1H-isoindole-based potential peptidomimetics

Article abstract of DOI:10.1002/ejoc.201200238

A variety of 1H-isoindole-based peptides was designed as potential mimics, and their efficient synthesis starting from 1-imino-1H-isoindol-3-amine by subsequent interaction with N-Boc-amino acid hydrazides and amino acid ester isocyanates generated in situ, followed by chain elongation using conventional peptide chemistry, was elaborated. A variety of potential peptidomimetics in which the 1H-isoindole unit is coupled by means of a hydrazide linkage from one side and a urea scaffold from other side, was developed. Copyright

Full text of DOI:10.1002/ejoc.201200238

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FULL PAPER
DOI: 10.1002/ejoc.201200238
1H-Isoindole-Based Potential Peptidomimetics
Angelina V. Biitseva,[a] Igor V. Rudenko,[a] Olga V. Hordiyenko,*[a]
Brigitte Jamart-Grégoire,[b] and Axelle Arrault[b]
Keywords: Amino acids / Peptidomimetics / Protein folding / Protein design / Hydrazones
A variety of 1H-isoindole-based peptides was designed as
potential mimics, and their efficient synthesis starting from
1-imino-1H-isoindol-3-amine by subsequent interaction with
N-Boc-amino acid hydrazides and amino acid ester isocyan-
ates generated in situ, followed by chain elongation using
conventional peptide chemistry, was elaborated.
ide chain (Scheme 1). Based on preferable Z-orientation of
substituents at the exocyclic C=N bonds,[5] we anticipated
that a 1,3-connected isoindole unit might direct the chain
to provide the necessary β-turn orientation of two peptide
strands. Isoindole-based mimics can be expected to present
several advantages compared to the other turn mimics de-
scribed; they can exhibit a planar and very constraint struc-
ture, and the conformational behaviour of the model com-
pounds have been examined in detail in preliminary stud-
ies.[5]
Introduction
Although native peptides have great potential for medical
applications, they often need to be modified to overcome
certain problems inherent in current drug delivery strate-
gies.[1] The properties that are desired but often not present
or optimized in the native ligand include: selectivity, sta-
bility against proteolytic breakdown, and potency. These is-
sues have been addressed by the design of peptidomimetics,
which are compounds bearing a restriction of conformation
by limiting the flexibility of the peptide backbone and in-
creasing its stability in vivo. Thus, the conformation of a
peptide can be stabilized or fixed by the introduction of
bridges between different parts of the molecule.[2] The stabi-
lization of turn structures mimicking β-turn, α-helix, or β-
sheet in biologically active peptides has been successful in
the design of a variety of peptidomimetics. There have been
increasing efforts to rationally design and synthesize non-
peptidic analogues of peptide reverse turns based on substi-
tuted cyclic templates as well as heterocyclic units. Among
them, 1,2,3-triazole ring-based β-turn mimics were created
in which the required geometry was provided by 1,4-con-
nection between two peptide strands.[3a] Peptidomimetics
based on diketopiperazine as a turn-inducing scaffold were
shown to form β-hairpin mimics involving 10-membered
and 18-membered H-bonded rings, and a reverse turn of
the growing peptide chain was described.[3b] Recently, re-
verse turns on a 3-iminoisoindolinone scaffold were de-
signed, and it was shown that they can adopt turn struc-
tures around a central 3-phenyliminoisoindolinone core.[4]
We propose a new variety of peptidomimetics 1, bearing
1H-isoindole nuclei as amino acid unit surrogates in a pept-
Scheme 1.
[a] Department of Chemistry, National Taras Shevchenko University
of Kyiv,
64, Volodymyrs’ka st., Kyiv, 01601, Ukraine
E-mail: ov_hordiyenko@univ.kiev.ua
Results and Discussion
[b] Laboratoire de Chimie Physique Macromoléculaire, UMR 7568
(CNRS-INPL),
During a preliminary study, the synthesis and the confor-
mational behaviour of a series of isoindole 2 was performed
(Scheme 1); a Z/E amide type isomerism was demonstrated
1 rue Grandville, BP 20451, 54001 Nancy Cedex, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200238.
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O. V. Hordiyenko et al.
FULL PAPER
and the dependence of the isomeric ratio upon steric factors Table 1. Synthesis of tert-butyl 2-[2-(3-amino-1H-isoindol-1-ylid-
ene)hydrazino]oxoalkylcarbamates 5a–d.
and solvent polarity was analyzed. The rotational barriers
around C(O)–N and electrostatic potentials were estimated
by NMR and by ab initio calculations.[5a]
From this study, it appears that a series of compounds
containing a 1H-isoindole cycle and an amino acid hydra-
zide moiety could constitute interesting new peptide turn
mimics. Recently, β-sheet mimetics based on m-hydrazino-
benzoic acid and diurea scaffolds showing the ability to
mimic the hydrogen pattern of an antiparallel β-sheet were
Entry
5
R1
Yield [%]
developed.[2,6] Symmetrical structures derived from dihy-
drazido derivatives 3[7] in which hydrazido peptides are C-
terminally linked through an isoindole unit will bear two
parallel attached peptide strands providing parallel β-sheet
formation, which, although less prevalent in protein–pro-
tein interactions is widely involved in peptide aggregation.[2]
Therefore, we developed the concept of type 1 peptidomi-
metics in which the isoindole units are coupled by means
of hydrazide linkage from one side and a urea scaffold from
other side to induce β-turn as well as β-sheet formation
between two antiparallel peptide strands that can be fixed
by C=O···H–N bridges.
1
2
3
4
5a
5b
5c
5d
H
91
93
89
90
Me
iPr
iBu
Table 2. Influence of solvent polarity on the Z/E isomeric ratio of
compounds 5a–d.
The first objective was to incorporate the heterocyclic
moiety into a peptidic chain and to prepare simple model
peptide systems with either rigid or semi-rigid conforma-
tions, and further to examine the impact of the presence of
the isoindole moiety. For the synthesis of the desired pept-
idomimics, 1-imino-1H-isoindol-3-amine (4) served as a
core unit, permitting the anchorage of two peptide chains
at the two amino functionalities.
The initial part of our work focussed on the development
of methods to combine amino acid residues with the 1H-
isoindole heterocycle in one molecule starting from either 4
or phthalonitrile. Our previous studies showed that each of
Entry
5
[D6]DMSO/CDCl3
1:0
1:1
1:3
1
2
3
4
5a
5b
5c
5d
Z/E
Z/E
Z/E
Z/E
1:0.59
1:0.32
1:0.27
1:0.59
1:0.78
1:0.42
1:0.38
1:0.62
1:1.22
1:0.66
1:0.55
1:0.93
In general, the main patterns were the same: the Z/E iso-
these substances interacts with carboxylic acid hydrazides meric ratio depends upon solvent polarity, with the Z-con-
to produce the derivatives 2 bearing only one hydrazide resi- former predominating in dimethyl sulfoxide (DMSO), and
due.[5a] Therefore, as starting amino acid derivatives, the the proportion of the E conformer increasing with decreas-
Boc-protected hydrazides were chosen to provide the selec- ing solvent polarity. As predicted for the structure of de-
tivity.
signed peptidomimics 1, Z amide conformation at the N-
Following a previously published procedure,[5a] tert-butyl acyl hydrazono unit of derivatives 5 would provide the opti-
2-[2-(3-amino-1H-isoindol-1-ylidene)hydrazino]oxoalkyl- mal orientation of the amino acid residue to form a hydro-
carbamates 5a–d were synthesized in high yields by reaction gen bonded β-turn.
of 1H-isoindol 4 with a set of corresponding Boc-protected
In an attempt to introduce the second amino acid resi-
hydrazides of amino acids (Gly, l-Ala, l-Val and l-Leu; due, we applied the methodology of the present amino
Table 1).
group transformation with highly reactive amino acid ester
Phthalonitrile can also be used as the starting compound isocyanates.[8,9] Thus, tripeptides 6 were synthesized in high
in the synthesis of 5a–d,[5a] however, in this case, the yields yields by the coupling of hydrazide derivatives 5 with a
of the reaction products were much lower than those ob- number of amino acid methyl ester isocyanates generated in
tained starting from 4.
situ from amino acid ester and triphosgene in the presence
1
In the H NMR spectra of amino acid derivatives 5, two of diisopropylethylamine (DIEA; Table 3).
sets of signals are observed for most of the protons; CH
The products 6, in most cases, were obtained in satisfied
protons of amino acids residues, NH protons that are asso- purity according to LC/MS analysis (Table 3, entries 2, 3
ciated with the Boc-group, H7 isoindole protons, amide NH and 5–7) and no additional purification steps were required.
protons, and amino groups. This indicates that compounds Compounds 6a and 6d (Table 3, entry 1 and 4) were puri-
5 exist as a mixture of Z and E amide isomers due to re- fied by flash column chromatography on silica.
stricted rotation about C(O)–N bond at the amide residue,
It was found that very slow addition of the amino acid
similar that found in carboxylic acid derivatives 2[5a] ester solution to triphosgene was essential for complete
(Table 2).
2
conversion of the starting amino derivatives 5 into peptides
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1H-Isoindole Based Potential Peptidomimetics
Table 3. Synthesis of methyl [(3-{2-[2-(tert-butoxycarbonylamino)-
3-methylalkanoyl]hydrazono}isoindolin-1-ylidene)ureido]alkanoates
6a–g.
Scheme 2.
For coupling of N-deprotected derivative 8 with Boc–l-
Ala–OH, N-ethyl-NЈ-(3-dimethylaminopropyl)carbodiimide
(EDCI) in the presence of hydroxybenzotriazole (HOBT)
and triethylamine was used.[11] As a result, a complex mix-
ture with a minor content of tetrapeptide 9 was obtained.
In contrast, Boc–l-Ala–F was found to be introduced more
successfully into intermediate 8 with new peptide bond for-
mation (Scheme 3).[12] The reaction product Ϫ peptide 9 Ϫ
was obtained in 69% yield after purification by flash col-
umn chromatography.
Entry
6
R1
R2
Purity [%]
Yield [%]
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
6f
H
H
H
Me
Me
iPr
iPr
H
89
99
97
80
100
95
60
96
94
78
96
89
92
Me
iPr
Me
iPr
Me
iPr
6g
100
Saponification of 6b, allowing peptide chain elongation
6 because the excess of triphosgene in the reaction mixture on the C-terminus, was carried out by using an excess of
is necessary to avoid the formation of a side product – a LiOH (4 equiv.) in MeOH/THF/H2O (3:2:5). The yield of
symmetrical N,NЈ-disubstituted urea.
crude acid 10 was 82%. Tetrapeptide 11, a structural isomer
The optimal ratio of starting amino acid ester/triphos- of 9, was prepared in 51% yield by coupling of the interme-
gene/DIEA was found to be 1:0.4:3.4. In the case of methyl diate acid 10 with H–l-Ala–OMe·HCl according to stan-
glycinate hydrochloride, the reaction yield was significantly dard coupling protocol[11] by stirring the reagents in THF
lower than for the other amino acids due to its low solu- with EDCI, HOBT and Et3N overnight at room tempera-
bility in dichloromethane. Attempts to improve the yield by ture, and purification by flash column chromatography
changing the solvent to dioxane or acetonitrile were unsuc- (Scheme 3).
cessful.
It was found that dipeptide hydrazides 12 could also be
Ureido peptides 6 probably have the preferable diimino used effectively for the preparation of the desired peptides
tautomeric form and Z-orientation of substituents at the from 4. The dipeptides were prepared by following a stan-
exocyclic C=N bonds similar to other members of the di- dard protocol[11] in excellent yields (93–95%) and then
substituted 1H-isoindole-1,3(2H)-diimine family. This transformed into the corresponding hydrazides 12 in high
suggestion was based on our studies with compounds of yields (95–98%). Boc-protected dipeptide hydrazides 12
similar structure such as NЈ,NЈЈ-1H-isoindole-1,3-diylidene- were reacted with 4 to afford derivatives 13 in yields of 95–
dicarbohydrazides (7A)[5b] and N-aryl-NЈ-[3-(arylimino)-2,3- 98% and purities of above 97%, according to the LC/MS
dihydro-1H-isoindol-1-ylidene]ureas (7B)[10] (Scheme 2).
analysis (Table 4).
For further elongation of the peptide chain, deprotection
Further extension of selected tripeptide derivative 13b
of the terminal extremities (NHBoc and COOMe groups) with H–l-Ala–OMe·HCl and triphosgene was carried out
of peptides 6 was necessary. To explore the experimental in a similar way to previous experiments. Crude tetrapept-
details of the desired transformations, tripeptide 6b was ide 14 was purified by flash gradient column chromatog-
chosen. Boc-deprotection on the N-terminal of 6b, leading raphy and isolated in an overall yield of 63% (Scheme 4).
to the formation of 8 as the trifluoroacetate, was carried
The use of dipeptide hydrazides led to higher overall
out in trifluoroacetic acid (TFA)/dichloromethane (1:8) yield of tetrapeptide 14 compared with those obtained for
with 100% conversion but in 75% yield of peptide 8 in the tetrapeptide 9 and 11 by successive addition of amino acid
mixture according to NMR and LC/MS analyses.
units to isoindole intermediates. Compound 14 was sub-
Scheme 3.
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O. V. Hordiyenko et al.
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Table 4. Synthesis of tert-butyl 1-{1-[2-(3-amino-1H-isoindol-1- preliminary information on the hydrogen bond pattern in
ylidene)hydrazinyl]-1-oxoalkan-2-ylamino}-1-oxoalkan-2-ylcarb-
amates 13a–c.
the molecules by monitoring the rate of deuterium exchange
1
of amide protons in H NMR spectrum upon addition of
D2O.[13] The 1H NMR spectrum of pentapeptide 16 in
CDCl3 reveals twelve NH-proton singlets at ca. δ = 9.00 to
12.60 ppm. A small aliquot of D2O was added to the sam-
1
ple of 16 to give a ca. 5% v/v mixture with CDCl3. The H
NMR spectrum obtained after 10 min showed the dis-
appearance of peaks corresponding to all but three NH sin-
1
Entry
13
R1
R2
Yield [%]
glets at δ = 9.05, 10.55 and 10.69 ppm. The H NMR spec-
trum obtained 24 h after addition of D2O showed a signifi-
cant decrease in the intensity of these three peaks. These
results suggest that these signals correspond to the intramo-
lecular H-bonded NH groups of the peptide 16, supporting
its β-turn-like structure.
1
2
3
13a
13b
13c
Me
Me
Bn
Me
Bn
Me
95
97
98
Conclusions
A new variety of peptidomimetics – di-, tri-, tetra-, and
pentapeptides – based on a 1H-isoindole template, pos-
sessing two peptide strands derived from an amino acid hy-
drazide and a urea scaffold linked through an isoindole
unit, was designed. For their synthesis, an efficient route
has been developed to introduce the amino acid residue into
N-Boc-amino acid (3-amino-1H-isoindol-1-ylidene)hydra-
zides by their reaction with amino acid ester isocyanates
generated in situ.
Scheme 4.
sequently converted into deprotected acid 15 with LiOH
(4 equiv.). Further coupling with H–l-Phe–OMe in the
presence of EDCI and HOBT allowed the preparation of
pentapeptide 16 (Scheme 5).
Experimental Section
General: Melting points were determined with a Boetius micro-
scope hot plate apparatus. Elemental analyses (C, H, N) were con-
ducted with a Vario Micro Cube. Mass spectra were recorded with
an Agilent 1100 LCMSD SL instrument by chemical ionization
(CI). IR spectra were recorded with a Perkin–Elmer Spectrum BX
FTIR Spectrometer. NMR spectra were measured with a Bruker
Avance 300 (300 MHz for 1H and 75 MHz for 13C) with tetrameth-
ylsilane as standard. Optical rotations were measured with an An-
ton Paar MCP 300 Polarimeter at λ = 589 nm at room temperature.
Preparative column chromatography was carried out with silica gel
60 (40–63 μm). Boc-protected amino acid hydrazides and dipeptide
hydrazides 12 were obtained from the corresponding methyl esters
and excess of hydrazine monohydrate in MeOH by stirring the re-
action mixture overnight at room temp., and then evaporation to
dryness (yields 90–98%) similar to a described procedure.[14]
Synthesis of tert-Butyl 2-[2-(3-Amino-1H-isoindol-1-ylidene)hydraz-
ino]oxoalkylecarbamates 5a–f. General Procedure: 1-Imino-1H-iso-
indol-3-amine 4 (726 mg, 5 mmol) was dissolved in methanol or
ethanol (50 mL) and the corresponding amino acid hydrazide
(5 mmol) was added. The mixture was heated to reflux for 4–5 h.
After cooling, the precipitate formed was filtered, washed with
methanol or ethanol and dried in vacuo.
Scheme 5.
The geometry of pseudopeptide molecule 16 with two
attached dipeptide strands linked by the isoindole heterocy-
cle was expected to facilitate C=O···H–N bridges between
the two antiparallel chains of the molecule and thus induce
the formation of hydrogen-bonded β-turn structures. Pept-
ides 6–16 exist as mixtures of several amide conformers in
(Z)-tert-Butyl 2-[2-(3-Amino-1H-isoindol-1-ylidene)hydrazinyl]-2-
oxoethylcarbamate (5a): Light-yellow solid (1.44 g, 91%); m.p. 248–
1
250 °C. H NMR (300 MHz, [D6]DMSO, 20 °C): δ = 1.40 [s, 9 H,
(CH3)3], 3.71 and 4.13 (2 d, J = 6.0 Hz, 2 H, CH2), 6.87 and 7.24
(2 t, J = 6.0 Hz, 1 H, NH), 7.51 (t, J = 6.0 Hz, 1 H, ArH), 7.55 (t,
J = 6.0 Hz, 1 H, ArH), 7.72 (d, J = 8.0 Hz, 1 H, ArH), 7.91 (d, J
CDCl3 solution, as can be concluded from their 1H and 13
NMR spectra. The assignment of signals in the 1D and 2D
C
NMR spectra is therefore complex. We decided to obtain = 6.0 Hz, 1 H, ArH), 8.24 and 8.45 (2 br. s, 2 H, NH2), 9.61 and
4
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1H-Isoindole Based Potential Peptidomimetics
10.34 (2 br. s, 1 H, NH) ppm. 13C NMR (75 MHz, [D6]DMSO,
in CH2Cl2 (30 mL) was added very slowly during 1 h at ambient
20 °C): δ = 28.12 and 28.18 [(CH3)3], 41.38 and 43.32 (CH2), 77.89 temperature. After further stirring for 5 min, a suspension of hydra-
and 78.43 (C), 120.05 and 120.30 (CH), 121.29 (CH), 129.17 (CH), zide derivative 5a–c (1.5 mmol) and DIEA (0.78 mL, 4.50 mmol)
130.75 (CH), 134.70 (C), 137.83 and 138.28 (C), 155.90, 156.70,
in CH2Cl2 (10 mL) was added in one portion and stirring was con-
tinued overnight. The suspension became a yellow solution, which
was subsequently washed with 10% HCl (2ϫ50 mL), saturated
NaHCO3 (2ϫ 50 mL), brine (2ϫ50 mL), dried with MgSO4 and
the solvents were evaporated to dryness.
165.12, 167.21, 167.41, 169.26 ppm. IR (KBr): ν = 3340, 3169,
˜
2974, 1711, 1658, 1547, 1512, 1434, 1283, 1253, 1165, 1133, 1003,
703 cm–1. MS (CI): m/z = 318 [M + H]+. C15H19N5O3 (317.34):
calcd. C 56.77, H 6.03, N 22.07; found C 56.70, H 6.10, N 22.11.
(S,Z)-tert-Butyl 1-[2-(3-Amino-1H-isoindol-1-ylidene)hydrazinyl]-1-
oxopropan-2-ylcarbamate (5b): Light-yellow solid (1.54 g, 93%);
Methyl
2-[(Z)-3-((Z)-3-{2-[2-(tert-Butoxycarbonylamino)acetyl]-
hydrazono}isoindolin-1-ylidene)ureido]acetate (6a): Purification by
flash column chromatography (CH2Cl2/acetone, 7:3) gave 6a as a
flesh-coloured solid (0.26 g, 60%); m.p. 198 °C. 1H NMR
(300 MHz, CDCl3, 20 °C): δ = 1.39 [br. s, 9 H, (CH3)3], 3.74 and
3.80 (2 s, 3 H, OCH3), 4.01, 4.14 and 4.36 (3 br. s, 4 H, 2 CH2),
5.39 and 5.50 (2 br. s, 1 H, NH), 7.33 (t, 1 H, J = 6.6 Hz, ArH),
7.40 (t, 1 H, J = 6.6 Hz, ArH), 7.62 and 7.73 (2 d, J = 6.6 Hz, 1
H, ArH), 7.89 (d, J = 6.6 Hz, 1 H, ArH), 9.90, 9.99, 10.34, 10.49,
10.65 and 11.08 (6 br. s, 3 H, 3 NH) ppm. 13C NMR (75 MHz,
CDCl3, 20 °C): δ = 29.15 [(CH3)3], 43.13 (CH2), 43.35 (CH2), 53.40
(OCH3), 80.38 (C), 122.00 (CH), 122.23 (CH), 123.06 (CH), 130.46
(CH), 132.38 (CH), 134.34 (C), 137.44 (C), 151.33, 155.75, 156.77,
1
m.p. 240 °C; [α]2D0 = –41.13 (c = 1, CH3OH). H NMR (300 MHz,
[D6]DMSO, 20 °C): δ = 1.25 and 1.29 (2 d, J = 6.0 Hz, 3 H, CH3),
1.38 [br. s, 9 H, (CH3)3], 4.10–4.14 and 4.88–4.97 (2 m, 1 H, CH),
7.00 and 7.29 (2 d, J = 6.0 Hz, 1 H, NH), 7.48–7.58 (m, 2 H, 2
ArH), 7.71 (d, J = 6.0 Hz, 1 H, ArH), 7.92 (d, J = 6.0 Hz, 1 H,
ArH), 8.27 and 8.45 (2 br. s, 2 H, NH2), 9.50 and 10.34 (2 br. s, 1
H, NH) ppm. 13C NMR (75 MHz, [D6]DMSO, 20 °C): δ = 16.88
and 17.58 (CH3), 28.13 [(CH3)3], 46.64 and 49.57 (CH), 77.82 and
78.41 (C), 120.00 (CH), 120.27 (CH), 121.28 (CH), 129.15 (CH),
130.75 (CH), 134.69 (C), 137.89 and 138.26 (C), 154.23, 155.27,
156.83, 167.20, 167.40, 168.36, 172.88 ppm. IR (KBr): ν = 3360,
˜
3299, 3180, 2979, 1716, 1657, 1623, 1541, 1508, 1249, 1163, 1135,
703 cm–1. MS (CI): m/z = 332 [M + H]+. C16H21N5O3 (331.37):
calcd. C 57.99, H 6.39, N 21.13; found C 58.02, H 6.44, N 21.14.
164.21, 171.67 ppm. IR (KBr): ν = 3428, 3252, 3122, 2979, 1688,
˜
1635, 1519, 1355, 1226, 1159, 701 cm–1. MS (CI): m/z = 433 [M +
H]+. C19H24N6O6 (432.43): calcd. C 52.77, H 5.59, N 19.43; found
C 52.81, H 5.64, N 19.41.
(S,Z)-tert-Butyl 1-[2-(3-Amino-1H-isoindol-1-ylidene)hydrazinyl]-3-
methyl-1-oxobutan-2-ylcarbamate (5c): Yellow solid (1.60 g, 89%);
m.p. 150–152 °C; [α]2D0 = +39.02 (c = 1, CH3OH). 1H NMR
(300 MHz, [D6]DMSO, 20 °C): δ = 0.89 and 0.94 [2 d, J = 8.0 Hz,
6 H, (CH3)2], 1.39 [br. s, 9 H, (CH3)3], 2.01–2.12 (m, 1 H, CH),
3.88 and 4.91 (2 t, J = 6.0 Hz, 1 H, CH), 6.64 and 7.13 (2 d, J =
6.0 Hz, 1 H, NH), 7.48–7.58 (m, 2 H, 2 ArH), 7.72 (d, J = 6.0 Hz,
1 H, ArH), 7.92 (d, J = 6.0 Hz, 1 H, ArH), 8.27 and 8.46 (2 br. s,
2 H, NH2), 9.58 and 10.30 (2 br. s, 1 H, NH) ppm. 13C NMR
(75 MHz, [D6]DMSO, 20 °C): δ = 18.27 and 19.15 (CH3)2, 28.15
[(CH3)3], 29.55 and 29.70 (CH), 59.70 (CH), 77.92 and 78.25 (C),
120.32, 121.29, 129.17, 130.76, 134.69 (C), 138.27 (C), 155.71,
(S)-Methyl 2-[(Z)-3-((Z)-3-{2-[2-(tert-Butoxycarbonylamino)acetyl]-
hydrazono}isoindolin-1-ylidene)ureido]propanoate (6b): Pale-yellow
solid (0.43 g, 96%); m.p. 177–178 °C; [α]2D0 = +0.29 (c = 1,
1
CH3OH). H NMR (300 MHz, CDCl3, 20 °C): δ = 1.45 and 1.48
[2 s, 9 H, (CH3)3], 1.63–1.68 (m, 3 H, CH3), 3.88 and 3.95 (2 s, 3
H, OCH3), 4.20 and 4.51 (2 br. s, 2 H, CH2), 4.60–4.68 (m, 1 H,
CH), 5.50, 5.64 and 5.83 (3 br. s, 1 H, NH), 7.47–7.59 (m, 2 H, 2
ArH), 7.82 and 8.02 (2 d, J = 9 Hz, 1 H, ArH), 8.11–8.15 (m, 1 H,
ArH), 9.88, 10.52, 10.55, 10.57, 11.07, 11.09 and 11.25 (7 br. s, 3
H, 3 NH) ppm. 13C NMR (75 MHz, CDCl3, 20 °C): δ = 19.25
(CH3), 29.04 [(CH3)3], 42.58 and 43.07 (CH2), 50.70 and 50.84
(CH), 53.75 and 54.31 (OCH3), 80.30 (C), 122.07, 122.39, 123.08,
130.50, 130.61, 132.46, 132.56, 134.40, 134.50, 137.27, 137.31,
151.28, 154.44, 154.93, 155.06, 156.68, 164.26, 164.32, 166.84,
156.78, 167.21 ppm. IR (KBr): ν = 3303, 3285, 2973, 1695, 1665,
˜
1542, 1501, 1165, 1135, 708 cm–1. MS (CI): m/z = 360 [M + H]+.
C18H25N5O3 (359.42): calcd. C 60.15, H 7.01, N 19.48; found C
60.21, H 7.04, N 19.52.
171.30, 173.60, 174.04, 174.89 ppm. IR (KBr): ν = 3423, 3372,
˜
3276, 2981, 1748, 1731, 1715, 1689, 1522, 1164, 768, 705 cm–1. MS
(CI): m/z = 447 [M + H]+. C20H26N6O6 (446.46): calcd. C 53.80,
H 5.87, N 18.82; found C 53.79, H 5.83, N 18.75.
(S,Z)-tert-Butyl 1-[2-(3-Amino-1H-isoindol-1-ylidene)hydrazinyl]-4-
methyl-1-oxopentan-2-ylcarbamate (5d): Light-yellow solid (1.68 g,
90%); m.p. 208 °C; [α]2D0 = –35.39 (c = 1, CH3OH). 1H NMR
(300 MHz, [D6]DMSO, 20 °C): δ = 0.86–1.03 [m, 6 H, (CH3)2], 1.38
and 1.40 [2 br. s, 9 H, (CH3)3], 1.48–1.73 (m, 3 H, CH + CH2),
4.02–4.09 and 4.95–5.03 (2 m, 1 H, CH), 6.92 and 7.29 (2 d, J =
6.0 Hz, 1 H, NH), 7.49–7.60 (m, 2 H, 2 ArH), 7.64 and 7.72 (2 d,
J = 6.0 Hz, 1 H, ArH), 7.92 (d, J = 6.0 Hz, 1 H, ArH), 8.28 and
8.46 (2 br. s, 2 H, NH2), 9.45 and 10.33 (2 br. s, 1 H, NH) ppm.
13C NMR (75 MHz, [D6]DMSO, 20 °C): δ = 21.21, 21.37, 22.97,
23.26, 24.28, 24.66, 28.13 and 28.20 [(CH3)3], 49.55, 52.60, 77.76,
78.41 (C), 119.65 (CH), 120.29 (CH), 121.31 (CH), 121.41 (CH),
129.17 (CH), 130.77 (CH), 134.69 (C), 138.01 and 138.23 (C),
(S)-Methyl 2-[(Z)-3-((Z)-3-{2-[2-(tert-Butoxycarbonylamino)acetyl]-
hydrazono}isoindolin-1-ylidene)ureido]-3-methylbutanoate (6c): Yel-
low solid (0.45 g, 94%); m.p. 175–176 °C; [α]2D0 = –119.75 (c = 0.63,
1
CH3OH). H NMR (300 MHz, CDCl3, 20 °C): δ = 1.03–1.13 [m,
6 H, (CH3)2], 1.46 and 1.49 [2 s, 9 H, (CH3)3], 2.34–2.45 (m, 1 H,
CH), 3.86 and 3.94 (2 s, 3 H, OCH3), 4.11–4.62 (m, 3 H, CH2 +
CH), 5.46 and 5.60 (t, J = 6 Hz and br. s, 1 H, NH), 7.49–7.62 (m,
2 H, 2 ArH), 7.85 and 8.05 (2 d, J = 7.5 Hz, 1 H, ArH), 8.14–8.20
(m, 1 H, ArH), 9.68, 10.42, 10.44, 11.03, 11.22 and 11.25 (6 br. s,
3 H, 3 NH) ppm. 13C NMR (75 MHz, CDCl3, 20 °C): δ = 19.00,
19.06, 19.24, 19.61, 29.06 [(CH3)3], 32.40 and 32.70 (CH), 43.09
and 43.75 (CH2), 53.34 and 53.90 (OCH3), 60.17 and 60.26 (CH),
80.33 (C), 122.10, 122.53, 123.14, 130.50, 130.60, 132.55, 132.62,
134.45, 134.55, 137.35, 151.27, 154.49, 155.41, 155.61, 156.68,
155.57, 156.88, 167.20, 167.38, 168.03 ppm. IR (KBr): ν = 3329,
˜
3191, 2958, 2932, 1661, 1541, 1506, 1367, 1164, 704 cm–1. MS (CI):
m/z = 374 [M + H]+. C19H27N5O3 (373.45): calcd. C 61.11, H 7.29,
N 18.75; found C 61.08, H 7.25, N 18.75.
Synthesis of Methyl [(3-{2-[2-(tert-Butoxycarbonylamino)-3- 164.36, 164.46, 166.68, 171.11, 172.22, 173.75 ppm. IR (KBr): ν =
˜
methylalkanoyl]hydrazono}isoindolin-1-ylidene)ureido]alkanoates 3285, 3071, 2974, 1748, 1697, 1683, 1669, 1646, 1538, 1528, 1434,
6a–g. General Procedure: Triphosgene (223 mg, 0.75 mmol) was
dissolved in CH2Cl2 (5 mL), and a mixture of amino acid methyl
ester hydrochloride (1.9 mmol) and DIEA (0.33 mL, 1.90 mmol)
1179, 1056, 759, 678 cm–1. MS (CI): m/z = 475 [M + H]+.
C22H30N6O6 (474.51): calcd. C 55.69, H 6.37, N 17.71; found C
55.60, H 6.29, N 17.68.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20238
/KAP1
Date: 28-06-12 10:27:16
Pages: 9
O. V. Hordiyenko et al.
FULL PAPER
(S)-Methyl 2-[(Z)-3-((Z)-3-{2-[(S)-2-(tert-Butoxycarbonylamino)- s, 3 H, OCH3), 4.36–4.69 and 5.30–5.56 (2 m, 3 H, 2 CH + NH),
propanoyl]hydrazono}isoindolin-1-ylidene)ureido]propanoate (6d): 7.48–7.61 (m, 2 H, 2 ArH), 7.86 and 8.06 (2 d, J = 6.0 Hz, 1 H,
Purification by flash column chromatography (CH2Cl2/methanol, ArH), 8.16–8.20 (m, 1 H, ArH), 9.65, 10.33, 10.40, 10.45, 10.88,
95:5) gave 6d as a yellow solid (0.36 g, 78%); m.p. 127–128 °C; 11.02, 11.22 and 11.43 (8 br. s, 3 H, 3 NH) ppm. 13C NMR
[α]2D0 = +55.63 (c = 1, CH3OH). 1H NMR (300 MHz, CDCl3,
(75 MHz, CDCl3, 20 °C): δ = 18.46, 18.64, 19.02, 19.66, 20.13,
20 °C): δ = 1.43 and 1.46 [2 s, 9 H, (CH3)3], 1.50–1.55 (m, 3 H, 20.46, 29.01 and 29.06 [(CH3)3], 31.71, 31.87, 32.06, 32.30, 32.43,
CH3), 1.63–1.70 (m, 3 H, CH3), 3.87, 3.88 and 3.93 (3 s, 3 H,
OCH3), 4.63–4.68 and 5.29–5.36 (2 m, 2 H, 2 CH), 5.53–5.63 (m,
1 H, NH), 7.50–7.59 (m, 2 H, 2 ArH), 7.86 and 8.04 (2 d, J =
32.87, 52.69, 53.31, 53.72, 58.84, 58.98, 60.19, 79.96, 122.14, 122.44
(CH), 123.14 (CH), 130.42 and 130.52 (CH), 132.45 and 132.57
(CH), 134.41 and 134.52 (C), 137.46 (C), 150.82, 154.43, 154.57,
7.2 Hz, 1 H, ArH), 8.14–8.18 (m, 1 H, ArH), 9.82, 9.85, 10.56, 155.43, 155.65, 156.18, 156.33, 156.67, 164.32, 164.40, 169.60,
10.60, 11.08, 11.13 and 11.16 (7 br. s, 3 H, 3 NH) ppm. 13C NMR
172.13, 172.23, 173.54, 173.66, 173.96 ppm. IR (KBr): ν = 3429,
(75 MHz, CDCl3, 20 °C): δ = 19.23, 19.51, 19.72, 20.28, 29.03 3322, 3278, 2967, 2935, 1734, 1697, 1681, 1644, 1522, 1164, 765,
[(CH3)3], 47.95, 49.97, 50.70, 50.85, 53.70 and 54.09 (OCH3), 80.19
705 cm–1. MS (CI): m/z = 517 [M + H]+. C25H36N6O6 (516.59):
˜
(C), 122.13, 122.39, 123.09, 130.51, 130.59, 132.42, 132.56, 134.43, calcd. C 58.12, H 7.02, N 16.27; found C 58.08, H 6.99, N 18.50.
134.50, 137.33, 137.44, 151.16, 154.54, 155.03, 155.14, 155.95,
Boc-Deprotection of 6b: A mixture of TFA (2 mL) in CH2Cl2
164.32, 170.62, 173.52, 174.81, 174,96. 175.15 ppm. IR (KBr): ν =
˜
(16 mL) was added to 6b (446 mg, 1 mmol) and the resulting solu-
tion was stirred for 1.5–2 h, then evaporated to dryness. To maxi-
mise removal of TFA, coevaporation techniques were used; the resi-
due was therefore washed and evaporated with CH2Cl2 (ϫ2), tolu-
ene (ϫ2) and diethyl ether (ϫ3). TFA salt 8 was obtained in 75%
purity, and was used for the next step without additional purifica-
tion.
3361, 3256, 3165, 3126, 2981, 1694, 1524, 1504, 1353, 1224, 1162,
771, 704 cm–1. MS (CI): m/z = 461 [M + H]+. C21H28N6O6 (460.48):
calcd. C 54.77, H 6.13, N 18.25; found C 54.78, H 6.13, N 18.20.
(S)-Methyl 2-[(Z)-3-((Z)-3-{2-[(S)-2-(tert-Butoxycarbonylamino)-
propanoyl]hydrazono}isoindolin-1-ylidene)ureido]-3-methylbutanoate
(6e): Yellow solid (0.47 g, 96%); m.p. 124–125 °C; [α]2D0 = –14.29 (c
1
= 1, CH3OH). H NMR (300 MHz, CDCl3, 20 °C): δ = 1.05–1.13
(S)-Methyl 2-{(Z)-3-[(Z)-3-(2-{2-[(S)-2-(tert-Butoxycarbonylamino)-
propanamido]acetyl}hydrazono)isoindolin-1-ylidene]ureido}prop-
anoate (9): Obtained from 8 (460 mg, 1 mmol) and Boc-Ala-F
(191 mg, 1 mmol) in the presence of NaHCO3 (168 mg, 2 mmol)
according to a reported protocol.[12] The reaction mixture was puri-
fied by chromatography with a gradient of CH2Cl2/MeOH to af-
[m, 6 H, (CH3)2], 1.44 and 1.46 [2 s, 9 H, (CH3)3], 1.48–1.53 (m, 3
H, CH3), 2.35–2.51 (m, 1 H, CH), 3.86 and 3.95 (2 s, 3 H, OCH3),
4.39–4.55 (m, 2 H, 2 CH), 5.31–5.62 (m, 1 H, NH), 7.48–7.62 (m,
2 H, 2 ArH), 7.88 and 8.06 (2 d, J = 7.5 Hz, 1 H, ArH), 8.15–8.21
(m, 1 H, ArH), 9.61, 10.38, 10.40, 10.49, 11.02, 11.15 and 11.39 (7
br. s, 3 H, 3 NH) ppm. 13C NMR (75 MHz, CDCl3, 20 °C): δ =
18.46, 19.01, 19.04, 19.25, 29.03 and 29.07 [(CH3)3], 32.07, 32.34,
32.65, 52.69 and 53.30 (OCH3), 60.14 and 60.27 (CH), 80.22 (C),
122.13, 122.41, 123.13, 130.46, 130.55, 132.50 and 132.61 (CH),
134.42 and 134.50 (C), 137.37 and 137.49 (C), 151.10, 154.58,
155.37, 155.58, 155.97, 164.38, 170.54, 172.27, 173.79, 174.57,
ford 9 (0.36 g, 69%) as a yellow solid; m.p. 203–205 °C; [α]2D0
=
1
–38.73 (c = 1, CH3OH). H NMR (300 MHz, CDCl3, 20 °C): δ =
1.33–1.39 [m, 12 H, CH3 + (CH3)3], 1.48–1.52 (m, 3 H, CH3), 3.66,
3.75 and 3.82 (3 s, 3 H, OCH3), 4.15–4.69 (m, 4 H, 2 CH + CH2),
5.35, 5.48 and 5.74 (3 br. s, 1 H, NH), 7.13 and 7.24 (2 br. s, 1 H,
NH), 7.38–7.52 (m, 2 H, 2 ArH), 7.76 and 7.92 (2 d, J = 7.5 Hz, 1
H, ArH), 8.04 (d, J = 7.5 Hz, 1 H, ArH), 9.84, 10.46, 10.48, 10.50,
11.03, 11.18, 11.30, 11.83 and 12.48 (9 br. s, 3 H, 3 NH) ppm. 13C
NMR (75 MHz, CDCl3, 20 °C): δ = 18.89, 19.15, 19.47, 19.69,
29.06 [(CH3)3], 42.10 and 42.79 (CH2), 50.63 (CH), 50.75 (CH),
53.73 and 54.46 (OCH3), 80.51 (C), 122.15, 122.43, 122.54, 123.00,
130.48, 130.55, 132.44, 132.47, 134.49, 134.68, 137.26, 151.40,
154.44, 154.81, 154.90, 156.15, 164.18, 164.32, 166.30, 170.72,
174.85 ppm. IR (KBr): ν = 3384, 3256, 3165, 3126, 2971, 1697,
˜
1522, 1507, 1354, 1164, 771, 706 cm–1. MS (CI): m/z = 489 [M +
H]+. C23H32N6O6 (488.54): calcd. C 56.55, H 6.60, N 17.20; found
C 56.50, H 6.55, N 17.18.
(S)-Methyl 2-[(Z)-3-((Z)-3-{2-[(S)-2-(tert-Butoxycarbonylamino)-3-
methylbutanoyl]hydrazono}isoindolin-1-ylidene)ureido]propanoate
(6f): Yellow solid (0.43 g, 89%); m.p. 129–130 °C; [α]2D0 = +111.58
(c = 0.14, CH3OH). 1H NMR (300 MHz, CDCl3, 20 °C): δ = 0.90–
1.02 [m, 6 H, (CH3)2], 1.44 and 1.48 [2 s, 9 H, (CH3)3], 1.54–1.60
(m, 3 H, CH3), 2.06–2.21 (m, 1 H, CH), 3.82 and 3.90 (2 s, 3 H,
OCH3), 4.55–4.81 (m, 1 H, CH), 5.31–5.64 (m, 2 H, NH + CH),
7.50–7.64 (m, 2 H, 2 ArH), 7.97 and 8.08 (2 d, J = 7.5 Hz, 1 H,
ArH), 8.17–8.23 (m, 1 H, ArH), 9.64, 10.45, 10.48, 10.54, 11.05,
11.14 and 11.19 (7 br. s, 3 H, 3 NH) ppm. 13C NMR (75 MHz,
CDCl3, 20 °C): δ = 18.54, 19.10, 19.77, 22.25, 29.16 [(CH3)3], 32.17,
48.06, 52.80, 53.39, 53.99, 58.93, 59.07, 60.26, 60.41, 80.30 (C),
122.14, 122.58, 123.20, 130.69 (CH), 132.55 and 132.65 (CH),
134.58 (C), 137.45 (C), 137.57, 151.19, 154.66, 155.46, 155.67,
156.04, 164.47, 170.63, 172.34, 173.87, 174.65, 174.95 ppm. IR
173.53, 173.99, 174.10, 174.65 ppm. IR (KBr): ν = 3428, 3305,
˜
3126, 2976, 2885, 1734, 1697, 1686, 1535, 1204, 11138, 722,
706 cm–1. MS (CI): m/z = 518 [M + H]+. C23H31N7O7 (517.53):
calcd. C 53.38, H 6.04, N 18.94; found C 53.29, H 6.01, N 18.90.
Saponification of Methyl Esters 6b and 14. General Procedure: The
corresponding compound (1 mmol) was dissolved in a mixture of
methanol (3 mL) and THF (2 mL), then a solution of lithium hy-
droxide (4 mmol) in water (5 mL) was added. The resulting solution
was stirred until complete transformation of the starting compound
into the product was observed (reaction monitored by TLC analy-
sis; plates eluted with ethyl acetate). The reaction mixture was
acidified to pH 5 with saturated aqueous citric acid and the formed
precipitate was filtered off and dried in an oven. Compound 10 was
obtained in 82% yield (87% purity); compound 15 was obtained
in 90% yield (86% purity), and both were used for the next steps
without additional purification.
(KBr): ν = 3285, 2979, 1680, 1644, 1521, 1160, 761, 680 cm–1. MS
˜
(CI): m/z = 489 [M + H]+. C23H32N6O6 (488.54): calcd. C 56.55,
H 6.60, N 17.20; found C 56.56, H 6.58, N 17.21.
(S)-Methyl 2-[(Z)-3-((Z)-3-{2-[(S)-2-(tert-Butoxycarbonylamino)-3-
methylbutanoyl]hydrazono}isoindolin-1-ylidene)ureido]-3-methyl-
butanoate (6g): Yellow solid (0.48 g, 92 %); m.p. 175–176 °C;
[α]2D0 = –66.74 (c = 1, CH3OH). 1H NMR (300 MHz, CDCl3,
20 °C): δ = 0.88–1.14 [m, 12 H, 2 (CH3)2], 1.42 and 1.46 [2 br. s, 9
(S)-Methyl 2-{(S)-2-[(Z)-3-((Z)-3-{2-[2-(tert-Butoxycarbonylamino)-
acetyl]hydrazono}isoindolin-1-ylidene)ureido]propanamido}prop-
anoate (11): Obtained according to a published procedure[11] from
10 (432 mg, 1 mmol) and H–Ala–OMe·HCl (140 mg, 1 mmol). Pu-
H, (CH3)3], 2.02–2.44 (m, 2 H, 2 CH), 3.74, 3.86, 3.93 and 3.98 (4 rification by flash column chromatography (EtOAc) gave 11 as a
6
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Job/Unit: O20238
/KAP1
Date: 28-06-12 10:27:16
Pages: 9
1H-Isoindole Based Potential Peptidomimetics
yellow solid (0.26 g, 51%); m.p. 145–146 °C, [α]2D0 = –80.00 (c = 1,
CH3OH). H NMR (300 MHz, CDCl3, 20 °C): δ = 1.46–1.61 [m, 28.92 and 28.97 [(CH3)3], 38.97 and 39.27 (CH2), 47.27, 48.78,
13C NMR (75 MHz, CDCl3, 20 °C): δ = 18.70 and 18.86 (CH3),
1
15 H, 2 CH3 + (CH3)3], 3.71, 3.77, 3.74 and 3.83 (4 s, 3 H, OCH3),
4.02–4.75 (m, 4 H, 2 CH + CH2), 5.56 and 5.82 (2 br. s, 1 H, NH),
56.42, 80.83 and 80.97 (C), 121.44, 122.37, 127.48, 127.58, 129.16,
129.22, 129.29, 129.97, 130.09, 131.51, 131.82, 134.68, 134.78,
7.22–8.03 (m, 5 H, 4 ArH + NH), 10.01, 10.06, 10.36, 10.45, 10.62, 137.07, 137.32, 138.75, 138.80, 156.25, 159.00, 168.93, 169.06,
10.80, 11.04, 11.12, 11.28, 12.13 and 12.42 (11 br. s, 3 H, 3
169.46, 172.25, 172.71, 173.22, 174.26 ppm. IR (KBr): ν = 3301,
˜
NH) ppm. 13C NMR (75 MHz, CDCl3, 20 °C): δ = 18.44, 18.68,
3204, 3064, 2978, 1748, 1697, 1683, 1508, 11164, 703 cm–1. MS
19.58, 20.55, 20.76, 29.03 and 29.07 [(CH3)3], 43.00 and 43.92 (CI): m/z = 479 [M + H]+. C25H30N6O4 (478.54): calcd. C 62.75,
(CH2), 48.97, 49.42, 51.00, 51.15, 51.37, 53.18 and 53.35 (OCH3),
80.19 and 80.38 (C), 121.78, 121.87, 122.39, 122.72, 122.92, 130.25,
130.46, 131.49, 132.29, 134.28, 134.52, 137.17, 154.31, 154.52,
154.61, 154.75, 155.06, 156.55, 156.89, 163.93, 164.16, 167.42,
H 6.32, N 17.56; found C 62.70, H 6.28, N 17.55.
(S)-Methyl 2-{(Z)-3-[(Z)-3-(2-{(S)-2-[(S)-2-(tert-Butoxycarbonyl-
amino)propanamido]-3-phenylpropanoyl}hydrazono)isoindolin-1-
ylidene]ureido}propanoate (14): Obtained in a similar way to com-
pounds 6 from 13b (479 mg, 1 mmol), triphosgene (223 mg,
0.75 mmol) and H–Ala–OMe·HCl (209 mg, 1.5 mmol). Purifica-
tion by flash column chromatography (gradient of EtOAc/petro-
leum ether) gave 14 as a pale-yellow solid (0.38 g, 63%); m.p. 185–
171.40, 172.80, 172.94, 173.98, 174.52, 174.70 ppm. IR (KBr): ν =
˜
3496, 3423, 3276, 2981, 1745, 1700, 1697, 1661, 1527, 1354, 11162,
770, 704 cm–1. MS (CI): m/z = 518 [M + H]+. C23H31N7O7 (517.53):
calcd. C 53.38, H 6.04, N 18.94; found C 53.44, H 6.11, N 19.08.
Preparation of tert-Butyl 1-{1-[2-(3-Amino-1H-isoindol-1-ylidene)-
hydrazinyl]-1-oxopalkan-2-ylamino}-1-oxoalkan-2-ylcarbamates
13a–c. General Procedure: 1-Imino-1H-isoindol-3-amine (4)
(290 mg, 2 mmol) was dissolved in methanol (25–30 mL) and the
corresponding dipeptide hydrazide 12 (2 mmol) was added. The
mixture was heated to reflux for 4 h and then evaporated to dry-
ness.
1
186 °C; [α]2D0 = –146.62 (c = 0.13, CH3OH). H NMR (300 MHz,
CDCl3, 20 °C): δ = 1.32–1.70 [m, 15 H, 2 CH3 + (CH3)3], 3.08–
3.38 (m, 2 H, CH2), 3.74, 3.76, 3.85 and 3.94 (4 s, 3 H, OCH3),
4.24 (br. s, 1 H, CH), 4.63–4.71 (m, 1 H, CH), 5.19–5.25 (m, 1 H,
CH), 5.55 and 5.85 (2 br. s, 1 H, NH), 7.14–7.24 (m, 6 H, 5 ArH
+ NH), 7.50–7.66 (m, 2 H, 2 ArH), 7.88, 8.03 and 8.18 (3 d, J =
7.5 Hz, 2 H, 2 ArH), 9.12, 9.94, 10.55, 10.57, 10.61, 10.81 and 10.99
(7 s, 3 H, 3 NH) ppm. 13C NMR (75 MHz, CDCl3, 20 °C): δ =
18.99, 19.26, 19.40, 19.48, 19.59, 29.00 [(CH3)3], 39.06 and 39.49
(CH2), 49.42, 50.82, 53.02, 53.70, 53.87, 54.31, 80.57 (C), 122.27,
122.64, 123.08, 127.44, 127.57, 128.94, 129.00, 130.27, 130.74,
132.58, 134.50, 134.68, 136.69, 137.11, 137.25, 151.53, 154.76,
154.87, 155.14, 155.90, 156.02, 157.28, 164.43, 164.55, 168.44,
tert-Butyl (S)-1-{(S)-1-[(Z)-2-(3-Amino-1H-isoindol-1-ylidene)hy-
drazinyl]-1-oxopropan-2-ylamino}-1-oxopropan-2-ylcarbamate (13a):
Yellow solid (0.76 g, 95%); m.p. 165–166 °C; [α]2D0 = –78.53 (c = 1,
1
CH3OH). H NMR (300 MHz, CDCl3, 20 °C): δ = 1.39–1.51 [m,
15 H, 2 CH3 + (CH3)3], 4.32 (br. s, 1 H, CH), 4.79–4.89 and 5.39–
5.48 (2 m, 1 H, CH), 5.63 and 6.01 (2 br. s, 1 H, NH), 7.22–7.39
(m, 3 H, 2 ArH + NH), 7.62–7.94 (m, 4 H, 2 ArH + NH2), 9.83
and 10.44 (2 br. s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3,
20 °C): δ = 18.63, 19.03, 19.15, 19.53, 29.01 and 29.06 [(CH3)3],
47.17, 48.80, 51.26, 80.79, 121.34, 121.50, 122.18, 129.93, 130.10,
131.54, 131.73, 134.71, 134.77, 138.74, 155.08, 156.30, 169.03,
172.73, 172.93, 173.51, 173.55, 174.60, 175.47 ppm. IR (KBr): ν =
˜
3334, 3285, 3175, 3031, 2982, 1734, 1689, 1664, 1636, 1525, 1222,
11165, 699 cm–1. MS (CI): m/z = 608 [M + H]+. C30H37N7O7
(607.66): calcd. C 59.30, H 6.14, N 16.14; found C 59.24, H 6.15,
N 16.11.
169.47, 173.89, 174.17, 174.51 ppm. IR (KBr): ν = 3445, 3305,
˜
(S)-Methyl 2-((S)-2-{(Z)-3-[(Z)-3-(2-{(S)-2-[(S)-2-(tert-Butoxy-
carbonylamino)propanamido]-3-phenylpropanoyl}hydrazono)isoind-
olin-1-ylidene]ureido}propanamido)-3-phenylpropanoate (16): Ob-
tained according to the published procedure[11] from 15 (297 mg,
0.5 mmol) and H–Phe–OMe·HCl (108 mg, 0.5 mmol). Purification
by flash column chromatography (CH2Cl2/MeOH, 90:10) gave 16
as a yellow solid (0.24 g, 68%); m.p. 178–179 °C; [α]2D0 = +16 (c =
1, CH3OH). 1H NMR (300 MHz, CDCl3, 20 °C): δ = 1.29–1.64 [m,
15 H, 2 CH3 + (CH3)3], 3.05–3.38 (m, 4 H, 2 CH2), 3.64, 3.73,
3.75, 3.76, 3.78 and 3.80 (6 s, 3 H, OCH3), 4.17–6.18 (m, 5 H, 4
CH + NH), 6.82–8.13 (m, 16 H, 14 ArH + 2 NH), 9.05, 9.08, 9.89,
10.23, 10.55, 10.66, 10.69, 10.77, 10.82, 10.94, 12.49 and 12.57 (12
br. s, 3 H, 3 NH) ppm. 13C NMR (75 MHz, CDCl3, 20 °C): δ =
19.49 and 19.57 (CH3), 19.82 (CH3), 28.91 and 29.02 [(CH3)3],
38.04, 38.28, 38.61, 38.79, 51.17, 52.71, 52.86, 52.96, 53.12, 53.62,
54.13, 80.45 and 80.49 (C), 121.98, 122.61, 122.85, 123.70, 124.29,
127.31, 127.55, 127.67, 128.81, 128.87, 128.99, 129.07, 129.11,
129.20, 129.50, 129.71, 129.84, 129.98, 130.14, 130.18, 131.70,
134.33, 134.60, 136.32, 136.71, 137.16, 137.30, 154.52, 154.99,
155.83, 155.91, 156.35, 160.06, 163.24, 164.14, 168.41, 172.43,
3120, 2978, 1731, 1694, 1636, 1539, 1508, 1204, 1138, 722,
706 cm–1. MS (CI): m/z = 403 [M + H]+. C19H26N6O4 (402.45):
calcd. C 56.70, H 6.51, N 20.88; found C 56.66, H 6.45, N 20.80.
tert-Butyl (S)-1-{(S)-1-[(Z)-2-(3-Amino-1H-isoindol-1-ylidene)hy-
drazinyl]-1-oxo-3-phenylpropan-2-ylamino}-1-oxopropan-2-ylcarb-
amate (13b): Yellow solid (0.93 g, 97%); m.p. 148–149 °C; [α]2D0
=
1
–62.30 (c = 1, CH3OH). H NMR (300 MHz, CDCl3, 20 °C): δ =
1.27–1.34 (m, 3 H, CH3), 1.40 and 1.42 [2 br. s, 9 H, (CH3)3], 2.98–
3.11 and 3.25–3.39 (2 m, 2 H, CH2), 4.25 (br. s, 1 H, CH), 4.72–
4.79, 4.97–5.05, 5.37, 5.51 and 5.71 (2 m, 3 br. s, 2 H, NH + CH),
7.12–7.78 (m, 12 H, 9 ArH + NH2 + NH), 8.93 and 10.20 (2 br. s,
1 H, NH) ppm. 13C NMR (75 MHz, CDCl3, 20 °C): δ = 19.00 and
19.42 (CH3), 29.03 [(CH3)3], 38.44 and 38.97 (CH2), 51.25, 52.55,
54.21, 80.79 (C), 121.32, 121.51, 121.61, 122.30, 127.40, 127.54,
129.00, 129.21, 130.06, 130.11, 131.52, 131.76, 134.83, 136.98,
137.76, 138.76, 155.23, 156.15, 156.22, 167.81, 168.96, 169.49,
172.86, 174.01, 174.11 ppm. IR (KBr): ν = 3301, 3204, 3064, 2978,
˜
2933, 1698, 1661, 1622, 1541, 1508, 1164, 702 cm–1. MS (CI): m/z
= 479 [M + H]+. C25H30N6O4 (478.54): calcd. C 62.75, H 6.32, N
17.56; found C 62.80, H 6.34, N 17.59.
172.46, 172.61, 173.22, 173.43, 173.60, 176.04 ppm. IR (KBr): ν =
˜
tert-Butyl (S)-1-{(S)-1-[(Z)-2-(3-Amino-1H-isoindol-1-ylidene)hy-
drazinyl]-1-oxopropan-2-ylamino}-1-oxo-3-phenylpropan-2-ylcarb-
3495, 3412, 3283, 3065, 3029, 2979, 2935, 1742, 1713, 1695, 1683,
1669, 1522, 1353, 1166, 701 cm–1. MS (CI): m/z = 755 [M + H]+.
C39H46N8O8 (754.83): calcd. C 62.06, H 6.14, N 14.84; found C
61.98, H 6.12, N 14.79.
amate (13c): Yellow solid (0.94 g, 98%); m.p. 150–151 °C; [α]2D0
=
1
+7.68 (c = 1, CH3OH). H NMR (300 MHz, CDCl3, 20 °C): δ =
1.35–1.48 [m, 12 H, CH3 + (CH3)3], 3.04–3.21 (m, 2 H, CH2), 4.54,
4.82, 5.43 and 5.94 (4 br. s, 3 H, NH + 2 CH), 7.11–7.86 (m, 12
H, 9 ArH + NH2 + NH), 9.81 and 10.10 (2 br. s, 1 H, NH) ppm.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for all products.
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Pages: 9
O. V. Hordiyenko et al.
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[6]
The authors thank for the financial support of this work by the
Ministry of Education and Science of Ukraine (French-Ukrainian
program DNIPRO), the Ministry for Foreign Affairs of France
(EGIDE), la Région Lorraine and INPL of Nancy.
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Received: February 28, 2012
Published Online: ᭿
8
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Eur. J. Org. Chem. 0000, 0–0

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Pages: 9
1H-Isoindole Based Potential Peptidomimetics
Peptidomimetics
A variety of potential peptidomimetics in
which the 1H-isoindole unit is coupled by
means of a hydrazide linkage from one side
and a urea scaffold from other side, was de-
veloped.
A. V. Biitseva, I. V. Rudenko,
O. V. Hordiyenko,* B. Jamart-Grégoire,
A. Arrault ......................................... 1–9
1H-Isoindole-Based Potential Peptidomi-
metics
Keywords: Amino acids / Peptidomimetics /
Protein folding / Protein design / Hydraz-
ones
Eur. J. Org. Chem. 0000, 0–0
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