Peptide-heterocycle chimera: New classes of more drug-like peptidomimetics by ligations of peptide-bis(electrophiles) with various bis(nucleophiles)

Article abstract of DOI:10.1002/ejoc.201001206

Several C-terminal peptidyl-substituted bis- and tris(electrophiles) were prepared by starting from polymeric phosphoranylidenacetates as acyl anion equivalents. After C-acylations with amino acids and peptide elongation, the obtained peptidyl-phosphorany

Full text of DOI:10.1002/ejoc.201001206

FULL PAPER
DOI: 10.1002/ejoc.201001206
Peptide–Heterocycle Chimera: New Classes of More Drug-Like
Peptidomimetics by Ligations of Peptide–Bis(electrophiles) with Various
Bis(nucleophiles)
Adeeb El-Dahshan,[a] Samina Nazir,[a,b] Ahsanullah,[a,c] Farzana Latif Ansari,[b] and
Jörg Rademann*[a,d]
Keywords: Medicinal chemistry / Peptidomimetics / Protein engineering / Protein design / N heterocycles
Several C-terminal peptidyl-substituted bis- and tris(electro-
philes) were prepared by starting from polymeric phosphor-
anylidenacetates as acyl anion equivalents. After C-acyla-
tions with amino acids and peptide elongation, the obtained
peptidyl-phosphoranylideneacetate resins were either
cleaved oxidatively, delivering peptidyl-diketo esters, or sa-
to yield peptidyl vinyl ketones or could be cleaved oxidat-
ively to yield peptidyl keto aldehydes. Ligation with various
bis(nucleophiles) including hydrazines, hydroxylamine, di-
amines, amino-thiols, amidines, and guanidines were inves-
tigated in the formation of peptide-heterocycle chimera con-
taining pyrazoline, pyrazole, isoxazole, isoxazoline, thiazep-
ponified, leading to immediate decarboxylation. The gener- ine, quinoxaline, and imidazolone heterocycles.
ated peptidyl-phosphorane could be treated with aldehydes
over, peptidic ligands are prone to proteolytic degradation
Introduction
under physiological conditions, often possess no significant
Most functions within biological systems are exerted by
bioavailability and in most instances do not permeate
through biological membranes.[5]
proteins and are based on the enormous diversity of their
secondary, tertiary and quaternary structures, which are en-
coded in sequences composed of a limited set of 20 amino
acids.[1]
For these reasons, small, nonpeptidic interfering mole-
cules can be a powerful complementation to peptides. Het-
erocycles are especially suitable as drugs, due to their lim-
ited flexibility and the low numbers of rotating bonds found
in these molecules (Scheme 1).[6] Moreover, many heterocy-
cles contain both hydrogen bond acceptor and donor sites.
Heterocycles often possess high polarizabilities for efficient
interactions with hydrophobic pockets and the release of
water from them, and many of these molecules are highly
membrane permeable and metabolically stable.
Protein binders are of primordial importance for the
study of functions and structures of proteins in chemical
biology and can in many cases be used as drug molecules.[2]
Methods to develop novel protein-binding molecules are
therefore of general interest. In many cases the native pro-
tein binders are other proteins or peptides derived thereof.[3]
Peptides are especially well suited as protein binders be-
cause they provide the hydrogen-bonding patterns of pro-
teins and their complete side chain diversity. The use of
peptide ligands in chemical biology and medicinal chemis-
try, however, is limited severely for several reasons.[3,4] Most
of the shorter peptides are conformationally flexible: they
do not possess rigid solution structures, which leads to de-
creased binding affinities and biological activities. More-
[a] Leibniz-Institute of Molecular Pharmacology (FMP),
Robert-Rössle-Str. 10, 13125 Berlin, Germany
[b] Department of Chemistry, Quaid-i-Azam University,
Islamabad 45320, Pakistan
[c] Institute of Chemistry and Biochemistry, Freie Universität
Berlin,
Takustr. 3, 14195 Berlin, Germany
[d] Chair of Medicinal Chemistry, Institute of Pharmacy, Leipzig
University,
Brüderstr. 34, 01403 Leipzig, Germany
Fax: +49-341-9736889
Scheme 1. Synthesis of peptidyl-substituted heterocycles from pep-
tidyl-bis(electrophiles) and bis(nucleophiles).
E-mail: rademann@uni-leipzig.de
Homepage: www.fmp-berlin.de/rademann.html
730
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Peptide–Heterocycle Chimera
Molecular combinations of peptides and heterocycles
have been investigated with the goal of blending the desir-
able properties of peptides with those of heterocycles to ob-
tain powerful, bioactive and still bioavailable, metabolically
stable and membrane-permeable molecules.[4c] Such combi-
nations have been especially successful in those cases in
which peptides are the native substrates of ligands of the
targeted protein, such as in the field of protease inhibitors.
Novel structural combinations of heterocycles and peptides
are therefore highly desirable.[6] Because many novel struc-
tures of this type can be envisioned, however, a rationale
for the selection of newly synthesized molecules is required.
Recently we have conducted a substructure analysis of the
World Drug Index (WDI) and have identified 561 privileged
substructures found with high probability in bioactive mo-
lecules.[7] As expected, the majority of these substructures
contain aromatic rings and heterocycles. The presence of
these heterocyclic substructures is highly characteristic for
newly admitted drugs, and also for those that contain new
Scheme 2. Synthesis of peptidyl-substituted bis(electrophiles):
i. BrCH2COOR (5 equiv.), toluene, 100 °C (MW), 15 min; ii. TEA
chemical entities (NCEs), which in the predominant (5 equiv.), CH2Cl2, room temp., 2 h; iii. Fmoc-AA (5 equiv.), 1-(2-
mesitylenesulfonyl)-3-nitro-1H-1,2,4-triazole (MSNT, 5 equiv.),
2,6-lutidine (5 equiv.), CH2Cl2, room temp., 12 h; iv. piperidine/
number of cases are novel combinations of the 561 privi-
leged substructures.
DMF (20%), acylation/coupling steps (SPPS; Fmoc-AA, DIC,
This maximum common substructure concept should be
HOBT); v. for R = C2H4Si(CH3)3: tris(dimethylamino)sulfonium
useful as well for the design of novel, potentially bioactive
peptide–heterocycle chimera. Hitherto the standard ap-
proach to combine heterocycles and peptide has been to
incorporate heterocycles in the side chains of amino acid
building blocks or/and to integrate heterocycles through
standard acylations of amino groups of the peptide and the
difluorotrimethylsilicate (TAS-F, 5 equiv.), DMF, room temp., 3 h;
vi. R*CHO (3 equiv.), THF, room temp. (R* aliphatic) or 60 °C
(R* aromatic), 12 h; vii. DMDO/acetone/CH2Cl2, 0 °C, 30 min;
viii. DMDO/acetone/CH2Cl2, room temp., 1 h.
Decarboxylative saponification followed by treatment
with an aldehyde furnished the peptidyl-1-aminobut-3-en-
4-ones (peptidyl vinyl ketones) 3a–i (Scheme 2, Table 1).
Decarboxylative saponification and oxidative cleavage of 2
provided the 2-oxo-3-(peptidylamino)propanals (peptidyl-
substituted α-keto aldehydes) 4, whereas immediate oxi-
dation provided the peptidyl-substituted 4-amino-2,3-di-
oxobutanoates (peptidyl-substituted 2,3-diketo esters) 5. In
this work we now have investigated applications of the
newly prepared peptidyl bis- and triselectrophiles 3, 4 and
5 for the preparation of peptide–heterocycle chimera.
heterocycles.[8] Only
a few examples have been ac-
complished in which heterocycles are integrated in the pep-
tide backbone itself, because this in most cases requires spe-
cific, C-terminal derivatization of peptides.[9]
Over recent years we have developed a set of methods
for the C-terminal variation of peptides through polymer-
supported synthesis on reagent linkers of type
1
(Scheme 2).[10] As a result, several novel peptidyl-substi-
tuted bis- and tris(electrophiles) – namely the peptidyl vinyl
ketones 3, the peptidyl-substituted α-keto aldehydes 4, and
the peptidyl diketo esters 5[10d] – have become accessible. In
this contribution we have now investigated the potential of
these starting materials to provide novel peptide–heterocy-
cle chimera.
Table 1. Synthesis of the peptidyl vinyl ketones 3a–3i.
Ac-peptidyl
R1
R*
Yield[a]
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ac-Phe
Ac-Phe
Ac-Phe
Ac-Leu
Ac-Phe
Ac-Phe
Ac-Phe-Ala
Ac-Phe-Ala
Ac-Val
benzyl
benzyl
isobutyl
2-chloro-6-fluorophenyl
2-thienyl
2-chloro-6-fluorophenyl
2-chloro-6-fluorophenyl
tribromomethyl
methyl
80
62
85
64
61
80
90
80
80
isopropyl
benzyl
isopropyl
isopropyl
benzyl
Results and Discussion
benzyl
benzyl
isobutyl
ethyl
Synthesis of Peptide Bis- and Triselectrophiles
[a] Isolated yields, purities of isolated products Ͼ95%.
We have recently reported that the C-acylation of poly-
mer-supported 2-phosphoranylidene acetates of type 1 and
subsequent peptide elongation yields the 3-oxo-4-(peptidyl-
amino)-2-phosphoranylidenebutanoates 2 (“peptidyl-phos-
phoranylidenacetates”, see Scheme 2).[10d] Oxidative cleav-
age with, for example, dimethyldioxirane (DMDO) or Wit-
Peptidyl-Pyrazolines 6a–d and Peptidyl-Pyrazoles 7a–d
Pyrazoles were selected as our primary heterocyclic
tig-type linker cleavage provided access to a wide variety of goals. They have been reported to display a wide range of
C-terminally modified peptide derivatives. biological activities and are commonly obtained from hy-
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drazines as bis(nucleophiles) and various 1,3-bis(electro-
Under air, mixtures of the pyrazolines 6 and the pyr-
philes). Accordingly, the peptidyl vinyl ketones 3a–i azoles 7 (Scheme 3) were obtained from the peptidyl vinyl
(Scheme 2, Table 1) appeared to be realistic starting points ketones 3a–i with use of several aliphatic or aromatic hy-
for the preparation of peptidyl-pyrazoles.[11]
drazines in DMSO at 80 °C. On switching to nitrogen, the
Reaction conditions yielding the desired peptidyl-pyraz- pyrazolines 6 were obtained in good purities and yields in
olines were investigated with respect to regioselective and THF at only 60 °C. The peptidyl-pyrazolines were stable
diastereoselective ring formation; in addition, the oxidation towards oxidation when stored for several months under
state of the resulting heterocyclic product had to be con- nitrogen at 4 °C.
trolled. The presence of a strong base such as sodium meth-
Consequently, the desired peptidyl-pyrazoles 6a–d were
oxide led to rapid cyclization at room temperature. Presum- prepared by oxidation of the peptidyl-pyrazolines. Oxi-
ably the hydrazines are deprotonated under these conditions dation was best accomplished with 2,3-dichloro-4,5-dicya-
and react by Michael addition followed by allowed 5-exo- noquinone (DDQ) as oxidant and was complete in 8 h at
tet ring closure. The products were obtained as dia- room temp. The 1,3,5-substituted peptidyl-pyrazoles 7a–d
stereomeric mixtures of pyrazolines with pyrazoles. In order were obtained regioselectively and in high purities and
to reduce epimerization, the reaction was conducted in the yields from both aliphatic and aromatic hydrazines
absence of a strong base, yielding exclusively 1,3,5-trisubsti- (Table 2). All compounds could be characterized by HPLC,
tuted heterocycles. Formation of these regioisomers can be high-resolution mass spectrometry and NMR spectroscopy.
explained by the initial formation of hydrazone intermedi- The spectra of the prevalent diastereomers have been fully
ates followed by formal 5-endo-trig cyclization. The occur- assigned. Epimeric products in the heterocyclic position
1
rence of this formally disfavoured cyclization step can be were quantified in the H NMR spectra and were found in
explained by assuming a 6π-electron electrocyclic mecha- the following ratios: 7b 1:3, 7c 1:4, and 7d 1:2.
nism.[12]
Table 2. Synthesis of peptidyl-pyrazolines 6a–6d, pyrazoles 7a–7d,
isoxazoles 8a, 8b, isoxazolines 9, thiazepines 10a, 10b, and oxiranes
11.
Ac-peptidyl R1
R*
RЈ
Yield[a]
6a Ac-Phe-Ala benzyl methyl
6b Ac-Phe-Ala benzyl methyl
6c Ac-Phe-Ala benzyl isobutyl
6d Ac-Phe-Ala benzyl isobutyl
7a Ac-Phe-Ala benzyl methyl
7b Ac-Phe-Ala benzyl methyl
7c Ac-Phe-Ala benzyl methyl
7d Ac-Phe-Ala benzyl methyl
H
methyl
H
methyl
H
methyl
isobutyl Ͼ90
phenyl
–
–
65
61
67
78
Ͼ90
Ͼ90
Ͼ90
80
85
8a Ac-Val
8b Ac-Phe
benzyl ethyl
benzyl 2-chloro-6-fluorophenyl
benzyl isobutyl
9
Ac-Phe
–
68
10a Ac-Phe
10b Ac-Phe
benzyl isobutyl
benzyl 2-chloro-6-fluorophenyl chloro
chloro
55
71
11 Ac-Phe-Ala benzyl methyl
–
40
[a] Isolated yields, purities of isolated products Ͼ95%.
Peptidyl-Isoxazoles 8a, 8b and Isoxazolines 9
Isoxazoles and isoxazolines were targeted as a second
family of heterocycles with interesting biological activi-
ties.[13] From the readily available starting peptidyl vinyl
ketones 3, isoxazole synthesis was conducted with hydroxyl-
amine in EtOH together with a catalytic amount of acetic
acid (5 mol-%) and a few crystals of sodium acetate under
air (Scheme 3, Table 2).[14] Under these conditions, the oxi-
dized isoxazoles 8a and 8b were obtained in cases of an
aliphatic substituent in the vinylic position (8a: R* = ethyl)
or of an aromatic vinyl ketone (8b: R* = 2-chloro-6-fluo-
rophenyl). When the same reaction was carried out under
nitrogen the non-oxidized isoxazoline 9 (R* = isobutyl) was
isolated. For both products, LC-MS and NMR experiments
indicated the predominant formation of a single enantiomer
that could be isolated by preparative HPLC.
Scheme 3. Synthesis of three- to seven-membered peptidyl-substi-
tuted heterocycles from peptidyl vinyl ketones: i. NH2-NHRЈ
(3 equiv.), THF, 60 °C, 8 h; ii. DDQ (1.2 equiv.), toluene, room
temp., 12 h; iii. hydroxylamine (1.2 equiv.), CH3COOH (5 mol-%)/
CH3COONa (few crystals), 80 °C, 8 h; iv) hydroxylamine
(1.2 equiv.), CH3COOH (5 mol-%)/CH3COONa (few crystals),
80 °C, 8 h, under N2; v) 2-aminothiophenol (3 equiv.), acetic acid
(5 mol-%), 80 °C, 12 h, under N2; vi) DMDO/acetone (3–4 equiv.),
CH2Cl2, –20 °C to room temp., 8 h.
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Peptide–Heterocycle Chimera
Peptidyl-Benzodiazepines
concept to peptidyl keto aldehydes and peptidyl diketo es-
ters as bis(electrophiles) (Scheme 4). The peptidyl keto alde-
hydes 4 were found to react smoothly with both amidines
and guanidines as bis(nucleophiles).
In our ongoing investigations into the preparation of
peptidyl-substituted heterocycles based on the peptidyl vin-
yl ketones 3 (Scheme 3), we decided to investigate the syn-
thesis of peptidyl-benzodiazepines. 1,4-Benzodiazepines are
privileged protein ligands with high pharmacological rele-
vance.[15] At first, the peptidyl vinyl ketones 3 were treated
with o-phenylenediamine at 80 °C without base. No desired
condensation product was detected under these conditions.
Instead, addition of Et3N at 80 °C led to the formation of
mixtures of compounds with the masses of the expected
dihydrobenzodiazepines detected by LC-MS, but
chromatography did not deliver pure diazepine deriva-
tives.[16]
Peptidyl-Thiazepines 10a, 10b
The peptidyl-thiazepines 10a and 10b, representing an-
other class of peptidyl-substituted heterocycles, were access-
ible through [4+3] annulations of the peptidyl vinyl ketones
3 with o-aminothiophenol. The literature suggested their
synthesis at elevated temperatures under acid catalysis con-
ditions (80 °C, 12 h, N2, AcOH).[17] The desired products
10a and 10b were formed, isolated by HPLC and charac-
Scheme 4. Synthesis of peptidylheterocycles from the peptidyl keto
aldehydes 4a–c and the peptidyl diketo ester 5; i) 1,2-phenylenedia-
mine (1.5 equiv.), CH2Cl2, room temp., N2, 12 h (14 was formed
within 8 h); ii) amidine or guanidine derivative (3 equiv.), DMF/
0.1% AcOH, room temp., 8 h.
1
terized by H NMR and LC-MS experiments. Attempts to
reduce the reaction times by elevating the temperature un-
der microwave irradiation conditions were unsuccessful. Af-
ter 15 min MW at 120 °C only traces of the products (3–
5%) were detected, with no starting materials left. The reac-
tivity of the vinyl ketones varied with the vinyl substituents;
the aromatic vinyl ketone 3b reacted more smoothly than
the aliphatic vinyl ketone 3a.
In both cases, 2-substituted imidazol-4-ones were iden-
tified and isolated as single products, the 2-phenyl-substi-
tuted imidazolones 12a and 12b from phenyl amidine and
the 2-phenyl-amino-imidazolone 13 from phenyl guanidine.
Peptidyl-Quinoxalines 14, 15
Peptidyl-Oxiranes 11
Analogous reactions of the peptidyl α-keto aldehyde 4 or
the peptidyl 2,3-diketo ester 5 were investigated with 1,2-
diamines as bis(nucleophiles) (Scheme 4, Table 3) Cyclocon-
densation of 5 with o-phenylenediamine was accomplished
in EtOH at 60 °C in 3 h or in CH2Cl2 at room temperature
in 12 h, leading to the peptidyl-quinoxaline 14 in very good
yield and high purity (Scheme 4, Table 3).[20] Characteriza-
tion by NMR spectroscopy confirmed the stereospecificity
of this reaction. The peptidyl-substituted keto aldehyde 4
was even more reactive under these conditions. The reaction
with 1,2-phenylenediamine in CH2Cl2 proceeded smoothly
at room temp. After 8 h the starting material had been con-
sumed, yielding the quinoxaline 15 again without epimeri-
zation of the peptide part.
In an extension of this approach to novel peptidyl-substi-
tuted heterocycles we investigated the syntheses of the pep-
tidyl-oxiranes 11 (Scheme 2, Table 2). DMDO is known as
an efficient and rapidly developing oxidant and operates
under strictly neutral conditions,[18] so we used DMDO for
the conversion of peptidyl vinyl ketones into their epoxides.
The epoxidation was conducted by adding freshly prepared
DMDO to the peptidyl vinyl ketone 3g at room temp. in
acetone under N2. The conversion of electron-rich olefins
should normally be complete within two hours according
to the reported literature.[19,18a] Because the peptidyl vinyl
ketone 3g is electron-poor in relation to the reported ole-
fins, 12 h were therefore required for its complete conver-
sion into the peptidyl-oxirane 11, with the workup simply
consisting of evaporation of excess DMDO and acetone.
The epoxide was obtained in good yield (80%) as a 1:1 ratio
Table 3. Synthesis of the peptidyl-imidazolones 12 and 13 and the
peptidyl-quinoxalines 14 and 15.
of epoxide diastereomers according to the H-1H COSY-
1
Ac-peptidyl
R1
RЈ
Yield[a]
NMR spectrum.
12a
12b
13
Ac-Val
Ac-Ala
Ac-Ala
Ac-Phe-Ala
Ac-Phe-Ala
benzyl
phenyl
phenyl
2-imidazolyl 75
–
–
67
70
isopropyl
isopropyl
benzyl
Peptidyl-Imidazolones 12, 13
14
75
64
15
isobutyl
Prompted by the positive results obtained from the pept-
idyl vinyl ketone bis(electrophiles) we decided to extend this [a] Isolated yields, purities of isolated products Ͼ95%.
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MS and single quadrupole detector. HRMS measurements were
conducted with an Agilent 6220 accurate mass ESI-ToF-MS. 1H
and 13C NMR spectra were recorded with a Bruker AVANCE
300 MHz instrument and chemical shifts were measured in parts
per million (ppm).
Conclusions
We have reported a flexible synthesis of the C-terminal
peptide bis- and tris(electrophiles) 3, 4 and 5 (Scheme 1).
All of these attractive peptide mimetics were successfully
converted into novel peptide–heterocycle chimera under
mild conditions. The peptidyl vinyl ketones served as start-
ing materials for the synthesis of C-terminal peptidyl-pyraz-
olines 6, pyrazoles 7, isoxazoles 8 and isoxazolines 9, which
were formed by gentle heating or with mild acid catalysis.
All five-membered ring heterocycles were formed regiose-
lectively and in good yields. The peptidyl-thiazepines 10
and oxiranes 11 were also obtained in high yields but as
diastereomeric mixtures.
The peptidyl diketo esters and keto aldehydes were lig-
ated smoothly with bis(nucleophiles) at room temperature.
Peptidyl-imidazolones were readily formed from the pept-
idyl α-keto aldehydes 4, phenylamidine delivered the 2-
phenyl-substituted imidazolones 12, whereas the corre-
sponding guanidine furnished the 2-amino-substituted
imidazolone 13. The peptidyl-quinoxalines 14 and 15 based
on the starting materials 4 and 5 were prepared without
epimerization as well.
In general, the peptidyl keto aldehydes were found to be
the most reactive bis(electrophiles), followed by the peptidyl
diketo esters and the peptidyl vinyl ketones. The reactions
with the peptidyl keto aldehydes especially proceed
smoothly at room temperature both in nonpolar and in po-
lar or protic solvents and so can be regarded as ligation
reaction. Although only amino acids without side chain
functionalities were used in all examples considered in this
article, one can already predict the reactivity of arginine
residues with peptidyl keto aldehydes and peptidyl diketo
esters.
The chemistry presented here should be of specific value
if heterocycles are to be integrated in peptidic ligands. In
order to select the best-fitting heterocycle for a given pro-
tein target, however, further studies considering the pre-
ferred conformations of peptide–heterocycle chimera will be
required.
General Procedure for the Preparation of the Peptidylvinyl Ketones
3a–3i: The aldehyde (2 equiv., 0.76 mmol) was added to a suspen-
sion of a peptidyl-substituted α-keto methylenetriphenylphos-
phorane generated from 2 after the saponification of the protecting
group (200 mg, 1.27 mmolg–1, 0.254 mmol) in dry THF (1 mL) and
the mixture was stirred for 8 h either at room temp. (aliphatic alde-
hydes) or at 60 °C (aromatic aldehydes). Solvent was removed un-
der reduced pressure with a rotary evaporator. The residue was
subjected to purification by preparative HPLC to afford the prod-
uct. The pure compounds were characterized by LC-MS and NMR
spectroscopy.
(1S,3E)-1-[(N-Acetyl-L-phenylalanyl)amino]-1-benzyl-6-methylhept-
3-en-2-one (3a): 1H NMR (300 MHz, CDCl3): δ = 0.89 (d, J =
9.8 Hz, 3 H, CH3, isobutyl), 0.95, (d, J = 8.5 Hz, 3 H, CH3, iso-
butyl), 1.65–1.81 (m, 1 H, CH, isobutyl), 1.94 (s, 3 H, CH3CO),
2.07 (bt, J = 6.1 Hz, 2 H, CH2, isobutyl), 2.9–3.2 (m, 4 H,
Cβ1,β1Ј,β2,β2ЈH, Phe, benzyl), 4.64–4.78 (m, 1 H, CαH, Phe), 4.85–
5.05 (m, 1 H, CαH, benzyl), 6.05 (d, J = 15.9 Hz, 1 H, CH, olefin),
6.15 (d, J = 7.3 Hz, 1 H, NHI), 6.56 (d, J = 7.3 Hz, 1 H, NHII),
6.86–7.06 (m, 10 H arom. Phe 1, Phe 2, CH, olefin) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.9, 22.7, 27.3, 37.6, 37.8, 41.4, 53.9, 56.6,
126.5, 126.5, 127.6, 127.9, 128.1, 128.7, 128.9, 135.3, 135.9, 148.9,
169.3, 169.9, 195.6 ppm. HRMS: calcd. [M + H]+ = [C26H33N2O3]
421.2481; found 421.2456; (85 mg, 80%).
(1S,3E)-1-[(N-Acetyl-L-phenylalanyl)amino]-1-benzyl-4-(2-chloro-
1
6-fluorophenyl)but-3-en-2-one (3b): H NMR (300 MHz, CDCl3): δ
= 1.95 (s, 3 H, CH3CO), 2.98–3.19 (m, 4 H, Cβ1,β2H2, benzyl,
C
β1,β2H2, Phe), 4.65–4.74 (m, 1 H, CαH, Phe), 4.99–5.06 (m, 1 H,
CαH, benzyl), 6.14–6.17 (d, J = 8.55 Hz, 1 H), 6.56–6.59 (d, J =
7.33 Hz, 1 H), 6.95–7.33 (m, 13 H, 2-chloro-6-fluorophenyl, benzyl,
Phe, CαH, CβH, vinyl), 7.80–7.81 (d, J = 4.88 Hz, 1 H, NHI), 7.85–
7.86 (d, J = 4.88 Hz, 1 H, NHII) ppm. 13C NMR (100 MHz,
CDCl3): δ = 22.7, 37.1, 37.9, 53.9, 57.9, 114.3, 114.7, 120.9, 121.1,
125.7, 126.7, 128.0, 128.1, 128.2, 128.3, 128.5, 128.6, 128, 128.9,
130.9, 133.9, 135.0, 135.9, 135.9, 136.2, 136.3, 169.5, 170.0,
195.7 ppm. HRMS: calcd. [M + H]+ = [C28H27ClFN2O3] + Et3N
595.2926; found 595.2939; (77.5 mg, 62%).
(1S,3E)-1-[(N-Acetyl-L-phenylalanyl)amino]-1-isopropyl-4-(2-thien-
1
yl)but-3-en-2-one (3c): H NMR (300 MHz, CDCl3): δ = 0.78 (d, J
= 8.95 Hz, 3 H, Cγ1H3, isopropyl), 0.96 (d, 3J = 8.94 Hz, 3 H,
Cγ2H, isopropyl), 2.0 (s, 3 H, CH3CO), 2.90–2.95 (m, 1 H, Cβ1,β2H2,
isopropyl), 3.08–3.11 (m, 2 H, Cβ1,β2H2, Phe), 4.64 (m, 1 H, CαH,
Phe), 4.74 (m, 1 H, CαH, isopropyl), 7.08–7.55 (m, 7 H, Phe, thio-
phene, CαH, CβH, vinyl) ppm. 13C NMR (100 MHz, CDCl3): δ =
13.0, 23.3, 32.0, 34.2, 50.1, 56.4, 121.3, 126.5, 127.6, 128.1, 128.5,
Experimental Section
General Methods: Unless otherwise stated, all reagents were ob-
tained from commercial suppliers and were used without further
purification. Dry solvents were purchased and stored over molecu-
lar sieves. Solid-phase chemistry was performed in polypropylene
syringes with Teflon® filters. Triphenylphosphane–polystyrene
resin was purchased from Fluka. Microwave-assisted solid-phase
reactions were performed with a Biotage Initiator monomodal mi-
crowave reactor. Resins were washed with DMF, THF, toluene and
CH2Cl2 unless otherwise stated. Resin loadings were determined
by photometric determination after Fmoc cleavage. Solid-phase re-
actions were monitored by FT-ATR-IR spectra of the resins re-
corded with a Bruker Tensor 27 FT-IR spectrometer. Purification
of products was performed with a semipreparative HPLC column
(10 μm, 250ϫ20 mm, Grom-SIL 300 ODS-5 ST RP-C18) with use
of individual gradients derived from analytical runs. LC-MS was
conducted with an Agilent 1100 Series HPLC system with an ESI-
128.7, 130.4, 132.4, 135.6, 143.5 ppm. HRMS: calcd. [M + H]+
[C22H27N2O3S] + Et3N 500.2959; found 500.2967; (85 mg, 85%).
=
(1S,3E)-1-[(N-Acetyl-L-leucinyl)amino]-1-benzyl-4-(2-chloro-6-
fluorophenyl)but-3-en-2-one (3d): 1H NMR (300 MHz, CDCl3): δ =
0.97 (d, J = 7.3 Hz, 3 H, CδH3, Leu), 0.98, (d, J = 6.1 Hz, 3 H,
Cδ2H3, Leu), 1.14–1.28 (m, 2 H, Cβ1,β2H2, Leu), 1.32–1.50 (m, 1
H, CγH, Leu), 1.76 (s, 3 H, CH3CO), 2.85 (dd, J1 = 15.0, J2
=
9.7 Hz, 1 H, Cβ1H, benzyl), 3.15 (dd, J1 = 15, J2 = 8.5 Hz, 1 H,
Cβ2H, Phe), 4.27 (m, 1 H, CαH, benzyl), 4.71 (m, 1 H, CαH, Leu),
7.13 (d, J = 15.8 Hz, 1 H, CαH, vinyl), 7.15–7.50 (m, 5 H, benzyl,
2-chloro-6-fluorophenyl), 7.6 (d, J = 14.7 Hz, 1 H, CβH, vinyl),
7.68 (dd, J = 8.5, J = 4.9 Hz, 1 H, 2-chloro-6-fluorophenyl), 7.95
734
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 730–739

Peptide–Heterocycle Chimera
(d, J = 8.6 Hz, 1 H, NHI), 8.54 (d, J = 8.6 Hz, 1 H, NHII) ppm.
13C NMR (100 MHz, CDCl3): δ = 21.8, 22.3, 22.6, 23.9, 37.9, 40.9,
50.8, 58.6, 115.9, 116.2, 121.1, 121.5, 126.2, 126, 127.9, 128, 129.2,
129.3, 136.1, 136.2, 137.5, 137.7, 160.6, 168.7, 168.8, 172.3, 172.5,
178.2 ppm. HRMS: calcd. [M + H]+ = [C25H29ClFN2O3] + Et3N
561.3082; found 561.3110; (73.6 mg, 64%).
196.9 ppm. HRMS: calcd. [M + H]+ = [C29H38N3O4] 492.2818;
found 492.2830; (100 mg, 80%).
(1S,3E)-1-[(N-Acetyl-L-valinyl)amino]-1-benzylhex-3-en-2-one (3i):
1H NMR (300 MHz, CDCl3): δ = 0.88–0.92 (dd, J1 = 1.83, J2
1.83 Hz, 6 H, Cγ1H3, Cγ1H3, Val), 1.00–1.05 (t, J1 = 7.32, J2
=
=
7.32 Hz, 3 H,CH3-CH2-vinyl), 2.02 (s, 3 H, CH3CO), 2.20–2.25 (m,
3 H, CβH and CH2CH3, Val), 2.98–3.14 (m, 2 H, CβH2, benzyl),
4.26–4.31 (t, J1 = 7.32, J2 = 7.48 Hz, 1 H, CαH, benzyl), 4.88–4.90
(d, J = 7.33 Hz, 1 H, NHI, benzyl), 5.06–5.13 (m, 1 H, CαH, Val),
6.08–6.13 (m, 1 H, CH, vinyl), 6.58–6.60 (d, J = 7.93 Hz, 1 H, CH,
vinyl), 6.99–7.00 (d, J = 7.33 Hz, 1 H, NHII, Val) 7.02–7.26 (m, 5
H, benzyl) ppm. HRMS: calcd. [M + H]+ = [C20H29N2O3]
345.2173; found 345.2170; (100 mg, 80%).
(1S,3E)-1-[(N-Acetyl-L-phenylalanyl)amino]-1-isopropyl-4-(2-chloro-
1
6-fluorophenyl)but-3-en-2-one (3e): H NMR (300 MHz, CDCl3): δ
= 0.82 (d, J = 7.3 Hz, 3 H, Cγ1H3 isopropyl), 0.89 (d, J = 7.3 Hz,
3 H, Cγ2H3 isopropyl), 1.74 (s, 3 H, CH3CO), 1.27 (m, 1 H, CβH,
isopropyl), 2.71 (dd, J1 = 14.6, J2 = 9.7 Hz, 1 H, Cβ1H, Phe), 2.95
(dd, J1 = 13.4, J2 = 4.9 Hz, 1 H, Cβ2H, Phe), 4.37 (t, J = 7.3 Hz,
1 H, CαH, isopropyl), 4.64 (ddd, J = 9.8, J = 9.8, 4.9 Hz, 1 H,
CαH, Phe), 7.07–7.24 (m, 5 H Phe, 2-chloro-6-fluorophenyl), 7.32
(dd, J1 = 7.3, J2 = 2.4 Hz, 1 H, 2-chloro-6-fluorophenyl), 7.40 (d,
J = 16.1 Hz, 1 H, CαH, vinyl), 7.45–7.51 (m, 2 H, Phe), 7.65 (d, J
= 15.9 Hz, 1 H, CβH, vinyl), 8.14 (d, J = 8.5 Hz, 1 H, NHI), 8.39
(d, J = 7.3 Hz, 1 H, NHII) ppm. 13C NMR (100 MHz, CDCl3): δ
= 18.1, 19.4, 22.4, 29.1, 37.5, 36.0, 53.4, 60.8, 115.4, 115.7, 120.9,
121.1, 126.1, 126.3, 126.4, 127.9, 129.1, 129.5, 129.7, 131.6, 131.7,
132.1, 132.3, 135.1, 135.2, 137.8, 159.6, 162.9, 169.0, 172.0,
197.2 ppm. HRMS: calcd. [M]+ = [C24H27ClFN2O3] + Et3N
546.2893; found 546.2912; (70.1 mg, 61%).
General Procedure for the Preparation of Peptidyl-Substituted α-
Keto Aldehydes (4): Peptidyl-substituted α-keto methylenetri-
phenylphosphoranes (200 mg, 1.27 mmolg–1, 0.254 mmol) were
pre-swollen in dry CH2Cl2 (6 mL) in a 50 mL round-bottomed
flask. Cold DMDO solutions (12 mL each, approx.
0.072 mmolmL–1, 0.864 mmol, 3–4 equiv., –20 °C) were carefully
added and the mixture was stirred for 30 min at 0 °C, during which
the yellow-coloured resins turned pale (Note: cleavage from the
resin can be accomplished by the use of only an equimolar amount
of DMDO: i.e., 2 equiv.). The remaining DMDO, acetone and
CH2Cl2 were removed in vacuo. The resulting white solids were
characterized by LC-MS and used directly as starting material for
the preparation of the peptidyl-imidazolinones 12 and the peptidyl-
quinoxaline 14.
(1S,3E)-1-[(N-Acetyl-L-phenylalanyl)amino]-5,5,5-tribromo-1-iso-
1
propylpent-3-en-2-one (3f): H NMR (300 MHz, [D6]DMSO): δ =
0.83 (d, J = 3.60 Hz, 3 H, Cγ1H3 isopropyl), 0.86 (d, J = 3.44 Hz,
3 H, Cγ2H3, isopropyl), 2.73 (s, 3 H, CH3CO), 2.52–2.56 (br. s, 1
H, CβH, isopropyl), 2.72 (br. s, 2 H, Cβ1β2H2, Phe), 4.3 (m, 1 H,
CαH, Phe), 4.60–4.62 (m, 1 H, CαH, isopropyl), 6.9–7.24 (m, 7 H,
(3S)-3-[(N-Acetyl-
L
-valinyl)amino]-3-benzyl-2-oxopropanal
(4a):
HRMS: calcd. {[M + H]+ = [C17H23N2O4] 319.1652; found
Phe., CαH, CβH, vinyl), 8.12, 8.93 (br. s, 2 H, NHI, NHII) ppm. 13
C
319.1659; 36 mg, 45%}.
NMR (100 MHz, CDCl3): δ = 17.6, 19.2, 22.4, 34.1, 36.2, 58.4,
93.8, 125.8, 126.5, 128.2, 136.3, 140.1, 167.2, 171, 178.4, 196.1;
(116 mg, 80%) ppm.
(3S)-3-[(N-Acetyl-
L
-alaninyl)amino]-5-methyl-2-oxohexanal
(4b):
HRMS: calcd. {[M + H]+ = [C11H19N2O4] 243.13186; found
243.1389; 42 mg, 67%}.
(3S)-3-[(N-Acetyl-L-phenylalanyl-L-alanyl)amino]-3-benzyl-2-oxo-
(1S,3E)-1-[(N-Acetyl-L-phenylalanyl-L-alanyl)amino]-1-benzylpent-
propanal (4c): HRMS: calcd. {[M + H]+ = [C24H28N3O5] 438.5113;
3-en-2-one (3g): 1H NMR (300 MHz, [D6]DMSO): δ = 1.14–1.16
(d, J = 7.33 Hz, 3 H, CβH3, Ala), 1.71 (s, 3 H, CH3, vinyl), 1.84 (s,
3 H, CH3CO), 2.66–2.77 (m, 2 H, Cβ1,β2H2, Phe), 2.94–3.06 (m, 2
H, Cβ1,β2H2, benzyl), 4.21–4.26 (m, 1 H, CαH, benzyl), 4.44–4.47
(m, 1 H, CαH, Phe), 4.66–4.68 (m, 1 H, CαH, Ala), 6.30–6.35 (d, J
= 15.87 Hz, 1 H, CαH, vinyl), 6.81–6.89 (m, 1 H, CβH, vinyl), 7.1–
7.25 (m, 10 H, benzyl, Phe), 8.14–8.16 (d, J = 8.55 Hz, 1 H, NHI,
Phe), 8.28–8.24 (d, J = 7.33 Hz, 1 H, NHII, Ala), 8.34–8.37 (d, J =
7.32 Hz, 1 H, NHII, Phe-Ac) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 18.1, 22.4, 30.4, 34.3, 48.3, 57.4, 124.8, 126.0, 126.2,
128.0, 127.9, 129.0, 129.1, 137.5, 137.6, 137.1, 138.1, 138.0, 139.1,
found 438.5118; 60 mg, 54%}.
Methyl (4S)-[(N-Acetyl-L-phenylalanyl)amino]-6-methyl-2,3-di-
oxoheptanoate (5): The resin 2 was pre-swollen in minimal dry
CH2Cl2 in 50 mL round-bottom flask. Freshly prepared cold
DMDO solutions (12 mL each, approx. 0.072 mmol mL–1
,
0.864 mmol, 3–4 equiv., –20 °C) were added and the mixtures were
stirred for 1 h at room temp., during which the yellow-coloured
resins turned pale. (Note: cleavage from the resin can be ac-
complished by the use of only an equimolar amount of DMDO:
i.e., 2 equiv.). DMDO, acetone and CH2Cl2 were removed in
vacuo. The obtained compounds were characterized by LC-MS and
NMR. 1H NMR (400 MHz, [D6]DMSO): δ = 0.78 (d, J = 7.84 Hz,
3 H, Cδ1H3, isopropyl), 0.82, (d, J = 7.81 Hz, 3 H, Cδ2H3, isobutyl),
1.13 (d, J = 6.95 Hz, 3 H, CβH3, Ala), 1.27 (m, 1 H, CγH, isobutyl),
1.57 (m, 2 H, Cβ1,β2H2, isobutyl), 1.66 (s, 3 H, CH3CO), 2.63 (dd,
J1 = 11.47, J2 = 7.50 Hz, 1 H, Cβ1H, Phe), 2.90 (dd, J1 = 11.23, J2
= 7.40 Hz, 1 H, Cβ2H, Phe), 3.56 (s, 3 H, CH3O), 4.23 (m, 1 H,
CαH, isobutyl), 4.43 (m, 1 H, CαH, Phe), 4.88 (m, 1 H, CαH, Ala),
7.08–7.22 (m, 5 H, Phe), 7.87 (d, J = 7.51 Hz, 1 H, NHI), 8.01 (d,
J = 7.58 Hz, 1 H, NHII), 8.10 (d, J = 7.87 Hz, 1 H, NHIII) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 17.7, 20.7, 22.1, 23.1, 24.0,
37.2, 47.6, 51.3, 52.0, 53.5, 125.9, 127.7, 128.8, 137.8, 168.8, 169.2,
170.8, 171.5, 204.4 ppm. HRMS: calcd. {[M + H]+ = [C23H31N3O7]
462.2240; found 462.2248; 90.1 mg, 77%}.
143.8, 169.1, 171.1, 172.1, 196.7 ppm. HRMS: calcd. [M + H]+
[C26H32N3O4] 450.2350; found 450.2347; (103 mg, 90%).
=
(1S,3E)-1-[(N-Acetyl-L-phenylalanyl-L-alanyl)amino]-1-benzyl-6-
1
methylhept-3-en-2-one (3h): H NMR (300 MHz, [D6]DMSO): δ =
0.82–0.85 (d, J = 4.88 Hz, 6 H, CH3CHCH2), 1.13–1.15 (d, J =
7.32 Hz, 3 H, CβH3, Ala), 1.71 (s, 3 H, CH3CO), 1.88 (m, 1 H,
CδH, vinyl), 2.03–2.17 (m, 2 H, CβH2, vinyl), 2.65–3.55 (m, 4 H,
C
β1,β2H2, benzyl, Cβ1,β2H2, Phe), 4.21–4.26 (t, J1 = 14.65, J2
=
7.32 Hz, 1 H, CαH, benzyl), 4.44–4.5 (m, 1 H, CαH, Phe), 4.67–4.7
(m, 1 H, CαH, Ala), 6.26–6.31 (d, J = 15.87 Hz, 1 H, CαH, vinyl),
6.7–6.86 (m, 1 H, CβH, vinyl), 7.1–7.28 (m, 10 H benzyl, Phe),
8.22–8.25 (d, J = 8.55 Hz, 1 H, NHI, Phe), 8.47–8.52 (d, J =
7.33 Hz, 1 H, NHII, Ala), 8.63–8.66 (d, J = 7.32 Hz, 1 H, NHIII
,
Phe-Ac) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 22.1, 22.4,
22.8, 25.6, 27.2, 30.4, 34.4, 46.4, 53.9, 124.9, 126.0, 126.2, 127.9,
Procedure for the Preparation of the Peptidyl-Pyrazolines 6a–d:
128.0, 128.1, 129.1, 137.6, 138.2, 139.2, 169.1, 171.1, 172.2, Hydrazine (3 equiv., 0.96 mg, 0.03 mmol) or methylhydrazine
Eur. J. Org. Chem. 2011, 730–739
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
735

A. El-Dahshan, S. Nazir, Ahsanullah, F. L. Ansari, J. Rademann
FULL PAPER
(3 equiv., 1.38 mg, 0.03 mmol) in THF was added under N2 to a
stirred solution of the peptidyl vinyl ketone 3g (1 equiv., 5 mg,
0.010 mmol), in THF. The reaction mixture was stirred at 60 °C for
8 h. By the same procedure, hydrazine (3 equiv., 1.0 mg,
0.033 mmol) or methylhydrazine (3 equiv., 1.5 mg, 0.033 mmol)
was added to a stirred solution of the peptidyl vinyl ketone 3h
(1 equiv., 5 mg, 0.011 mmol). The solvent was removed under re-
duced pressure with a rotary evaporator. The resulting crude prod-
uct was subjected to purification by preparative HPLC to afford
the pyrazoline as a white solid. The obtained compounds were
characterized by LC-MS and NMR spectroscopy.
The purified compounds were characterized by LC-MS and NMR
spectroscopy.
Pyrazole 7a: 1H NMR (300 MHz, [D6]DMSO): δ = 1.22 (br. s, 3
H, CβH3, Ala), 1.73 (s, 3 H, CH3CO), 1.98 (s, 3 H, CH3-pyrazole),
2.65–2.73 (m, 2 H, Cβ1,β2H2, Phe), 2.91–2.95 (m, 2 H, Cβ1,β2H2,
benzyl), 4.20–4.24 (m, 1 H, CαH, Ala), 4.46–5.49 (m, 1 H, CαH,
benzyl), 4.99–5.05 (m, 1 H, CαH, Phe), 5.31 (s, 1 H, CH-pyrazole),
5.86 (s, 1 H, NHI, pyrazole), 6.64 (d, J = 8.45 Hz, 1 H, NHI, Phe),
7.12–7.25 (m, 10 H benzyl, Phe), 8.02 (d, J = 8.45 Hz, 1 H, NHII,
Phe), 8.19–8.21 (d, J = 8.45 Hz, 1 H, NHIII, Ala) ppm. HRMS:
calcd. [M + H]+ = [C26H32N5O3] 462.2508; found 462.2505;
(3.24 mg, 90%).
Pyrazoline 6a: 1H NMR (300 MHz, [D6]DMSO): δ = 1.14–1.16 (d,
J = 6.11 Hz, 3 H, CH3-pyrazoline), 1.19–1.22 (d, J = 9.77 Hz, 3 H,
CβH3, Ala), 1.73 (s, 3 H, CH3CO), 2.53–2.54 (d, J = 4.89 Hz, 2 H,
CH2-pyrazoline), 2.63–2.71 and 2.93–3.11 (m, 4 H, Cβ1,β2H2,
benzyl, Cβ1,β2H2, Phe), 4.16–4.20 (m, 1 H, CH, pyrazoline), 4.45–
4.50 (m, 1 H, CαH, Ala), 4.65–4.75 (m, 1 H, CαH, benzyl), 5.0–
5.10 (m, 1 H, CαH, Phe), 5.86 (s, 1 H, NHI, pyrazoline), 7.16–7.27
(m, 10 H, arom. benzyl, Phe), 8.05–8.16 (d, J = 7.33 Hz, 1 H, NHI,
Phe), 8.19–8.21 (d, J = 8.55 Hz, 1 H, NHII, Ala) ppm. HRMS:
calcd. [M + H]+ = [C26H34N5O3] 464.2508; found 464.2501;
(3.6 mg, 65%).
1
Pyrazole 7b: H NMR (300 MHz, [D6]DMSO): δ = 1.12–1.13 (d,
J = 7.33 Hz, 3 H, CβH3, Ala), 1.72 (s, 3 H, CH3CO), 2.16 (s, 3 H,
CH3-pyrazole), 2.64–2.68 (m, 2 H, Cβ1,β2H2, Phe), 2.92–2.94 (m, 2
H, Cβ1,β2H2, benzyl), 3.60 (s, 3 H, CH3-N-pyrazole), 4.20–4.26 (m,
1 H, CαH, Ala), 4.47–4.49 (m, 1 H, CαH, Phe), 4.92–4.98 (m, 1 H,
CαH, benzyl), 5.87 (s, 1 H, CH-pyrazole), 7.12–7.22 (m, 10 H,
benzyl, Phe), 7.96–7.97 (d, J = 8.45 Hz, 1 H, NHI, Phe), 8.04–8.08
(d, J = 7.66 Hz, 1 H, NHII, Ala), 8.10–8.12 (d, J = 7.31 Hz, 1 H,
NHII, Ala) ppm. HRMS: calcd. [M + H]+ = [C27H34N5O3]
476.2700; found 462.2692; (2.7 mg, 90%).
Pyrazoline 6b: 1H NMR (300 MHz, [D6]DMSO): δ = 1.14–1.22 (m,
6 H, CH3-pyrazoline, CβH3, Ala), 1.73 (s, 3 H, CH3CO), 2.09–2.16
(m, 2 H, CH2-pyrazoline), 2.55–3.0 (m, 8 H, CH-pyrazoline, CH3-
N-pyrazoline, Cβ1,β2H2 benzyl, Cβ1,β2H2, Phe), 4.16–4.20 (m, 1 H,
CαH, Ala), 4.45–4.50 (m, 1 H, CαH, benzyl), 7.15–7.23 (m, 10 H,
benzyl, Phe), 8.05–8.16 (d, J = 8.55 Hz, 1 H, NHI, Phe), 8.19–8.21
1
Pyrazole 7c: H NMR (300 MHz, [D6]DMSO): δ = 0.85–0.87 [m,
6 H, (CH3)2, isobutyl], 1.12–1.14 (d, J = 7.35 Hz, 3 H CβH3, Ala),
1.72 (s, 3 H, CH3CO), 1.80–1.95, [brs, 1 H, CH(CH3)2], 2.39–2.41
[d, J = 6.10 Hz, 2 H CH2CH(CH3)2], 2.61–2.71 (m, 2 H, Cβ1,β2H2,
Phe), 2.89–2.97 (m, 2 H, Cβ1,β2H2, Phe), 3.60 (s, 3 H, CH3-N pyr-
azole), 4.17–4.28 (m, 1 H, CαH, Ala), 4.42–4.50 (m, 1 H, CαH Phe),
4.92–5.02 (m, 1 H, CαH, benzyl), 5.84 (s, 1 H, CH-pyrazole), 7.09–
7.23 (m, 10 H, benzyl, Phe), 7.93 (d, J = 8.55 Hz, 1 H, NHI, Phe),
(d, J = 7.33 Hz, 1 H, NHII, Ala) ppm. HRMS: calcd. [M + H]+
=
[C27H36N5O3] 478.2673; found 478.2693; (3.0 mg, 61%).
7.96 (d, 1 H, NHII, Ala), 8.03–8.06 (d, J = 8.54 Hz, 1 H, NHIII
,
Pyrazoline 6c: 1H NMR (300 MHz, [D6]DMSO): δ = 0.79–0.85 [m,
6 H, (CH3)2, isobutyl], 1.12–1.34 (br. s, 5 H, CH2-CH-isobutyl,
CβH3, Ala), 1.51–1.58 (m, 1 H, CH-isobutyl), 1.73 (s, 3 H,
CH3CO), 1.76–1.78 (m, 2 H, CH2-pyrazoline), 2.68–2.72, 2.84–3.01
(m, 4 H, Cβ1,β2H2, benzyl, Cβ1,β2H2, Phe), 3.49–3.53 (m, 1 H, CH-
pyrazoline), 4.16–4.21 (m, 1 H, CαH, Ala), 4.43–4.50 (m, 1 H, CαH,
benzyl), 4.65–4.70 (m, 1 H, CαH, Phe), 6.39 (s, 1 H, NH-pyraz-
oline), 7.13–7.25 (m, 10 H, benzyl, Phe), 8.08–8.11 (d, J = 8.55 Hz,
1 H, NHI, Phe), 8.19–8.22 (d, J = 8.45 Hz, 1 H, NHII, Ala), 8.30–
8.33 (d, J = 8.54 Hz, 1 H, NHIII, Phe) ppm. HRMS: calcd. [M +
H]+ = [C29H40N5O3] 506.3086; found 506.3099; (4.0 mg, 67%).
Phe) ppm. HRMS: calcd. [M + Na]+ = [C26H32N5O3] 540.2955;
found 540.2950; (4.23 mg, 90%).
1
Pyrazole 7d: H NMR (300 MHz, [D6]DMSO): δ = 1.16–1.18 (d,
J = 7.32 Hz, 3 H, CβH3, Ala), 1.74 (s, 3 H, CH3CO), 2.28 (s, 3 H,
CH3-pyrazole), 2.62–2.71 (m, 2 H, Cβ1,β2H2 benzyl), 2.91–3.04,
3.12–3.21 (m, 2 H, Cβ1,β2H2, Phe), 4.21–4.28 (m, 1 H, CαH, Ala),
4.43–4.52 (m, 1 H, CαH, Phe), 5.05–5.13 (m, 1 H, CαH benzyl),
6.16 (s, 1 H, CH-pyrazole), 7.14–7.25 and 7.36–7.50 (m, 15 H, aro-
matic), 8.04 (d, J = 8.55 Hz, 1 H, NHI, Phe), 8.12 (d, J = 8.54 Hz,
1 H, NHIl, Phe) ppm. HRMS: calcd. [M + H]+ = [C26H32N5O3]
538.2821; found 538.2810; (5.4 mg, 90%).
Pyrazoline 6d: 1H NMR (300 MHz, [D6]DMSO): δ = 0.81–0.82 (d,
J = 2.44 Hz, 3 H, CH3, isobutyl), 0.85–0.86 (d, J = 4.88 Hz, 3 H,
CH3, isobutyl), 1.11–1.14 (d, J = 7.33 Hz, 3 H, CβH3, Ala), 1.22–
1.28 (m, 2 H, CH2, isobutyl), 1.59–1.66 (m, 1 H, CH, isobutyl),
1.72 (s, 3 H, CH3CO), 1.93–1.94 (d, J = 2.44 Hz, 2 H, CH2, pyraz-
oline), 2.19–3.24 (m, 8 H, CH3 pyrazoline, Cβ1,β2H2, Cβ1,β2H2 Phe,
CH, pyrazoline), 4.14–4.18 (m, 1 H, CαH, Ala), 4.43–4.50 (m, 1 H,
CαH, Phe), 4.63–4.67 (m, 1 H, CαH, benzyl), 6.85 (br. s, 1 H, NHI,
benzyl), 7.15–7.22 (m, 10 H, benzyl, Phe), 8.14–8.17 (d, J =
8.55 Hz, 1 H, NHII), 8.31–8.33 (d, J = 7.33 Hz, 1 H, NHIII) ppm.
HRMS: calcd. [M + H]+ = [C30H42N5O3] 520.3148; found
520.3133; (4.7 mg, 67%).
General Procedure for the Preparation of the Peptidyl-Isoxazoles 8a
and 8b and the Isoxazoline 9: Hydroxylamine hydrochloride
(3 equiv.) was added under air to a stirred solution of a peptidyl
vinyl ketone 3 (1 equiv.) in EtOH, together with a catalytic amount
of acetic acid (5 mol-%) and a few crystals of sodium acetate. The
reaction mixture was heated at reflux at 80 °C for 8 h. The solvent
was removed under reduced pressure with a rotary evaporator. The
residue was subjected to purification by preparative HPLC to af-
ford the isoxazole 8 as a white solid. The resulting compound was
characterized by LC-MS and NMR spectroscopy. The peptidyl-
isoxazoline 9 was obtained by the same procedure but under N2.
1
General Procedure for the Preparation of the Peptidyl-Pyrazoles 7a–
7d: 2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ, 1.2 equiv.,
0.012 mmol) in toluene was added to a stirred solution of a pept-
idyl-pyrazoline (1 equiv., 0.01 mmol) in toluene. The reaction mix-
ture was stirred at room temp. for 12 h. The mixture was filtered
through a plug of celite with diethyl ether. The filtrate was concen-
trated in vacuo. The residue was subjected to purification by pre-
parative HPLC to afford the peptidyl-pyrazole as a white solid.
Isoxazole 8a: H NMR (300 MHz, [D6]DMSO): δ = 0.68–0.73 (t,
J1 = 6.71, J2 = 6.72 Hz, 6 H, Cγ1H3, Cγ2H3, Val), 1.01–1.08 (t, J1
= 7.94, J2 = 7.32 Hz, 3 H, CH3, 5-ethyl), 1.82 (s, 3 H, CH3CO),
2.23–2.27 (m, 1 H, CβH, Val), 2.66–2.74 (m, 2 H, CH2, 5-ethyl),
3.00–3.06 (m, 2 H, CβH2, benzyl), 4.06–4.11 (t, J1 = 9.15, J2
=
8.55 Hz, 1 H, CαH, Val), 5.11–5.17 (m, 1 H, CαH, benzyl), 6.15 (s,
1 H, CH, isoxazole), 7.15–7.21 (m, 5 H C6H5, benzyl), 7.76–7.79 (d,
J = 9.15 Hz, 1 H, NIH), 8.46–8.49 (d, J = 8.55 Hz, 1 H, NIIH) ppm.
736
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 730–739

Peptide–Heterocycle Chimera
HRMS: calcd. [M + H]+ = [C20H27N3O3] 358.2125; found
358.2130; (4.2 mg, 80%).
sultant compound was characterized by LC-MS and NMR spec-
troscopy.
Oxirane 11: 1H NMR (300 MHz, [D6]DMSO): δ = 1.03 (d, J =
7.32 Hz, 3 H, CβH3, Ala), 1.23–1.24 (d, J = 4.88 Hz, 3 H, CH3,
oxirane), 1.72–1.73 (s, 3 H, CH3CO), 2.6–2.7 (m, 2 H, Cβ1,β2H2,
benzyl), 2.84–2.90 (m, 2 H, Cβ1,β2H2, Phe), 2.92–2.93 (m, 1 H, CH-
oxirane), 3.12–3.13 (m, 1 H, CHCH3-oxirane), 4.26–4.27 (m, 1 H,
CαH, benzyl), 4.48–4.49 (m, 1 H, CαH, Phe), 4.6–4.65 (m, 1 H,
CαH, Ala), 7.14–7.24 (m, 10 H, benzyl, Phe), 8.02–8.06 (d, J =
8.54 Hz, 1 H, NHI), 8.12–8.13 (d, J = 7.33 Hz, 1 H, NHII), 8.33–
1
Isoxazole 8b: H NMR (300 MHz, [D4]MeOH): δ = 1.84 (s, 3 H,
CH3CO), 2.68–2.76 (m, 2 H, Cβ1,β2H benzyl, Phe), 2.93–3.04 (m, 2
H, Cβ1,β2H Phe), 4.52 (dd, J1 = 15.9, J2 = 7.3 Hz, 1 H, CαH Phe),
5.38 (dd, J1 = 15.9, J2 = 7.3 Hz, 1 H,CαH benzyl), 6.71 (s, 1 H,
arom.), 6.92 (s, 1 H, arom.), 7.03–7.22 (m, 12 H, arom.) ppm. 13C
NMR (100 MHz, CDCl3): δ = 22.3, 30.6, 53.6, 53.6, 64.9, 64.9,
115.1, 115.4, 125.9, 126.1, 126.3, 127.5, 127.5, 127.9, 128.0, 128.1,
128.9, 128.9, 128.9, 129.0, 129.2, 137.8, 137.8, 168.9, 170.6, 170.8,
206.4, 207.1 ppm. LCMS: calcd. [M + H]+ = [C28H28ClFN3O3]
507.0; found 507.1; (8.9 mg, 85%).
8.39 (d, J = 7.32 Hz, 1 H, NHIII) ppm. HRMS: calcd. [M + H]+
=
[C26H32N3O5] 466.2285; found 466.2291; (20 mg, 40%).
Isoxazoline 9: 1H NMR (300 MHz, CDCl3): δ = 0.90 (d, J = 7.3 Hz,
3 H, CH3, isobutyl), 0.95 (d, J = 7.3 Hz, 3 H, CH3, isobutyl), 1.40–
1.56 [m, 3 H, CH-(CH3)2, CH2-CH-(CH3)2], 2.16 (s, 3 H, CH3CO),
2.9–3.1 (m, 4 H, Cβ1,β1Ј,β2,β2ЈH, benzyl, Phe), 4.1 (dd, J1 = 9.8, J2
= 3.7 Hz, 1 H, CαH, Phe), 4.09 (dd, J1 = 14.6, J2 = 4.9 Hz, 1
H,CαH, benzyl), 7.11–7.39 (m, 11 H, benzyl, Phe), 6.3 (s, 1 H,
NHI), 7.6 (s, 1 H, NHII) ppm. 13C NMR (100 MHz, CDCl3): δ =
22.0, 22.1, 28.9, 35.9, 37.2, 48.6, 60.1, 85.7, 126.2, 127.9, 128.0,
128.1, 129.0, 129.1, 135.9, 137.0, 164.9, 173.3, 173.6 ppm. HRMS:
calcd. [M + H]+ = [C26H34N3O3] + Et3N 433.2831; found 433.2832;
(6.8 mg, 68%).
General Procedure for the Preparation of the Peptidyl-Imidazol-
inones 12a, 12b, and 13: The desired amidine derivative (3 equiv.,
0.03 mmol), dissolved in DMF/AcOH (0.1%), was added to a
stirred solution of the peptidyl α-keto aldehyde (1 equiv.,
0.01 mmol) in DMF/AcOH (0.1%). The reaction mixture was
stirred at room temp. for 8 h. The solvent was removed under re-
duced pressure with a rotary evaporator. The crude product was
purified by preparative HPLC to afford the peptidyl-imidazolone.
The resulting compounds were characterized by LC-MS and NMR
spectroscopy.
Imidazol-5-one 12a: 1H NMR (300 MHz, CDCl3): δ = 0.84–0.85
(d, J = 3.05 Hz, 3 H, Cγ1H3, Val), 0.87–0.88 (d, J = 3.05 Hz, 3 H,
Cγ2H3, Val), 1.95 (s, 3 H, CH3CO), 1.99–2.04 (m, 2 H, Cβ1,2H2,
Val), 3.02–3.04 (d, J = 6.72 Hz, 1 H, CαH, Val), 4.02–4.07 (t, J1 =
7.91, J2 = 8.55 Hz, 1 H, CαH, benzyl), 4.16–4.25 (m, 1 H, Cβ1,2H2,
benzyl), 5.92–5.98 (d, J = 9.14 Hz, 1 H, NIH), 7.19–7.30 (m, 10
General Procedure for the Preparation of the Peptidyl-Thiazepines
10a and 10b: 1,2-Amino-4-chlorothiophenol (3 equiv.) was added
under N2 to a stirred solution of a peptidyl vinyl ketone (1 equiv.)
in EtOH, together with catalytic amounts of acetic acid (5 mol-%).
The reaction mixture was stirred at 80 °C for 12 h. The solvent
was removed under reduced pressure with a rotary evaporator. The
residue was subjected to purification by preparative HPLC to af-
ford the benzothiazepines as off-white to pale yellow solids.
H, benzyl, benzylimidazolinone) ppm. HRMS: calcd. [M + H]+
[C24H28N4O3] 421.605; found 421.2608; (4.5 mg, 66.6%).
=
Imidazol-5-one 12b: 1H NMR (300 MHz, [D6]DMSO): δ = 0.78–
0.83 (t, J1 = 7.33, J2 = 6.71 Hz, 6 H, Cγ1H3, Cγ2H3, isopropyl),
1.21–1.24 (d, J = 7.32 Hz, 3 H, Cβ3 H, Ala), 1.86 (s, 3 H, CH3CO),
2.72–2.82 (m, 1 H, CβH, isopropyl), 3.64–3.66 (m, 1 H, CαH, Ala),
4.27–4.31 (t, J1 = 6.71, J2 = 7.32 Hz, 1 H, CαH), 7.433–7.64 (d, J
= 6.10 Hz, 1 H, NIH), 7.61–7.64 (m, 3 H, phenyl), 7.91–7.92 (d, J
= 1.83 Hz, 1 H, CH, phenyl), 7.94–7.95 (d, J = 2.44 Hz, 1 H, CH,
phenyl), 8.15–8.18 (d, J = 7.32 Hz, 1 H, NIIH) ppm. HRMS: calcd.
[M + H]+ = [C18H27N4O3] 347.2078; found 347.2075; (6 mg, 70%).
Imidazol-5-one 13: 1H NMR (300 MHz, [D6]DMSO): δ = 0.78–0.81
(d, J = 6.71 Hz, 3 H, Cγ1H3, isopropyl), 0.87–0.89 (d, J = 6.72 Hz,
3 H, Cγ2H3, isopropyl), 1.07–1.10 (d, J = 7.32 Hz, 3 H, CβH3, Val,
isopropyl), 1.79 (s, 3 H, CH3CO), 2.25–2.27 (m, 1 H, CβH, isopro-
2,3-Dihydro-1,5-benzothiazepine 10a: 1H NMR (300 MHz, CDCl3):
δ = 0.87 (d, J = 7.3 Hz, 3 H, CH3, isobutyl), 0.93 (d, J = 7.3 Hz,
3 H, CH3, isobutyl), 1.42–1.60 (m, 1 H, CH2, isobutyl), 1.81–2.20
[m, 5 H, CH(CH3)2, CH2CH(CH3)2, CH3CO], 2.82–3.18 (m, 6 H,
C
β1,β2H2, benzyl, Cβ1,β2H2 Phe, CH2CH–S), 4.70 (m, 1 H, CH–S),
4.03 (dd, J1 = 14.6, J2 = 6.1 Hz, 1 H, CαH Phe), 5.60 (dd, J1
=
15.9, J2 = 7.3 Hz, 1 H, CαH, benzyl), 7.04–7.37 (m, 13 H, arom.
CH), 7.82 (d, J = 7.3 Hz, arom. CH), 4.16 (d, J = 6.1 Hz, 1 H,
NHI), 8.32 (br. s, 1 H, NHII) ppm. HRMS: calcd. [M – H]+
=
[C32H36N3O2S] + Et3N 624.2409; found 624.2421; (8.2 mg, 55%).
2,3-Dihydro-1,5-benzothiazepine 10b: 1H NMR (300 MHz, CDCl3):
δ = 2.02 (s, 3 H, CH3CO), 2.90–3.18 (m, 5 H, Cβ1,β2H2, benzyl,
pyl), 3.83–3.89 (m, 1 H, CαH, Ala), 4.19–4.21 (t, J1 = 1.83, J2
=
C
β1,β2H2, Phe, CH2CH–S), 4.70–4.82 (m, 2 H, CH2CH–S, CH–S),
2.44 Hz, 1 H, CαH, isopropyl), 7.51–7.55 (d, J = 7.93 Hz, 1 H, CH,
imidazolinone), 7.83 (s, 1 H, NIH), 7.90–7.93 (d, J = 7.93 Hz, 1 H,
CH, imidazolinone), 8.03 (s, 1 H, CH, imidazolinone), 10.5 (s, 1
5.04 (dd, J1 = 13.4, J2 = 7.3 Hz, 1 H, CαH, Phe), 5.39 (dd, J =
14.6, 7.3 Hz, 1 H, CαH, benzyl), 7.06–7.58 (m, 16 H, arom.), 7.85
(d, J = 7.3 Hz, 1 H, arom.), 6.18 (br. s, 1 H, NHI), 8.08 (s, 1 H,
NHII) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.2, 35.3, 35.3,
37.7, 39.2, 48.9, 54.8, 54.9, 59.5, 114.4, 114.8, 117.9, 118.2, 121.2,
122.1, 125.8, 125.8, 126.5, 126.9, 128.3, 128.3, 128.4, 128.5, 128.5,
128.6, 128.7, 128.8, 129.0, 129.1, 129.8, 129.9, 131.3, 136.4, 151.4,
H, OH, imidazolinone) ppm. HRMS: calcd. [M
+ =
H]+
[C15H24N6O3] 337.0222; found 337.0232; (5 mg, 75%).
General Procedure for the Preparation of the Peptidyl-Quinoxalines
14 and 15: 1,2-Phenylenediamine (1.5 equiv., 0.034 mmol, 2.98 mg)
dissolved in dry CH2Cl2 was added carefully to a stirred solution
of a peptidyl α,β-keto aldehyde (1 equiv., 0.023 mmol, 10 mg) in
dry CH2Cl2. The reaction mixture was stirred under N2 at room
temp. for 12 h. The solvent was removed under reduced pressure
with a rotary evaporator. The crude product was purified by pre-
parative HPLC to afford the peptidyl-quinoxaline as a white or
yellow solid. The resulting compounds were characterized by LC-
MS and NMR spectroscopy.
155.3, 158.5, 163.2, 173.2, 173.3 ppm. HRMS: calcd. [M + H]+
[C34H32ClFN3O2S] 600.1845; found 600.1852; (9.3 mg, 71%).
=
Preparation of the Peptidyl-Oxirane 11: A solution of freshly pre-
pared and cooled DMDO in acetone (12 mL, 0.86 mmol, 8 equiv.,
–20 °C) was added dropwise to a stirred solution of the peptidyl
vinyl ketone (50 mg, 0.11 mmol) in CH2Cl2. The reaction mixture
was stirred at room temperature for 8 h. Solvent and residual
DMDO were removed under reduced pressure with a rotary evapo-
rator. The crude product was subjected to purification by prepara-
tive HPLC to afford the peptidyl-oxirane as a white solid. The re-
1
Quinoxaline 14: H NMR (300 MHz, [D6]DMSO): δ = 1.17 (d, J
= 7.50 Hz, 3 H, CβH3, Ala), 1.72 (s, 3 H, CH3CO), 2.95–3.0 (m, 2
Eur. J. Org. Chem. 2011, 730–739
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
737

A. El-Dahshan, S. Nazir, Ahsanullah, F. L. Ansari, J. Rademann
FULL PAPER
H, Cβ1,β2H2, benzyl), 3.35–3.55 (m, 1 H, Cβ1,β2H2, Phe), 4.27–4.30
(m, 1 H, CαH, Ala), 4.46–4.50 (m, 1 H, CαH, Phe), 5.35–5.39 (m,
1 H, CαH, benzyl), 7.1–7.28 (m, 10 H, benzyl, Phe), 7.82–783 (d, J
= 8.55 Hz, 1 H, NHI), 8.01–8.14 (m, 4 H, 1,2-phenylenediamine),
8.50–8.52 (d, J = 7.33 Hz, 1 H, NHII), 8.84 (s, 1 H, CH-N, 1,2-
phenylenediamine) ppm. HRMS: calcd. [M + H]+ = [C30H32N5O3]
510.2460; found 510.2458; (8.4 mg, 75%).
Quinoxaline 15: 1H NMR (300 MHz, [D6]DMSO): δ = 0.92–0.96
(t, J = 6.10 Hz, 6 H, Cδ1H3, Cδ2H3, isobutyl), 1.13–1.15 (d, J =
7.33 Hz, 3 H, CβH3, Ala), 1.19–1.29 (m, 3 H, Cβ1,β2H2, isobutyl,
CγH, isobutyl), 1.71 (s, 3 H, CH3CO), 2.62–2.70 and 2.96–2.99 (br.
s, 2 H, Cβ1,β2H2, Phe), 3.99 (s, 3 H, CH3COOMe), 4.26–4.33 (m, 1
H, CαH, Ala), 4.45–5.0 (m, 1 H, CαH, Phe), 5.56–5.63 (t, 1 H, CαH,
isobutyl), 7.1–7.23 (m, 5 H, Phe), 7.90–8.78 (m, 4 H, arom., 1,2-
phenylenediamine), 8.14–8.18 (d, J = 8.55 Hz, 1 H, NHI), 8.34–
8.36 (d, J = 7.33 Hz, 1 H, NHII) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 17.9, 21.4, 22.4, 23.2, 24.6, 37.5, 43.0, 47.9, 49.2,
53.1, 53.7, 126.1, 127.9, 129.1, 132.3, 138.0, 139.3, 143.7, 155.7,
165.4, 169.1, 171.9 ppm. HRMS: calcd. [M + Na]+ = [C18H26N4O3]
387.2001; found 387.2008; (6.8 mg, 64%).
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Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG) (SFB 786, FOR 806; grant number Ra895/2), Boehringer
Ingelheim Pharma, the Fonds der Chemischen Industrie, the Deut-
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Received: August 26, 2010
Published Online: December 22, 2010
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