Enantioselective synthesis of tryptophan derivatives by a tandem friedel-crafts conjugate addition/asymmetric protonation reaction

Article abstract of DOI:10.1021/ja209390d

The tandem Friedel-Crafts conjugate addition/asymmetric protonation reaction between 2-substituted indoles and methyl 2-acetamidoacrylate is reported. The reaction is catalyzed by (R)-3,3′-dibromo-BINOL in the presence of stoichiometric SnCl₄, and is the first example of a tandem conjugate addition/asymmetric protonation reaction using a BINOLSnCl₄ complex as the catalyst. A range of indoles furnished synthetic tryptophan derivatives in good yields and high levels of enantioselectivity, even on a preparative scale. The convergent nature of this transformation should lend itself to the preparation of unnatural tryptophan derivatives for use in a broad array of synthetic and biological applications.

Full text of DOI:10.1021/ja209390d

Article
pubs.acs.org/JACS
Enantioselective Synthesis of Tryptophan Derivatives by a Tandem
Friedel−Crafts Conjugate Addition/Asymmetric Protonation
Reaction
Madeleine E. Kieffer, Lindsay M. Repka, and Sarah E. Reisman*
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
ABSTRACT: The tandem Friedel−Crafts conjugate addition/
asymmetric protonation reaction between 2-substituted indoles
and methyl 2-acetamidoacrylate is reported. The reaction is
catalyzed by (R)-3,3′-dibromo-BINOL in the presence of
stoichiometric SnCl4, and is the first example of a tandem
conjugate addition/asymmetric protonation reaction using a
BINOL·SnCl4 complex as the catalyst. A range of indoles
furnished synthetic tryptophan derivatives in good yields and high levels of enantioselectivity, even on a preparative scale. The
convergent nature of this transformation should lend itself to the preparation of unnatural tryptophan derivatives for use in a
broad array of synthetic and biological applications.
of the pyrroloindoline products relative to the N-protio-indoles
(Table 1, entry 1 versus entry 10).
INTRODUCTION
■
Tryptophan and unnatural tryptophan derivatives are important
building blocks for the total synthesis of natural products, as
well as the development of new drugs,1 biological probes,2,3 and
chiral small molecule catalysts.4 For example, functionalized
tryptophan derivatives have served as key intermediates in the
syntheses of the bioactive natural products indolactam V5 and
stephacidin A.6 Alternatively, unnatural tryptophan derivatives
have been employed as probes for studying protein conforma-
Unexpectedly, our studies revealed that the initially formed
exo and endo diastereomers of 3 were generated in opposite
enantiomeric series. These findings led us to propose that
pyrroloindoline formation proceeds by a stepwise mechanism,
in which an initial conjugate addition of indole 1 to 2a is
followed by a catalyst-controlled protonation to give 5 (part a of
Scheme 1). Subsequent cyclization of the amide onto the
iminium ion provides the pyrroloindoline product (3). We
hypothesized that the (R)-BINOL·SnCl4 complex (9a·SnCl4, as
seen in Figure 1) served as a chiral Lewis acid-assisted Brønsted
acid (LBA)9,10 to effect an asymmetric protonation of the
enolate intermediate. Whereas Yamamoto and co-workers
initially developed (R)-BINOL·SnCl4 as an LBA to effect
enantioselective protonation of silyl enolates, these complexes
had never previously been used in tandem conjugate addition/
asymmetric protonation reactions.
Herein, we report our efforts to expand the scope of products
accessible by (R)-BINOL·SnCl4-catalyzed conjugate addition/
asymmetric protonation processes. These studies have resulted
in the direct, enantioselective synthesis of tryptophan
derivatives by a tandem Friedel−Crafts conjugate addition/
asymmetric protonation reaction (part b of Scheme 1).11 The
reactions require no preactivation of the indole substrates and
provide convergent access to a range of substituted tryptophan
derivatives in enantioenriched form. Friedel−Crafts conjugate
addition reactions in which a new stereogenic center is set solely
at the α-position of the conjugate acceptor through an
enantioselective protonation event are rare,12 and have only
tional dynamics by way of Forster resonance energy transfer
̈
(FRET) experiments,2 as well as for elucidating cation−π
binding interactions by linear free energy relationship studies.3
As a result, the development of new catalytic asymmetric
methods to prepare enantioenriched unnatural tryptophans is
an important area of chemical research.7
As part of our research program aimed at establishing new
methods for the enantioselective synthesis of alkaloids, we are
interested in developing convergent syntheses of tryptophans
and cyclo-tryptophans (also known as pyrroloindolines) from
simple indole starting materials. In 2010, we reported a new
reaction for the preparation of enantioenriched pyrroloindo-
lines (3) in which (R)-BINOL·SnCl4 catalyzes a formal (3 + 2)
cycloaddition reaction between 1,3-disubstituted indoles (1)
and benzyl 2-trifluoroacetamidoacrylate (2a) (part a of Scheme
1).8 Good yields, moderate exo:endo diastereoselectivities, and
high enantioselectivities were obtained for a variety of indole
substrates (Table 1). The enantio- and diastereoselectivity of
pyrroloindoline formation were found to be dependent on the
identity of the acrylate; the highest ee values were observed
using acrylate 2a. Use of the commercially available methyl 2-
acetamidoacrylate (2c) provided higher drs but attenuated ees.
N-Alkyl substitution on the indole substrates gave higher yields
Received: October 5, 2011
Published: March 5, 2012
© 2012 American Chemical Society
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Scheme 1
Table 1. Catalytic Asymmetric Synthesis of Pyrroloindolines
recently been reported with indole nucleophiles.13−16 Genet
and Darses have reported the synthesis of α-amino acids by a
Rh-catalyzed conjugate addition of aryl trifluoroborate salts to
2-amidoacrylates with in situ asymmetric protonation;14d,h
however, there are no examples using indole-based nucleophiles
to give tryptophan derivatives.
RESULTS AND DISCUSSION
■
Our studies commenced with efforts to promote the Friedel−
Crafts conjugate addition/asymmetric protonation reaction
between 2-phenylindole (6a) and benzyl 2-trifluoroacetami-
doacrylate (2a) under the reaction conditions previously
optimized for the enantioselective formal (3 + 2) cycloaddition
reaction. Somewhat surprisingly, the desired reaction was
sluggish under these conditions: after 2 h, trifluoroacetamido
ester 7a was formed in low yield and poor enantiomeric excess
(Table 2, entry 1). In an effort to improve the reactivity, a
screen of additional 2-amidoacrylates was conducted. Gratify-
ingly, the use of commercially available methyl 2-acetamidoa-
crylate (2c) gave substantially improved results, providing
acetamido ester 7c in 73% yield and 78% ee. As we observed in
the enantioselective pyrroloindoline formation,8 SnCl4 pro-
motes the reaction between 6a and 2c in the absence of (R)-
BINOL (9a) (entry 4); however, 9a produces a substantial
acceleration in the rate of the SnCl4-promoted reaction.17 No
reaction is observed in the absence of SnCl4 (entry 5).
a
b
Determined by chiral stationary phase SFC or HPLC. Determined
c
1
by H NMR analysis of mixture. 1.6 equivs SnCl4 were employed.
the use of activated powdered 4 Å molecular sieves increased
both the yield and selectivity of the reaction, furnishing
acetamido ester 7c in 86% yield and 81% ee, while also
improving the reproducibility (entry 8).
We suspected that the reaction of adventitious water and
SnCl4 might generate HCl, which could erode the apparent ee
of 7c by promoting a racemic background protonation reaction;
thus, additives known to scavenge water or HCl were evaluated.
Whereas insoluble inorganic bases such as K2CO3 showed no
effect (entry 6), the use of soluble bases such as 2,6-lutidine
completely inhibited the reaction (entry 7). On the other hand,
Figure 1. (R)-BINOL-derived catalysts.
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a
Table 2. Optimization of Reaction Parameters
b
c
entry
R3, R4
pdt
solvent
additive
yield (%)
ee (%)
1
2
Bn, CF3 (2a)
Me, CF3 (2b)
Me, Me (2c)
Me, Me (2c)
Me, Me (2c)
Me, Me (2c)
Me, Me (2c)
Me, Me (2c)
Me, Me (2c)
Me, Me (2c)
7a
7b
7c
7c
7c
7c
7c
7c
7c
7c
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
12
12
73
13
0
35
42
78
3
d
e
4
5
6
K2CO3
2,6-lutidine
4 Å MS
73
0
78
7
8
86
87
80
81
79
9
4 Å MS
10
CHCl3
4 Å MS
72
a
b
c
d
Reactions conducted under inert atmosphere on 0.2 mmol scale for 2 h. Isolated yield. Determined by chiral stationary phase SFC. No (R)-
e
BINOL was employed. No SnCl4 was employed.
At this stage, our efforts to further improve the
enantioselectivity of this transformation turned to optimization
of the catalyst structure. We were pleased to find that 3,3′-
disubstitution with halides furnished improved selectivities and
comparable yields (Table 3, entries 5 and 6).
were also evaluated. However, no linear dependence between
the BINOL electronics and the ee of 7c was observed (Table 3,
entries 1, 8−10). Of the catalysts evaluated, the commercially
available (R)-3,3′-dibromo-BINOL catalyst 9f18 gave optimal
results, delivering acetamido ester 7c in 76% yield and 93% ee
(entry 6).19 Whereas 10 mol % 9f provided comparable
selectivity for the formation of 7c (entry 13), use of 5 mol % 9f
resulted in diminished ee (entry 14). The decreased selectivity
likely results from competition by the achiral SnCl4-promoted
background reaction at low catalyst loadings. Because 20 mol %
catalyst imparted consistently higher enantioselectivities for
more functionalized substrates (vide infra), this catalyst loading
was utilized in subsequent experiments.
a
Table 3. Catalyst Optimization
Having identified conditions to prepare acetamido ester 7c in
high yield and enantiomeric excess, a survey of indole substrates
was conducted to evaluate the scope of the reaction (Table 4).
In contrast to our observations in the formal (3 + 2)
cycloaddition,8 methylation or allylation of the indole nitrogen
provides tryptophans 7d and 7e in slightly lower yields and ee
(entries 2 and 3).20 Similarly, use of unsubstituted indole as the
nucleophile provides N-α-acetyltryptophan methyl ester in 31%
yield and 67% ee (not shown, Supporting Information).21
Alternatively, substitution of the 2-phenylindole backbone at
the 4, 5, 6, and 7-positions is well tolerated (entries 4−7).
Whereas substrates bearing either electron-donating or
electron-withdrawing substituents furnish products with high
enantioselectivity, the more electron-poor indoles are less
reactive and provide lower yields of the acetamido ester
products even with increased loadings of SnCl4 (entries 9 and
10).
A range of substituents are tolerated at the 2-position of the
indole, including both aryl and alkyl groups. 2-Arylindoles
bearing substituents in either the m- or p-position of the arene
are accommodated; on the other hand, o-substituted arenes are
substantially less reactive (entries 12 and 16). For indoles
containing 2-alkyl substituents, the ee improves in switching
from a methyl group to the slightly larger n-butyl and i-propyl
substituents (entries 18−20); however, both the yield and
selectivity are diminished in the case of bulky t-butyl
substitution (7w, entry 21). Notably, a phthalimide-protected
amine functionality is also compatible, as demonstrated in 7x
b
c
entry
catalyst
loading (mol %)
yield (%)
ee (%)
1
2
9a
9b
9c
9d
9e
9f
20
20
20
20
20
20
20
20
20
20
40
15
10
5
86
17
83
76
85
76
7
81
37
87
84
90
93
1
3
4
5
6
7
9g
9h
9i
8
86
88
82
76
77
75
72
54
78
78
93
93
92
88
9
10
11
12
13
14
9j
9f
9f
9f
9f
a
Reactions conducted under inert atmosphere on 0.2 mmol scale for 2
h. Isolated yield. Determined by chiral stationary phase SFC.
b
c
Interestingly, dimethoxy catalyst 9g provided acetamido ester
7c as a racemate in low yield (entry 7). It is proposed that the
coordinating ability of the methoxy groups may permit
alternative binding modes between SnCl4 and 9g resulting in
mixtures of less reactive and less selective catalyst systems. To
probe whether the electronic or steric properties of the 3,3′-
substituents were responsible for modulating the selectivities of
catalysts 9a−g, several 6,6′-disubstituted BINOL derivatives
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orthogonal conditions. Heating 7c to 75 °C with HCl in
aqueous methanol cleaves the acetamide group to deliver free
amine 10 in 76% yield and 93% ee.22 Alternatively, exposure of
7c to aqueous LiOH in THF at 0 °C provides carboxylic acid
11 in 92% yield and 92% ee.23
Table 4. Substrate Scope of the Tandem Friedel−Crafts
a
Conjugate Addition/Asymmetric Protonation
Scheme 2. Functionalization of Tryptophan 7c and 7d
Upon treatment with NBS and TFA, tryptophan 7c can be
converted to bromo-dehydroindoline 12, which is formed as a
1:1 mixture of diastereomers. Interestingly, 12 does not
undergo cyclization to the pyrroloindoline under the reaction
conditions. However, exposure of N-methyl derivative 7d to
NCS24 and TFA in acetonitrile provides the corresponding
chloro-pyrroloindoline, as detected by HRMS. Subsequent
silica gel-promoted hydrolysis then delivers the more stable
hydroxy-pyrroloindoline 13 in 52% yield and 6:1 dr, favoring
the endo diastereomer.
Mechanistically, it seems likely based on Yamamoto’s prior
reports of catalytic asymmetric protonation of silyl enol ethers
and silyl ketene acetals9b,c that catalytically generated 9f·SnCl4
is serving as a chiral LBA to protonate an intermediate Sn-
enolate. Whether 9f·SnCl4 is the species responsible for
activating acrylate 2c toward conjugate addition by the indole
is unclear. Although 9f·SnCl4 is proposed to serve as the
catalyst, stoichiometric tin is required due to binding of the
acetamido ester product to tin resulting in product inhibition.
Notably, no significant nonlinear effects are observed when
using scalemic BINOL to catalyze the reaction (Chart 1).25
Chart 1. Nonlinear Effects Study
a
Reactions conducted under inert atmosphere on 0.1 or 0.2 mmol
scale for 2 h. Isolated yields are reported. Enantiomeric excess was
b
determined by chiral stationary phase SFC. 1.6 equivs SnCl4 were
employed.
(entry 22). Attempts to further expand the scope of C2-
substituents were unfruitful. For example, 2-iodoindole under-
went decomposition under the reaction conditions, whereas 2-
(trimethylsilyl)indole returned unreacted starting material.
Using 2-phenylindole (6a), this reaction has been conducted
on a 5 mmol scale, providing acetamido ester 7c in 77% yield
and 93% ee. Although our screening protocol was conducted in
a glovebox, this preparative scale reaction could be run using
standard Schlenk techniques. We have also demonstrated that
the acetamide and methyl ester groups can be hydrolyzed under
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Table 5. Comparison of Conditions for Pyrroloindoline Formation
a
b
c
entry
conditions
R1, R2
pdt
yield (%)
dr
ee (%)
d
1
9a
Me, Me (2c)
Me, Me (2c)
CF3, Bn (2a)
CF3, Bn (2a)
3k
3k
3a
3a
70
58
86
39
5:1
8:1
4:1
7:1
66/80
87/85
94/91
98/92
e
2
9f, 4 Å MS
9a
d
3
e
4
9f, 4 Å MS
a
b
c
d
Isolated yield. Determined by 1H NMR analysis of mixture. Determined by chiral stationary phase SFC. Reaction run with 1.0 equiv acrylate, 1.2
e
equivs SnCl4. Reaction run with 1.2 equivs acrylate, 1.0 equiv SnCl4.
chloroform were distilled over calcium hydride. Powdered 4 Å
molecular sieves were flame-dried under vacuum immediately prior to
use. Potassium carbonate was dried for 12 h at 130 °C under vacuum
and 2,6-lutidine was distilled over AlCl3. All other commercially
obtained reagents were used as received unless specifically indicated.
(R)−BINOL (9a), 2-phenylindole (6a) and 2-methylindole (6r) were
purchased from Alfa Aesar, N-methyl-2-phenylindole (6b) was
obtained from Sigma-Aldrich, and 1 M SnCl4 in CH2Cl2 was
purchased from Acros Organics. (R)-3,3′-diphenyl-BINOL (9b),26
(R)-3,3′-dimethyl-BINOL (9c),27 (R)-3,3′-dichloro-BINOL (9e),28
(R)-3,3′-dibromo-BINOL (9f),18 (R)-3,3′-dimethoxy-BINOL (9g),18
(R)-6,6′-dimethyl-BINOL (9i),29 and (R)-6,6′-dibromo-BINOL (9j)30
were prepared according to literature procedures. All reactions were
monitored by thin-layer chromatography using EMD/Merck silica gel
60 F254 precoated plates (0.25 mm). Silica gel column chromatog-
raphy was performed either as described by Still et al.31 using silica gel
(particle size 0.032−0.063) purchased from Silicycle or using
prepackaged RediSepRf columns on a CombiSilica gel Rf system
(Teledyne ISCO Inc.). Optical rotations were measured on a Jasco P-
Given the proposed mechanistic similarities between the
reactions to give pyrroloindoline 3 and tryptophan 7, we were
interested in whether the conditions optimized for tryptophan
formation would catalyze the formal (3 + 2) cycloaddition
reaction with improved selectivity. Treatment of 1a and methyl
2-acetamidoacrylate (2c) with 1.0 equiv SnCl4 and 20 mol %
catalyst 9f in the presence of 4 Å MS furnished pyrroloindoline
3k in 58% yield as an 8:1 mixture of exo and endo diastereomers
in 87 and 85% ee, respectively (Table 5, entry 2). Although
these conditions provide pyrroloindoline 3k with improved dr
and ee relative to the originally reported conditions (Table 5,
entry 1), they are less enantioselective then when benzyl 2-
trifluoromethylacetamidoacrylate (2a) is employed (entry 3).
Finally, use of acrylate 2a with catalyst 9f and 4 Å MS provided
pyrroloindoline 3a with high dr and exceptional ee;
unfortunately 3a was isolated in unacceptably low yield. The
lower reactivity of acrylate 2a is consistent with the reactivity
trend observed for tryptophan formation (Table 2, entry 1).
Taken together, these data highlight that an appropriate
matching of the acrylate and catalyst is required to obtain 3
with both high yields and high enantioselectivity.
1
2000 polarimeter using a 100 mm path-length cell at 589 nm. H and
13C NMR spectra were recorded on a Varian Inova 500 (at 500 and
125 MHz, respectively) or a Varian Inova 600 (at 600 and 150 MHz,
respectively) and are reported relative to internal chloroform (1H, δ =
7.26, 13C, δ = 77.0) or internal acetonitrile (1H, δ = 1.94, 13C, δ =
1.32). Data for 1H NMR spectra are reported as follows: chemical shift
(δ ppm) (multiplicity, coupling constant (Hz), integration). Multi-
plicity and qualifier abbreviations are as follows: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad. IR spectra
were recorded on a PerkinElmer Paragon 1000 spectrometer and are
reported in frequency of absorption (cm−1). Analytical SFC was
performed with a Mettler SFC supercritical CO2 analytical
chromatography system with Chiralcel AD-H, OD-H, AS-H, OB-H,
and OJ-H columns (4.6 mm × 25 cm). HRMS were acquired using
either an Agilent 6200 Series TOF with an Agilent G1978A
Multimode source in electrospray ionization (ESI), atmospheric
pressure chemical ionization (APCI) or mixed (MM) ionization
mode, or obtained from the Caltech Mass Spectral Facility.
General Procedure for the Synthesis of Tryptophan
Derivatives. An oven-dried vial was charged with the indole (1.00
equiv), methyl 2-acetamidoacrylate (2c, 1.20 equivs), (R)-3,3′-
dibromo-BINOL (9f, 0.20 equivs), and pumped into a glovebox. To
the vial was added flame-dried powdered 4 Å molecular sieves (200 wt
% relative to indole). The vial was charged with CH2Cl2 to an indole
concentration of 0.12 M, and SnCl4 (1.00 equiv as a 1 M solution in
CH2Cl2) was added. The reaction was stirred at 20 °C for 2 h, after
which time it was removed from the glovebox and quenched by
dilution with 1 M HCl (5 mL) and CH3CN (1 mL). The aqueous
layer was extracted with EtOAc (2 × 5 mL) and the combined organic
layers were washed with saturated aqueous NaHCO3 (5 mL), dried
(Na2SO4), filtered, and concentrated. The crude residue was purified
by silica gel chromatography.
CONCLUSIONS
■
In conclusion, 9f·SnCl4 catalyzes a tandem Friedel−Crafts
conjugate addition/asymmetric protonation reaction between
2-substituted indoles (6) and methyl 2-acetamidoacrylate (2c).
A range of indoles furnished synthetic tryptophan derivatives 7
in good yields and high levels of enantioselectivity, even on
preparative scale. We have shown that such tryptophan
derivatives can be orthogonally deprotected, or converted to
more functionalized derivatives. This is the first example of a
chiral diol·SnCl4-catalyzed Friedel−Crafts conjugate addition
reaction in which the new stereogenic centers are set solely at
the α-position of the conjugate acceptor by an asymmetric
protonation. The convergent nature of this transformation
should lend itself to the preparation of unnatural tryptophan
derivatives for use in a broad array of synthetic and biological
applications. Further mechanistic studies and the development
of related asymmetric protonation reactions are the subject of
continued research in our laboratory.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise stated, reactions were
performed under a nitrogen atmosphere using freshly dried solvents.
Methylene chloride, ether, tetrahydrofuran, and dioxane were dried by
passing through activated alumina columns. Dichloroethane and
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Preparative Scale Procedure for the Synthesis of Trypto-
phan 7c. To a flame-dried flask under nitrogen containing freshly
activated powdered 4 Å molecular sieves (200 wt %) was added 2-
phenylindole (1a, 1.00 g, 5.20 mmol, 1.00 equiv), methyl 2-
acetamidoacrylate (2c, 890 mg, 6.20 mmol, 1.20 equivs), and (R)-
3,3′-dibromo-BINOL (9f, 457 mg, 1.00 mmol, 0.20 equivs). The flask
was charged with 40 mL DCM and SnCl4 (1 M in DCM, 5.20 mL,
5.20 mmol, 1.00 equiv) was added. The reaction was stirred at room
temperature for 2 h, then quenched by addition of 1 M HCl (50 mL).
The aqueous layer was extracted with EtOAc (2 × 50 mL) and the
combined organic layers were washed with saturated aqueous
NaHCO3 (50 mL), dried (Na2SO4), filtered, and concentrated. The
crude residue was purified by silica gel chromatography (40:60 to
100:0 EtOAc:hexanes) to yield 1.33 g (77% yield) of 7c as a pale
yellow foam. The enantiomeric excess was determined to be 93% by
chiral SFC analysis (Chiracel AD-H, 2.5 mL/min, 30% IPA in CO2, λ
= 254 nm): tR(major) = 5.7 min tR(minor) = 6.9 min.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Information regarding materials and methods, and NMR
spectra of compounds from this study. This material is available
free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: reisman@caltech.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Brian Stoltz, Dr. Scott Virgil, and the Caltech
Center for Catalysis and Chemical Synthesis for access to
analytical equipment, and Dr. David VanderVelde for assistance
with NMR structure determination. Fellowship support was
provided by the NSF (M. E. K., Graduate Research Fellowship
under Grant No. DGE-1144469) and the ACS Division of
Organic Chemistry (L.M.R., sponsored by Genentech). Nadine
Currie is acknowledged for assistance in the preparation of
several indole substrates. Financial support from the California
Institute of Technology, the NIH (NIGMS RGM097582A),
and the donors of the ACS Petroleum Research Foundation are
gratefully acknowledged.
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