A simple route towards peptide analogues containing substituted (S)- or (R)-tryptophans

Article abstract of DOI:10.1016/j.tetlet.2010.03.017

We investigated the Lewis acid-promoted Friedel-Crafts alkylation of indole and substituted indoles with dehydroalanine-containing dipeptides R-Xaa-Dha-OR¹. The reaction proceeded with modest to sufficient diastereoselectivity, and yields strongly varied depending on the Lewis acid selected. The substituent R¹ of the ester group revealed some impact on the preferential formation of (S)-Trp or (R)-Trp. We exploited the reaction to prepare different peptides containing substituted tryptophans. To test the efficacy of this method for preparing biologically relevant compounds, we synthesized two unprecedented analogues of endomorphin-1, the endogenous agonist of the μ-opioid receptor, having either (S)- or (R)-2-methyltryptophan in position 3.

Full text of DOI:10.1016/j.tetlet.2010.03.017

Tetrahedron Letters 51 (2010) 2576–2579
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A simple route towards peptide analogues containing substituted
(S)- or (R)-tryptophans
*
Luca Gentilucci , Lucia Cerisoli, Rossella De Marco, Alessandra Tolomelli
Department of Chemistry ‘G. Ciamician’, University of Bologna, via Selmi 2, 40126 Bologna, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
We investigated the Lewis acid-promoted Friedel–Crafts alkylation of indole and substituted indoles with
dehydroalanine-containing dipeptides R-Xaa-Dha-OR1. The reaction proceeded with modest to sufficient
diastereoselectivity, and yields strongly varied depending on the Lewis acid selected. The substituent R1
of the ester group revealed some impact on the preferential formation of (S)-Trp or (R)-Trp. We exploited
the reaction to prepare different peptides containing substituted tryptophans. To test the efficacy of this
method for preparing biologically relevant compounds, we synthesized two unprecedented analogues of
Received 13 January 2010
Revised 25 February 2010
Accepted 5 March 2010
Available online 12 March 2010
Keywords:
Peptidomimetics
Alkylation
Aromatic substitution
Amino acids
endomorphin-1, the endogenous agonist of the
ptophan in position 3.
l
-opioid receptor, having either (S)- or (R)-2-methyltry-
Ó 2010 Elsevier Ltd. All rights reserved.
Opioid peptide
1. Introduction
ladium-mediated heteroannulation of a chiral auxiliary;11 by
electrochemical oxidation of proline followed by Fischer indole
synthesis;12 from serine, by means of the lysate of a commercially
available microorganism containing tryptophan synthase.13
Peptides based on natural amino acids are widely used as ther-
apeutic agents.1 However, their efficacy is hampered by several
problems, in particular high conformational flexibility, low
in vivo stability against proteolysis and scarce ability to cross bio-
logical barriers, resulting in poor receptor selectivity, short dura-
tion of action and poor bioavailability.
The preparation of unusual amino acids and their introduction
in peptide sequences have attracted considerable interest to over-
come the pharmacological limitations of bioactive peptides.1,2
Modification of individual amino acids has been shown to be
responsible for changes in peptide conformation and for increased
enzymatic stability.3 Besides, the introduction of modified amino
acids has been utilized for the elucidation of an individual residue’s
biological function.3,4
(S)- and (R)-Br-tryptophans have been obtained with
L-aminoacy-
lase or
D
-aminoacylase.14 More often, reactions lead to the prepara-
tion of racemates. Very recently, the regioselective electrophilic
substitution of indoles with N-acetyl dehydroalanine (Dha),
promoted by different transition metal salts, provided an efficient
protocol towards racemic-functionalized tryptophans.15
In this context, we envisaged the opportunity to develop a
simple procedure to synthesize modified (S)- or (R)-tryptophans
within a peptide sequence. Herein, we report our results on the
Friedel–Crafts alkylation of indoles15,16 with dipeptides contain-
ing dehydroalanine (Xaa-Dha) in the presence of different Lewis
acids.
In connection with ongoing projects5 on the synthesis, confor-
mational analysis and pharmacological behaviour of endomor-
phin-16 (H-Tyr-Pro-Trp-Phe-NH2) analogues as potential drugs
for pain management,7 we have been interested in the preparation
of new peptide derivatives containing modified tryptophans. Sev-
eral examples of tryptophans bearing substituent on the indole
ring can be found in complex structures. For instance, halotrypto-
phans are present in peptides of microbial8 or marine origins.9
A few preparations of (S)- or (R)-Trp analogues have been re-
ported in the literature.10 Halotryptophans can be obtained by pal-
Further, to endorse the methodology, we describe the prelimin-
ary synthesis in a few steps of two novel endomorphin-16 analogues,
[(S)-2-MeTrp]-endomorphin-1 and [(R)-2-MeTrp]-endomorphin-1.
Among the different endogenous opioid peptides,1 endomophin-1
is unique for high receptor affinity and selectivity, being considered
the endogenous agonist of the l-opioid receptor (MOR). Since none
of the other naturally occurring opioid peptides contain a Trp in the
sequence, the preparation and pharmacological assay of endomor-
phin-1 analogues containing modified Trp in position 3 could be of
help to investigate the role of this pharmacophore in ligand-receptor
recognition.17 Besides, the presence of substituted Trp can also en-
hance lipophilicity and blood–brain barrier (BBB) permeability of
peptide active towards the CNS.18
* Corresponding author. Tel.: +39 0512099462; fax: +39 0512099456.
E-mail address: luca.gentilucci@unibo.it (L. Gentilucci).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.017

L. Gentilucci et al. / Tetrahedron Letters 51 (2010) 2576–2579
2577
Table 1
2. Results and discussion
Synthesis of dipeptides Xaa-Trp 3a–d by F-C reaction of indole with dipeptides Xaa-
Dha 2a–d promoted by different Lewis acids, at 0 °C for 24 h in DCM (with the
exception of entries 1 and 2)
As anticipated in the introduction, indoles undergo Friedel-
Crafts (F-C.) alkylation with N-Ac-Dha methyl ester in the presence
Entry
Lewis acid
Equiv
3
Yieldc (%)
S,S/S,R
of Lewis acids, giving racemic 3-indolyl-a
-amino acids.15 Since we
a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Yb(OTf)3
1
1
4
2
4
2
2
2
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
a
a
a
a
a
a
a
a
a
a
b
b
c
20
55
5
—
22/78
—
—
—
—
—
—
50/50
24/76
45/55
35/65
55/45
62/38
50/50
30/70
were interested in optically pure amino acids, we thought to carry
out a diastereoselective version of this reaction with dipeptides of
type Xaa-Dha, taking advantage of the asymmetric induction ex-
erted by Xaa. The protected dipeptides Xaa-Dha 2 were easily ob-
tained from dipeptides Xaa-serine 1, prepared in turn by standard
in-solution peptide synthesis, using 1-ethyl-3-[3-dimethylamino-
propyl]carbodiimide hydrochloride (EDC-HCl) and 1-hydroxyben-
zotriazole hydrate (HOBt) as activating agents (Supplementary
data). The dehydration of 1 with N,N0-disuccinimidyl carbonate
(DSC) and N,N-diisopropylethylamine (DIPEA) gave 2 in very
good yield,19 isolated by flash chromatography over silica gel
(Scheme 1).
Initially, the reaction was tested with indole. The treatment of
Pro-Dha 2a with a Lewis acid and indole, in the presence of 3 Å
molecular sieves, afforded the protected dipeptide Pro-Trp 3a as
a mixture of diastereoisomers (Scheme 1). Yields and diastereo-
meric ratios strongly varied depending on the Lewis acid selected
(Table 1). In the absence of molecular sieves, the reaction gave var-
iable quantities of by-products arising from peptide bond and/or
ester hydrolysis, as revealed by reversed phase (RP)-HPLC and elec-
tron-spray (ES)-MS analyses. On the other hand, molecular sieves
lead to better yields, while the unreacted starting material was
recovered unaltered.
The diastereomeric ratios of the reaction mixtures (Table 1)
were measured by normal phase-HPLC, with an analytical Kromasil
Diol column. The separation of the diastereoisomers by analytical
RP-HPLC under different conditions was unfeasible. Racemization
was excluded on the basis of chiral HPLC by using a CHIRALPAK
IC column. The configuration of the newly created stereocentre
on Trp was determined by comparison with that of the authentic
samples of (S,S)-3a and (S,R)-3a, prepared by standard peptide syn-
thesis in solution from the commercially available amino acids.
Yields (Table 1) were determined after isolation by flash chroma-
tography over silica gel.
The use of 1 equiv of ZnOTf2, FeCl3, InF3, CeCl3, RuCl3 and
Yb(OTf)3 gave no reaction or traces of the dipeptide 3a. Other Lewis
acids, MgBr2, BBu2OTf, TiCl4, Cu(OTf)2, Sc(OTf)3, ZrCl4, AlEtCl2 and
AlEt2Cl (1 equiv), gave the product 3a in low yields (<5%, data
not shown). All reactions were carried out at 0 °C for 24 h in dichlo-
romethane (DCM).
b
Yb(OTf)3
MgBr2
BBu2OTf
TiCl4
CuOTf2
ScOTf3
ZrCl4
AlEtCl2
AlEt2Cl
AlEtCl2
AlEt2Cl
AlEtCl2
AlEt2Cl
AlEtCl2
AlEt2Cl
5
15
10
10
25
70
60
65
55
65
55
55
35
c
d
d
a
b
c
DCE, reflux.
DCE, MW, 400 W.
After isolation by flash chromatography over silica gel.
(DCE) for 24 h, 3a was obtained in 20% yield (entry 1) and when
the reaction was conducted under microwave (MW) irradiation
(400 W) for 3.5 h, yield increased up to 55%, with a satisfactory
22/78 diastereomeric ratio in favour of (S,R)-3a (entry 2).
Making use of a catalytic amount of Yb(OTf)3 led to a drop of the
yield, while the use of a excess seemed inexpedient, for the high
molecular weight of such Lewis acid. Reactions with MgBr2,
BBu2OTf, TiCl4, Cu(OTf)2, Sc(OTf)3 and ZrCl4 were slightly improved
by increasing the amount of Lewis acid (yields 5–25%, Table 1,
entries 3–8).
Finally, in the presence of an excess of AlEtCl2 (3.5 equiv)15 the
reaction gave the desired dipeptide 3a in reasonable yield, after
isolation by flash chromatography over silica gel, albeit with a dis-
appointing 50/50 diastereomeric ratio (entry 9). On the other hand,
in the presence of AlEt2Cl (3.5 equiv) the reaction gave lesser
amount of 3a, but with a reasonable 24/76 diastereomeric ratio,
in favour of the (S,R)-3a stereoisomer (entry 10).
The eventual effect of the residue Xaa preceding Dha and the
protecting groups R, R1 on yield and stereoselectivity was exam-
ined. The reaction of indole with the dipeptide Phe-Dha 2b oc-
curred with comparable yield, but with lower stereoselectivity
(entries 11 and 12). Changing the methyl ester with a benzyl ester
(2c) lead to a moderate stereoselectivity, in favour of the isomer
(S,S)-3c (entries 13 and 14). The presence of a Boc-protecting group
(2d) instead of Fmoc gave lower yield and selectivity (entries 15
and 16).
Increasing time and temperature gave negligible improve-
ments. The only exception was Yb(OTf)3; indeed, performing the
reaction with 1 equiv of Yb(OTf)3 at 80 °C in dichloroethane
O
O
H
N
aa
H
N
aa
The configuration of Trp in the dipeptides 3b–d was determined
by comparison with authentic samples, prepared by standard pep-
tide synthesis in solution. Interestingly, apart from the slightly dif-
ferent yields, changing the ester allowed preparing preferentially
the dipeptides containing either (S)-Trp or (R)-Trp. Besides, the
analysis of the crude reaction mixtures revealed no trace of concur-
DSC, DIPEA
R
R
OR1
X
OR1
X
DCM/CH3CN
r.t.
OH
2
(90%)
1
Indole, Lewis acid
3Å mol sieves, DCM
0ºC
rent a
-amidoalkylation reaction.15,20
The reaction of 2a with substituted indoles in the presence of
3.5 equiv of AlEt2Cl or AlEtCl2 (Scheme 2) was performed at 0 °C
for 24 h in DCM and in the presence of 3 Å molecular sieves (Sup-
plementary data). The reaction afforded the dipeptides 3e–o (Table
2). For the moment, we were mainly interested in verifying the
applicability of the procedure to diverse kinds of indoles, therefore
the diastereoselectivity issue was not faced in detail. The absolute
configurations of the diastereoisomers were determined by com-
parison of the chiral-HPLC analyses with that of 3a.
O
H
N
R
a: R = Fmoc, Xaa = Pro, R1 = Me
b: R = Fmoc, Xaa = Phe, R1 = Me
c: R = Fmoc, Xaa = Pro, R1 = CH2Ph
d: R = Boc, Xaa = Pro, R1 = Me
X
OR1
NH
aa
3
Scheme 1. Synthesis of the protected dipeptides Xaa-Dha 2a–d and Lewis acid-
induced F-C alkylation of indole.

2578
L. Gentilucci et al. / Tetrahedron Letters 51 (2010) 2576–2579
O
H
HN BOC
O
N
N
OMe
R2-Indole, Lewis acid
Fmoc
Fmoc
O
HO
O
N
O
2a
N
H
H
N
NH
3Å mol sieves, DCM
0°C
N
OMe
OMe
O
O
1) DMA/THF, r.t.
2) Boc-Tyr-OH
R2
3e-o
Me
Me
Scheme 2. Synthesis of the dipeptides 3e–o by Lewis acid-induced F-C alkylation of
N
N
HOBt/EDC, TEA
DCM/DMF, rt
H
H
substituted indoles.
4: [(S)-2-MeTrp]3, 88%
5: [(R)-2-MeTrp]3, 86%
(S,S)-3i
(S,R)-3i
The reaction of 2a with 50-fluoroindole promoted by AlEtCl2
(entry 1) or AlEt2Cl (entry 2) gave 3e in sufficient yield, albeit only
AlEt2Cl ensured acceptable stereoselectivity. The reaction of 2a and
50-chloro indole or 50-bromoindole with AlEtCl2 proceeded in lower
yields of 3f and 3g, respectively (entries 3 and 4), while AlEt2Cl was
almost ineffective.
In a similar way, 2a reacted with 1-methylindole in the pres-
ence of AlEtCl2 affording 3h (entry 5) with scarce selectivity. The
reaction with 2-methylindole in the presence of AlEtCl2 (entry 6)
or AlEt2Cl (entry 7) gave 3i in excellent yields. 7-Methylindole,
20-methyl-70-bromoindole, 20-methyl-50-bromoindole and 2-amin-
ophenylindole gave 3l, 3m, 3n and 3o, respectively (entries 8–11),
in sufficient to good yields. Finally, 5-nitroindole scarcely reacted
with 2a giving 3p (entry 12), while 2-benzylsulfonylindole gave
only traces of the corresponding product (not shown).
O
H
N
NH2
N
N
H
1) LiOH H2O/THF
.
TFA H2N
O
O
O
2) HOBt/EDC, TEA
H-Phe-NH2
DCM/DMF, r.t.
3) TFA, DCM, r.t.
Me
N
H
HO
6: [(S)-2-MeTrp]3, 73%
7: [(R)-2-MeTrp]3, 71%
Scheme 3. Synthesis of the endomorphin-1 analogues 6 and 7 starting from the
dipeptides (S,S)-3i and (S,R)-3i.
In addition, we confirmed that changing the methyl ester with a
benzyl ester gave a moderate switch of stereoselectivity, from (S,R)
to (S,S), also with some substituted indoles. Indeed, the reaction of
50F-indole with 2c in the presence of AlEt2Cl, under the same con-
ditions reported for 2a, gave the 50F-Trp-containing dipeptide in
55% yield and 65/35 d.r., while 20Me-indole gave the corresponding
product in 70% yield with the same d.r.
In order to validate the procedure as a facile access to analogues
containing modified Trp in either (S) or (R) configuration, we syn-
thesized in a few steps the unprecedented analogues of endomor-
Activation of the tripeptide acids with HOBt/EDC and coupling
with H-Phe-NH2 gave Boc-6 and Boc-7, isolated by flash chroma-
tography. Final deprotection with TFA gave the endomorphin-1
analogues 6 and 7 in good yields, 95% pure after semi-preparative
RP-HPLC.
3. Conclusions
In summary, we have proposed a practical route for the prepa-
ration of protected dipeptides containing substituted tryptophans
in either (S) or (R) configuration. The F-C alkylation of dipeptides
containing Dha allowed the direct asymmetric synthesis of the try-
ptophanes within the peptidic structure.
The reaction gave (S,S)- or (S,R)-dipeptides, albeit with moder-
ate stereoselectivity. After isolation by normal-phase chromatogra-
phy, the diastereomeric dipeptides can be readily utilized for
preparing peptides of pharmacological interest. As a preliminary
demonstration, we synthesized analogues of endomorphin-1 with
a 2-methyltryptophan in position 3.
Work is in progress to expand the scope of the reaction, in par-
ticular to improve the stereoselectivity. Further, the procedure will
be utilized to synthesize a mini-library of endomorphin analogues,
aiming to obtain new opioid peptides with improved performances
as in vivo analgesic,21 as well as new clues about the role of Trp in
receptor recognition and activation.
phin-1
6 and 7, containing (S)-2-MeTrp and (R)-2-MeTrp,
respectively (Scheme 3).
The endomorphin analogues 6 and 7 were obtained from the
dipeptides (S,S)-3i and (S,R)-3i, obtained in turn by alkylation of
2-methylindole with 2a (Table 2, entry 6). The identities of all
the intermediates were confirmed by ES-MS analyses. Purities
were determined by RP-HPLC and by normal phase HPLC. After
separation by flash chromatography over silica gel, (S,S)-3i (41%)
and (S,R)-3i (49%) were quantitatively deprotected by treatment
with 2 M DMA in THF and reacted without prior purification with
Boc-Tyr-OH in the presence of HOBt/EDC. The tripeptides Boc-Tyr-
Pro-[(S)-2-MeTrp]-OMe, or Boc-Tyr-Pro-[(R)-2-MeTrp]-OMe, were
isolated in high yield by flash chromatography over silica gel.
The tripeptides were treated with LiOH in H2O/THF and the result-
ing tripeptide acids were utilized without further purification.
Table 2
Acknowledgements
Synthesis of dipeptides 3e–p by F-C. reaction of substituted indoles with 2a,
promoted by 3.5 equiv of Lewis acids, at 0 °C for 24 h in DCM.
We thank MIUR (Cofin 2004, PRIN 2006), Bologna University
(proj. ID 450), ‘Fondazione del Monte di Bologna e Ravenna’, the
Italian Minister for Foreign Affairs (bilateral proj. Italy-Mexico),
Consorzio Spinner, Bologna (proj. 023/08) and Fondazione CARI-
SBO, Bologna for financial support. We also thank Stepbio s.r.l.,
Bologna for technical support.
Entry
R2
Lewis acid
3
Yielda (%)
S,S/S,R
1
2
3
4
5
6
7
8
9
50-F
AlEtCl2
AlEt2Cl
AlEtCl2
AlEtCl2
AlEtCl2
AlEtCl2
AlEt2Cl
AlEtCl2
AlEtCl2
AlEtCl2
AlEtCl2
AlEtCl2
e
e
f
g
h
i
i
l
m
n
o
p
65
55
30
20
45
90
75
60
50
40
50
15
45/55
25/75
45/55
—
45/55
45/55
28/72
40/60
40/60
40/60
—
50-F
50-Cl
50-Br
10-Me
20-Me
20-Me
70-Me
Supplementary data
20-Me-70-Br
20-Me-50-Br
2-amino Ph
50-NO2
10
11
12
Supplementary data (general experimental methods, typical
reaction conditions and spectroscopic characterization of repre-
sentative compounds) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2010.03.017.
—
a
After isolation by flash chromatography over silica gel.

L. Gentilucci et al. / Tetrahedron Letters 51 (2010) 2576–2579
2579
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