Synthesis of chiral threefold and sixfold functionalized macrocyclic imidazole?peptides

Article abstract of DOI:10.1016/j.tet.2009.01.047

Starting from 4-oxa- or 4-azasubstituted 2-amino-3-oxoesters and (S)-valine, chiral imidazole diamino monocarboxylic acids as well as diamino dicarboxylic acids were prepared in a few synthetic steps. Macrolactamization of the side chain protected imidazo

Full text of DOI:10.1016/j.tet.2009.01.047

Tetrahedron 65 (2009) 2217–2225
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of chiral threefold and sixfold functionalized macrocyclic
imidazole peptides
´
*
´
Aron Pinter, Gebhard Haberhauer
Institut fu¨r Organische Chemie, Fachbereich Chemie, Universita¨t Duisburg-Essen, Universita¨tsstraße 7, D-45117 Essen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from 4-oxa- or 4-azasubstituted 2-amino-3-oxoesters and (S)-valine, chiral imidazole diamino
monocarboxylic acids as well as diamino dicarboxylic acids were prepared in a few synthetic steps.
Macrolactamization of the side chain protected imidazole amino acids yields the corresponding 18- and
24-membered ring analogues of the naturally occurring cyclic peptide Westiellamide with various an-
choring sites. The threefold functionalized scaffolds 2b–4b and the sixfold functionalized scaffold 5 are
versatile central modules for artificial receptors and ligands. Structural investigations of threefold
functionalized scaffolds based on oxazole and N-methylimidazole units by DFT modeling are provided.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 24 October 2008
Received in revised form 12 January 2009
Accepted 13 January 2009
Available online 20 January 2009
Keywords:
Amino acids
Cyclization
Imidazoles
Macrocycles
Peptidomimetics
1. Introduction
Macrocycles with a constrained conformation and therefore
with a fixed considerable diameter offering binding sites for a par-
The unique and aesthetic chemical structure of C3-symmetric
molecules inspired chemists to a detailed investigation of the role
of threefold rotational symmetry in chiral molecular recognition
and catalytic processes.1 However the importance of C3-symmetric
chiral catalytic systems is still inferior to the ones with rotational
axes of lower order and the usefulness of C3-symmetric receptors
concerning enantiodiscrimination was in the beginning a subject of
some controversy.2 Nevertheless, chiral transition metal complexes
as well as organocatalysts with threefold symmetry gave rise to
promising enantioselectivities in various synthetic operations, such
ticular guest substrate or catalytically active metal centre are con-
sidered as useful keystones both in supramolecular chemistry and
in catalysis. These structural features in addition to chemical sta-
bility are characteristic for azole-containing cyclic peptides of the
chiral pool.19,20 The first synthetic analogues of the C3-symmetric
peptide alkaloid Westiellamide with oxazole and thiazole units
bearing various electrophilic and nucleophilic coupling sites in the
aliphatic section of the macrocyclic backbone were developed by
Rebek et al.21 The synthesis of similar cyclohexapeptides with thi-
azole heterocycles alternating with proteinogenic Glu, Lys, and Orn
amino acid residues were reported by others.22–24 However, no
further information was provided to date about the complexation
properties of the tubular and conical cages obtained by threefold
linking of two macrocycles.
as alkene reduction,3 direct aldol addition,4
a
-alkylation,5 allylic
substitution,6 allylic oxidation,7 cyclopropanation,8 trans-
esterification,9 carbonyl addition,10 sulfide oxidation,11
a-amina-
tion,12 and ketone reduction.13 In addition chiral C3-symmetric host
molecules of various chemical structures showed remarkable en-
Recently, we reported the synthesis and structure of cyclic
peptides having imidazole and oxazole units in the backbone for
the control of axial and planar chirality25,26 and for chirality
transfer in C3-symmetric compounds.27 For instance, to the imid-
azole cyclopeptide 1, three arms can be attached by simple alkyl-
ation of the secondary nitrogen atoms of the imidazoles (red
arrows in Fig. 1).28 The resulting tripodal system is able to transfer
chiral information via these three arms from its scaffold to a distant
metal or non-metal centre.29 The C3-symmetric oxazole-containing
scaffolds 2a–4a exhibit three easily modifiable functional groups
(blue arrows in Fig. 1), which are coupling sites for the synthesis of
ligands forming diastereoselective octahedral metal complexes.30
Moreover, we were able to synthesize the first configurationally
antiomeric recognition toward peptides,14
a
-amino acid esters,15
a
-amino acid amides,16 and ammonium salts.17 Enantiofacial dis-
crimination of caffeine by C3-symmetric chiral receptors was also
disclosed.18
Abbreviations: Bn, benzyl; Boc, tert-butyloxycarbonyl; DCM, dichloromethane;
DMF, N,N-dimethylformamide; NMM, N-methylmorpholine; PhtN, phthalimido;
PyBOP, benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate;
THF, tetrahydrofuran; TFA, trifluoroacetic acid; Z, benzyloxycarbonyl.
* Corresponding author. Tel.: þ49 201 183 3615; fax: þ49 201 183 4252.
E-mail address: gebhard.haberhauer@uni-due.de (G. Haberhauer).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.047

´
2218
A. Pinte´r, G. Haberhauer / Tetrahedron 65 (2009) 2217–2225
X
X
H
N
H
N
Y
O
O
O
N
N
N
NH
N
NH
N
NH
N
NH
NH
NH
O
O
O
N
N
N
NH
NH
Y
H
N
H
N
H
N
X
X
N
H
N
H
Y
X
X
O
O
O
1
2 a X = OH, Y = O
5 X = NPht
b X = OH, Y = NMe
3 a X = Cl, Y = O
b X = Cl, Y = NMe
4 a X = NH2, Y = O
b X = NH2, Y = NMe
Figure 1. Structural formula of chiral macrocyclic scaffolds with three or six anchoring sites.
stable, propeller-like triarylphosphine by linking a triphenylphos-
phine moiety via three peptide bonds to the chiral scaffold 4a.31
Herein we report the synthesis of threefold substitutable N-
methylimidazole scaffolds 2b–4b, which are insofar of interest as
the structure and the flexibility of synthetic analogues of West-
iellamide depends on the used azole system.32 Furthermore, the
synthesis of the C3-symmetric scaffold 5 with six anchoring sites for
two sets of further substituents (red and blue arrows in Fig. 1) is
presented.
8a upon treatment with methylamine and trifluoroacetic acid in
refluxing xylene. As a side product enamine 9a could be detected in
ESI mass spectra of the reaction mixture, but chromatography gave
only 8a. However, if ammonia along with trifluoroacetic acid were
used for intramolecular condensation, a mixture of the corre-
sponding imidazole ester 8b and the enamine 9b was obtained,
which couldn’t be separated upon column chromatography due to
their identical polarity. Any attempts to drive imidazole formation
to completion failed. Prolongated reaction time resulted in lower
total product yield without affecting the 8b/9b ratio of almost 2:3
as judged by 1H NMR spectra. This may be explained by the pref-
erential formation of the (E)-configurated enamine, which cannot
undergo cyclization due to steric inaccessibility. In addition, we
attempted to synthesize the corresponding N-ethylimidazole ester.
Using ethylamine under the same conditions led to the fast for-
mation of the enamine 9c, but no imidazole could be isolated.
Saponification of N-methylimidazole ester 8a afforded carbox-
ylic acid 10, which could be selectively deprotected upon reduction
with 1,4-cyclohexadiene and palladium(II)hydroxide catalyst.33
The unprotected imidazole 11 was treated with PyBOP and
Hu¨nig’s base in DMF to obtain cyclohexapeptide 12a and cyclo-
octapeptide 12b with moderate total yield (Scheme 2). Debenzy-
lation of 12a was accomplished by catalytic hydrogenation in
dichloromethane to afford the threefold alcohol 2. The tripodal
chloride platform 3 could be obtained upon treatment of 2 with
thionyl chloride in chloroform.
2. Results and discussion
2.1. Synthesis
The synthesis of the tripodal imidazole platforms 2b and 3b
starts from aminoketone 6 (Scheme 1). Peptide coupling of 6 with
Z-(S)-valine using isobutyl chloroformate gave amidoketone 7,
which can smoothly be converted to the N-methylimidazole ester
b.) or
c.) or
d.)
BnO
O
NH CO2Me
a.)
ZNH
CO2Me
NH3+ Cl-
O
O
OBn
(S/R)-6
(S,S/R)-7
The synthesis of chiral imidazole scaffolds 4b and 5 is based on
the phthalimido-substituted aminoketone 13. Peptide coupling and
R
N
OBn
CO2Me
NH
ZNH
O
+
ZNH
N
NH
OBn R
OBn
CO2Me
X
N
O
(S)-8a R = Me
(S)-8b R = H
(S)-9a R = Me
(S)-9b R = H
(S)-9c R = Et
N
N
O
O
NH
NH
OBn
N
N
e.)
NH
N
NH
a.)
N
O
11
+
N
N
R
N
OBn
R
N
OBn
N
OBn
NH
N
O
NH
H
N
N
f.)
X
N
ZNH
H2N
X
O
N
N
N
O
CO2H
(S)-10 R = Me
CO2H
(S)-11 R = Me
BnO
12b
12a X = OBn
2b X = OH
3b X = Cl
b.)
c.)
Scheme 1. Reagents and conditions: (a) Z-(S)-Val-OH, iBuOCOCl, NMM, DCM, ꢀ50 ꢁC,
65%; (b) TFA, MeNH2/EtOH, xylene,
D, 69% for 8a; (c) TFA, NH3/MeOH, xylene, D, 75%
(mixture of 8b and 9b); (d) TFA, EtNH2/H2O, xylene,
D
, 70% for 9c; (e) aq NaOH, MeOH,
Scheme 2. Reagents and conditions: (a) PyBOP, iPr2NEt, DMF, 20 ꢁC, 21% for 12a and
9% for 12b; (b) H2, Pd/C, DCM, 97%; (c) SOCl2, CHCl3, , 99%.
dioxane, 20 ꢁC then aq HCl, 99%; (f) 1,4-cyclohexadiene, EtOH, Pd(OH)2/C, 20 ꢁC, 97%.
D

´
A. Pinte´r, G. Haberhauer / Tetrahedron 65 (2009) 2217–2225
2219
phthalimido side arms with Boc protecting groups followed by the
nonaqueous cleavage of 19 proved to be the most convenient
method for the preparation of the triamine 4b.
PhtN
O
b.) or
c.)
NH CO2Bn
a.)
ZNH
CO2Bn
NH3+ Cl-
(S/R)-13
O
O
2.2. Structural investigations
NPht
(S,S/R)-14
The structures of the imidazole tripodal scaffolds 2b–4b and of
the oxazole cyclopeptides 2a–4a30 were determined by geometry
R
N
NPht
NH CO2Bn
optimizations at B3LYP/6-31G
level of theory.34 The optimized
*
ZNH
+
ZNH
O
structures show a bowl-like conformation where the isopropyl
groups adopt a quasi-axial orientation on the convex-side of the 18-
membered backbone. The conformers of the individual cyclo-
peptides differ only in the orientation of the CH2X-group relative to
the cycle. The peptide backbone of the conformers is essentially the
same, thus suggesting that the cyclic peptides are indeed rigid. For
simplicity only the conformers were calculated in which the di-
hedral angles of the valine side-chains around the Ca–Cb bond have
the same values as those found in solid structures obtained for
analogous systems.35 In the case of the tripodal alcohol platforms
2a,b the hydroxyl groups are involved in intramolecular hydrogen
bonds with the neighboring amide oxygens of the peptide back-
bone (Fig. 2). In the case of oxazole platform 2a the C3-symmetric
conformations with hydrogen bonded side arms are 76–
79 kJ molꢀ1 stabilized in favor of the conformations with free
hydroxymethyl groups. However, the hydrogen bonded confor-
mations of the imidazole trialcohol 2b are only stabilized by 51–
54 kJ molꢀ1. This effect is probably due to the different shapes of the
scaffolds. In the oxazole platforms 2a–4a the cone angle defined by
the plane of the aromatic rings ranges from 113ꢁ to 121ꢁ, while for
the imidazole macrocycles 2b–4b it only varies between 93ꢁ and
105ꢁ. The change of the cone angle is affected mainly by the di-
hedral angles Ccarbonyl–Namide–Ca–Cazole and Namide–Ca–Cazole–Yazole
in the 18-membered backbone (definition for the used abbrevia-
tions see Fig. 3). This difference in the conformations can be well
N
NH
NPht R
(S)-16a R = Me
(S)-16b R = H
CO2Bn
(S)-15a R = Me
(S)-15b R = H
d.)
R
N
NPht
Cl- H3N+
N
CO2H
(S)-17a R = Me
(S)-17b R = H
Scheme 3. Reagents and conditions: (a) Z-(S)-Val-OH, iBuOCOCl, NMM, DCM, ꢀ30 ꢁC,
88%; (b) TFA, MeNH2/EtOH, xylene, D, 63% for 15a and 7% for 16a; (c) TFA, NH3/MeOH,
xylene,
for 17b.
D, 34% for 15b and 44% for 16b; (d) H2, Pd/C, MeOH, aq HCl, 99% for 17a, 99%
imidazole formation were performed according to standard pro-
cedures (Scheme 3). Reaction of amidoketone 14 with methylamine
or ammonia gave the corresponding imidazoles 15a,b along with
enamines 16a,b. In the case of ammonia the yield of the imidazole
ester 15b remained rather low and enamine 16b was isolated as
major product. Neither longer reaction times nor treatment of the
isolated 16b with different strong acids (TFA, TsOH, H3PO4) in
refluxing xylene enhanced the yield of 15b. Hydrogenolytic cleav-
age of both benzyloxycarbonyl and benzyl ester protective groups
in one step afforded the hydrochloride salts 17a and 17b,
respectively.
explained by the strong interaction of the
the imidazole ring with the almost parallel
while in the case of the oxazoles the interaction of the
Nazole)-orbitals with the (Ca-Cb) and (Ca-Ha)-orbitals is more
p
(Cazole–Nazole)-orbital of
(Ca–Namide)-orbital,
(Cazole
s
*
p
*
–
s
s
Cyclooligomerisation of imidazole 17a using the same protocol
as above led to the cyclic trimer 18a and cyclic tetramer 18b, while
in the case of 17b only the cyclic trimer 5 could be isolated
(Scheme 4). The yields for the C3-symmetric platforms are quiet
good and vary between 40 and 51%. Hydrazinolysis of platform 18a
followed by acidic work-up afforded the tripodal amine scaffold 4b
as hydrochloride salt. In addition, the threefold Boc and Z-protected
amine scaffolds 19 and 20 were synthesized. Exchange of the
distinctive, thus resulting in a nearly coplanar arrangement of the
oxazole rings.32
The H–Namide–Ca–H dihedral angles obtained from the opti-
mized structures are in good agreement with the data obtained
3
from the corresponding JH,H coupling constants of the 1H NMR
spectra using the Karplus equation36 (Table 1), which is an evidence
that in apolar solvents platforms 2 and 3 exist in a structure quiet
similar to that calculated in the gas phase. This also applies to the
NPht
O
R
X
R
N
N
N
O
NH
O
NH
N
NH
R
NPht
N
N
NH
N
a.)
17a or
17b
O
+
N
N
N
R
NPht
R
X
NH
N
O
NH
H
N
X
N
N
R
O
N
O
R
PhtN
18a R = Me X = NPht
R = H X = NPht
19 R = Me X = NHBoc
20 R = Me X = NHZ
4b R = Me X = NH2
18b R = Me
b.)
d.)
5
c.)
e.)
f.)
Scheme 4. Reagents and conditions: (a) PyBOP, iPr2NEt, DMF, 20 ꢁC, 51% for 18a and 8% for 18b (starting from 17a); 40% for 5 (starting from 17b); (b) N2H4$H2O, THF/DCM/EtOH
then Boc2O, 20 ꢁC, 97%; (c) (1) N2H4$H2O, THF/DCM/EtOH, 20 ꢁC, (2) ZCl, Et3N, DCM, 20 ꢁC, 77%; (d) HCl/EtOAc, 20 ꢁC, 99%; (e) H2, Pd/C, aq HCl, MeOH, 88%; (f) N2H4$H2O, THF/DCM/
EtOH, 20 ꢁC then acidic work-up, 74%.

´
A. Pinte´r, G. Haberhauer / Tetrahedron 65 (2009) 2217–2225
2220
Figure 2. Molecular structures of the energetically preferred conformers of 2a and 2b calculated using B3LYP/6-31G*; all non-polar hydrogen atoms have been omitted for clarity.
a central building block. Applications of the presented scaffolds
for the construction of ligands and molecular devices are part of
our current investigations.
Hα
Cα Yazole
Cβ
H
Y
X
Ccarbonyl
N
N
*
3
*
H
4. Experimental section
4.1. General remarks
Cazole
O
Namide Nazole
Figure 3. Definition of the used abbreviations.
All chemicals were reagent grade and used as purchased. Re-
actions were monitored by TLC analysis using silica gel 60 F254 thin
layer plates. Flash chromatography was carried out on silica gel 60
(230–400 mesh). 1H and 13C NMR spectra were measured on Bruker
Avance DMX 300 and Avance DRX 500 spectrometers. All chemical
Table 1
Dihedral angles H–Namide–Ca–H and distances in 2, 3, and 4
3
Scaffold JH,H [Hz] Dihedral angles [ꢁ] calculated by
Distance a [Å] between
shifts (d) are given in parts per million relative to TMS. The spectra
neighboring CCH X—CCH
2X
were referenced to deuterated solvents indicated in brackets in the
analytical data. HRMS spectra were recorded with a Bruker BioTOF
III Instrument. IR spectra were measured on a Varian 3100 FT-IR
Excalibur Series spectrometer. UV–vis absorption spectra were
obtained with a Varian Cary 300 Bio spectrophotometer.
2
Karplus equation B3LYP/6-31G*
2a
3a
4a
2b
3b
4b
7.8
7.9
7.9
9.5
9.1
9.4
147
148
148
162
158
161
153
150
152
162
161
163
9.59
9.58
9.59
9.25
9.15
9.12
4.2. Preparation of scaffolds 2b and 3b
4.2.1. (2RS,20S)-4-Benzyloxy-2-{[20-(benzyloxycarbonylamino)-30-
methylbutanoyl]amino}-3-oxobutanoic acid methyl ester (7)
triamine scaffolds 4, which could be isolated as hydrochloride salts,
of which 1H NMR spectra were measured in MeOH-d4. The slow
H/D exchange of the amide protons allowed the evaluation of
the coupling constants.
Z-(S)-Valine (15.077 g, 60.0 mmol) and NMM (6.069 g,
60.0 mmol) were dissolved in dry DCM (180 mL) under Ar, then
cooled to ꢀ30 ꢁC and isobutyl chloroformate (8.195 g, 60.0 mmol)
in DCM (60 mL) was slowly added. After complete addition the
resulting solution was maintained at ꢀ30 to ꢀ25 ꢁC for 60 min,
then cooled down to ꢀ50 ꢁC, while aminoketone 6 (16.423 g,
60.0 mmol) was placed in a second round-bottom flask equipped
with a mechanical stirrer and cooled to ꢀ50 ꢁC. Mixing of the
components was achieved by injecting the cold solution via
a double-tipped needle to the solid followed by the addition of
a second equivalent of NMM (6.069 g, 60.0 mmol) in DCM (30 mL)
over a period of 30 min. While stirred vigorously the mixture was
allowed to warm up to room temperature within 3 h. The mixture
was then diluted with DCM (300 mL) and extracted with water
(1ꢂ100 mL), 1 M KHSO4 (1ꢂ100 mL), and brine (1ꢂ100 mL). The
organic layer was dried over MgSO4, filtered, and concentrated in
vacuo. The resulting thick oil was subjected to column chroma-
tography on silica gel (DCM/EtOAc 95:5/70:30) to yield 18.229 g
(65%) of 7 (1:1 mixture of two diastereomers) as a yellowish oil.
TLC: Rf¼0.37 (DCM/EtOAc 90:10; silica). 1H NMR (500 MHz,
Due to the different shapes, the distance between two adja-
cent CCH X-atoms in the oxazole-containing cyclopeptides 2a–4a
2
is around 9.6 Å, while in the imidazole peptides 2b–4b this
distance has a value of only 9.12–9.25 Å (Table 1). This distance is
of importance in that the CCH X-atoms can serve as anchor
2
groups for further functional units. As a matter of course, the
functioning of these groups essentially depends on the distance
between each other. Interestingly, the difference in this distance
between the oxazole 2a–4a and imidazole cyclopeptides 2b–4b
(around 0.3–0.4 Å) is not as large as the difference found for the
unsubstituted analogues (X¼H), where a value of 1.0 Å was
calculated.32
3. Conclusion
In summary, we could synthesize the chiral C3-symmetric
macrocyclic imidazoles 2b–4b bearing three functional groups.
The distance between the anchoring groups in the imidazole
macrocycles 2b–4b is smaller than that calculated for the known
corresponding oxazole macrocycles 2a–4b. This expands our
toolbox of rigid 18-membered core molecules with various di-
ameters and a variety of anchoring groups. The macrocycle 5
possesses even six anchoring sites, where N-alkylation of the
imidazole rings followed by deprotection and N-acylation of the
aminomethyl side arms should allow its convenient utilization as
CDCl3):
d
¼7.36–7.29 (m, 10H, Z and Bn CH-2,3,4,5,6), 7.11 (d,
3JH,H¼5.7 Hz, 1H, amide NH), 5.44–5.40 (2ꢂd, 2H, Z NH and
CHCO2Me), 5.12 (d, 2JH,H¼12.2 Hz, 1H, Z CH2), 5.08 (d, 2JH,H¼12.2 Hz,
2
1H,
Z
CH2), 4.62 (d, JH,H¼12.2 Hz, 1H, PhCH2O), 4.59 (d,
2JH,H¼12.2 Hz, 1H, PhCH2O), 4.42 (d, JH,H¼17.6 Hz, 1H, BnOCH2CO),
2
2
3
4.35 (d, JH,H¼17.6 Hz, 1H, BnOCH2CO), 4.19 (dd, JH,H¼8.0 Hz,
3JH,H¼6.0 Hz, 1H, Val
a-CH), 3.73 (s, 3H, CO2CH3), 2.18–2.12 (m, 1H,
Val
b
-CH), 0.97 (d, 3JH,H¼6.8 Hz, 3H, Val CH3), 0.92 (d, 3JH,H¼6.8 Hz,

´
A. Pinte´r, G. Haberhauer / Tetrahedron 65 (2009) 2217–2225
2221
3H, Val CH3) ppm. 13C NMR (125 MHz, CDCl3):
d
¼198.9 (q, CO), 171.2
3JH,H¼6.5 Hz, 3H, Val CH3) ppm. 13C NMR (75 MHz, CDCl3):
d
¼157.0
(q, amide CONH), 166.0 (q, CO2Me), 156.3 (q, Z CONH), 136.7 (q, Z C-
1), 136.1 (q, Bn C-1), 128.49 (t, Ph CH), 128.14 (t, Ph CH), 128.10 (t, Ph
CH), 128.03 (t, Ph CH), 128.00 (t, Ph CH), 127.98 (t, Bn CH), 73.62 (s,
BnOCH2), 73.49 (s, PhCH2O), 67.1 (s, Z CH2), 59.8 (t, CHCO2Me), 58.8
(q, CO2H),150.0 (q, Z CONH),137.0 (q, imidazole C-2),136.2 (q, Bn C-1),
134.1 (q, Z C-1),128.51 (t, Z CH-2,6),128.46 (q, imidazole C-5),128.35
(t, BnCH-2,6),128.14(t,ZCH-4),128.06(t,BnCH-3,5),127.86(t,BnCH-
4),127.58 (t, Z CH-3,5),127.0 (q, imidazole C-4), 72.9 (s, PhCH2O), 67.0
(t, Val
a
-CH), 53.4 (p, CO2CH3), 31.1 (t, Val
b
-CH), 19.0 (p, Val CH3),
(s, Z CH2), 59.6 (s, CH2OBn), 53.4 (t, Val
a-CH), 32.6 (p, NCH3), 32.2 (t,
17.5 (p, Val CH3) ppm. IR (KBr):
n
¼3289, 3066, 3035, 2959, 2898,
Val -CH), 19.7 (p, Val CH3), 19.4 (p, Val CH3) ppm. IR (KBr): n
b
¼3405,
2872,1731,1689,1651,1541,1455,1436,1390,1333,1291,1250,1146,
3242, 3032, 2965, 2874,1716,1635,1518,1455,1373,1317,1272,1236,
1191, 1068, 1027, 913, 869, 742, 699 cmꢀ1. ESI-HRMS: m/z calcd for
[C25H30N3O5]þ 452.2180, found 452.2182.
1044, 970, 912, 860, 842, 733, 695 cmꢀ1. UV–vis (DCM): lmax
(log
3
)¼253 (2.72), 258 (2.77), 264 (2.72), 283 (2.30) nm. ESI-HRMS:
m/z calcd for [C25H31N2O7]þ 471.2126, found 471.2113.
4.2.4. (10S)-2-(10-Amino-20-methylpropyl)-5-(benzyloxymethyl)-1-
methyl-1H-imidazole-4-carboxylic acid (11)
4.2.2. (10S)-2-[10-(Benzyloxycarbonylamino)-20-methylpropyl]-
5-(benzyloxymethyl)-4-methoxycarbonyl-1-methyl-1H-
imidazole (8a)
To
a solution of imidazole carboxylic acid 10 (4.515 g,
10.0 mmol) in MeOH (200 mL) Pd(OH)2-catalyst (20 wt % Pd on
charcoal, 1.000 g) and 1,4-cyclohexadiene (12.020 g, 150.0 mmol)
were added at room temperature. The mixture was stirred vigor-
ously for 90 min, then a second portion of 1,4-cyclohexadiene
(4.007 g, 50.0 mmol) was added followed by stirring for further
30 min. After completion (control by ESI-MS) the catalyst was fil-
tered off and the filtrate was evaporated to obtain 3.084 g (97%) of
11 as a colorless solid.
To a slurry of amidoketone 7 (9.410 g, 20.0 mmol) in xylene
(300 mL), TFA (6.0 mL, 80.0 mmol) and 8 M methylamine in EtOH
(7.5 mL, 60.0 mmol) were added. The mixture was heated under
intensive reflux with a Dean–Stark trap for 2 h while the trap was
discharged (w10 mL) every 15 min. After completion of the re-
action, volatiles were removed in a rotary evaporator. The residual
solid was subjected to column chromatography on silica gel (DCM/
EtOAc/MeOH 75:25:0/75:25:3) to obtain 6.462 g (69%) of 8a as
a white fluffy solid.
Mp: 115 ꢁC. 1H NMR (500 MHz, MeOH-d4):
d
¼7.33–7.30 (m, 5H,
2
Ph CH-2,3,4,5,6), 4.95 (s, 2H, CH2OBn), 4.54 (d, JH,H¼11.7 Hz, 1H,
TLC: Rf¼0.40 (DCM/EtOAc/MeOH 75:25:0; silica). Mp: 140 ꢁC. 1H
PhCH2O), 4.51 (d, 2JH,H¼11.7 Hz, 1H, PhCH2O), 4.40 (d, 3JH,H¼8.3 Hz,
NMR (500 MHz, CDCl3):
d
¼7.35–7.28 (m, 10H, Z and Bn CH-
1H, Val a-CH), 3.70 (s, 3H, NCH3), 2.40–2.33 (m, 1H, Val b-CH), 1.12
2,3,4,5,6), 5.61 (d, 3JH,H¼9.5 Hz,1H, Z NH), 5.10 (d, 2JH,H¼12.4 Hz,1H,
(d, JH,H¼6.8 Hz, 3H, Val CH3), 0.89 (d, JH,H¼6.8 Hz, 3H, Val
3
3
2
2
Z CH2), 5.04 (d, JH,H¼12.4 Hz, Z CH2), 4.98 (d, JH,H¼12.7 Hz, 1H,
CH3) ppm. 13C NMR (125 MHz, MeOH-d4):
(q, imidazole C-2), 139.3 (q, Ph C-1), 136.2 (q, imidazole C-5), 129.48
(t, Ph CH-2,6), 129.11 (t, Ph CH-3,5), 128.94 (t, Ph CH-4), 132.5 (q,
d
¼166.8 (q, CO2H), 146.2
CH2OBn), 4.93 (d, 2JH,H¼12.7 Hz, 1H, CH2OBn), 4.59 (t, 3JH,H¼9.2 Hz,
2
1H, Val
a
-CH), 4.54 (d, JH,H¼11.9 Hz, 1H, PhCH2O), 4.52 (d,
2JH,H¼11.9 Hz, 1H, PhCH2O), 3.86 (s, 3H, CO2CH3), 3.68 (s, 3H, NCH3),
imidazole C-4), 73.5 (s, PhCH2O), 61.4 (s, CH2OBn), 53.3 (t, Val
33.9 (t, Val -CH), 31.8 (p, NCH3), 18.8 (p, Val CH3) ppm. IR (KBr):
¼3425, 3030, 2967, 2877, 1990, 1967, 1706, 1603, 1507, 1476, 1455,
1394, 1376, 1356, 1225, 1193, 1062, 1027, 1007, 934, 869, 822, 802,
771, 743, 699 cmꢀ1. UV–vis (MeOH): lmax (log
a-CH),
2.30–2.22 (m, 1H, Val
b
-CH), 1.03 (d, 3H, 3JH,H¼6.7 Hz, Val CH3), 0.82
b
(d, 3H, JH,H¼6.7 Hz, Val CH3) ppm. 13C NMR (125 MHz, CDCl3):
n
3
d
¼163.7 (q, CO2Me), 156.3 (q, Z CONH), 149.7 (q, imidazole C-2),
137.6 (q, Bn C-1), 136.3 (q, Z C-1), 134.5 (q, imidazole C-5), 130.0 (q,
imidazole C-4),128.41 (t, Z/Bn CH),128.40 (t, Z/Bn CH),128.0 (t, Z/Bn
CH), 127.92 (t, Z/Bn CH), 127.87 (t, Z/Bn CH), 127.79 (t, Z/Bn CH), 72.2
3
)¼209 (4.08), 214
(sh., 4.06), 224 (sh., 3.99) nm. ESI-HRMS: m/z calcd for
[C17H24N3O3]þ 318.1812, found 318.1838.
(s, PhCH2O), 66.8 (s, Z CH2), 60.4 (s, CH2OBn), 52.7 (t, Val
(p, CO2CH3), 33.2 (t, Val -CH), 30.9 (p, NCH3), 19.5 (p, Val CH3), 18.7
(p, Val CH3) ppm. IR (KBr):
2956, 2925, 2869, 2799, 1688, 1578, 1536, 1455, 1414, 1362, 1324,
1302, 1256, 1225, 1199, 1155, 1123, 1092, 1061, 1026, 996, 939, 917,
879, 795, 776, 740, 695, 611, 591, 515 cmꢀ1. UV–vis (DCM): lmax
a-CH), 51.7
b
4.2.5. Scaffolds 12a,b
n
¼3296, 3090, 3066, 3035, 3001, 2980,
To a solution of the free amino acid 11 (1.587 g, 5.0 mmol) in
anhydrous DMF (125 mL), PyBOP (3.903 g, 7.5 mmol) was added at
room temperature followed by the addition of iPr2NEt (4.201 g,
32.5 mmol), and the mixture was stirred under Ar for 3 days. For
work-up MeOH (20 mL) was added and the solvents were removed
in a rotary evaporator. The remaining brown slurry was taken up in
EtOAc (500 mL), then washed with 2 M HCl (2ꢂ50 mL), water
(1ꢂ50 mL), concd sodium bicarbonate (1ꢂ50 mL), water
(1ꢂ50 mL), and brine (1ꢂ50 mL). The organic layer was dried over
MgSO4, filtered, concentrated, and the oily residue was subjected to
column chromatography on silica gel (DCM/EtOAc/MeOH
75:25:0/75:25:5). Separation of the products was completed by
a second chromatographic step on silica gel using PE/EtOAc
(20:80/0:100) to obtain 0.319 g (21%) of imidazole trimer 12a and
0.128 g (8.5%) of imidazole tetramer 12b as white powders.
(log
3
)¼248 (4.68), 289 (3.62) nm. ESI-HRMS: m/z calcd for
[C26H32N3O5]þ 466.2336, found 466.2346.
4.2.3. (10S)-2-[10-(Benzyloxycarbonylamino)-20-methylpropyl]-5-
(benzyloxymethyl)-1-methyl-1H-imidazole-4-carboxylic acid (10)
Imidazole ester 8a (9.311 g, 20.0 mmol) was dissolved in a mix-
ture of methanol (120 mL) and dioxane (80 mL) followed by slow
addition of 2 M NaOH solution (50 mL, 100.0 mmol) at 0 ꢁC. The ice
bath was removed and stirring was continued overnight. After TLC
showed consumption of the starting material the mixture was di-
luted with brine (400 mL) and acidified with 2 M HCl (100 mL). The
mixture was then repeatedly extracted with DCM (3ꢂ100 mL),
the organic layers were combined, dried over MgSO4, filtered, and
the filtrate was concentrated in vacuo to give 8.962 g (99%) of the
free acid 10 as a white powder, which was used without further
purification for the next step.
4.2.5.1. Data for cyclic trimer 12a. TLC: Rf¼0.60 (DCM/EtOAc/MeOH
75:25:5; silica), Rf¼0.55 (EtOAc; silica). Mp: >200 ꢁC. 1H NMR
3
(500 MHz, CDCl3):
d
¼8.52 (d, JH,H¼9.3 Hz, 1H, amide NH), 7.29–
7.20 (m, 5H, Ph CH-2,3,4,5,6), 5.17 (dd, 3JH,H¼9.3, 5.7 Hz, 1H, Val
a-
TLC: Rf¼0.30 (DCM/EtOAc/MeOH 75:25:5; silica). Mp: 73 ꢁC. 1H
CH), 5.12 (d, 2JH,H¼12.8 Hz, 1H, CH2OBn), 5.04 (d, 2JH,H¼12.8 Hz, 1H,
CH2OBn), 4.52 (d, 2JH,H¼11.4 Hz, 1H, PhCH2O), 4.48 (d, 2JH,H¼11.4 Hz,
NMR (500 MHz, CDCl3):
d
¼9.54 (br s, 1H, CO2H), 7.89 (br s, 1H, Z
CONH), 7.35–7.20 (m, 10H,
Z
and Bn CH-2,3,4,5,6), 5.11 (d,
1H, PhCH2O), 3.63 (s, 3H, NCH3), 2.17–2.08 (m, 1H, Val b-CH), 1.07 (d,
2JH,H¼12.5 Hz,1H, CH2OBn), 5.06 (d, 2JH,H¼13.2 Hz,1H, Z CH2), 4.99 (d,
3JH,H¼6.8 Hz, 3H, Val CH3), 1.05 (d, 3JH,H¼6.8 Hz, 3H, Val CH3) ppm.
2JH,H¼12.5 Hz,1H, CH2OBn), 4.93 (d, 2JH,H¼13.2 Hz,1H, Z CH2), 4.62 (t,
13C NMR (125 MHz, CDCl3):
d
¼162.5 (q, CONH), 148.2 (q, imidazole
3JH,H¼9.6 Hz, 1H, Val
a
b
-CH), 4.50 (s, 2H, PhCH2O), 3.87 (s, 3H, NCH3),
C-2), 138.0 (q, Ph C-1), 131.9 (q, imidazole C-5), 131.2 (q, imidazole
C-4), 128.22 (t, Ph CH-2,6), 127.81 (t, Ph CH-3,5), 127.57 (t, Ph CH-4),
2.75–2.67 (m,1H,Val
-CH),1.15(d, 3JH,H¼6.5 Hz, 3H,ValCH3), 0.74 (d,

´
A. Pinte´r, G. Haberhauer / Tetrahedron 65 (2009) 2217–2225
2222
72.0 (s, PhCH2O), 60.6 (s, CH2OBn), 49.4 (t, Val
a
-CH), 34.7 (t, Val
b
-
(300 mL) and NMM (6.069 g, 60.0 mmol) was added. The solution
was cooled to ꢀ30 ꢁC and a solution of isobutyl chloroformate
(8.195 g, 60.0 mmol) in DCM (60 mL) was added while the inner
temperature was maintained at ꢀ30 to ꢀ25 ꢁC. After further 60 min
ketoamine 13 (23.328 g, 60.0 mmol) was added in one portion
followed by a solution of NMM (6.069 g, 60.0 mmol) in DCM
(30 mL) over a period of 30 min. Stirring was continued for 3 h at
ꢀ30 ꢁC, then the mixture was allowed to warm up to room tem-
perature resulting in a thick suspension. The white solid was fil-
tered off and the filtrate was evaporated to dryness. The remaining
solids were merged and washed on a funnel sequentially with
water (1ꢂ300 mL), 1 M HCl (2ꢂ150 mL), and water (1ꢂ300 mL) and
dried in vacuo. The crude product was recrystallized from EtOH/
iPrOH to yield 30.85 g (88%) of 14 (1:1 mixture of two dia-
stereomers) as a white powder.
CH), 30.8 (p, NCH3), 19.5 (p, Val CH3), 17.7 (p, Val CH3) ppm. CD
(MeOH): lmax
(
D3 [dm3 molꢀ1 cmꢀ1])¼220 (þ17.3), 239 (0.0), 256
(ꢀ62.0) nm. ESI-HRMS: m/z calcd for [C51H64N9O6]þ 898.4970,
found 898.5101.
4.2.5.2. Data for cyclic tetramer 12b. TLC: Rf¼0.60 (DCM/EtOAc/
MeOH 75:25:5; silica), Rf¼0.70 (EtOAc; silica). Mp: 158 ꢁC. 1H NMR
(500 MHz, CDCl3):
d
¼7.62 (d, 3JH,H¼9.4 Hz,1H, amide NH), 7.24–7.19
2
(m, 5H, Ph CH-2,3,4,5,6), 5.08 (d, JH,H¼12.6 Hz, 1H, CH2OBn), 4.94
(t, 3JH,H¼9.4 Hz, 1H, Val
a
-CH), 4.89 (d, 2JH,H¼12.6 Hz, 1H, CH2OBn),
2
2
4.48 (d, JH,H¼11.6 Hz, 1H, PhCH2O), 4.45 (d, JH,H¼11.6 Hz, 1H,
PhCH2O), 3.73 (s, 3H, NCH3), 2.50–2.40 (m, 1H, Val b-CH), 1.11 (d,
3JH,H¼6.7 Hz, 3H, Val CH3), 0.87 (d, 3JH,H¼6.7 Hz, 3H, Val CH3) ppm.
13C NMR (125 MHz, CDCl3):
d
¼162.9 (q, CONH), 148.5 (q, imidazole
C-2), 138.0 (q, Ph C-1), 131.8 (q, imidazole C-4), 131.2 (q, imidazole
C-5), 128.28 (t, Ph CH-2,6), 127.92 (t, Ph CH-3,5), 127.67 (t, Ph CH-4),
TLC: Rf¼0.62 (DCM/EtOAc 3:1; silica). Mp: 90 ꢁC. 1H NMR
(500 MHz, CDCl3):
d
¼7.87–7.83 (2ꢂdd, 2H, PhtN CH-2,5), 7.74–7.72
72.2 (s, PhCH2O), 60.7 (s, CH2OBn), 49.6 (t, Val
a
-CH), 32.6 (t, Val
b
-
(2ꢂdd, 2H, PhtN CH-3,4), 7.40–7.32 (m, 10H, Z and Bn CH-2,3,4,5,6),
3
CH), 30.9 (p, NCH3), 19.8 (p, Val CH3), 19.1 (p, Val CH3) ppm. CD
7.21–7.19 (2ꢂd, JH,H¼5.6 Hz, 1H, amide NH), 5.53–5.49 (2ꢂd,
3
(DCM): lmax
(
D3 [dm3 molꢀ1 cmꢀ1])¼231 (þ30.7), 243 (0.0), 258
3JH,H¼7.8 Hz, 1H, NHCHCO2Bn), 5.44–5.40 (2ꢂd, JH,H¼9.6 Hz, 1H, Z
(ꢀ63.7) nm. ESI-HRMS: m/z calcd for [C68H85N12O8]þ 1197.6608,
NH), 5.31–5.25 (4ꢂd, 2H, Z CH2), 5.12–5.04 (4ꢂd, 2H, CO2CH2Ph),
found 1197.6745.
4.85 (d, 2JH,H¼18.2 Hz, 0.5H, PhtNCH2), 4.84 (d, 2JH,H¼18.2 Hz, 0.5H,
2
PhtNCH2), 4.75 (d, JH,H¼18.2 Hz, 0.5H, PhtNCH2), 4.71 (d,
4.2.6. Scaffold 2b
2JH,H¼18.2 Hz, 0.5H, PhtNCH2), 4.20 (br d, 3JH,H¼5.6 Hz, 0.5H, Val
a-
To a solution of 12a (0.090 g, 0.10 mmol) in DCM (100 mL),
palladium–charcoal catalyst (10 wt % Pd, 0.150 g) was added, and
the mixture was stirred under hydrogen atmosphere (105 Pa) at
room temperature for 60 min. Then the catalyst was removed by
filtration and the solvent was distilled off in a rotary evaporator to
yield 0.057 g (97%) of 2b as a colorless solid.
CH), 4.18 (br d, 3JH,H¼6.6 Hz, 0.5H, Val
a-CH), 2.20–2.11 (m, 1H, Val
3
3
b
-CH), 0.95 (ps t, JH,H¼6.9 Hz, 3H, Val CH3), 0.90 (d, JH,H¼6.9 Hz,
3H, Val CH3) ppm. 13C NMR (125 MHz, CDCl3):
d
¼193.71 (q,
PhtNCH2CO), 193.66 (q, PhtNCH2CO), 171.2 (q, amide CO), 167.1 (q,
2ꢂPhtN CO), 164.92 (q, CO2Bn), 164.89 (q, CO2Bn), 156.4 (q, Z CO),
136.13 (q, Z C-1), 136.12 (q, Bn C-1), 134.21 (t, PhtN CH-3,4), 134.20
(t, PhtN CH-3,4),131.92 (q, PhtN C-1,6),131.90 (q, PhtN C-1,6),128.80
(t, Z/Bn CH), 128.71 (t, Z/Bn CH), 128.67 (t, Z/Bn CH), 128.47 (t, Z/Bn
CH), 128.46 (t, Z/Bn CH), 128.11 (t, Z/Bn CH), 128.08 (t, Z/Bn CH),
128.04 (t, Z/Bn CH), 123.60 (t, PhtN CH-2,5), 68.92 (s, Z CH2), 68.90
Mp: >200 ꢁC. 1H NMR (500 MHz, CDCl3):
d¼8.46 (d,
3JH,H¼9.4 Hz, 1H, amide NH), 5.66 (t, 3JH,H¼6.6 Hz, 1H, CH2OH), 5.06
(dd, 3JH,H¼9.4, 6.1 Hz, 1H, Val
a
-CH), 4.97 (dd, 3JH,H¼14.4, 7.0 Hz, 1H,
2
3
CH2OH), 4.67 (dd, JH,H¼14.4 Hz, JH,H¼6.1 Hz, 1H, CH2OH), 3.60 (s,
3H, NCH3), 2.14–2.07 (m, 1H, Val
b
-CH), 1.03 (d, 3JH,H¼6.8 Hz, 6H, Val
(s, Z CH2), 67.1 (s, Bn CH2), 60.6 (t, NHCHCO2Bn), 59.90 (t, Val
59.88 (t, Val -CH), 45.27 (s, PhtNCH2), 45.07 (s, PhtNCH2), 31.0 (t,
Val -CH), 19.09 (p, Val CH3), 19.02 (p, Val CH3), 17.52 (p, Val CH3),
17.44 (p, Val CH3) ppm. IR (KBr):
a-CH),
CH3) ppm. 13C NMR (125 MHz, CDCl3):
d¼163.4 (q, CONH), 147.3 (q,
a
imidazole C-2), 136.2 (q, imidazole C-5), 130.6 (q, imidazole C-4),
54.4 (s, CH2OH), 49.7 (t, Val -CH), 34.8 (t, Val -CH), 30.8 (s, NCH3),
D3
b
a
b
n
¼3289, 3065, 3034, 2958, 2935,
19.4 (p, Val CH3), 17.8 (p, Val CH3) ppm. CD (MeOH): lmax
(
2907, 2872, 1778, 1727, 1692, 1653, 1539, 1468, 1455, 1414, 1387,
[dm3 molꢀ1 cmꢀ1])¼223 (þ15.8), 243 (0.0), 252 (ꢀ60.5) nm. ESI-
1273, 1249, 1109, 1041, 950, 843, 732, 714, 696, 531 cmꢀ1. UV–vis
HRMS: m/z calcd for [C30H45N9O6]þ 628.3644, found 628.3566.
(MeOH): lmax (log
3
)¼217 (4.81), 240 (sh., 4.08), 280 (3.68) nm. ESI-
HRMS: m/z calcd for [C32H32N3O8]þ 586.2184, found 586.2180.
4.2.7. Scaffold 3b
A solution of 2b (0.063 g, 0.10 mmol) in CHCl3 (10 mL) was
mixed with thionyl chloride (0.119 g, 1.0 mmol) for 15 min, then
evaporated and dried in vacuo to give 0.068 g (99%) of 3b as a col-
orless solid.
4.3.2. (10S)-4-(Benzyloxycarbonyl)-2-[10-(benzyloxycarbonylamino)-
20-methylpropyl]-1-methyl-5-(phthalimidomethyl)-
1H-imidazole (15a)
To a slurry of amidoketone 14 (11.712 g, 20.0 mmol) in xylene
(300 mL) TFA (6.0 mL, 80.0 mmol) and 8 M methylamine in EtOH
(7.5 mL, 60.0 mmol) were added. The mixture was heated under
intensive reflux with a Dean–Stark trap for 4 h while the trap was
discharged (w10 mL) every 30 min. After the completion of the
reaction volatiles were removed in a rotary evaporator. The residual
solid was subjected to column chromatography on silica gel (DCM/
EtOAc/MeOH 75:25:0/75:25:3) to obtain 7.297 g (63%) of 15a as
a white fluffy solid.
Mp: 145 ꢁC. 1H NMR (500 MHz, CDCl3):
d
¼8.41 (d, 3JH,H¼9.1 Hz,
2
1H, amide NH), 5.16 (d, JH,H¼12.5 Hz, 1H, CH2Cl), 5.15 (dd,
3JH,H¼9.0, 6.3 Hz, 1H, Val
-CH), 5.11 (d, 1H, JH,H¼12.5 Hz, CH2Cl),
a
2
3.67 (s, 3H, NCH3), 2.18–2.11 (m, 1H, Val
b
-CH), 1.06 (d, 3JH,H¼6.7 Hz,
3H, Val CH3), 1.05 (d, 3H, JH,H¼6.7 Hz, Val CH3) ppm. 13C NMR
3
(125 MHz, CDCl3):
d
¼162.1 (q, CONH),148.9 (q, imidazole C-2),131.5
(q, imidazole C-4), 130.3 (q, imidazole C-5), 49.7 (t, Val a-CH), 34.8
(t, Val
b-CH), 33.8 (s, CH2Cl), 30.7 (p, NCH3), 19.5 (p, Val CH3), 18.0 (p,
Val CH3) ppm. CD (DCM): lmax
(
D3 [dm3 molꢀ1 cmꢀ1])¼233 (þ10.8),
TLC: Rf¼0.50 (DCM/EtOAc 75:25; silica). Mp: 71 ꢁC. 1H NMR
3
246 (0.0), 254 (ꢀ62.5) nm. ESI-HRMS: m/z calcd for
(500 MHz, CDCl3):
d
¼7.79 (dd, JH,H¼5.5, 3.1 Hz, 2H, PhtN CH-2,5),
[C30H42Cl3N9O3]þ 684.2525, found 684.2553.
7.70 (dd, JH,H¼5.5, 3.1 Hz, 2H, PhtN CH-3,4), 7.42 (dd, JH,H¼8.1,
3
3
3
1.6 Hz, 2H, Ar CH); 7.34–7.24 (m, 8H, Ar CH), 5.74 (d, JH,H¼9.5 Hz,
2
4.3. Preparation of scaffolds 4b and 5
1H,
Z
NH), 5.39 (d, JH,H¼12.3 Hz, 1H, PhtNCH2), 5.36 (d,
2JH,H¼12.3 Hz, 1H, PhtNCH2), 5.26 (d, JH,H¼15.6 Hz, 1H, Bn CH2),
2
2
2
4.3.1. (2RS,20S)-2-{[20-(Benzyloxycarbonylamino)-30-
methylbutanoyl]amino}-3-oxo-4-phthalimidobutanoic
acid benzyl ester (14)
In a round-bottomed flask equipped with a mechanical stirrer,
Z-(S)-Val-OH (15.077 g, 60.0 mmol) was dissolved in dry DCM
5.09 (d, JH,H¼12.5 Hz, 1H, Z CH2), 5.04 (d, JH,H¼15.6 Hz, 1H, Bn
2 3
CH2), 5.01 (d, JH,H¼12.5 Hz, 1H, Z CH2), 4.61 (t, JH,H¼9.0 Hz, 1H,
Val a-CH), 3.74 (s, 3H, NCH3), 2.27–2.20 (m, 1H, Val b-CH), 1.01 (d,
3JH,H¼6.7 Hz, 3H, Val CH3), 0.83 (d, JH,H¼6.7 Hz, 3H, Val
3
CH3) ppm. 13C NMR (125 MHz, CDCl3):
d¼167.5 (q, 2ꢂPhtN CO),

´
A. Pinte´r, G. Haberhauer / Tetrahedron 65 (2009) 2217–2225
2223
162.8 (q, Z CO), 156.3 (q, CO2Bn), 149.5 (q, imidazole C-2), 136.28
4.3.5. (10S)-2-(10-Amino-20-methylpropyl)-5(4)-
(phthalimidomethyl)-1H-imidazole-4(5)-carboxylic
acid hydrochloride (17b)
(q, Bn C-1), 136.27 (q, Z C-1), 134.1 (t, PhtN CH-3,4), 131.7 (q, PhtN
C-1,6), 131.3 (q, imidazole C-4), 130.6 (q, imidazole C-5), 128.48 (t,
Z/Bn CH), 128.38 (t, Z/Bn CH), 128.29 (t, Z/Bn CH), 127.93 (t, Z/Bn
CH), 127.91 (t, Z/Bn CH), 127.75 (t, Z/Bn CH), 123.4 (t, PhtN CH-2,5),
Deprotection of imidazole ester 15b (5.666 g, 10.0 mmol) was
performed as for compound 15a to give 3.732 g (99%) of 17b as
a yellowish powder.
66.8 (s, Z CH2), 66.1 (s, Bn CH2), 52.8 (t, Val a-CH), 33.4 (t, Val b-
CH), 31.57 (s, PhtNCH2), 31.15 (p, NCH3), 19.4 (p, Val CH3), 18.6 (p,
Val CH3) ppm. ESI-HRMS: m/z calcd for [C33H33N4O6]þ 581.2395,
found 581.2416.
Mp: 105 ꢁC. 1H NMR (500 MHz, MeOH-d4):
d
¼7.90–7.88 (m,
2H, PhtN CH-2,5), 7.84–7.83 (m, 2H, PhtN CH-3,4), 5.22 (s, 2H,
3
PhtNCH2), 4.31 (d, JH,H¼8.5 Hz, 1H, Val
a-CH), 2.44–2.36 (m, 1H,
Val
b
-CH), 1.10 (d, 3JH,H¼6.7 Hz, 3H, Val CH3), 0.90 (d, 3JH,H¼6.7 Hz,
4.3.3. (10S)-4(5)-(Benzyloxycarbonyl)-2-[10-(benzyloxycarbonyl-
amino)-20-methylpropyl]-5(4)-(phthalimidomethyl)-
1H-imidazole (15b)
3H, Val CH3) ppm. 13C NMR (125 MHz, MeOH-d4):
d
¼169.3 (q,
2ꢂPhtN CO), 161.5 (q, CO2H), 144.9 (q, imidazole C-2), 143.8 (q,
imidazole C-5), 139.3 (q, imidazole C-4), 135.6 (t, PhtN CH-3,4),
To a slurry of amidoketone 14 (11.712 g, 20.0 mmol) in xylenes
(300 mL), TFA (4.5 mL, 60.0 mmol) and 7 M NH3 in MeOH (6.0 mL,
42.0 mmol) were added. The mixture was heated under intensive
reflux with a Dean–Stark trap for 12 h. For work-up the mixture was
concentrated in a rotary evaporator and the remaining solid was
subjected to column chromatography on silica gel (DCM/EtOAc/
MeOH 75:25:0/75:25:3) to obtain 3.90 g (34%) of 15b as a yel-
lowish powder.
133.5 (q, PhtN C-1,6), 124.4 (t, PhtN CH-2,5), 54.7 (t, Val
34.6 (s, PhtNCH2), 33.1 (t, Val -CH), 19.1 (p, Val CH3), 18.7 (p, Val
CH3) ppm. IR (KBr):
¼3420, 2969, 1770, 1617, 1538, 1469, 1423,
1395, 1307, 1213, 1191, 1110, 1034, 944, 797, 716 cmꢀ1. UV–vis
a-CH),
b
n
(MeOH): lmax (log
3
)¼220 (4.48), 231 (sh., 4.31), 238 (sh., 4.22),
292 (3.13) nm. ESI-HRMS: m/z calcd for [C17H19N4O4]þ 343.1401,
found 343.1492.
TLC: Rf¼0.50 (DCM/EtOAc 75:25; silica). Mp: 88 ꢁC. 1H NMR
4.3.6. Scaffolds 18a,b
3
(500 MHz, MeOH-d4):
d
¼7.82 (dd, JH,H¼5.5, 3.0 Hz, 2H, PhtN CH-
Starting from amino acid 17a (1.964 g, 5.0 mmol) preparation
and work-up was performed as in the case of macrocycles 12a,b.
Isolation of the macrocycles was accomplished by column chro-
matography on silica gel (EtOAc/MeOH 100:0/100:2) to obtain
0.868 g (51%) of cyclic trimer 18a and 0.128 g (7.6%) of cyclic tet-
ramer 18b as light yellowish powders.
3
2,5), 7.76 (dd, JH,H¼5.5, 3.0 Hz, 2H, PhtN CH-3,4), 7.43 (d,
3JH,H¼7.1 Hz, 1H, Ar CH), 7.34–7.26 (m, 8H, Ar CH), 5.32 (s, 2H, Bn
CH2), 5.08 (s, 2H, PhtNCH2), 5.04 (d, 2JH,H¼12.5 Hz, 1H, Z CH2), 4.99
2
3
(d, JH,H¼12.5 Hz, 1H, Z CH2), 4.47 (d, JH,H¼8.0 Hz, 1H, Val
a-CH),
3
2.03–1.96 (m, 1H, Val
b
-CH), 0.89 (d, JH,H¼6.7 Hz, 3H, Val CH3),
0.74 (d, JH,H¼6.7 Hz, 3H, Val CH3) ppm. 13C NMR (125 MHz,
3
MeOH-d4):
d
¼169.4 (q, 2ꢂPhtN CO), 161.2 (q, CO2Bn), 158.3 (q, Z
4.3.6.1. Data for cyclic trimer 18a. TLC: Rf¼0.40 (EtOAc/MeOH
CO), 152.5 (q, imidazole C-2), 144.7 (q, imidazole C-5), 138.1 (q, Z C-
1), 137.5 (q, Bn C-1), 135.6 (q, imidazole C-4), 135.4 (t, PhtN CH-
3,4), 133.5 (q, PhtN C-1,6), 129.62 (t, Bn CH-2,6), 129.49 (t, Bn CH-
4), 129.46 (t, Z CH-2,6), 129.34 (t, Z CH-4), 129.02 (t, Bn CH-3,5),
128.81 (t, Z CH-3,5), 124.2 (t, PhtN CH-2,5), 67.8 (s, Z CH2), 67.5 (s,
100:2; silica). Mp: >200 ꢁC. 1H NMR (500 MHz, CDCl3):
d
¼8.43 (d,
3
3JH,H¼9.1 Hz, 1H, amide NH), 7.78 (dd, JH,H¼5.4, 3.2 Hz, 2H, PhtN
3
CH-2,5), 7.66 (dd, JH,H¼5.4, 3.2 Hz, 2H, PhtN CH-3,4), 5.37 (d,
2
2JH,H¼15.4 Hz, 1H, PhtNCH2), 5.16 (d, JH,H¼15.4 Hz, 1H, PhtNCH2),
3
5.15 (dd, JH,H¼9.3, 5.8 Hz, 1H, Val
a-CH), 3.62 (s, 3H, NCH3), 2.12–
Bn CH2), 56.6 (t, Val
19.6 (p, Val CH3), 19.0 (p, Val CH3) ppm. IR (KBr):
3033, 2963, 1773, 1718, 1615, 1569, 1519, 1455, 1425, 1396, 1347,
1278, 1237, 1189, 1116, 1087, 1027, 949, 913, 851, 737, 714, 697 cmꢀ1
UV–vis (MeOH): lmax (log
a
-CH), 36.4 (s, PhtNCH2), 34.2 (t, Val
b-CH),
2.05 (m, 1H, 3JH,H¼6.6 Hz, Val
b
-CH), 0.98 (ps t, 3JH,H¼6.6 Hz, 6H, Val
n
¼3317, 3064,
CH3) ppm. 13C NMR (125 MHz, CDCl3):
d¼167.6 (q, 2ꢂPhtN CO),
162.0 (q, CONH), 147.9 (q, imidazole C-2), 133.9 (t, PhtN CH-3,4),
132.2 (q, imidazole C-5), 131.8 (q, PhtN C-1,6), 128.3 (q, imidazole C-
.
3
)¼216 (4.64), 231 (sh., 4.33), 239 (4.29),
4), 123.3 (t, PhtN CH-2,5), 49.4 (t, Val
(s, PhtNCH2), 31.1 (p, NCH3), 19.2 (p, Val CH3), 17.9 (p, Val CH3) ppm.
IR (KBr):
¼3622, 3476, 3383, 2964, 2934, 2874, 1775, 1718, 1662,
1593,1521,1506,1467,1388, 1349,1233,1204, 1172,1118,1086,1071,
1024, 930, 849, 790, 760, 714 cmꢀ1
UV–vis (MeOH): lmax
(log
(4.03) nm. CD (DCM): lmax
a-CH), 34.8 (t, Val b-CH), 31.4
248 (sh., 4.17), 291 (3.34) nm. ESI-HRMS: m/z calcd for
[C32H31N4O6]þ 567.2238, found 567.2255.
n
4.3.4. (10S)-2-(10-Amino-20-methylpropyl)-1-methyl-5-
(phthalimidomethyl)-1H-imidazole-4-carboxylic acid
hydrochloride (17a)
Imidazole ester 15a (5.806 g, 10.0 mmol) was dissolved in
methanol (175 mL), acidified with 2 M aqueous HCl (25 mL) and
palladium–charcoal catalyst (5 wt % Pd, 0.100 g) was added. Hy-
drogenation was performed at room temperature and atmo-
spheric pressure with monitoring by TLC. On completion (8 h) the
catalyst was filtered off, then the filtrate was evaporated and
dried in vacuo to obtain 3.901 g (99%) of the free acid 17a as
a white solid.
.
3
)¼218 (5.27), 231 (sh., 5.08), 240 (sh., 4.98), 248 (sh., 4.80), 295
(
D3 [dm3 molꢀ1 cmꢀ1])¼232 (þ11.3),
245 (0.0), 250 (ꢀ66.1), 300 (ꢀ1.2) nm. ESI-HRMS: m/z calcd for
[C54H55N12O9]þ 1015.4209, found 1015.4251.
4.3.6.2. Data for cyclic tetramer 18b. TLC: Rf¼0.48 (EtOAc/MeOH
100:2; silica). Mp: >200 ꢁC. 1H NMR (500 MHz, CDCl3):
d
¼7.74
3
3
(dd, JH,H¼5.4, 3.1 Hz, 2H, PhtN CH-2,5), 7.67 (dd, JH,H¼5.4,
3
3.1 Hz, 2H, PhtN CH-3,4), 7.55 (d, JH,H¼9.8 Hz, 1H, amide NH),
3
3
5.33 (d, JH,H¼15.4 Hz, 1H, PhtNCH2), 5.18 (d, JH,H¼15.4 Hz, 1H,
Mp: 127 ꢁC. 1H NMR (500 MHz, MeOH-d4):
d
¼7.86–7.84 (m, 2H,
PhtNCH2), 5.02 (dd, JH,H¼9.1, 9.2 Hz, 1H, Val
a-CH), 3.69 (s, 3H,
3
PhtN CH-2,5), 7.82–7.81 (m, 2H, PhtN CH-3,4), 5.37 (d,
NCH3), 2.45–2.37 (m, 1H, Val
b
-CH), 1.09 (d, 3JH,H¼6.6 Hz, 3H, Val
2
3
2JH,H¼15.8 Hz, 1H, PhtNCH2), 5.22 (d, JH,H¼15.8 Hz, 1H, PhtNCH2),
CH3), 0.87 (d, JH,H¼6.6 Hz, 3H, Val CH3) ppm. 13C NMR
3
4.79 (d, JH,H¼9.5 Hz, 1H, Val
a
-CH), 4.02 (s, 3H, NCH3), 2.62–2.54
(125 MHz, CDCl3):
d
¼167.6 (q, 2ꢂPhtN CO), 162.8 (q, CONH),
3
(m, 1H, Val
b
-CH), 1.24 (d, JH,H¼6.7 Hz, 3H, Val CH3), 0.95 (d,
148.1 (q, imidazole C-2), 134.0 (t, PhtN CH-3,4), 132.4 (q, imid-
azole C-4), 131.8 (q, PhtN C-1,6), 128.4 (q, imidazole C-5), 123.3
3JH,H¼6.7 Hz, 3H, Val CH3) ppm. 13C NMR (125 MHz, MeOH-d4):
d
¼168.9 (q, 2ꢂPhtN CO), 161.5 (q, CO2H), 145.0 (q, imidazole C-2),
(t, PhtN CH-2,5), 49.4 (t, Val
PhtNCH2), 30.9 (p, NCH3), 19.7 (p, Val CH3), 18.7 (p, Val CH3) ppm.
IR (KBr):
¼3638, 3476, 3399, 2963, 2875, 1775, 1718, 1660, 1590,
1505, 1468, 1388, 1349, 1263, 1230, 1201, 1173, 1119, 1070, 1025,
936, 849, 791, 761, 715 cmꢀ1. UV–vis (DCM): lmax (log
)¼240
(sh., 4.90), 248 (sh., 4.66), 295 (3.84) nm. CD (DCM): lmax D3
a-CH), 32.6 (t, Val b-CH), 31.5 (s,
135.8 (q, imidazole C-5),135.7 (t, PhtN CH-3,4),133.1 (q, PhtN C-1,6),
127.9 (q, imidazole C-4), 124.5 (t, PhtN CH-2,5), 52.9 (t, Val -CH),
a
n
34.1 (p, NCH3), 33.5 (t, Val b-CH), 32.3 (s, PhtNCH2), 19.1 (p, Val CH3),
18.8 (p, Val CH3) ppm. ESI-HRMS: m/z calcd for [C18H21N4O4]þ
3
357.1557, found 357.1573.
(

´
A. Pinte´r, G. Haberhauer / Tetrahedron 65 (2009) 2217–2225
2224
[dm3 molꢀ1 cmꢀ1])¼234 (þ59.1), 243 (0.0), 257 (ꢀ76.4), 277
hydrazine monohydrate (0.250 g, 5.0 mmol) was added at room
temperature and the mixture was stirred for further 24 h. The
resulting suspension was concentrated and dried in vacuo, then
treated with 2 M HCl (100 mL) and unsoluble phthalylhydrazide
was filtered off. The filtrate was extracted with DCM (3ꢂ30 mL),
then evaporated and dried in vacuo to yield 0.055 g (74%) of 4b.
þ
(0.0), 287 (þ1.1) nm. ESI-HRMS: m/z calcd for [C72H73N16O12
]
1353.5588, found 1353.5645.
4.3.7. Scaffold 19
To a solution of 18a (0.203 g, 0.20 mmol) in a 2:2:1 mixture
of DCM, THF, and EtOH (50 mL) hydrazine monohydrate (0.501 g,
10.0 mmol) was added at room temperature and the mixture
was stirred for further 24 h. The resulting suspension was cooled to
0 to 5 ꢁC and a solution of di-tert-butyldicarbonate (5.456 g,
25.0 mmol) in DCM (25 mL) was slowly added. After completion
of addition the resulting solution was stirred without cooling for
further 6 h. Then the solvents were evaporated in vacuo and column
chromatography of the residue on silica gel (DCM/EtOAc/MeOH
75:25:0/75:25:3) yielded 0.180 g (97%) of 19 as a colorless solid.
TLC:Rf¼0.60(DCM/EtOAc/MeOH75:25:5;silica).Mp: >200 ꢁC.1H
4.3.9.2. Preparation from 19. Scaffold 19 (0.093 g, 0.10 mmol) was
treated with HCl/EtOAc solution (15%, 20 mL) at room tempera-
ture for 3 h. Volatiles were then removed in a rotary evaporator
and the resulting white solid was exhaustively dried in vacuo to
afford 0.073 g (99.4%) of 4b.
4.3.9.3. Preparation from 20. Platform 20 (0.103 g, 0.10 mmol) was
dissolved in MeOH (40 mL), then treated with 2 M HCl (10 mL) and
palladium on charcoal catalyst (5 wt % Pd; 0.050 g) was added. The
mixture was hydrogenated at atmospheric pressure for 4 h, then
filtered and evaporated to give 0.070 g (95%) of 4b.
NMR(500 MHz,CDCl3):
d
¼8.35 (d, 3JH,H¼9.4 Hz,1H,CONH), 5.75(brt,
3
3JH,H¼5.4 Hz, 1H, BocNHCH2), 5.10 (dd, JH,H¼9.5, 6.0 Hz, 1H, Val
a-
CH), 4.59 (dd, 2JH,H¼15.5, 5.7 Hz,1H, BocNHCH2), 4.46 (dd, 2JH,H¼15.5,
7.3 Hz,1H, BocNHCH2), 3.70 (s, 3H, NCH3), 2.14–2.07 (m, 3JH,H¼6.6 Hz,
Mp: 155 ꢁC. 1H NMR (500 MHz, MeOH-d4):
d
¼5.34 (d,
3JH,H¼5.4 Hz, 1H, Val
a
-CH), 4.46 (d, JH,H¼14.8 Hz, 1H, CH2NH3þ),
2
1H, Val
b
-CH), 1.35 (s, 9H, Boc C(CH3)3), 1.04 (d, 3JH,H¼6.6 Hz, 3H, Val
4.42 (d, 2JH,H¼14.8 Hz, 1H, CH2NH3þ), 3.81 (s, 3H, NCH3), 2.27–2.21
3
3
3
CH3), 1.03 (d, JH,H¼6.6 Hz, 3H, Val CH3) ppm. 13C NMR (125 MHz,
(m, JH,H¼6.6 Hz, 1H, Val
b
-CH), 1.11 (d, JH,H¼6.6 Hz, 3H, Val CH3),
CDCl3):
d¼162.9 (q, CONH),156.1 (q, Boc CO),147.4 (q, imidazole C-2),
1.04 (d, 3JH,H¼6.6 Hz, 3H, Val CH3) ppm. 13C NMR (125 MHz, MeOH-
134.0 (q, imidazoleC-5),131.1 (q,imidazole C-4), 79.4(q, Boc C(CH3)3),
49.7(t, Val -CH), 34.7(t, Val -CH), 33.3(s, BocNHCH2), 30.9(p, NCH3),
28.3 (p, Boc C(CH3)3),19.5 (p, Val CH3),17.9 (p, Val CH3) ppm. IR (KBr):
¼3385, 2968, 2934, 2875, 1713, 1656, 1592, 1499, 1467, 1417, 1391,
d4):
d
¼164.3 (q, CONH), 150.0 (q, imidazole C-2), 133.4 (q, imidazole
a
b
C-5), 130.3 (q, imidazole C-4), 51.5 (t, Val
33.8 (t, Val -CH), 31.9 (p, NCH3), 19.8 (p, Val CH3), 17.8 (p, Val
CH3) ppm. IR (KBr):
¼3430, 3378, 2965, 2621, 1644, 1596, 1529,
1470, 1418,1390, 1370, 1310,1287, 1242,1205,1150, 1121, 1070,1020,
a
-CH), 35.8 (s, CH2NH3þ),
b
n
n
1367, 1328, 1275,1250, 1170,1046,1007, 965, 941, 864, 800, 780, 728,
640 cmꢀ1. CD (MeOH): lmax
(
D3 [dm3 molꢀ1 cmꢀ1])¼214 (þ11.4), 233
982, 939, 878, 811, 778, 747, 658 cmꢀ1. CD (MeOH): lmax
(D3
(þ31.8), 244 (0.0), 258 (ꢀ66.6) nm. ESI-HRMS: m/z calcd for
[dm3 molꢀ1 cmꢀ1])¼216 (þ10.8), 228 (þ12.3), 240 (0.0), 258
(ꢀ51.3) nm. ESI-HRMS: m/z calcd for [C30H49N12O3]þ 625.4045,
found 625.4110.
[C45H73N12O9]þ 925.5618, found 925.5686.
4.3.8. Scaffold 20
To a solution of 18a (0.102 g, 0.10 mmol) in a 2:2:1 mixture of
DCM, THF, and EtOH (25 mL) hydrazine monohydrate (0.250 g,
5.0 mmol) was added at room temperature and the mixture was
stirred for further 24 h. The resulting suspension was concentrated
and dried in vacuo, then covered with DCM (30 mL) followed by the
addition of benzyl chloroformate (0.341 g, 2.0 mmol) and Et3N
(0.304 g, 3.0 mmol). After stirring at room temperature for 6 h the
mixture was quenched with MeOH (10 mL), concentrated, and the
residue was subjected to column chromatography on silica gel
(DCM/EtOAc/MeOH 75:25:0/75:25:5) to yield 0.079 g (77%) of 20
as a colorless glassy solid.
4.3.10. Scaffold 5
Starting from amino acid 17b (1.894 g, 5.0 mmol) preparation
and work-up was performed as in the case of macrocycles 12a,b.
Isolation was accomplished by column chromatography on silica
gel (DCM/EtOAc/MeOH 75:25:0/75:25:5) to obtain 0.655 g (40%)
of cyclic trimer 5 as a light yellowish solid.
TLC: Rf¼0.55 (DCM/EtOAc/MeOH 75:25:5; silica). Mp: 95 ꢁC. 1H
NMR (500 MHz, CDCl3):
d
¼10.15 (br s,1H, imidazole NH), 8.43 (d,1H,
3JH,H¼8.7 Hz, amide NH), 7.69 (br s, 2H, PhtN CH-2,5), 7.59 (br s, 2H,
2
PhtN CH-3,4), 5.52 (d, JH,H¼14.9 Hz, 1H, PhtNCH2), 5.08 (d,
2JH,H¼14.9 Hz, 1H, PhtNCH2), 5.01 (t, JH,H¼6.6 Hz, 1H, Val
a-CH),
3
TLC: Rf¼0.65 (DCM/EtOAc/MeOH 75:25:5; silica). Mp: >200 ꢁC.
2.16–2.10 (m, 1H, Val
b
-CH), 1.00 (d, 3JH,H¼6.6 Hz, 3H, Val CH3), 0.94
3
3
1H NMR (500 MHz, CDCl3):
d
¼8.36 (d, JH,H¼9.3 Hz, 1H, CONH),
(d, JH,H¼6.6 Hz, 3H, Val CH3) ppm. 13C NMR (125 MHz, CDCl3):
3
7.29–7.23 (m, 5H, Ph CH-2,3,4,5,6), 6.23 (t, JH,H¼6.1 Hz, 1H,
d
¼168.3 (q, 2ꢂPhtN CO), 162.3 (q, CONH), 146.7 (q, imidazole C-2),
3
ZNHCH2), 5.10 (dd, JH,H¼9.2, 6.1 Hz, 1H, Val
a
-CH), 5.04 (d,
134.1 (t, PhtN CH-3,4), 131.6 (q, PhtN C-1,6), 131.0 (q, imidazole C-4),
128.1 (q, imidazole C-5), 123.5 (t, PhtN CH-2,5), 52.0 (t, Val -CH),
34.3 (t, Val
-CH), 31.8 (s, PhtNCH2), 18.6 (p, 2ꢂVal CH3) ppm. IR
(KBr):
¼3555, 3376, 3221, 2964, 2932, 2874, 1774, 1716, 1655, 1603,
1543, 1510, 1408, 1432, 1391, 1350, 1281, 1226, 1188, 1108, 1087, 1037,
2JH,H¼12.3 Hz, 1H, Z CH2), 4.95 (d, JH,H¼12.3 Hz, 1H, Z CH2), 4.54
a
2
(dd, 2JH,H¼15.4 Hz, 3JH,H¼5.5 Hz, 1H, ZNHCH2), 4.47 (dd,
b
2JH,H¼15.4 Hz, JH,H¼7.1 Hz, 1H, ZNHCH2), 3.69 (s, 3H, NCH3), 2.13–
n
3
3
2.07 (m, 1H, Val
b
-CH), 1.04 (d, JH,H¼6.6 Hz, 3H, Val CH3), 1.03 (d,
3JH,H¼6.6 Hz, 3H, Val CH3) ppm. 13C NMR (125 MHz, CDCl3):
1029, 942, 850, 782, 743, 714, 648 cmꢀ1. CD (DCM): lmax
(D3
d
¼162.7 (q, CONH), 156.6 (q, Z CO), 147.4 (q, imidazole C-2), 136.3
[dm3 molꢀ1 cmꢀ1])¼239 (0.0), 246 (ꢀ46.5), 269 (0.0), 303 (þ1.6) nm.
(q, Ph C-1), 133.4 (q, imidazole C-5), 131.1 (q, imidazole C-4),
128.29 (t, Ph CH-3,5), 127.86 (t, Ph CH-4), 127.74 (t, Ph CH-4,6),
ESI-HRMS: m/z calcd for [C51H49N12O9]þ 973.3740, found 973.3853.
66.6 (s, Z CH2), 49.7 (t, Val
a-CH), 34.7 (t, Val b-CH), 33.8 (s,
Acknowledgements
ZNHCH2), 30.8 (p, NCH3), 19.4 (p, Val CH3), 17.8 (p, Val CH3) ppm.
CD (DCM): lmax
(
D3 [dm3 molꢀ1 cmꢀ1])¼234 (þ16.6), 242 (0.0),
This work was generously supported by the Deutsche For-
schungsgemeinschaft. The authors thank Dr. Andreea Schuster for
helpful discussions.
256 (ꢀ57.3) nm. ESI-HRMS: m/z calcd for [C54H67N12O9]þ
1027.4940, found 1027.4972.
4.3.9. Scaffold 4b
References and notes
4.3.9.1. Preparation from 18a. To
0.10 mmol) in a 2:2:1 mixture of DCM, THF, and EtOH (25 mL)
a solution of 18a (0.102 g,
1. (a) Moberg, C. Angew. Chem., Int. Ed. 1998, 37, 248–268; (b) Gibson, S. E.; Cas-
taldi, M. P. Chem. Commun. 2006, 3045–3062.

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A. Pinte´r, G. Haberhauer / Tetrahedron 65 (2009) 2217–2225
2225
2. (a) Moberg, C. Angew. Chem., Int. Ed. 2006, 45, 4721–4723; (b) Gibson, S. E.;
Castaldi, M. P. Angew. Chem., Int. Ed. 2006, 45, 4718–4720.
(c) Haberhauer, G.; Somogyi, L.; Rebek, J. Tetrahedron Lett. 2000, 41,
5013–5016.
3. Burk, M., Jr.; Harlow, R. L. Angew. Chem., Int. Ed. Engl. 1990, 29, 1462–1464.
4. Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc.
1999, 121, 4168–4178.
22. (a) Pattenden, G.; Thompson, T. Chem. Commun. 2001, 717–718; (b) Singh, Y.;
Sokolenko, N.; Kelso, M. J.; Gahan, L. R.; Abbenante, G.; Fairlie, D. P. J. Am. Chem.
Soc. 2001, 123, 333–334.
5. Mase, N.; Ohno, T.; Hoshikawa, N.; Ohishi, K.; Morimoto, H.; Yoda, H.; Takabe, K.
Tetrahedron Lett. 2003, 44, 4073–4075.
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