found 374.1633.
10064
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The Journal of Organic Chemistry
Article
3-Methyl-3-(3-methylbut-2-en-1-yl)indolin-2-one (18f). Following
general procedure D, under thermal rearrangement conditions in
decalin, C3-reverse prenyl oxindole (56 mg, 0.26 mmol) 16f gave
product 18f in 98% yield (55 mg, 0.25 mmol) as a pale yellow oil. 1H
NMR (400 MHz, CDCl3): δ 8.19 (s, 1H), 7.22−7.14 (m, 2H), 7.02
(td, J = 7.5, 1.0 Hz, 1H), 6.91−6.84 (m, 1H), 4.92−4.82 (m, 1H), 2.49
(qd, J = 14.2, 7.5 Hz, 2H), 1.58 (d, J = 1.0 Hz, 3H), 1.52 (s, 3H), 1.39
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 182.8, 140.2, 135.4, 134.7,
127.7, 123.5, 122.4, 118.2, 109.5, 49.0, 36.8, 26.0, 22.8, 18.1. FT-IR
(KBr, νmax): 3210, 2916, 2850, 1710, 1620, 1463, 1377 cm−1. HRMS
(EI): calcd for C14H17NO [M]+ 215.1310, found 215.1308.
3-Hydroxy-3-(3-methylbut-2-en-1-yl)indolin-2-one (22a). Precur-
sor 21a was synthesized according to published methods.6 Following
general procedure D, under thermal rearrangement conditions in
decalin, C3-reverse prenyl oxindole (78 mg, 0.36 mmol) 21a gave
product 22a in 50% yield (39 mg, 0.18 mmol) as a colorless oil.
Microwave irradiation (at the same power levels as in procedure C) of
C3-reverse prenyl oxindole (6.0 mg, 0.03 mmol) 21a in phosphate
1
buffer provided product 22a in 89% yield (5.3 mg, 0.025 mmol). H
NMR (400 MHz, CDCl3): δ 7.62 (s, 1H), 7.39−7.34 (m, 1H), 7.28−
7.23 (m, 1H), 7.07 (td, J = 7.5, 0.9 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H),
5.05−5.01 (m, 1H), 2.85 (s, 1H, exchangeable with D2O), 2.65 (d, J =
7.6 Hz, 2H), 1.67 (s, 3H), 1.56 (s, 3H). 13C NMR (150 MHz,
CDCl3): δ 179.8, 140.3, 137.7, 130.6, 129.7, 124.6, 123.1, 115.7, 110.1,
76.5, 37.5, 26.1, 18.1. FT-IR (KBr, νmax): 3238, 2919, 1705, 1616,
1475, 1115 cm−1. HRMS (EI): calcd for C13H15NO2 [M]+ 217.1103,
found 217.1106.
6-Fluoro-3-(3-methylbut-2-en-1-yl)-3-(3-oxobutyl)indolin-2-one
(18h). In an attempt to obtain the [3,3]-rearrangement product 17h
following general procedure B, under thermal rearrangement
conditions in DMAc, C3-reverse prenyl oxindole (22 mg, 0.076
mmol) 16h gave product 18h (as a minor product) in 20% yield as a
colorless oil. This product was verified as the [1,3]-rearrangement
5-Bromo-3-hydroxy-3-(3-methylbut-2-en-1-yl)indolin-2-one
(22b). Precursor 21b was synthesized according to published
methods.6 Following general procedure B/D, under thermal rearrange-
ment conditions in DMAc or decalin, C3-reverse prenyl oxindole (28
mg, 0.095 mmol) 21b gave product 22b in 50% yield (14 mg, 0.047
mmol) as a colorless oil. Microwave irradiation (at the same power
levels as in procedure C) of C3-reverse prenyl oxindole (15.0 mg, 0.05
mmol) 21b in phosphate buffer provided product 22b in 75% yield
1
product through spectral analysis as follows. H NMR (400 MHz,
CDCl3): δ 7.81 (s, 1H), 7.06 (dd, J = 8.2, 5.3 Hz, 1H), 6.78−6.69 (m,
1H), 6.63 (dd, J = 8.7, 2.3 Hz, 1H), 4.86 4.78 (m, 1H), 2.50 (ddd, J =
20.9, 14.1, 7.6 Hz, 2H), 2.34−2.23 (m, 1H), 2.15 (dd, J = 8.9, 6.7 Hz,
2H), 2.03−1.91 (m, 4H), 1.58 (s, 3H), 1.50 (s, 3H). HRMS (EI):
calcd for C17H20FNO2 [M]+ 289.1478, found 289.1473.
(E)-2-(2-(3-Cinnamyl-2-oxoindolin-3-yl)ethyl)isoindoline-1,3-
dione (18l). Following general procedure B, under thermal rearrange-
ment conditions in DMAc, C3-reverse prenyl oxindole (45 mg, 0.107
mmol) 16l gave product 18l in 46% yield (20.7 mg, 0.05 mmol) as a
colorless oil as the only product, and no [3,3]-rearrangement was
observed. 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.71−7.65 (m,
2H), 7.64−7.60 (m, 2H), 7.24−7.11 (m, 6H), 6.97 (td, J = 7.7, 1.2 Hz,
1H), 6.83−6.74 (m, 2H), 6.33 (d, J = 15.8 Hz, 1H), 5.86 (dt, J = 15.5,
7.6 Hz, 1H), 3.57 (tdd, J = 14.0, 10.7, 6.2 Hz, 2H), 2.71−2.60 (m,
2H), 2.54−2.44 (m, 1H), 2.40−2.31(m, 1H). 13C NMR (100 MHz,
CDCl3): δ 180.3, 168.0 (2 × C), 140.7, 137.2, 134.4, 133.8 (2 × C),
132.0 (2 × C), 131.1, 128.5 (2 × C), 128.0, 127.4, 126.4 (2 × C),
123.4, 123.1 (2 × C), 122.5, 110.1, 52.2, 42.3, 34.4, 33.7; FTIR (KBr,
νmax): 3432, 2253, 1713, 1620, 1470, 911.7 cm−1. HRMS (EI): calcd
for C27H22N2O3 [M]+ 422.1630, found 422.1627.
1
(11.3 mg, 0.038 mmol). H NMR (400 MHz, CD3OD): δ 7.44−7.42
(m, 1H), 7.38 (dd, J = 8.2, 2.1 Hz, 1H), 6.80 6.76 (m, 1H), 4.87−4.80
(m, 1H), 2.61 (d, J = 7.6 Hz, 2H), 1.59 (d, J = 1.0 Hz, 3H), 1.49 (d, J
= 0.9 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): δ 178.6, 140.9,
134.8, 134.3, 131.4, 126.9, 116.8, 113.2, 111.4, 75.7, 36.3, 25.7, 17.8.
HRMS (EI): calcd for C13H14BrNO2 [M]+ 295.0208, found 295.0207.
5-Chloro-3-hydroxy-3-(3-methylbut-2-en-1-yl)indolin-2-one
(22c). Precursor 21c was synthesized according to published
methods.6 Following general procedure B/D, under thermal rearrange-
ment conditions in DMAc or decalin, C3-reverse prenyl oxindole (33
mg, 0.13 mmol) 21c gave product 22c in 41% yield (13.5 mg, 0.053
mmol) as colorless oil as the only product, and no [3,3]-rearrangement
was observed. Microwave irradiation (at the same power levels as in
procedure C) of C3-reverse prenyl oxindole (9.0 mg, 0.035 mmol) 21c
in phosphate buffer provided product 22a in 87% yield (7.8 mg, 0.03
C3-n-Prenylated Products of [1,3]-Prenyl Transfer Reaction on
C3-Hydroxy Substrates. 5-Bromo-3-hydroxy-3-(2-methylbut-3-en-2-
yl)indolin-2-one (21b). Prenyl bromide (400 μL, 3.55 mmol) was
added to a magnetically stirred solution of 5-bromoisatin (400 mg,
1.78 mmol), indium powder (255 mg, 2.22 mmol), and sodium iodide
(531 mg, 3.55 mmol) in DMF (5 mL) at 0 °C. The resulting mixture
was stirred at the same temperature until complete disappearance of
starting material (TLC). Saturated aqueous sodium hydrogen
carbonate (2.5 mL) was added, and the mixture was warmed to
room temperature before being extracted with ethyl acetate (3 × 10
mL). The organic extract was washed with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The resulting mass
was subjected to silica gel chromatography (17% ethyl acetate in
hexanes) to give the purified product 21b in 57% isolated yield as a
1
mmol). H NMR (400 MHz, CD3OD): δ 7.30 (d, J = 2.2 Hz, 1H),
7.24 (dd, J = 8.3, 2.2 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 4.88−4.77 (m,
1H), 2.61 (d, J = 7.6 Hz, 2H), 1.58 (s, 3H), 1.49 (s, 3H); 13C NMR
(100 MHz, CD3OD): δ 181.7, 141.5, 137.7, 134.8, 130.1, 128.7, 125.6,
117.2, 112.1, 77.9, 37.6, 26.0, 18.0. FT-IR (KBr, νmax): 3358, 2493,
2245, 2209, 2072, 1123, 976 cm−1. HRMS (EI): calcd for
C13H14ClNO2 [M]+ 251.0713, found 251.0705.
C3-n-Prenyl-L-Trp-pyrroloindoline Methyl Ester (13 and 14).
Following general procedure E, treatment of L-trp-methyl ester (400
mg, 1.83 mmol) 11 gave products 13 and 14 (in a 4:1 ratio) as mixture
of diastereomers in 67% overall yield (358 mg, 1.25 mmol) (based on
recovered starting material) as a pale oil. Data for major diastereomer
13 are as follows. 1H NMR (400 MHz, CDCl3): δ 7.06−7.01 (m, 2H),
6.72 (dt, J = 7.4, 0.9 Hz, 1H), 6.56 (d, J = 7.9 Hz, 1H), 5.09 (t, J = 7.3
Hz, 1H), 4.91 (s, 1H), 3.71 (dd, J = 10.5, 5.8 Hz, 1H), 3.70 (s, 3H),
3.42 (br s, 2H), 2.47−2.41 (m, 2H), 2.38 (dd, J = 12.0, 5.8 Hz, 1H),
2.00 (dd, J = 12.0, 10.7 Hz, 1H), 1.68 (s, 3H), 1.55 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 174.4, 150.0, 134.7, 133.1, 128.2, 123.6, 119.6,
118.8, 109.1, 82.2, 59.4, 58.8, 52.2, 44.2, 36.9, 26.0, 18.2. FT-IR (KBr,
νmax): 3366, 3044, 2933, 1823, 1737, 1672, 1605, 1477, 1365, 1225,
1110, 1024, 942, 833, 747 cm−1. HRMS (ESI+): calcd for C17H23O2N2
[M + H]+ 287.1681, found 287.1683.
N1-Me-C3-n-Prenyl-L-Trp-pyrroloindoline Methyl Ester (28 and
29). Following general procedure E, treatment of N-Me L-Trp-methyl
ester 27 (680 mg, 2.93 mmol) gave product 28 in 21% yield and 29 in
11% yield as a diastereomeric mixture as a pale oil along with a 40%
recovery of 27 amounting to a 53% overall yield (466 mg, 1.55 mmol).
Data for diastereoisomer 28 are as follows. 1H NMR (400 MHz,
CDCl3): δ 7.08 (dt, J = 7.7, 1.2 Hz, 1H), 7.00 (dd, J = 7.3, 1.2 Hz,
1H), 6.63 (dt, J = 7.4, 0.9 Hz, 1H), 6.34 (d, J = 7.8 Hz, 1H), 5.09 (qt, J
= 6.7, 1.3 Hz, 1H), 4.67 (s, 1H), 3.71 (s, 3H), 3.66 (dd, J = 10.3, 6.2
1
pale oil. H NMR (400 MHz, CD3OD): δ 7.41 (dd, J = 2.0, 0.4 Hz,
1H), 7.37 (dd, J = 8.2, 2.0 Hz, 1H), 6.75 (dd, J = 8.2, 0.4 Hz, 1H), 6.09
(dd, J = 17.6, 10.9 Hz, 1H), 5.06 (dd, J = 10.9, 1.4 Hz, 1H), 4.95 (dd, J
= 17.6, 1.4 Hz, 1H), 1.22 (s, 3H), 1.03 (s, 3H). 13C NMR (100 MHz,
CD3OD): δ 181.3, 143.5, 142.5, 134.4, 133.0, 130.1, 114.9, 114.2,
112.2, 81.4, 44.2, 21.9, 20.6. FT-IR (KBr, νmax): 3347, 3230, 2988,
1702, 1616, 1475, 1442, 1313, 1170 cm−1. HRMS (EI): calcd for
C13H14BrNO2 [M]+ 295.0208, found 295.0214.
5-Chloro-3-hydroxy-3-(2-methylbut-3-en-2-yl)indolin-2-one
(21c). Colorless solid (mp 230 °C), 60%. 1H NMR (400 MHz,
DMSO-d6): δ 10.31 (s, 1H), 7.20 (dd, J = 8.2, 2.2 Hz, 1H), 7.13 (d, J =
2.2 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 5.98 (s, 1H, −OH), 5.98 (dd, J
= 17.6, 11.2 Hz, 1H), 4.99 (dd, J = 10.8, 1.4 Hz, 1H), 4.86 (dd, J =
17.6, 1.5 Hz, 1H), 1.14 (s, 3H), 0.93 (s, 3H). 13C NMR (100 MHz,
DMSO-d6): δ 178.4, 142.5, 141.1, 133.1, 128.5, 125.6, 124.6, 113.1,
110.4, 79.1, 42.7, 21.2, 19.8. FT-IR (KBr, νmax): 3347, 3230, 2988,
1702, 1616, 1475, 1442, 1313, 1170 cm−1. HRMS (EI): calcd for
C13H14ClNO2 [M]+ 251.0713, found 251.0714.
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Article
Hz, 1H), 3.08 (br s, 1H), 2.83 (s, 3H), 2.45−2.38 (m, 2H), 2.35 (dd, J
= 12.2, 6.2 Hz, 1H), 2.00 (t, J = 11.2 Hz, 1H), 1.68 (s, 3H), 1.56 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 174.6, 151.20, 134.6, 133.4,
128.3, 123.0, 119.7, 117.0, 105.6, 88.8, 59.5, 57.1, 52.2, 44.0, 36.7, 31.7,
26.0, 18.2. FT-IR (KBr, νmax): 3366, 3044, 2933, 1823, 1737, 1672,
1605, 1477, 1365, 1225, 1110, 1024, 942, 833, 747, 662 cm−1. HRMS
(EI): calcd for C18H24O2N2 [M]+ 300.1838, found 300.1838. Data for
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1
diastereoisomer 29 are as follows. H NMR (400 MHz, CDCl3): δ
7.05 (dt, J = 7.6, 1.2 Hz, 1H), 6.98 (dd, J = 7.3, 0.9 Hz, 1H), 6.60 (dt, J
= 7.4, 0.8 Hz, 1H), 6.29 (d, J = 7.8 Hz, 1H), 5.13 (qt, J = 6.7, 1.2 Hz,
1H), 4.63 (s, 1H), 3.91 (dd, J = 7.8, 3.1 Hz, 1H), 3.50 (br s, 1H), 3.33
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ASSOCIATED CONTENT
* Supporting Information
■
S
Text, figures, and tables giving general methods and procedures
for all known precursors along with their syntheses, NMR
spectra (1H and 13C) of all new compounds, and conversion of
compounds 16 and 17 as a function of substituent effects. This
material is available free of charge via the Internet at http://
pubs.acs.org.
6861.
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AUTHOR INFORMATION
Corresponding Author
* E-mail for R.V.: rajesh.viswanathan@case.edu.
■
I. Org. Lett. 2012, 14, 3080.
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Chem. 2013, 85, 1935.
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Present Address
‡Shasun Research Centre, 27, Vandaloor Kelambakkam Road,
Chennai, India 600048.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Dr. James Faulk (Dept. of Chemistry, Case
Western Reserve University) for support with mass spectral
data acquisition. D.S. thanks the Department of Chemistry for
graduate financial support. We thank Prof. Amy Lane
(University of North Florida) and Prof. Eric Schmidt
(University of Utah) for informative discussions on mechanistic
and biomimetic relevance to prenyltransferases. The authors
thank Case Western Reserve University for funding the study.
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DEDICATION
■
†Authors dedicate this manuscript to Prof. Jeffrey N. Johnston
(VICB) on the occasion of his 2014 Arthur C. Cope Scholar
Award.
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