Enantioselective Copper(II)/Box-Catalyzed Synthesis of Chiral β3-Tryptophan Derivatives

Article abstract of DOI:10.1002/cctc.201900575

β-Amino acids and their derivatives are important building blocks for the preparation of various bioactive compounds and materials. We developed a highly efficient method for the synthesis of β³-tryptophan derivatives based on enantioselective Friedel-Crafts alkylation of indoles with phthaloyl-protected aminomethylenemalonate in the presence of chiral Cu(OTf)₂/iPrBox complex as a catalyst. A wide range of indoles with electron-donating and electron-withdrawing substituents gave the desired products in high yields (up to 99 %) and excellent enantioselectivities (up to 99 % ee). In the case of pyrrole the Friedel-Crafts product was obtained in up to 90 % yield and up to 82 % ee.

Full text of DOI:10.1002/cctc.201900575

Accepted Article
Title: Enantioselective Copper(II)/Box-catalyzed Synthesis of Chiral β3-
tryptophan derivatives
Authors: Elena A. Tarasenko, Ivan V. Shestakov, Victor B. Rybakov,
and Irina P. Beletskaya
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemCatChem 10.1002/cctc.201900575
Link to VoR: http://dx.doi.org/10.1002/cctc.201900575
A Journal of
www.chemcatchem.org

10.1002/cctc.201900575
ChemCatChem
FULL PAPER
Enantioselective Copper(II)/Box-catalyzed Synthesis of Chiral
β3-tryptophan derivatives
Elena A. Tarasenko, Ivan V. Shestakov, Victor B. Rybakov, and Irina P. Beletskaya*[a]
β-Amino acids and their derivatives are important building blocks for
compounds. The asymmetric Friedel-Crafts reaction of indoles
with various electrophiles is one of the most straightforward
methods to afford chiral indole derivatives.[11] Using this method
β2- and β2,2-tryptophan derivatives were obtained by the reaction
of indoles and Michael acceptors such as β-nitroacrylates and α-
substituted β-nitroacrylates. For asymmetric induction chiral β-
nitroacrylate was used in the case of β2-derivatives,[12] whereas
either Ni (II) chiral complex[13] or chiral phosphoric acid[14] were
employed as a catalyst to prepare optically active β2,2-derivatives.
the preparation of various bioactive compounds and materials. We
developed
tryptophan derivatives based on enantioselective Friedel-Crafts
alkylation of indoles with phthaloyl-protected
a
highly efficient method for the synthesis of β3-
aminomethylenemalonate in the presence of chiral Cu(OTf)2/iPrBox
complex as a catalyst. A wide range of indoles with electron-
donating and electron-withdrawing substituents gave the desired
products in high yields (up to 99%) and excellent enantioselectivities
(up to 99% ee). In the case of pyrrole the Friedel-Crafts product was
obtained in up to 90% yield and up to 82% ee.
R
O
O
∗
∗
H2N
OH
acid
H2N
OH
NH
R
3
2
O
acid
OH
-amino
-amino
β
β
Introduction
∗
R2
H2N
OH
O
O
∗
∗
β-Amino acid moiety is an important structural unit of many
bioactive natural compounds[1] used as effective drugs, e.g.,
paclitaxel[2] (antitumor), ubenimex[3] (immunosuppressant,
antitumor), bleomycin[4] (antibiotic, antitumor), penicillins[5a-d] and
cephalosporins[5b-f] (antibiotics). In recent years enantiopure β-
amino acids and their derivatives have attracted attention due to
their application in the synthesis of new biologically active
compounds[6] and materials[7] on the base of α,β- and β-peptides.
The incorporation of β-amino acid residues into peptides and
proteins renders new important properties such as improved
bioactivity, enhanced resistance to enzymatic degradations,
propensity to fold and form well-defined secondary structures
(helices, sheets, turns). In this aspect β-peptide oligomers
(foldamers[8]) are considered as promising protease-resistant
peptidomimetics.[9] Moreover, β-peptide secondary structural
units are capable of self-assembly that leads to forming
nanostructured materials with varied morphologies: fibrils,
vesicles, liquid crystals, hydrogels, microtubes, etc.[7]
β3
∗
H2N
H2N
-tryptophan
OH
acid
R
1 R2
R1
β2,2
β2,3
acid
-amino
-amino
Figure 1. The most common types of β-amino acids and β3-tryptophan.
L.
G. Cardillo, Gentilucci
a)
(2000)
NH2
O
NH2
1) BnC(O)Cl
Et3N
COOH
AcONH4
EtOH
reflux, 6 h
+
COOH
COOH
PGA
7
2)
pH
COOH
N
N
buffer
MeOH
N
H
H
H
=
PGA
penicillin G-acylase
40-50%
yield
K. Tomioka
b)
(2013)
CO2tBu
Ph
Ph
NHBn
CO2tBu
MeO
TMS
OMe NH4Cl
H2O
Bn
+
N
Li
toluene
-78
°
N
C
N
Boc
Boc
ee
89%,
97%
yield
There are many ways to synthesize different types of β-amino
acids (Figure 1). Particularly important is the asymmetric
synthesis leading to enantiopure β-amino acids.[10] Among the
latter, special place is occupied by β-amino acids bearing indole
moiety as a privileged group for organic synthesis of bioactive
Scheme 1. Literature examples of the synthesis of β3-tryptophan (a) and its
derivative (b).
According to our knowledge, the general method of the
preparation of β3-tryptophans (Figure 1) has not been reported.
Until now there are only two examples of the synthesis of
unsubstituted β3-tryptophan[15] (Scheme 1a) and its derivative[16]
(Scheme 1b). It is known that indoles can be alkylated with the
benzylidene malonates.[17] To our surprise, we could not find any
mention of such Friedel-Crafts alkylation for the synthesis of β3-
tryptophan derivatives. One may assume that the application of
N-protected aminomethylenemalonates as the alkylating agents
could hamper the reaction. However, we have shown that the
reaction proceeds successfully to give good yields and excellent
[a]
Dr. E. A. Tarasenko, I. V. Shestakov, Dr. V. B. Rybakov,
Prof. Dr. I. P. Beletskaya
Department of Chemistry
M. V. Lomonosov Moscow State University
Leninskie Gory, GSP-1, Moscow 119991, Russian Federation
E-mail: beletska@org.chem.msu.ru
This article is protected by copyright. All rights reserved.

10.1002/cctc.201900575
ChemCatChem
FULL PAPER
enantioselectivity under mild conditions with properly chosen
protective group, Lewis acid, ligand and solvent.
Table 1. Optimization of the reaction conditions.
Herein, we present the first enantioselective Friedel–Crafts
reaction of indoles with protected aminomethylenemalonates as
a highly efficient method for the preparation of the β3-tryptophan
derivatives.
Et
CO2
PhthN
∗
Lewis acid
mol%)
(10
mol%)
Et
CO2
-
Et
Et
PhthN
+
CO2
L1 L
6
(10
N
H
solvent, RT
CO2
N
H
2
3a
1a
′
′
′
R
R
Results and Discussion
L2
L3
L4
L5
L6
R=iPr; R =Me
′
O
O
O
O
R=tBu; R =Me
N
′
′
′
R=Ph; R =Me
N
N
Initially, aminomethylenemalonate with phthlaloyl protective
group was chosen as Michael acceptor. Phthalimide group has
planar structure, and, according to our assumption,
phthalimidomethylenemalonate could react with indole similar to
benzylidenemalonates.[17] In addition, the phthalimide group
itself can impart a certain biological activity to the amino acid
derivatives. For example, phthaloyl-protected L-tryptophan
(RG108) is an inhibitor of DNA-methyltransferase of the DNMT1
family.[18]
N
N
R=Ph; R =H
-
R
R
R=Bn; R =Me
L1
L2 L6
Entry[a]
Lewis
acid
Ligand
Solvent
t
[h]
Yield
[%][b]
ee [%][c]
1
Yb(OTf)3
Sc(OTf)3
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
L1
L1
L2
L2
L2
L2
L2
L2
L2
L2
L2
CH2Cl2 or Et2O
CH2Cl2 or Et2O
CH2Cl2
24
24
24
24
24
24
24
24
24
24
24
0
−
2
0
−
3
89
92
73
86
88
82
85
95
99
88
75
57
67
70
96
93
95
93
At first we investigated the non-asymmetric reaction of indole
(1a) with phthalimidomethylenemalonate 2 using Yb(III), Sc(III),
Cu(II), Mg(II), Zn(II), Ni(II), In(III) salts as catalysts in СH2Cl2 at
room temperature (See Supporting Information, Table S1). This
screening revealed that Yb(OTf)3, Sc(OTf)3, Cu(OTf)2 are by far
the best Lewis acids for this reaction. Then the enantioselective
reaction with chiral complexes of Yb(OTf)3 and Sc(OTf)3 with
(S,S)-iPrPyBox (L1) ligand (Table 1, entries 1 and 2) and
Cu(OTf)2 with (S,S)-iPrBox ligand (L2) (Table 1, entries 3–13)
was studied in different solvents. Surprisingly, Yb(OTf)3/L1 or
Sc(OTf)3/L1 complexes did not promote this reaction in either
CH2Cl2 or Et2O (entries 1 and 2). To our delight, the reaction in
the presence of 10 mol% of Cu(OTf)2/L2 proceeded smoothly at
room temperature, and the best result was achieved in 1,4-
dioxane (entry 10). The product 3a was obtained in high isolated
yield (95%) and high enantioselectivity (95%) after 24 h. The
addition of molecular sieves 4Å resulted in an increase of yield
up to 99%, but the enantiomeric excess (93%) slightly
decreased (entry 11). The reactions in CH2Cl2 (entry 3) and
CHCl3 (entry 4) gave the product also in high yields (89% and
92%), but enantiomeric excesses were even lower (88% and
75% ee). In the cases of trifluoromethylbenzene (entry 5) and
toluene (entry 6) both lower yields (73% and 86%) and lower
enantioselectivity (57% and 67% ee) were observed. The use of
oxygen-containing aprotic solvents (entries 8–12) except diethyl
ether (entry 7) led to the product in good to excellent yields (82–
95%) and high enantioselectivity (90–96% ee). Ethanol and
propan-2-ol are not useful as solvents, because the Michael
addition of these alcohols to the alkene 2 is observed. The non-
nucleophilic tert-butanol did not react with 2, but in this solvent
the yield of Friedel-Crafts product 3a (74%) and enantiomeric
excess (83% ee) were not as high (entry 13).
4
CHCl3
5
PhCF3
6
PhCH3
7
Et2O
8
THF
9
DME
10
11
1,4-dioxane
1,4-dioxane +
4Å MS
12
13
14
15
16
17
18
19[d]
Cu(OTf)2
Cu(OTf)2
Сu(SbF6)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
L2
L2
L2
L3
L4
L5
L6
L2
MTBE
24
24
24
24
24
24
24
48
91
74
85
39
90
84
97
94
90
83
92
90
34
51
94
98
tBuOH
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane/DME
(10:1)
20[d]
Cu(OTf)2
L6
1,4-dioxane/DME
(10:1)
48
94
97
[a] Reaction conditions: indole (1a) (0.275 mmol), phthalimidomethylenemalonate 2
(0.25 mmol), Lewis acid (10 mol%), ligand L1–L6 (10 mol%), solvent (1.5 ml), room
temperature. [b] Yield of isolated product. [c] Determined by chiral HPLC analysis.
[d] The reaction was carried out at +5°C.
The effect of counter-ion type and structure of Box ligand on the
reaction outcome was investigated in the next series of
experiments. The use of Cu(SbF6)2/L2 complex with weakly
coordinating counter-ion led to decrease in the yield (85%) and
ee (92%) (entry 14). Ligands L3–L5 were less effective than L2.
With tBuBox (L3) the product was obtained in lower yield (39%)
but good enantioselectivity (90%) (entry 15), while with two
types of PhBox (L4 and L5) the product was obtained with lower
enantioselectivity (34% and 51% ee) but in good yields (90%
This article is protected by copyright. All rights reserved.

10.1002/cctc.201900575
ChemCatChem
FULL PAPER
Et
CO2
and 84%) (entries 16 and 17). BnBox ligand (L6) showed the
same efficiency as iPrBox (L2), giving the product in high yield
(97%) and high enantiomeric excess (94% ee) (entry 18).
Further, these two ligands (L2 and L6) were used in the reaction
at +5 °C to further enhance the enantioselectivity (entries 19 and
20). Although the reaction time then had to be increased to 48 h,
excellent enantiomeric excesses (98% ee for L2 and 97% for
L6) and high yield in both cases (94%) were achieved. It should
be noted that in all of the experiments (Table 1) the same
enantiomer was predominantly formed according to the HPLC
data.
Since the removal of phthaloyl group from product 3a happened
to be difficult,[19] we tried in the reaction with indole several
aminomethylenemalonates with other protective groups but
without success. The reaction did not proceed with BocNH- and
CbzNH-substituted methylenemalonates 4 and 5 in the presence
of 10 mol% Cu(OTf)2/L2 even at room temperature. For AcNH-
substituted methylenemalonate 6 low conversion was observed
and we obtained complex mixture of products. Low reactivity of
the compounds 4–6 can be explained by the formation of an
intramolecular hydrogen bond between NH-hydrogen and the
carbonyl oxygen of the ester group (Figure 2a), which would
prevent the complexation of Lewis acid with the substrate. This
problem does not arise in the case of phthalimidomethylene-
malonate 2 (Figure 2b). The formation of an intramolecular
hydrogen bond in compounds 4–6 is confirmed by 1H NMR- and
IR-spectroscopy. The signals of NH-protons appear in the low
field region at 10.13, 10.35 and 10.85 ppm for 4, 5 and 6
respectively. In the IR-spectra of these compounds, the
absorption bands at 3270, 3298 and 3293 cm-1 for 4, 5 and 6
respectively, can be assigned to vibration modes of the
hydrogen-bonded NH-groups.[20]
EtO
EtO
mol%)
Cu(OTf)2 (10
Et
CO2
Boc2N
O
O
L2
mol%)
(10
+
+
Boc2NH
1,4-dioxane
RT, 24 h
N
N
H
H
1a
7
8
9
Scheme 2. Reaction of the indole (1a) and alkene 7.
EtO
Boc2N
H
N
O
Cu2+
O
EtO
EtO
N
Cu2+
N
Boc2N
O
O
+
N
EtO
N
N
H
H
A
1a
EtO
EtO
EtO
N
O
O
Cu2+
N
+Boc2NH
O
O
9
EtO
N
N
H
H
8
Scheme 3. A plausible mechanism of the formation of compounds 8 and 9.
Since the use of other protective groups did not lead to the
desired
result,
the
studies
were
continued
with
phthalimidomethylenemalonate 2. Under the optimized
conditions established for indole (1a) (Table 2, entry 1), the
scope of reaction was extended by using indoles with electron-
donating and electron-withdrawing substituents in 1,2,4,5 and 6
positions. N-methyl substituted indole (1b) gave 83% and only
74% ee (Table 2, entry 2). This fact can indicate that the NH-
proton of indole plays an essential role in providing high
enantioselectivity. A decrease in the enantiomeric excess was
also observed previously in the asymmetric reactions of N-
methylindole with benzylidenemalonates.[17a, 21] Reaction with 2-
phenylindole (1c) did not proceed even at room temperature
probably due to steric effect (entry 3), but indole 1d with smaller
methyl group in position 2 reacted smoothly in high yield (99%)
and good enantioselectivity (79% ee) (entry 3). All 4- and 5-
substituted indoles independently of substituent (entries 5–8,
a)
b)
O
H
O
R
R
O
EtO
N
N
Cu2+
N
N
OEt
O
O
O
Et
CO2
:
=
:
=
:
6
OBn;
=
R
CH3
4
5
tBu
R
O
EtO
;
10–12)
gave high yields
(89–97%)
and excellent
Figure 2. Intramolecular hydrogen bond formation in compounds 4–6 (a);
Lewis acid activation of compound 2 (b).
enantioselectivity (96–99% ee). Only 5- and 6-chloroindoles (1i)
and (1m) gave products in 78% and 83% yields but excellent ee
(98%) (entries 9 and 13). The reaction with indoles 1n and 1o
bearing strong withdrawing CO2Me group in position 5 and 6
proceeded slowly and the yields of products were only 54% and
37% after 72 h, but enantioselectivity was again excellent (98
and >99%, respectively) (entries 14 and 15).
To determine the absolute configuration of products 3, prepared
by reaction of indoles 1 with phthalimidomethylenemalonate 2, a
single crystal of compound 3k with bromine as the heavy atom
was obtained by recrystallization from hexane/dichloromethane.
The absolute configuration of the chiral center in the product 3k
has been determined to be (R) by X-ray analysis (Figure 3).[22]
The configurations of other products 3 were tentatively assigned
To avoid the formation of an intramolecular hydrogen bond in
the substrate, Boc2N-substituted alkene 7 was tested in the
reaction with indole. However, in the place of expected product,
Boc2N group was cleaved to give only 2-((1H-indol-3-
yl)methylene)malonate (8) and Boc2NH (9) (Scheme 2) instead
with isolated yields of 79% and 88%, respectively. The proposed
reaction mechanism is presented in Scheme 3. Apparently,
Boc2N makes a good leaving group in β-elimination from
intermediate A, and such pathway, quite common in indole
chemistry, is favored here by steric congestion in the
intermediate, and the formation of the energetically favorable
conjugated system 8.
This article is protected by copyright. All rights reserved.

10.1002/cctc.201900575
ChemCatChem
FULL PAPER
to be the same by the assumption of a uniform mechanistic
pathway.
phthalimide fragment. When using the same catalytic system
and oxygen-containing solvents in the reaction with
dialkylbenzylidenemalonate, indole is likely to attack in a similar
manner since an (S)-isomer[24] is formed. Perhaps π-π stacking
the indole aromatic system with the benzene ring of the
substrate takes place, and therefore this attack direction (Si-
face) becomes preferable to the Re-face attack from the
hydrogen side. The Si-face attack from the hydrogen side and
Re-face attack from the side of the aromatic substituent are
blocked by isopropyl groups of the bis(oxazoline) ligand.
To determine the absolute configuration of products 3, prepared
by reaction of indoles 1 with phthalimidomethylenemalonate 2, a
single crystal of compound 3k with bromine as the heavy atom
was obtained by recrystallization from hexane/dichloromethane.
The absolute configuration of the chiral center in the product 3k
has been determined to be (R) by X-ray analysis (Figure 3).[22]
The configurations of other products 3 were tentatively assigned
to be the same by the assumption of a uniform mechanistic
pathway.
Table 2. Enantioselective Friedel-Crafts reaction of indoles 1a–o with
phthalimidomethylenemalonate 2.
Et
CO2
PhthN
mol%)
Cu(OTf)2 (10
L2
Et
CO2
Et
Et
PhthN
CO2
R
mol%)
+
(10
R
N
CO2
N
1,4-dioxane/DME
H
(10:1)
°
H
+5
48 h
C,
1a-o
2
3a-o
Entry[a]
1
Indole
R
Product
3a
Yield [%][b]
ee [%][c]
98
1a
1b
1c
1d
1e
1f
Н
94
83
0
Figure 3. X-ray crystal structure of 3k with displacement ellipsoids drawn at
the 30% probability level. H atoms are presented as small spheres of arbitrary
radius.
2
1-Me
2-Ph
3b
3c
74
3[d]
4
−
a)
b)
2-Me
4-OMe
5-OMe
5-Me
5-F
3d
3e
99
93
93
93
94
78
89
97
90
83
54
37
79
O
O
O
O
O
O
O
5
96
N
N
O
N
O
N
O
Cu
Cu
6
3f
98
O
7
1g
1h
1i
3g
3h
3i
97
O
Si face
O
8
98
Re
face
N
9
5-Cl
98
O
10
11
12
13
14[e]
15[e]
1j
4-Br
3j
99
1k
1l
5-Br
3k
99
Figure 4. Proposed stereochemical models for the approach of indole to the
a) phthalimidomethylenemalonate and b) diethyl benzylidenemalonate,
coordinated to Cu(OTf)2/L2 complex.
2
5-I
3l
99
1m
1n
1o
6-Cl
3m
3n
3o
98
5-CO2Me
6-CO2Me
98
Encouraged by the results described above, we attempted to
extend the method to the Friedel-Crafts alkylation of pyrroles
˃99
with phthalimidomethylenemalonate
2
to obtain pyrrole
analogues of β3-tryptophan. The unsubstituted pyrrole 10a and
N-methylpyrrole 10b were tested under the optimized conditions
(Scheme 4). To avoid the formation of disubstituted pyrrole as a
side-product, 10 equiv of 10a and 10b were used. The addition
of pyrrole 10a to substrate 2 led to product 11a in high yield
(90%) and moderate enantioselectivity (55% ee) within 24 h.
The reaction of N-methylpyrrole with 2 did not run to completion
even after 48 h. In this instance, product 11b was obtained in
good yield (83%), but with poor enantiomeric excess (12% ee). It
is known that the enantioselectivity of Friedel-Crafts asymmetric
[a]
Reaction
conditions:
indole
1
(0.275
mmol),
phthalimidomethylenemalonate 2 (0.25 mmol), Cu(OTf)2 (10 mol%), L2 (10
mol%), 1,4-dioxane/DME 10:1 (1.5 ml). [b] Yield of isolated product.
[c] Determined by chiral HPLC analysis. [d] The reaction was carried out at
room temperature. [e] The reaction was carried out for 72 h.
Based on the absolute configuration of the chiral centre in 3k
and on crystallographic data obtained by Evans and co-
workers,[23] the Si-face attack of the indole on the intermediate
complex of phthalimidomethylenemalonate 2 with Cu(OTf)2/L2
(Figure 4) can be assumed to take place from the side of the
This article is protected by copyright. All rights reserved.

10.1002/cctc.201900575
ChemCatChem
FULL PAPER
The crude residue was purified by column chromatography to afford the
desired product.
reactions of pyrroles is usually lower than indoles, for example,
in
the
reaction
with
benzylidenemalonates[17a,i]
and
ethenetricarboxylates,[25] probably because of the smaller size of
pyrrole molecules. However, the use of more sterically hindered
ligand tBuBox (L3) instead of L2 allowed us to increase the Acknowledgements
enantioselectivity of the reaction with pyrrole 10a to 82%, albeit
in slightly lower yield (80%).
We thank the Russian Science Foundation (grant no. 14-23-
00186) for financial support. The research work was carried out
using NMR spectrometer Agilent 400-MR and STOE
STADIVARI PILATUS-100K diffractometer purchased under the
program of MSU development. The authors would like to
acknowledge Thermo Fisher Scientific Inc., MS Analytica
(Moscow, Russia), and personally to Prof. Alexander Makarov
for providing mass spectrometry equipment for this work.
Et
CO2
mol%)
mol%)
PhthN
Cu(OTf)2 (10
or
∗
Et
Et
PhthN
+
CO2
L2
L
3
(10
Et
CO2
N
R
1,4-dioxane/DME
(10:1)
CO2
N
R
°
+5
C
10a, R=H
2
24h
11a
ee
ee
L2
L3
90%
80%
55%
yield,
yield,
(with
(with
)
)
82%
10b R=Me
48h
11b
ee
12%
,
Keywords: amino acids • asymmetric catalysis • copper •
L2
83%
yield,
(with
)
enantioselectivity • indoles
[1]
“β-Amino Acids in Natural Products”: P. Spiteller, F. von Nussbaum in
Enantioselective Synthesis of β-Amino Acids (Eds.: E. Juaristi, V. A.
Soloshonok), John Wiley & Sons, Inc., Hoboken, 2005, pp. 19–91; b)
“β-Amino Acids in Nature”: F. von Nussbaum, P. Spiteller in Highlights
in Bioorganic Chemistry: Methods and Applications (Eds.: C. Schmuck,
H. Wennemers), Wiley-VCH, Weinheim, 2004, pp. 63–89; с) “β-Amino
Acid Biosynthesis”: P. Spiteller in Amino Acids, Peptides and Proteins
in Organic Chemistry, Vol.1 (Ed.: A. B. Hughes), Wiley-VCH, Weinheim,
2009, pp. 119–161; d) F. Kudo, A. Miyanaga, T. Eguchi, Nat. Prod.
Rep., 2014, 31, 1056–1073.
Scheme 4. Enantioselective Friedel-Crafts reaction of pyrroles 10a,b with
phthalimidomethylenemalonate 2.
Conclusions
In conclusion, we have demonstrated the enantioselective
Friedel-Crafts alkylation of indoles and pyrroles with protected
aminomethylenmalonate to afford β3-amino acid derivatives.
Different amino-protective groups have been investigated.
[2]
[3]
a) K. C. Nicolaou, W.-M. Dai, R. K. Guy, Angew. Chem. 1994, 106, 38–
69; Angew. Chem. Int. Ed. 1994, 33, 15–44; b) D. G. I. Kingston, Chem.
Commun. 2001, 867–880.
However,
only
the
use
of
phthaloyl-protected
aminomethylenmalonate allowed the desired products to be
obtained. The reactions were performed in the presence of
commercially available copper (II) triflate and iPrBox ligand
under mild conditions. Friedel-Crafts alkylation products of
various indoles were obtained in high yields with excellent
a) M. Ishizuka, T. Masuda, N. Kanbayashi, S. Fukasawa, T. Takeuchi,
T. Aoyagi, H. Umesawa, J. Antibiot. 1980, 33, 642–652; b) T. Koya, J.
Narita, S. Honda and T. Abo, Biomed. Res. 1999, 20, 161–167; c) X.
Chen, N. Li, S. Wang, N. Wu, J. Hong, X. Jiao, M. J. Krasna, D. G.
Beer, C. S. Yang, J. Natl. Cancer Inst. 2003, 95, 1053–1061.
D. L. Boger, H. Cai, Angew. Chem. 1999, 111, 470–500; Angew. Chem.
Int. Ed. 1999, 38, 448–476.
enantioselectivity.
Pyrroles
reacted
with
[4]
[5]
phthalimidomethylenemalonate 2 under the same conditions
also in high yields, but with low to moderate enantiomeric
excess. The good enantioselectivity in the reaction with pyrrole
was achieved using Cu(OTf)2/tBuBox complex as a catalyst. The
amino group deprotection step demands additional studies and
is in progress in our laboratory.
a) A. Fleming, Br. J. Exp. Pathol. 1929, 10, 226–236; b) D. J. Waxman,
J. L. Strominger, Annu. Rev. Biochem. 1983, 52, 825–869; c) “140 – β-
lactam antibiotics”: R. R. Watkins, R. A. Bonomo in Infectious Diseases,
Vol. 2 (Eds.: J. Cohen, W. Powderly, S. Opal), 2017, Elsevier, pp.
1203–1216.e2; d) R. P. Elander, Appl. Microbiol. Biotechnol. 2003, 61,
385–392; e) H. S. Sader, R. N. Jones, Antimicrob. Newsl. 1992, 8, 75–
84; f) A. R. Ribeiro, B. Sures, T. C. Schmidt, Environ. Pollut. (Oxford, U.
K.) 2018, 241, 1153–1166.
[6]
For selected examples, see: a) D. E. Mortenson, D. F. Kreitler, N. C.
Thomas, I. A. Guzei, S. H. Gellman, K. T. Forest, ChemBioChem 2018,
19, 604–612; b) J.-S. Yu, H. Noda, M. Shibasaki, Angew.Chem. 2018,
130, 826–830; Angew. Chem. Int. Ed. 2018, 57, 818–822; c) M.-R. Lee,
N. Raman, S. H. Gellman, D. M. Lynn, S. P. Palecek, ACS Chem. Biol.
2017, 12, 2975–2980; d) C. Mayer, M. M. Müller, S. H. Gellman, D.
Hilvert, Angew. Chem. 2014, 126, 7098–7101; Angew. Chem. Int. Ed.
2014, 53, 6978–6981; e) L. M. Johnson, S. Barrick, M. V. Hager, A.
McFedries, E. A. Homan, M. E. Rabaglia, M. P. Keller, A. D. Attie, A.
Saghatelian, A. Bisello, S. H. Gellman, J. Am. Chem. Soc. 2014, 136,
12848−12851; f) G. A. Lengyel, W. S. Horne, J. Am. Chem. Soc. 2012,
134, 15906–15913.
Experimental Section
General Procedure for the enantioselective Friedel-Crafts alkylation
of indoles 1a–o with phthalimidomethylenmalonate 2.
A screw-top glass vial with a magnetic stir bar was charged with Cu(OTf)2
(9.0 mg, 0.025 mmol, 10 mol%) and the solution of iPrBox ligand L2 (6.7
mg, 0.025 mmol, 10 mol%) in a 1,4-dioxane/DME 10:1 mixture (1.5 ml)
was added. The reaction mixture was stirred for 15 min followed by the
addition of phthalimidomethylenmalonate 2 (79.3 mg, 0.25 mmol). The
stirring was continued for 15 min, after that the resulting mixture was
cooled to +5 °C and appropriate indole 1a–o (0.275 mmol) was added.
Then the reaction mixture was stirred at +5 °C for 48 or 72 h (for indoles
1n and 1o only), filtered through a plug of silica gel with EtOAc/CH2Cl2
(1:1) flushing, and the solvent was evaporated under reduced pressure.
[7]
[8]
For a review, see: M. P. Del Borgo, K. Kulkarni, M.-I. Aguilar, Aust. J.
Chem. 2017, 70, 126−129.
S. H. Gellman, Acc. Chem. Res. 1998, 31, 173−180.
This article is protected by copyright. All rights reserved.

10.1002/cctc.201900575
ChemCatChem
FULL PAPER
[9]
For reviews, see: a) R. Gopalakrishnan, A. I. Frolov, L. Knerr, W. J.
[16] S. Harada, T. Sakai, K. Takasu, K. Yamada, Y. Yamamoto, K. Tomioka,
Tetrahedron 2013, 69, 3264–3273.
Drury III, E. Valeur, J. Med. Chem. 2016, 59, 9599−9621; b) C. Cabrele,
T. A. Martinek, O. Reiser, Ł. Berlicki, J. Med. Chem. 2014, 57,
9718−9739; c) T. A. Martinek, F. Fülöp, Chem. Soc. Rev. 2012, 41,
687–702; d) D. Seebach, J. Gardiner, Acc. Chem. Res. 2008, 41,
1366–1375; e) C. M. Goodman, S. Choi, S. Shandler, W. F. DeGrado,
Nat. Chem. Biol. 2007, 3, 252–262; f) D. L. Steer, R. A. Lew, P.
Perlmutter, A. I. Smith, M.-I. Aguilar, Curr. Med. Chem. 2002, 9, 811–
822; g) R. P. Cheng, S. H. Gellman, W. F. DeGrado, Chem. Rev. 2001,
101, 3219–3232.
[17] For selected examples, see: a) W. Zhuang, T. Hansen, K. A. Jørgensen,
Chem. Commun. 2001, 347–348; b) J. Zhou, Y. Tang, J. Am. Chem.
Soc. 2002, 124, 9030–9031; c) J. Zhou, Y. Tang, Chem. Commun.
2004, 432–433; d) R. Rasappan, M. Hager, A. Gissibl, O. Reiser, Org.
Lett., 2006, 8, 6099-6102; e) A. Schätz, R. Rasappan, M. Hager, A.
Gissibl, O. Reiser, Chem. Eur. J. 2008, 14, 7259–7265; f) Y.-J. Sun, N.
Li, Z.-B. Zheng, L. Liu, Y.-B. Yu, Z.-H. Qin, B. Fu, Adv. Synth. Catal.
2009, 351, 3113–3117; g) Y. Liu, D. Shang, X. Zhou, X. Liu, X. Feng,
Chem. Eur. J. 2009, 15, 2055–2058; h) V. G. Desyatkin, M. V. Anokhin,
V. O. Rodionov, I. P. Beletskaya, Russ. J. Org. Chem. 2016, 52,
1717−1727; i) M. V. Anokhin, M. N. Feofanov, A. D. Averin, I. P.
Beletskaya, ChemistrySelect 2018, 3, 1388–1391.
[10] For reviews, see: a) Enantioselective Synthesis of β-Amino Acids (Eds.:
E. Juaristi, V. A. Soloshonok), John Wiley & Sons, Inc., Hoboken, 2005;
b) G. Cardillo, C. Tomasini, Chem. Soc. Rev. 1996, 25, 117–128; c) M.
Liu, M. P. Sibi, Tetrahedron 2002, 58, 7991–8035; d) “Recent
Developments in the Synthesis of β-Amino Acids”: Y. Bandala, E.
Juaristi in Amino Acids, Peptides and Proteins in Organic Chemistry.
Vol.1 – Origins and Synthesis of Amino Acids (Ed. A. B. Hughes), 2009,
WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, pp. 291–365; e) D.
Seebach, A. K. Beck, S. Capone, G. Deniau, U. Grošelj, E. Zass,
Synthesis 2009, 1, 1–32; f) B. Weiner, W. Szymański, D. B. Janssen, A.
J. Minnaard, B. L. Feringa, Chem. Soc. Rev. 2010, 39, 1656–1691; g)
L. Kiss, F. Fülöp, Chem. Rev. 2014, 114, 1116−1169; h) M. Ashfaq, R.
Tabassum, M. M. Ahmad, N. A. Hassan, H. Oku, G. Rivera, Med.
Chem. 2015, 5, 295–309; i) O. O. Grygorenko, Tetrahedron 2015, 71,
5169–5216.
[18] B. Brueckner, R. G. Boy, P. Siedlecki, T. Musch, H. C. Kliem, P.
Zielenkiewicz, S. Suhai, M. Wiessler, F. Lyko, Cancer Res. 2005, 65,
6305–6311.
[19] The application of conventional phthalimide deprotection methods using
hydrazine hydrate, ethane-1,2-diamine, NaBH4/acetic acid did not allow
to obtain corresponding derivatives with free amino group, and only
mixture of unidentified products was formed in all cases. The attempts
at first to decarboxylate product 3a were also unsuccessful, since the
elimination of phthalimide took place on heating or in the presence of
inorganic bases.
[20] a) H. W. Dürbeck, L. L. Duttka, Tetrahedron 1973, 29, 4285–4290; b) G.
O. Dudek, J. Org. Chem. 1965, 30, 548–552.
[11] For selected reviews, see: a) M. Bandini, A. Eichholzer, Angew. Chem.
2009, 121, 9786–9824; Angew. Chem. Int. Ed. 2009, 48, 9608–9644; b)
S.-L. You, Q. Cai, M. Zeng, Chem. Soc. Rev. 2009, 38, 2190–2201; c)
G. Bartoli, G. Bencivenni, R. Dalpozzo, Chem. Soc. Rev. 2010, 39,
4449–4465; d) H. Wu, Y.-P. He, F. Shi, Synthesis 2015, 47, 1990–
2016; e) A. H. Sandtorv, Adv. Synth. Catal. 2015, 357, 2403–2435; f) R.
Dalpozzo, Chem. Soc. Rev. 2015, 44, 742–778; g) I. P. Beletskaya, A.
D. Averin, Curr. Organocatal. 2016, 3, 60–83; h) J.-B. Chen, Y.-X. Jia,
Org. Biomol. Chem. 2017, 15, 3550–3567.
[21] a) L. Liu, J. Li, M. Wang, F. Du, Z. Qin, B. Fu, Tetrahedron: Asymmetry
2011, 22, 550–557; b) J. Wu, D. Wang, F. Wu, B. Wan, J. Org. Chem.
2013, 78, 5611−5617.
[22] CCDC-1564542 (for 3k) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
[23] a) D. A. Evans, T. Rovis, M. C. Kozlowski, J. S. Tedrow, J. Am. Chem.
Soc. 1999, 121, 1994–1995; b) D. A. Evans, S. J. Miller, T. Lectka, P.
von Matt, J. Am. Chem. Soc. 1999, 121, 7559–7573.
[12] N. Pavlov, P. Gilles, C. Didierjean, E. Wenger, E. Naydenova, J.
Martinez, M. Calmès, J. Org. Chem. 2011, 76, 6116–6124.
[13] J.-Q. Weng, Q.-M. Deng, L. Wu, K. Xu, H. Wu, R.-R. Liu, J.-R. Gao, Y.-
X. Jia, Org. Lett. 2014, 16, 776−779.
[24] J. Zhou, M.-C. Ye, Y. Tang, J. Comb. Chem. 2004, 6, 301–304.
[25] S. Yamazaki, Y. Iwata, J. Org. Chem. 2006, 71, 739–743.
[14] K. Mori, M. Wakazawa, T. Akiyama, Chem. Sci. 2014, 5, 1799–1803.
[15] G. Cardillo, L. Gentilucci, P. Melchiorre, S. Spampinato, Bioorg. Med.
Chem. Lett. 2000, 10, 2755–2758.
This article is protected by copyright. All rights reserved.

10.1002/cctc.201900575
ChemCatChem
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
Text for Table of Contents
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here: max.
width: 5.5 cm; max. height: 5.0 cm))
Layout 2:
FULL PAPER
Et
CO2
PhthN
Dr. Elena A. Tarasenko, Ivan V.
Shestakov, Dr. Victor B. Rybakov, Prof.
Dr. Irina P. Beletskaya *
∗
Cu(II)/Box∗
Et
Et
PhthN
CO2
Et
CO2
R
+
N
R
CO2
H
N
Page No. – Page No.
alkene with
-amino ester moiety
H
β3
-tryptophan
derivatives
β
Enantioselective Copper(II)/Box-
catalyzed Synthesis of Chiral
β3-tryptophan derivatives
The straightforward way to highly enantioenriched β3-amino acid derivatives using
chiral copper complex catalyzed Friedel-Crafts reaction was developed.
This article is protected by copyright. All rights reserved.