Oxazole cyclopeptides for chirality transfer in C3-symmetric octahedral metal complexes

Article abstract of DOI:10.1002/ejoc.200701153

A straightforward synthesis of C₃-symmetric oxazole-containing macrocyclic peptide scaffolds is presented. This type of macrocycles bears three functional groups on the oxazole rings, which allows fixing of various receptor arms on them in an easy manner. The chiral backbone of the macrocycle proved to be a powerful tool for chirality induction, thus predetermining the configuration of helically coordinated metal centres. The diastereoselective formation of Co^II, Ni^II, Cu^II and Zn ^II complexes with tripodal bipyridyl ligand 4 was proved by UV- and CD-absorption spectrophotometric titration experiments. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701153

FULL PAPER
DOI: 10.1002/ejoc.200701153
Oxazole Cyclopeptides for Chirality Transfer in C3-Symmetric Octahedral
Metal Complexes
Áron Pintér[a] and Gebhard Haberhauer*[a]
Keywords: Amino acids / Chirality / Cyclization / Macrocycles / Oxazoles
A straightforward synthesis of C3-symmetric oxazole-con-
taining macrocyclic peptide scaffolds is presented. This type
of macrocycles bears three functional groups on the oxazole
rings, which allows fixing of various receptor arms on them
in an easy manner. The chiral backbone of the macrocycle
proved to be a powerful tool for chirality induction, thus pre-
determining the configuration of helically coordinated metal
centres. The diastereoselective formation of CoII, NiII, CuII
and ZnII complexes with tripodal bipyridyl ligand 4 was
proved by UV- and CD-absorption spectrophotometric ti-
tration experiments.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Herein we report an extended study of the synthesis of
oxazole-containing C3-scaffolds 1–3 with three easily modi-
Introduction
C3-symmetric systems have been studied extensively dur- fiable functional groups as potential coupling sites for the
ing the last decade[1] as they can be used as catalysts[2] in synthesis of new ligands, supramolecular hosts or container
organic syntheses, ligands[3] for metal complexes, supramo- molecules. In particular, we show that the backbone of
lecular hosts[4] or nanoscale devices.[5] Inspired by nature, these macrocycles is a powerful tool for chirality transfer in
we turned our attention to the design and synthesis of novel C3-symmetric octahedral metal complexes: The CoII, NiII,
macrocyclic ligands and cages based on the structural motif CuII and ZnII complexes of tripodal bipyridyl ligand 4 are
of Lissoclinum cyclopeptide alkaloids like Westiellamide formed diastereoselectively.
and Bistratamide C.[6] Functionalized C3-symmetric syn-
thetic analogues of these natural products having three car-
boxy or aminoalkyl linkers as side chains of the α-C-atoms
Results and Discussion
Synthesis of the Scaffolds
of the amino acid residues are already known and were ap-
plied for the assembly of different cage structures.[7] The
In the synthesis of platforms 2 and 3 the oxazole building
volume of the cavity of such systems can be considerably
expanded by introducing additional functionalities in the
positions 1 or 5 of the azole rings. In these systems, intra-
molecular steric interactions and hydrogen bonding con-
tribute to a better preorganisation of planar side chains if
attached directly to the conformationally fixed azole rings.
In our earlier work we presented cyclic hexapeptides con-
taining three imidazole units, each carrying on its second-
ary nitrogen atom various benzyl-type bidental ligand
arms.[8] We showed that this system is able to transfer chiral
information from its scaffold to a distant metal or non-
metal centre.[9] Furthermore, we were able to synthesize the
first configurationally stable, propeller-like triarylphos-
phane by linking a triphenylphosphane moiety via three
peptide bonds to the chiral oxazole scaffold 1.[10]
block 8 bearing orthogonally protected carboxylic acid,
amino and hydroxy functions plays a key role (Scheme 1).
This compound is available in three steps starting from N-
(diphenylmethylene)glycine methyl ester (5) using a modi-
fied procedure of Singh et al.[11] Deprotonation of 5 with
potassium-tert-butoxide, followed by the C-acylation with
benzyloxyacetyl chloride and one-pot hydrolysis afforded
keto amine hydrochloride 6 in satisfactory yield and purity.
This substrate was coupled with Boc--valine using isobutyl
chloroformate as activating agent. As compound 6 could
only be obtained as an amorphous, tacky solid rather in-
convenient to handle, the solution of the mixed anhydride
of Boc--valine and isobutyl chloroformate in dichloro-
methane was introduced by Schlenk-technique into the ves-
sel containing the amine salt 6. By lowering of the reaction
temperature from –25 °C to –40 °C, the yield of keto amide
7 could be enhanced from 30% up to 55% after chromato-
graphic purification.
[a] Institut für Organische Chemie, Fachbereich Chemie, Uni-
versität Duisburg-Essen,
Cyclodehydration of 7 under Mitsunobu conditions[11b]
with triphenylphosphane, hexachloroethane and triethyl-
amine gave oxazole 8 in 71% yield.
Universitätsstraße 5, 45117 Essen, Germany
E-mail: gebhard.haberhauer@uni-due.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Scheme 1. Synthesis of scaffolds 2 and 3: i) BnOCH2COCl, KOtBu, THF, then 2  HCl/H2O, –60 °C, 76%. ii) Boc--Val-OH, iBuOCOCl,
NMM, DCM, –40 °CǞr.t., 55%. iii) PPh3, Et3N, C2Cl6, DCM, room temp., 71%. iv) 2  NaOH, MeOH/1,4-dioxane, 97%; v) HCl,
EtOAc, 99%; vi) PyBOP, iPr2NEt, DMF, room temp., 39% for 10 and 13% for 11. vii) Pd/C, H2, DCM, 99%. viii) SOCl2, CHCl3, ∆,
99%.
Removal of the methyl ester protective group by gentle
Macrolactamization of 9 with different peptide coupling
treatment with sodium hydroxide in methanol/dioxane/ agents (FDPP, DPPA, PyBOP) under high-dilution condi-
water followed by the fast cleavage of the Boc group with tions (cmonomer = 0.040 ) in polar, aprotic solvents (aceto-
hydrochloric gas in ethyl acetate afforded amino acid 9 in nitrile or DMF) in the presence of Hünig’s base gave a mix-
almost quantitative amount.
ture of cyclic trimer 10 and cyclic tetramer 11, which were
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Oxazole Cyclopeptides for Chirality Transfer
separated by column chromatography on silica gel. In order
The key compound for the tripodal amine platform 1 is
to enhance the yield of the cyclohexapeptide 10 at the ex- the oxazole module 15 (Scheme 2). For the protection of
pense of the cyclooctapeptide 11, we tried to optimize the its N-terminus we chose Boc as well as Z groups. For the
reaction parameters for the macrocyclization. Use of FDPP protection of the side arm, both the Fmoc and the phthali-
in acetonitrile gave the highest overall yields (34.9% for 10 mido group were first taken into consideration. As both
and 25.1% for 11, respectively), but the smallest trimer to protective groups are base labile, we planned the protection
tetramer product ratio (1.4:1). In the case of DPPA, tetra- of the C-terminal function as its benzyl ester which can be
mer 11 could not be isolated, but the yield for trimer 10 selectively cleaved by hydrogenolysis. Unfortunately, the use
remained low (24.1%) even after prolonged reaction time of the Fmoc group resulted in low yields of the desired ox-
(up to 10 d). The use of PyBOP in DMF proved to be the azole building blocks, accompanied by large amounts of
best choice for our requirements providing the best yield of undesired side products. In contrast, the preparation and
the cyclic trimer (39.1%) accompanied by less cyclic tetra- peptide coupling of phthalimido-protected keto amine hy-
mer (12.5%; product ratio trimer to tetramer: 3.1:1).
drochloride 13 with both Boc--Val-OH and Z--Val-OH
In the next step, the benzyloxy protective groups in 10 proceeded smoothly to afford keto amides 14a (65%) and
were cleaved by catalytic hydrogenation. As both carbon– 14b (88%), respectively (Scheme 2).
oxygen single bonds of the benzyloxymethyl side arms are
The conversion of the dipeptides 14a,b to the corre-
weakened by the connected aromatic systems, unwanted sponding oxazoles 15a,b required uncommonly long reac-
cleavage of the (oxazole)CH2–OBn bond is a serious risk. tion times (1–2 weeks at r.t.) to obtain acceptable yields
Indeed, if debenzylation was conducted in methanol, etha- (52% for 15a and 76% for 15b, respectively) of the products,
nol or tetrahydrofuran as solvents using 10% Pd/C catalyst which may be the result of the high steric demand of the
under atmospheric pressure of hydrogen, a mixture of prod- phthalimidomethyl side chain. On the other hand, TLC and
ucts was obtained, containing fully debenzylated platform ESI-MS analysis of the reaction mixture indicated the pres-
2 along with the one-, two- and threefold dehydroxylated ence of a Ph3PO adduct of 15a, in contrast to similar ox-
macrocycles. While catalytic hydrogenation in ethyl acetate azole forming reactions, where a persistent 5-chlorooxazol-
gave no cleavage of the protecting groups, the use of dichlo- ine was observed.[12] Column chromatography of the reac-
romethane afforded a fast removal of all benzyl ether tion mixture after 3 d on silica gel gave 15a in low yield,
groups without damaging the desired product 2 even after followed by a second uniform substrate as judged by TLC
prolonged (8 h) reaction time. The trihydric alcohol 2 can and ESI-MS in larger amount, before eluting pure tri-
be easily converted into the corresponding tripodal chloride phenylphosphane oxide from the column. After evaporating
3 by treatment with thionyl chloride in chloroform at room and drying, 1H NMR spectra of the second fraction showed
temperature.
the peaks of 15a with minor intensity and those of a major
Scheme 2. Synthesis of scaffolds 17 and 18: i) PhtNCH2COCl, KOtBu, THF, then 2  HCl/H2O, –60 °C, 84%. ii) Boc--Val-OH or Z--
Val-OH, iBuOCOCl, NMM, THF or DCM, –25 °CǞr.t., 65% for 14a and 88% for 14b. iii) PPh3, Et3N, C2Cl6, DCM, room temp.,
52% for 15a and 76% for 15b. (iv) 15a: Pd(OH)2/C, H2, MeOH, 98% and HCl, EtOAc, 98%; 15b: Pd(OH)2/C, H2, aq. HCl, MeOH,
99%; (v) PyBOP, iPr2NEt, DMF, room temp., 32% for 17 and 11% for 18.
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Á. Pintér, G. Haberhauer
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substrate. This indicates that the major compound decom- phthalylhydrazide can hardly be separated from the desired
poses to the oxazole 15a. The attempt to perform the cyclis- amine 1, and consequently the yield of 1 decreases after
ation of the keto amide 14b in a more time-saving manner several necessary separation steps to 81%. To avoid this
by using POCl3 in pyridine failed.
costly procedure, we investigated two two-steps procedures.
Finally, we removed the benzyl ester group in 15a by First, the phthalimido groups can be replaced by Z-groups
catalytic hydrogenolysis followed by elimination of the Boc and the so formed scaffold 19 can easily be separated from
protecting group with hydrochloric gas in ethyl acetate to the phthalylhydrazide. The Z-groups are smoothly removed
afford the free dipeptide 16 in excellent yield. The free by hydrogenolysis. The product obtained by this method
amino acid 16 can also be formed in only one step by cata- was very pure, but the overall yield turned out to be even
lytic hydrogenolysis of 15b. Macrocyclization of 16 was car- worse (50%) than in the first procedure. However, the sec-
ried out with PyBOP in dry DMF at room temperature to ond two-step variant, where we replaced the PhtN residues
furnish the cyclic trimer 17 and the cyclic tetramer 18.
by three Boc groups, proved to be superior. The threefold
The deprotection of the trimer 17 to the free amine 1 can Boc-protected trimer 20 could be isolated in yields of 92%.
be performed by three different ways. The shortest one is The removal of the Boc groups is performed by means of
the deprotection of the phthalimido units using hydrazine HCl in ethyl acetate which provides the HCl salt of the de-
in ethanol (Scheme 3). However, the hereby formed sired amine 1 in almost quantitative yield.
Investigation of the Chirality Transfer
The predetermination of the configuration caused by the
oxazole scaffold can best be proven by the diastereoselective
synthesis of helix-like metal complexes. As model com-
pound we chose the tripodal bipyridyl ligand 4, as three
bipyrdine units tends to form helical octahedral metal com-
plexes with a variety of doubly positive metal ions. The li-
gand 4 was synthesized by treating the triol 2 with an excess
of 5-bromomethyl-5Ј-methyl-2,2Ј-bipyridine along with so-
dium hydride in tetrahydrofuran (Scheme 4).
Ligand 4 was treated with various divalent metal salts
and the respective UV and CD spectra were recorded. For
all metal ions the formation of the corresponding bipyridyl
metal complexes was observed in the UV spectra. In the
CD spectra, all metal complexes show a positive Cotton
effect at about 318 nm and a negative Cotton effect at about
295 nm (Figure 1 and Table 1). The sign and the magnitude
of these values are characteristic for octahedral trisbipyridyl
metal complexes exhibiting an M helicity.[13] This clearly
indicates that predetermination of the helicity at the metal
centre was successful.
Scheme 3. Synthesis of scaffold 1: i) NH2NH2·H2O, THF/DCM/
EtOH, r.t. then acidic work-up, 81%. ii) 1. NH2NH2·H2O, THF/
DCM/EtOH, room temp., 2. Z-Cl, Et3N, DCM, room temp., 57%.
iii) NH2NH2·H2O, THF/DCM/EtOH then Boc2O, room temp.,
92%. iv) Pd/C, H2, aq. HCl, MeOH, room temp., 88%. v) HCl,
EtOAc, room temp., 100%.
Scheme 4. Synthesis of ligand 4: i) NaH, THF, r.t.Ǟ∆, 33%.
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Oxazole Cyclopeptides for Chirality Transfer
Figure 1. CD spectra of the ligand 4 (green) with CuCl2 (red) and ZnCl2 (blue) in MeOH/H2O (1:1; buffer: 0.10  TRIS, 0.02  HCl in
H2O) ([4] = 1.6ϫ10–5  and 4/2+ = 1:1).
For the CuII and the ZnII complexes we further per-
formed CD titration experiments. In the case of the zinc
ion, a singular 1:1 complex is formed, which can be proved
by the shape of the titration curve and the location of the
maximum in the Job-plot (Figure 2). The association
constant of the zinc complex 4·Zn2+ amounts to
2.1Ϯ0.1ϫ106 –1. For copper, the situation is slightly dif-
ferent. Here besides the 1:1 complex at least one complex
with a lower coordination number is formed. The shape of
Table 1. CD spectra of the complexes of ligand 4 with metal ions
in MeOH/H2O (1:1; buffer: 0.10  TRIS, 0.02  HCl in H2O) ([4]
= 1.6ϫ10–5  and 4/2+ = 1:1).
M2+
∆ε [–1 cm–1] (wavelength [nm])
–
+76.3 (318), –7.3 (295), +22.2 (263), –125.9 (235)
+145.6 (318), –30.9 (296), +46.7 (260), –140.5 (234)
CoIICl2
NiII(NO3)2 +304.9 (318), –79.9 (295), +104.9 (259), –167.5 (234)
CuIICl2
ZnIICl2
+144.4 (318), –26.9 (293), +54.6 (259), –140.3 (230)
+206.6 (316), –44.4 (294), +76.3 (260), –176.0 (230)
Figure 2. Plot of ∆∆ε vs. equivalents of metal ions and Job-plots {y = θobs. – θL – (θM – θL)*x vs. x = [M]/([M] + [L])} for complexation
of 4 with ZnII (a) and CuII (b), respectively. The values were recorded at 318 nm.
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Avance DMX 300 and Avance DRX 500 spectrometers. All chemi-
cal shifts (δ) are given in ppm relative to TMS. The spectra were
referenced to deuterated solvents indicated in brackets in the ana-
lytical 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, CD-absorption spectra were
taken with a Jasco J-815 spectrophotometer equipped with a Jasco
ATS-443 automatic titration accessory. Elemental microanalyses
were performed at the microanalytical laboratory of the University
the titration curve does not fit a 1:1 binding curve and the
maximum in the Job-plot is about 0.65. This behavior is
probably due to the tendency of copper to prefer complexes
with a coordination number of 4 rather than 6.
The predetermination of the helicity at the metal centre
by the chiral oxazole scaffold was further investigated by
molecular modeling studies. The relative stabilities of the
stereoisomers of the zinc complex 4·Zn2+ were calculated
by Gaussian software program.[14] The structures were de-
termined by geometry optimizations at HF-level using the of Heidelberg.
3-21G* basis set. The structures optimized by HF/3-21G*
Abbreviations: Bn: benzyl, Boc: tert-butyloxycarbonyl, FDPP:
were further used in single-point calculations with B3LYP/
6-31G* and BP86/6-31G* methods (Table 2). In principle,
the zinc complex 4·Zn2+ can adopt four different conforma-
tions (P1, P2, M1 and M2): on the one side, the three bipyr-
idine rings can be present in two opposite helicities (P or
M isomer), and on the other side, the lone pairs of the ether
units connecting the chiral scaffold with the bipyridine rings
pentafluorophenyl diphenylphosphinate, DCM: dichloromethane,
DMF: N,N-dimethylformamide, DPPA: diphenylphosphoryl azide,
NH: n-hexane, NMM: N-methylmorpholine, PE: petroleum ether,
PhtN: phthalimido, PyBOP: benzotriazole-1-yloxytripyrrolidino-
phosphonium hexafluorophosphate, THF: tetrahydrofuran; TRIS:
tris(hydroxymethyl)aminomethane, Z: benzyloxycarbonyl.
N-(Diphenylmethylene)glycine Methyl Ester 5: To a slurry of glycine
can adopt two different orientations. Viewing the molecule methyl ester hydrochloride (25.111 g, 200.0 mmol) in DCM
(200 mL) was added benzophenone imine (36.247 g, 200.0 mmol)
in DCM (200 mL), and the mixture was stirred for 24 h at ambient
temperature. Then the white milky mixture was extracted with
water (2ϫ50 mL) and brine (1ϫ50 mL). The organic layer was
separated, dried with MgSO4, then filtered and the solvents evapo-
rated. The solidified raw product was crystallised from petroleum
ether to obtain compound 5 (43.045 g, 83.0%) as a white powder.
from the zinc atom along the main C3-axis, the lone pairs
of the three ether units are pointing clockwise in the case
of conformers (M1)-4·Zn2+ and (P1)-4·Zn2+ and anticlock-
wise for isomers (M2)-4·Zn2+ and (P2)-4·Zn2+. All calcula-
tions reveal that the M-isomers of 4·Zn2+ are stabilized in
preference to the P-isomers. This is in accordance with the
results obtained by the CD measurements.
3
4
1H NMR (300 MHz, CDCl3): δ = 7.66 (dd, JH,H = 8.3, JH,H
=
1.5 Hz, 2 H; cis Ph CH-2,6), 7.49–7.42 (m, 3 H), 7.41–7.29 (m, 3
H), 7.17 (m, 2 H), 4.22 (s, 2 H, CH2), 3.74 (s, 3 H, CO2CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 171.8 (q, Ph2C=N), 171.0 (q,
CO2CH3), 139.1 (q, cis/trans Ph C-1), 128.8 (t, trans Ph CH-4),
128.7 (t, trans Ph CH-3,5), 128.6 (t, cis Ph CH-2,6), 128.2 (t, cis
Ph CH-4), 128.0 (t, trans Ph CH-2,6), 127.6 (t, cis Ph CH-3,5), 55.5
Table 2. Relative energies of the conformers of 4·Zn2+ calculated
with the 6-31G* basis set.
∆E [kJmol–1]
M1
Method[a]
M2
P1
P2
B3LYP
BP86
0.0
0.0
0.4
5.3
11.6
28.0
37.8
37.9
(s, CH ), 51.9 (p, CO CH ) ppm. IR (KBr): ν = 3045, 1756, 1626,
˜
2
2
3
1576, 1491, 1448, 1433, 1386, 1363, 1316, 1290, 1202, 1163, 1065,
993, 785, 773, 713, 694, 679 cm–1. UV/Vis (CH2Cl2, c = 0.075 mg/
mL): λmax (log ε) = 250 (0.43) nm. ESI-HRMS: m/z calcd. for
C16H16NO2 [MH+] 254.1176, found 254.1167. C16H15NO2
(253.30): calcd. C 75.87, H 5.97, N 5.53; found C 75.81, H 6.03, N
5.67.
[a] Single-point calculations employing the indicated method based
on the structure optimized with HF/3-21G*.
Conclusions
Benzyloxyacetic Acid: To a suspension of NaH (16.000 g, 60% dis-
persion in mineral oil, 400.0 mmol) in dry toluene (100 mL) agi-
tated by a mechanical stirrer a solution of benzyl alcohol (21.628 g,
200.0 mmol) in toluene (40 mL) was added at 0 °C under Ar. After
mixing for 1 h at room temperature, a solution of bromoacetic acid
(27.790 g, 200.0 mmol) in toluene (100 mL) was added. The re-
sulting slurry was stirred without heating for 60 min, then at 80 °C
for 2 h, finally allowed to chill down to room temperature and
stirred overnight. Then water (300 mL) was added, and the mixture
was washed with diethyl ether (100 mL). The aqueous layer was
acidified with concd. HCl (23 mL) to pH 2 and extracted repeatedly
with DCM (3ϫ100 mL). The combined organic extracts were
dried with MgSO4, filtered, and the solvent was evaporated to give
the crude product as a slightly yellow oil. Further purification was
accomplished by distillation to obtain 27.920 g (84.0%) of pure
product as a colorless liquid; b.p. 146 °C at 1.5 mbar.
In summary, we could show that C3-symmetric oxazole-
containing macrocyclic peptidic scaffolds carrying three
functional groups on the oxazole rings can be obtained in
good yields. Starting from this scaffold, a tripodal bipyridyl
ligand can be prepared. Furthermore, we were able to show
that the chiral backbone of the macrocycle predetermines
the helicity of the metal complexes of this tripodal ligand.
This concept of using a chiral oxazole scaffold for the dia-
stereoselective structure formation in supramolecular sys-
tems should be applicable to other systems, too.
Experimental Section
General Remarks: All chemicals were of reagent grade and used as
purchased. All moisture-sensitive reactions were performed under
an inert atmosphere of argon using distilled dry solvents. Reactions
were monitored by TLC analysis using silica gel 60 F254 thin-layer
plates. Flash chromatography was carried out on silica gel 60 (230–
TLC: Rf = 0.12 (PE/EtOAc, 2:1; silica). 1H NMR (300 MHz,
CDCl3): δ = 9.09 (br. s, 1 H; CO2H), 7.39–7.32 (m, 5 H, Ph CH-
2,3,4,5,6), 4.65 (s, 2 H, PhCH2O), 4.15 (s, 2 H, CH2CO2H) ppm.
13C NMR (75 MHz, CDCl3): δ = 175.3 (q, CO2H), 136.4 (q, Ph C-
1), 128.4 (t, Ph CH-4), 128.1 (t, Ph CH-3,5), 128.0 (t, Ph CH-2,6),
1
400 mesh). H and 13C NMR spectra were measured on a Bruker
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Oxazole Cyclopeptides for Chirality Transfer
73.2 (s, PhCH O), 66.4 (s, CH CO H) ppm. IR (film): ν = 3031,
warmed up to room temperature within a few hours. The mixture
was then diluted with DCM (300 mL) and extracted with water
(1ϫ 100 mL), 1  KHSO4 (1ϫ 100 mL) and brine (1ϫ 100 mL).
˜
2
2
2
2927, 1730, 1497, 1455, 1428, 1370, 1209, 1116, 1029, 949, 910,
749, 699, 605, 467 cm–1. UV/Vis (CH2Cl2, c = 0.742 mg/mL): λmax
(log ε) = 252 (1.07), 258 (1.01), 282 (0.13) nm. EI-MS: m/z = 166.1 The organic layer was dried with MgSO4, filtered off and the sol-
[M]+, 122.1, 107.1, 105.1, 91.1, 79.1, 65.2, 60.1, 51.1, 39.2, 32.2, vent was removed on a rotary evaporator. Purification was ac-
28.2.
complished by flash-chromatography on silica gel (PE/EtOAc,
70:30Ǟ50:50) to yield 14.404 g (55.0%) of 7 as a 1:1 mixture of
two diastereomers as a yellowish oil. TLC: Rf = 0.40 (PE/EtOAc,
60:40, silica). 1H NMR (500 MHz, CDCl3): δ = 7.37–7.32 (m, 5 H,
Benzyloxyacetyl Chloride: Benzyloxyacetic acid (16.617 g,
100.0 mmol) was dissolved in CHCl3 (50 mL) and thionyl chloride
(9.5 mL, 15.466 g, 130.0 mmol) was added at room temperature un-
der Ar. The solution was stirred for 4 h under reflux then the sol-
vent was removed on a rotary evaporator, and the crude product
was distilled under reduced pressure to give 16.800 g (91.0%) of
acid chloride as a colorless liquid; b.p. 78 °C at 1.0 mbar. 1H NMR
(300 MHz, CDCl3): δ = 7.42–7.34 (m, 5 H, Ph CH-2,3,4,5,6), 4.67
(s, 2 H, CH2COCl), 4.44 (s, 2 H, PhCH2O) ppm. 13C NMR
(75 MHz, CDCl3): δ = 171.8 (q, COCl), 136.0 (q, Ph C-1), 128.6
(t, Ph CH-2,6), 128.4 (t, Ph CH-3,5), 128.1 (t, Ph CH-4), 74.7 (s,
3
Ph CH-2,3,4,5,6), 7.09 (d, JH,H = 6.3 Hz, 1 H; amide NH), 5.41
3
3
(d, JH,H = 6.3 Hz, 1 H; CHCO2Me), 5.05 (br. d, JH,H = 7.5 Hz,
2
1 H; Boc NH), 4.62 (d, JH,H = 11.8 Hz, 1 H; PhCH2O), 4.59 (d,
2JH,H = 11.8 Hz, 1 H; PhCH2O), 4.42 (d, JH,H = 17.6 Hz, 0.5 H;
2
2
BnOCH2CO), 4.41 (d, JH,H = 17.6 Hz, 0.5 H; BnOCH2CO), 4.36
(d, 2JH,H = 17.6 Hz, 0.5 H; BnOCH2CO), 4.35 (d, 2JH,H = 17.6 Hz,
0.5 H; BnOCH2CO), 4.07 (br. s, 1 H; Val α-CH), 3.734 (s, 1.5 H;
CO2CH3), 3.731 (s, 1.5 H; CO2CH3), 2.23–2.11 (m, 1 H, Val β-
CH), 1.441 (s, 4.5 H; Boc CH3), 1.438 (s, 4.5 H; Boc CH3), 0.97
(d, 3JH,H = 6.9 Hz, 3 H; Val CH3), 0.908 (d, 3JH,H = 6.9 Hz, 1.5 H;
CH COCl), 73.5 (s, PhCH O) ppm. IR (film): ν = 3065, 3033, 2875,
˜
2
2
1802, 1497, 1455, 1412, 1390, 1264, 1211, 1134, 1027, 944, 758,
699, 605, 559, 477, 430 cm–1. UV/Vis (CH2Cl2, c = 0.138 mg/mL):
λmax (log ε) = 254 (0.15), 258 (0.16), 264 (0.14) nm. EI-MS: m/z =
184.1 [M]+, 121.1, 107.1, 91.1, 79.1, 65.2, 51.1, 39.1, 32.2, 28.2.
3
Val CH3), 0.906 (d, JH,H = 6.9 Hz, 1.5 H; Val CH3) ppm. 13C
NMR (125 MHz, CDCl3): δ = 198.95 (q, CO), 198.84 (q, CO),
171.5 (q, amide CONH), 166.09 (q, CO2Me), 166.06 (q, CO2Me),
155.75 (q, Boc CONH), 155.72 (q, Boc CONH), 136.7 (q, Ph C-1),
128.48 (t, Ph CH), 128.09 (t, Ph CH), 128.00 (t, Ph CH), 127.98 (t,
Ph CH), 80.1 (q, Boc C), 73.59 (s, BnOCH2), 73.52 (s, PhCH2O),
73.50 (s, PhCH2O), 59.45 (t, Val α-CH), 59.41 (t, Val α-CH), 58.8
(t, CHCO2Me), 53.31 (p, CO2CH3), 53.27 (p, CO2CH3), 30.83 (t,
Val β-CH), 30.74 (t, Val β-CH), 28.2 (p, Boc CH3), 19.1 (p, Val
Methyl 2-Amino-4-benzyloxy-3-oxobutanoate Hydrochloride Salt
(6): To a solution of KOtBu (13.47 g, 120.0 mmol) in dry THF
(250 mL) a solution of 5 (25.33 g, 100.0 mmol) in THF (200 mL)
was added dropwise while maintaining the inner temperature below
–50 °C. After addition was completed (15 min) the resulting orange
mixture was stirred for further 30 min at –60 to –50 °C, then trans-
ferred by a long, flexible double-tipped needle to a pre-cooled solu-
tion of benzyloxyacetyl chloride (20.31 g, 110.0 mmol) in dry THF
(200 mL) at –60 °C being stirred vigorously by a mechanical stirrer.
After completion of the addition (30 min) the mixture was stirred
further 60 min at –60 to –50 °C, then quenched by rapidly adding
2  aqueous HCl solution (200 mL), and stirred at room tempera-
ture for 2 h. THF was then removed in a rotary evaporator
(150 mbar, 35 °C) and the mixture was extracted with EtOAc
(3ϫ100 mL). The organic layers were re-extracted with 2  HCl
(1ϫ50 mL) then discarded. The aqueous layers were combined and
the solvents evaporated. The residue solidified upon exhaustive
drying in vacuo (Ͻ 1.0 mbar, 35 °C, 6–8 h) and this raw product
(contains 0.120 mol of KCl; calcd. yield 76.3%; yellow glassy solid)
was used without further purification for the next synthetic step.
1H NMR (300 MHz, [D6]DMSO): δ = 9.18 (br. s, 3 H; NH3+),
7.37–7.34 (m, 5 H, Ph CH-2,3,4,5,6), 5.34 (s, 1 H, CHCO2Me),
4.58 (s, 2 H, PhCH2O), 4.55 (s, 2 H, BnOCH2CO), 3.76 (s, 3 H,
CO2CH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 197.0 (q,
CO), 164.0 (q, CO2Me), 137.5 (q, Ph C-1), 128.3 (t, Ph CH-2,6),
127.8 (t, Ph CH-3,4,5), 73.4 (s, BnOCH2CO), 72.4 (s, PhCH2O),
57.9 (t, CHCO2Me), 53.7 (s, CO2CH3) ppm. ESI-HRMS: m/z
calcd. for C12H16NO4 [MH+] 238.1085, found 238.1054.
CH ), 17.4 (p, Val CH ) ppm. IR (KBr): ν = 3320, 2968, 2931,
˜
3
3
2875, 1700, 1519, 1454, 1392, 1368, 1248, 1166, 1045 (m 1018), 873,
739, 700, 605 cm–1. UV/Vis (CH2Cl2, c = 0.015 mg/mL): λmax (log
ε) = 236 (4.48), 256 (4.15), 274 (3.97), 322 (3.37) nm. ESI-HRMS:
m/z calcd. for C22H32N2O7 [MH+] 437.2282, found 437.2306.
Oxazole 8: To a solution of 7 (4.365 g, 10.0 mmol) in anhydrous
DCM (100 mL) at 5 °C under Ar a solution of triphenylphosphane
(2.885 g, 11.0 mmol) and hexachloroethane (4.735 g, 20.0 mmol) in
dry DCM (50 mL) was added followed by immediate addition of a
solution of triethylamine (10.119 g, 100.0 mmol) in DCM (50 mL).
The cooling bath was removed and the reaction mixture was stirred
at ambient temperature for 2 d. The solvent was evaporated and
purification was accomplished by flash chromatography on silica
gel (DCM/EtOAc, 95:5Ǟ75:25) to yield 2.953 g (70.5%) of 8 as a
white foam. TLC: Rf = 0.72 (DCM/EtOAc, 75:25, silica). 1H NMR
(500 MHz, CDCl3): δ = 7.35–7.27 (m, 5 H, Ph CH-2,3,4,5,6), 5.27
3
(br. d, JH,H = 7.6 Hz, 1 H; Boc CONH), 4.86 (s, 1 H, CH2OBn),
3
4.85 (s, 1 H, CH2OBn), 4.80 (dd, 3JH,H = 8.8, JH,H = 6.4 Hz, 1 H;
Val α-CH), 4.58 (s, 2 H, PhCH2O), 3.88 (s, 3 H, CO2CH3), 2.20–
3
2.15 (m, 1 H, Val β-CH), 1.42 (s, 9 H, Boc CH3), 0.92 (d, JH,H
=
6.7 Hz, 6 H; Val CH3) ppm. 13C NMR (125 MHz, CDCl3): δ =
163.9 (q, CO2Me), 161.9 (q, oxazole C-5), 155.2 (q, oxazole C-2),
154.4 (q, Boc CONH), 137.2 (q, Ph C-1), 129.6 (q, oxazole C-4),
128.4 (t, Ph CH-2,6), 127.9 (t, Ph CH-4), 127.8 (t, Ph CH-3,5), 79.9
(q, Boc C), 72.8 (s, PhCH2O), 61.1 (s, CH2OBn), 54.1 (t, Val α-
CH), 52.2 (p, CO2CH3), 32.9 (t, Val β-CH), 28.2 (p, Boc CH3), 18.7
Amido Ketone 7: Boc--Val-OH (13.036 g, 60.0 mmol) was dis-
solved in DCM (120 mL), NMM (6.069 g, 60.0 mmol) was added,
and the solution was cooled to –35 °C under Ar. Isobutyl chloro-
formate (8.195 g, 60.0 mmol) in DCM (30 mL) was slowly added
while the inner temperature was maintained at –35 °C. After an
hour, the resulting suspension was transferred via cannula into a
second round-bottom flask equipped with a mechanical stirrer and
containing the amino ketone 6 (16.423 g, 60.0 mmol) covered by
DCM (120 mL) and pre-cooled to –40 °C. Right after the transfer
was completed, a second equivalent of NMM (6.069 g, 60.0 mmol)
in DCM (30 mL) was added to the vigorously stirred mixture at
–35 °C. Stirring was continued for 8 h while the mixture was
(p, Val CH ), 17.8 (p, Val CH ) ppm. IR (KBr): ν = 3357, 2968,
˜
3
3
2933, 2874, 1721, 1620, 1578, 1509, 1454, 1441, 1391, 1367, 1344,
1301, 1244, 1210, 1173, 1094, 1013, 878, 741, 699 cm–1. UV/Vis
(CH2Cl2, c = 0.040 mg/mL): λmax (log ε) = 236 (4.93), 278 (3.62)
nm. ESI-HRMS: m/z calcd. for C22H30N2O6 [MH+] 419.2177,
found 419.2216.
Oxazolecarboxylic Acid 21: Oxazole 8 (8.370 g, 20.0 mmol) was dis-
solved in a mixture of methanol (80 mL) and dioxane (20 mL) fol-
lowed by slow addition of 2  NaOH solution (20 mL, 40.0 mmol)
Eur. J. Org. Chem. 2008, 2375–2387
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2381

Á. Pintér, G. Haberhauer
at 0 °C. The ice bath was removed and stirring was continued over- 5.14 (dd, JH,H = 7.9, JH,H = 4.8 Hz, 1 H; Val α-CH), 4.98 (s, 2
FULL PAPER
3
3
night. After TLC showed consumption of all starting material the
H, CH2OBn), 4.60 (s, 2 H, PhCH2O), 2.42–2.33 (m, 1 H, Val β-
CH), 1.09 (d, JH,H = 6.9 Hz, 3 H; Val CH3), 1.05 (d, JH,H =
3
3
mixture was diluted with brine (400 mL) and acidified with 2 
HCl (25 mL). The mixture was then repeatedly extracted with 6.9 Hz, 3 H; Val CH3) ppm. 13C NMR (125 MHz, CDCl3): δ =
DCM (3ϫ100 mL), the organic layers were combined, dried with
MgSO4, filtered off, and the filtrate was concentrated in vacuo to
give 7.871 g (97.3%) of the free acid 21, which was used without
162.5 (q, oxazole C-2), 160.0 (q, CONH), 152.1 (q, oxazole C-5),
137.5 (q, Ph C-1), 131.1 (q, oxazole C-4), 128.3 (t, Ph CH-2,6),
127.8 (t, Ph CH-3,5), 127.7 (t, Ph CH-4), 72.9 (s, PhCH2O), 61.3
(s, CH2OBn), 53.1 (t, Val α-CH), 33.6 (t, Val β-CH), 18.43 (p, Val
further purification for the next step. TLC: Rf = 0.30 (DCM/
1
EtOAc/MeOH, 75:25:5, silica). H NMR (300 MHz, CDCl3): δ = CH ), 18.27 (p, Val CH ) ppm. IR (KBr): ν = 3390, 3089, 3064,
˜
3
3
9.00 (br. s, 1 H; CO2H), 7.35–7.28 (m, 5 H, Ph CH-2,3,4,5,6), 6.45
3032, 2965, 2931, 2873, 1731, 1682, 1575, 1519, 1455, 1435, 1390,
1373, 1316, 1271, 1205, 1140, 1088, 1072, 1028, 1001, 946, 902,
2
(br. d, 3JH,H = 9.3 Hz, 1 H; Boc CONH), 4.97 (d, JH,H = 13.8 Hz,
1 H; CH2OBn), 4.88 (d, 2JH,H = 13.8 Hz, 1 H; CH2OBn), 4.85 (dd, 853, 793, 749, 697 cm–1. UV/Vis (CH2Cl2, c = 0.0115 mg/mL): λmax
3
3JH,H = 9.3, JH,H = 6.6 Hz, 1 H; Val α-CH), 4.61 (s, 2 H,
(log ε) = 235 (sh, 4.58), 292 (3.60) nm. CD (CH2Cl2, c = 0.0115 mg/
mL): λ (∆ε) = 230 (–37.6), 256 (0.0) nm (–1 cm–1). ESI-HRMS:
m/z calcd. for C48H55N6O9 [MH+] 859.4025, found 859.4127.
PhCH2O), 2.28–2.17 (m, 1 H, Val β-CH), 1.39 (s, 9 H, Boc CH3),
3
3
0.98 (d, JH,H = 6.8 Hz, 3 H; Val CH3), 0.94 (d, JH,H = 6.8 Hz, 3
H; Val CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.4 (q,
CO2H), 163.8 (q, oxazole C-5), 155.8 (q, Boc CONH), 155.2 (q,
oxazole C-2), 137.2 (q, Ph C-1), 129.3 (q, oxazole C-4), 128.4 (t,
Ph CH-2,6), 128.0 (t, Ph CH-3,5), 127.9 (t, Ph CH-4), 79.8 (q, Boc
C), 72.9 (s, PhCH2O), 61.1 (s, CH2OBn), 54.5 (t, Val α-CH), 32.7
(t, Val β-CH), 28.2 (p, Boc CH3), 18.9 (p, Val CH3), 18.1 (p, Val
1
Data for 11: TLC: Rf = 0.50 (PE/EtOAc, 60:40, silica). H NMR
3
(500 MHz, CDCl3): δ = 7.31 (d, JH,H = 9.7 Hz, 1 H; amide NH),
7.27–7.23 (m, 4 H, Ph CH-2,3,5,6), 7.22–7.18 (m, 1 H, Ph CH-4),
3
3
5.20 (dd, JH,H = 9.7, JH,H = 7.6 Hz, 1 H; Val α-CH), 4.94 (d,
2JH,H = 13.1 Hz, 1 H; CH2OBn), 4.83 (d, JH,H = 13.1 Hz, 1 H;
2
CH2OBn), 4.54 (s, 2 H, PhCH2O), 2.38–2.28 (m, 1 H, Val β-CH),
CH ) ppm. IR (KBr): ν = 3424, 2973, 2933, 1717, 1625, 1573, 1518,
˜
3
3
3
1.04 (d, JH,H = 6.7 Hz, 3 H; Val CH3), 0.97 (d, JH,H = 6.7 Hz, 3
H; Val CH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 162.4 (q,
oxazole C-2), 160.2 (q, CONH), 152.1 (q, oxazole C-5), 137.5 (q,
Ph C-1), 131.1 (q, oxazole C-4), 128.3 (t, Ph CH-2,6), 127.84 (t, Ph
CH-3,5), 127.76 (t, Ph CH-4), 73.1 (s, PhCH2O), 61.4 (s, CH2OBn),
51.4 (t, Val α-CH), 32.5 (t, Val β-CH), 19.1 (p, Val CH3), 18.4 (p,
1455, 1393, 1368, 1282, 1246, 1170, 1072, 1014, 877, 738, 698, 604,
463 cm–1. UV/Vis (CH2Cl2, c = 0.132 mg/mL): λmax (log ε) = 236
(3.87), 294 (2.49) nm. ESI-HRMS: m/z calcd. for C21H29N2O6
[MH+] 405.2020, found 405.2057.
Oxazolecarboxylic Acid Hydrochloride Salt 9: Boc-protected amino
acid 21 (6.067 g, 15.0 mmol) was dissolved in EtOAc (60 mL) and
concentrated (5 , 20%) solution of HCl in EtOAc (30 mL,
150.0 mmol) was added. After 30 min the ice bath was removed and
stirring was continued at room temperature for two hours. Then
the solvent was removed on a rotary evaporator to provide 5.050 g
(98.9%) of the hydrochloride salt 9 as a slightly grey hygroscopic
Val CH ) ppm. IR (KBr): ν = 3412, 3334, 3063, 3032, 2965, 2929,
˜
3
2873, 1728, 1678, 1531, 1572, 1507, 1468, 1455, 1391, 1372, 1330,
1270, 1204, 1140, 1087, 1072, 1028, 1000, 939, 895, 934, 782, 741,
698 cm–1. UV/Vis (CH2Cl2, c = 0.0199 mg/mL): λmax (log ε) = 240
(sh, 4.59) nm. CD (CH2Cl2, c = 0.0199 mg/mL): λ (∆ε) = 231
(–53.0), 267 (0.0) nm (–1 cm–1). ESI-HRMS: m/z calcd. for
powder. 1H NMR (300 MHz, [D6]DMSO): δ = 9.10 (br. s, 4 H; C64H73N8O12 [MH+] 1145.5342, found 1145.5465.
CO2H und NH3+), 7.37–7.26 (m, 5 H, Ph CH-2,3,4,5,6), 4.86 (s, 2
Scaffold 2: To a solution of 10 (0.172 g, 0.20 mmol) in DCM
(200 mL) Palladium/charcoal catalyst (10%, 0.300 g) was added,
3
H, CH2OBn), 4.55 (s, 2 H, PhCH2O), 4.43 (d, JH,H = 6.8 Hz, 1
3
H; Val α-CH), 2.37–2.26 (m, 1 H, Val β-CH), 1.01 (d, JH,H
=
and the mixture was stirred under hydrogen atmosphere (105 Pa) at
room temperature for 60 min. Then catalyst was removed by fil-
tration and solvent was distilled off in a rotary evaporator to yield
0.117 g (99.4%) of 2 as a colorless solid. TLC: Rf = 0.32 (DCM/
3
6.8 Hz, 3 H; Val CH3), 0.86 (d, JH,H = 6.8 Hz, 3 H; Val CH3)
ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 162.0 (q, oxazole C-
5), 159.0 (q, CO2H), 154.6 (q, oxazole C-2), 137.6 (q, Ph C-1),
130.1 (q, oxazole C-4), 128.2 (t, Ph CH-2,6), 127.7 (t, Ph CH-3,5),
127.6 (t, Ph CH-4), 71.7 (s, PhCH2O), 60.8 (s, CH2OBn), 52.8 (t,
Val α-CH), 30.6 (t, Val β-CH), 18.5 (p, Val CH3), 17.3 (p, Val CH3)
1
EtOAc/MeOH, 75:25:5, silica). H NMR (500 MHz, CDCl3): δ =
8.26 (d, 3JH,H = 7.8 Hz, 1 H; amide NH), 5.38 (br. s, 2 H; CH2OH),
3
3
5.07 (dd, JH,H = 7.7, JH,H = 4.8 Hz, 1 H; Val α-CH), 4.87 (d,
ppm. IR (KBr): ν = 3406, 3031, 2969, 2878, 1968, 1718, 1605, 1517,
˜
2JH,H = 15.6 Hz, 1 H; CH2OH), 4.84 (d, JH,H = 15.6 Hz, 1 H;
2
1455, 1429, 1398, 1361, 1314, 1186, 1097, 1070, 1028, 920, 809,
741, 699 cm–1. UV/Vis (MeOH, c = 0.0134 mg/mL): λmax (log ε) =
207 (4.21), 218 (sh, 4.14), 257 (2.71) nm. ESI-HRMS: m/z calcd.
for C16H21N2O4 [MH+] 305.1496, found 305.1517.
3
CH2OH), 2.40–2.31 (m, 1 H, Val β-CH), 1.06 (d, JH,H = 6.8 Hz,
3 H; Val CH3), 1.02 (d, JH,H = 6.8 Hz, 3 H; Val CH3) ppm. 13C
3
NMR (125 MHz, CDCl3): δ = 161.3 (q, oxazole C-2), 160.9 (q,
CONH), 156.7 (q, oxazole C-5), 130.0 (q, oxazole C-4), 56.1 (s,
CH2OH), 53.3 (t, Val α-CH), 33.4 (t, Val β-CH), 18.3 (p, 2 Val
Scaffolds 10 and 11: To a solution of the free amino acid 9 (1.704 g,
5.0 mmol) in anhydrous DMF (125 mL) at room temperature
PyBOP (3.903 g, 7.5 mmol) was added followed by addition of
iPr2NEt (4.201 g, 32.5 mmol) and the mixture was stirred under Ar
for 4 d. The solvent was evaporated and the residue was taken up
in EtOAc (500 mL), then washed with 2  HCl (2ϫ50 mL), water
(2ϫ50 mL) and brine (1ϫ50 mL). The organic layer was dried
with MgSO4, filtered, concentrated and the residue was subjected
to column chromatography on silica gel (PE/EtOAc, 80:20Ǟ60:40)
to obtain 0.490 g (34.5%) of oxazole trimer 10 and 0.340 g (23.8%)
of oxazole tetramer 11 as white powders.
CH ) ppm. IR (KBr): ν = 3389, 2966, 2934, 2876, 2513, 1664, 1635,
˜
3
1577, 1526, 1449, 1392, 1373, 1193, 1139, 1115, 1031, 967, 899,
782, 615, 473 cm–1. ESI-HRMS: m/z calcd. for C27H37N6O9 [MH+]
589.2617, found 589.2686.
Scaffold 3: A solution of 2 (0.029 g, 0.05 mmol) in CHCl3 (5 mL)
was mixed with thionyl chloride (0.060 g, 0.50 mmol) for 15 min,
then evaporated and dried in vacuo to give 0.0318 g (98.8%) of 3
1
3
as a white solid. H NMR (500 MHz, CDCl3): δ = 8.20 (d, JH,H
3
3
= 7.9 Hz, 1 H; amide NH), 5.12 (dd, JH,H = 7.9, JH,H = 4.9 Hz,
2
1 H; Val α-CH), 5.04 (d, JH,H = 12.9 Hz, 1 H; CH2Cl), 4.96 (d,
1
Data for 10: TLC: Rf = 0.55 (PE/EtOAc, 60:40, silica). H NMR
2JH,H = 12.9 Hz, 1 H; CH2Cl), 2.41–2.34 (m, 1 H, Val β-CH), 1.10
3
3
3
(500 MHz, CDCl3): δ = 8.24 (d, JH,H = 7.9 Hz, 1 H; amide NH),
(d, JH,H = 6.8 Hz, 3 H; Val CH3), 1.04 (d, JH,H = 6.8 Hz, 3 H;
7.34–7.29 (m, 4 H, Ph CH-2,3,5,6), 7.27–7.24 (m, 1 H, Ph CH-4),
Val CH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 162.76 (q,
2382
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2375–2387

Oxazole Cyclopeptides for Chirality Transfer
CONH), 162.72 (q, CONH), 159.64 (q, oxazole C-2), 159.59 (q,
oxazole C-2), 150.7 (q, oxazole C-5), 130.43 (q, oxazole C-4),
and excess of thionyl chloride were removed in a rotary evaporator
to obtain 43.92 g (98.2%) of the acid chloride as a slightly grey-
1
130.40 (q, oxazole C-4), 53.29 (t, Val α-CH), 53.20 (t, Val α-CH), brownish solid. H NMR (300 MHz, CDCl3): δ = 7.94–7.88 (m, 2
33.67 (t, Val β-CH), 33.56 (s, CH2Cl), 18.38 (p, Val CH3), 18.35 (p, H, PhtN CH-2,5), 7.82–7.74 (m, 2 H, PhtN CH-3,4), 4.82 (s, 2 H,
Val CH3) ppm. ESI-HRMS: m/z calcd. for C27H34O6N635Cl237Cl CH2COCl) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.1 (q, COCl)
[MH+] 645.1576, found 645.1609.
166.6 (q, 2 PhtN CO), 134.6 (t, PhtN CH-3,4), 131.6 (q, PhtN C-
1,6), 124.0 (t, PhtN CH-2,5), 47.6 (p, CH2COCl) ppm. IR (KBr):
N-(Diphenylmethylene)glycine Benzyl Ester 12: To a stirred slurry
of glycine benzyl ester 4-toluenesulfonate (67.48 g, 200.0 mmol) in
DCM (400 mL) was added benzophenone imine (36.25 g,
200.0 mmol) in DCM (200 mL) over a period of 15 min, and then
the mixture was stirred for 24 h at ambient temperature. The re-
sulting white milky mixture was extracted with water (3ϫ200 mL)
and brine (100 mL), then the organic layer was separated, dried
with MgSO4, filtered and the solvents evaporated. The solidified
raw product was grinded and stirred in petroleum ether (200 mL)
for a half hour, then filtered and dried to obtain 52.70 g (80.0%)
of 12 as a white powder. TLC: Rf = 0.63 (PE/EtOAc, 3:1, silica).
ν = 3422, 2979, 2936, 1804, 1774, 1722, 1468, 1418, 1313, 1195,
˜
1117, 1088, 998, 957, 937, 736, 715, 609, 531, 521 cm–1. UV/Vis
(CH2Cl2, c = 0.137 mg/mL): λmax (log ε) = 240 (3.98), 296 (3.29),
306 (3.21) nm. EI-MS: m/z (%) = 223.0 (1) [M]+, 160.0 (100) [M –
63u]+. C10H6ClNO3 (223.613): calcd. C 53.71, H 2.70, N 6.26;
found C 53.86, H 2.81, N 6.29.
Benzyl 2-Amino-3-oxo-4-phthalimidobutanoate Hydrochloride Salt
13: A solution of KOtBu (11.22 g, 100.0 mmol) in dry THF
(200 mL) was cooled under argon to –60 °C, and a solution of N-
(diphenylmethylene)glycine benzyl ester (32.94 g, 100.0 mmol) in
THF (200 mL) was added dropwise while maintaining the inner
temperature below –50 °C. After addition was completed (15 min)
the resulting orange mixture was stirred for further 30 min at –60
to –50 °C, then transferred by a long, flexible double-tipped needle
to a pre-cooled solution of phthalimidoacetyl chloride (22.36 g,
200.0 mmol) in dry THF (200 mL) at –60 °C being stirred vigor-
ously by a mechanical stirrer. After completion of the addition
(30 min) the mixture was stirred for further 60 min at –60 to
–50 °C, then quenched by rapidly adding 2  aqueous HCl solution
(100 mL), and stirred at room temperature for 2 h. Then THF was
removed in a rotary evaporator (200Ǟ120 mbar, 40 °C) and the
remaining mixture was transferred into a separation funnel. The
lower oily layer was separated, then mixed with cold EtOAc
(100 mL) to induce precipitation of the product. The resulting
white solid was filtered off, washed with cold EtOAc (50 mL) and
dried. A second crop of the product could be obtained from the
aqueous layer by shaking it with EtOAc (100 mL) followed by fil-
tration. Overall product yield: 32.54 g (83.7%) of 13 as a white
powder. 1H NMR (500 MHz, [D6]DMSO): δ = 9.21 (br. s, 3 H;
NH3+), 7.95–7.92 (m, 2 H, PhtN CH-2,5), 7.92–7.88 (m, 2 H, PhtN
3
4
1H NMR (300 MHz, CDCl3): δ = 7.81 (dd, JH,H = 8.1, JH,H
=
1.5 Hz, 1 H), 7.67 (dd, 3JH,H = 8.1, 4JH,H = 1.5 Hz, 2 H), 7.50 (dd,
3JH,H = 6.0, JH,H = 1.5 Hz, 1 H), 7.44 (d, JH,H = 6.6 Hz, 2 H),
4
3
7.35 (d, 3JH,H = 6.6 Hz, 2 H), 7.35 (s, 5 H), 7.17 (d, 3JH,H = 6.6 Hz,
3
1 H), 7.15 (d, JH,H = 6.6 Hz, 1 H), 5.20 (s, 2 H, CO2CH2Ph), 4.27
(s, 2 H, CH2CO2Bn) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.0
(q, Ph2C=N), 170.4 (q, CO2Bn), 139.1 (q), 135.9 (q), 135.7 (q),
130.5 (t), 128.8 (t), 128.75 (t, 2 C), 128.65 (t, 2 C), 128.5 (t, 2 C),
128.3 (t, 2 C), 128.2 (t, 2 C), 128.0 (t), 127.6 (t, 2 C), 66.5 (s,
CO CH Ph), 55.6 (s, CH CO Bn) ppm. IR (KBr): ν = 3432, 3060,
˜
2
2
2
2
2955, 2900, 2870, 1960, 1894, 1829, 1748, 1624, 1596, 1444, 1386,
1351, 1313, 1288, 1220, 1177, 1054, 958, 918, 908, 780, 758, 706,
696, 583 cm–1. UV/Vis (CH2Cl2, c = 0.012 mg/mL): λmax (log ε)
= 250 (4.164) nm. ESI-HRMS: m/z calcd. for C22H20NO2 [MH]+
330.1489, found 330.1498. C22H19NO2 (329.392): calcd. C 80.22, H
5.81, N 4.25; found C 80.12, H 5.82, N 4.25.
Phthalimidoacetic Acid: In a three-necked round-bottom flask were
placed glycine (22.52 g, 300.0 mmol), phthalic anhydride (44.44 g,
300.0 mmol), triethylamine (3.036 g, 30.0 mmol) and toluene
(180 mL). The flask was equipped with a stirring bar, a Dean–Stark
trap and a reflux condenser. The mixture was heated to reflux tem-
perature and stirred for further 6 h with azeotropic removal of
water. After completion of the reaction the solvent was removed in
a rotary evaporator. The resulting white solid was taken up in water
(450 mL) and the mixture was acidified by adding concd. hydro-
chloric acid (6.0 mL, 66.0 mmol). The product was collected by
filtration, washed with water (2ϫ30 mL) and dried to yield 60.87 g
(98.9%) of the carboxylic acid as a white powder. TLC: Rf = 0.12
(PE/EtOAc, 2:1, silica). 1H NMR (300 MHz, [D6]DMSO): δ =
12.80 (br. s, 1 H; CO2H), 7.95–7.85 (m, 4 H, PhtN CH-2,3,4,5),
4.32 (s, 2 H, CH2CO2H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 168.7 (q, CO2H), 167.1 (q, 2 PhtN CO), 134.7 (t, PhtN CH-3,4),
131.3 (q, PhtN C-1,6) 123.3 (t, PhtN CH-2,5), 38.8 (s, CH2CO2H)
3
CH-3,4), 7.52 (d, JH,H = 7.0 Hz, 2 H; Bn CH-2,6), 7.43–7.37 (m,
2
3 H, Bn CH-3,4,5), 5.84 (s, 1 H, CHNH3+), 5.41 (d, JH,H
=
2
12.3 Hz, 1 H; Bn CH2), 5.32 (d, JH,H = 12.3 Hz, 1 H; Bn CH2),
2
2
4.99 (d, JH,H = 18.9 Hz, 1 H; PhtNCH2CO), 4.94 (d, JH,H
=
18.9 Hz; PhtNCH2CO) ppm. 13C NMR (125 MHz, [D6]DMSO): δ
= 193.2 (q, PhtNCH2CO), 166.9 (q, 2 PhtN CO), 162.9 (q, CO2Bn),
134.8 (t, PhtN CH-3,4), 134.4 (q, Bn C-1), 131.2 (q, PhtN C-1,6),
128.46, (t, Bn CH-4), 128.43 (t, Bn CH-3,5), 128.3 (t, Bn CH-2,6),
123.4 (t, PhtN CH-2,5), 68.5 (s, Bn CH2), 59.5 (t, CHNH3+), 45.3
(s, PhtNCH CO) ppm. IR (KBr): ν = 3474, 3319, 3170, 3125, 3087,
˜
2
3065, 3031, 2970, 2887, 2818, 2779, 2663, 2593, 1957, 1777, 1761,
1741, 1721, 1578, 1525, 1501, 1468, 1419, 1377, 1329, 1266, 1233,
1196, 1171, 1146, 1103, 1048, 1012, 947, 907, 882, 854, 820, 803,
753, 735, 713, 697, 618 cm–1. UV/Vis (MeOH, c = 0.0058 mg/mL):
λmax (log ε) = 218 (4.46), 239 (3.88), 268 (4.03) nm. ESI-HRMS:
m/z calcd. for [C19H17N2O5]+ 353.1132, found 353.1108.
C19H17ClN2O5 (388.802): calcd. C 58.69, H 4.41, N 7.21; found C
58.44, H 4.58, N 7.00.
ppm. IR (KBr): ν = 3433, 2935, 1773, 1724, 1616, 1469, 1418, 1391,
˜
1319, 1248, 1195, 1119, 1087, 957, 800, 738, 715, 623, 563, 531
cm–1. UV/Vis (CH2Cl2, c = 0.147 mg/mL): λmax (log ε) = 234 (4.08),
240 (3.97), 294 (3.22) nm. EI-MS: m/z (%) = 205.0 (5) [M]+, 165.0
(100) [M – 40u]+. C10H7NO4 (205.167): calcd. C 58.54, H 3.44, N
6.83; found C 58.30, H 3.51, N 6.87.
Amido Ketone 14a: In a round-bottomed flask equipped with a
mechanical stirrer Boc--Val-OH (13.04 g, 60.0 mmol) was dis-
solved in dry THF (120 mL) and N-methylmorpholine (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 THF
(30 mL) was added while the inner temperature was maintained at
–30 to –25 °C. After 60 min keto amine 13 (23.33 g, 60.0 mmol)
was added in one portion followed by a solution of NMM (6.069 g,
Phthalimidoacetyl Chloride: In a round-bottom flask were placed
phthalimidoacetic acid (41.03 g, 200.0 mmol) and chloroform
(40 mL), then thionyl chloride (20.0 mL, 275.0 mmol) was cau-
tiously added. The flask was equipped with a reflux condenser,
flushed with argon, and the mixture was stirred at reflux tempera-
ture for 3 h, to obtain a light yellowish, clear solution. Then solvent
Eur. J. Org. Chem. 2008, 2375–2387
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2383

Á. Pintér, G. Haberhauer
FULL PAPER
60.0 mmol) in THF (30 mL) over a period of 30 min. Stirring was
continued for 3 h at –30 °C then the mixture was warmed up to
room temperature in further 2 h. The solvent was evaporated and
the residue was taken up in water (300 mL) and DCM (300 mL).
The mixture was thoroughly shaken and the layers were separated
then the aqueous layer was further extracted with DCM
(2ϫ100 mL). The collected organic layers were washed with 1 
KHSO4 (50 mL), concd. NaHCO3 (50 mL) and brine (50 mL), then
dried with MgSO4, filtered, and concentrated in vacuo. Purification
of the crude product was accomplished by chromatography on sil-
ica gel (DCM/EtOAc, 95:5Ǟ70:30) to yield 21.51 g (65.0%) of 14a
H; PhtNCH2), 4.71 (d, 2JH,H = 18.2 Hz, 0.5 H; PhtNCH2), 4.20 (br.
d, 3JH,H = 5.6 Hz, 0.5 H; Val α-CH), 4.18 (br. d, 3JH,H = 6.6 Hz, 0.5
3
H; Val α-CH), 2.20–2.11 (m, 1 H, Val β-CH), 0.95 (pst, JH,H
=
3
6.9 Hz, 3 H; Val CH3), 0.90 (d, JH,H = 6.9 Hz, 3 H; Val CH3)
ppm. 13C NMR (125 MHz, CDCl3): δ = 193.71 (q, PhtNCH2CO),
193.66 (q, PhtNCH2CO), 171.2 (q, amide CO), 167.1 (q, 2 PhtN
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
as a 1:1 mixture of two diastereomers as a white powder. TLC: Rf
1
= 0.70 (DCM/EtOAc, 3:1, silica). H NMR (300 MHz, CDCl3): δ CH-2,5), 68.92 (s, Z CH2), 68.90 (s, Z CH2), 67.1 (s, Bn CH2), 60.6
3
4
= 7.86 (dd, JH,H = 5.3, JH,H = 3.0 Hz, 2 H; PhtN CH-2,5), 7.73 (t, NHCHCO2Bn), 59.90 (t, Val α-CH), 59.88 (t, Val α-CH), 45.27
3
4
(dd, JH,H = 5.3, JH,H = 3.0 Hz, 2 H; PhtN CH-3,4), 7.41–7.33
(s, PhtNCH2), 45.07 (s, PhtNCH2), 31.0 (t, Val β-CH), 19.09 (p,
Val CH3), 19.02 (p, Val CH3), 17.52 (p, Val CH3), 17.44 (p, Val
3
(m, 5 H, Z CH-2,3,4,5,6), 7.15–7.11 (2 d, JH,H = 5.5 Hz, 1 H;
amide NH), 5.51–5.47 (2 d, JH,H = 6.8 Hz, 1 H; NHCHCO2Bn), CH ) ppm. IR (KBr): ν = 3289, 3065, 3034, 2958, 2935, 2907, 2872,
3
˜
3
5.34–5.24 (4 d, 2 H; CO2CH2Ph), 5.05–5.00 (2ϫbr. d, 1 H; Boc
1778, 1727, 1692, 1653, 1539, 1468, 1455, 1414, 1387, 1273, 1249,
1109, 1041, 950, 843, 732, 714, 696, 531 cm–1. UV/Vis (MeOH, c
= 0.0051 mg/mL): λmax (log ε) = 217 (4.806), 240 (sh, 4.077), 280
(3.684) nm. ESI-HRMS: m/z calcd. for [C32H32N3O8]+ 586.2184,
2
NH), 4.89–4.82 (2 d, JH,H = 18.1 Hz, 1 H; PhtNCH2), 4.76–4.69
2
(2 d, JH,H = 18.1 Hz, 1 H; PhtNCH2), 4.08 (br. m, 1 H; Val α-
CH), 2.23–2.13 (m, 1 H, Val β-CH), 1.43–1.42 (2 s, 9 H; Boc CH3),
0.97–0.94 (2 d, 3JH,H = 6.8 Hz, 3 H; Val CH3), 0.90–0.87 (2 d, 3JH,H found 586.2180.
= 6.8 Hz, 3 H; Val CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
Oxazole 15a: To a solution of 14a (5.516 g, 10.0 mmol) in dry
193.76 (q, PhtNCH2CO), 193.67 (q, PhtNCH2CO), 171.6 (q, amide
CO), 167.13 (q, 2 PhtN CO), 167.10 (q, 2 PhtN CO), 164.9 (q,
CO2Bn), 155.8 (q, Boc CO), 134.8 (q, Bn C-1), 134.22 (t, PhtN
CH-3,4), 134.20 (t, PhtN CH-3,4), 132.0 (q, PhtN C-1,6), 128.81
(t, Bn CH), 128.74 (t, Bn CH), 128.72 (t, Bn CH), 123.6 (t, PhtN
CH-2,5), 80.19 (q, Boc C(CH3)3), 80.16 (q, Boc C(CH3)3), 68.93
(s, Bn CH2), 68.90 (s, Bn CH2), 60.68 (t, NHCHCO2Bn), 60.66 (t,
NHCHCO2Bn), 59.51 (t, Val α-CH), 59.47 (t, Val α-CH), 45.28 (s,
PhtNCH2), 45.20 (s, PhtNCH2), 30.75 (t, Val α-CH), 28.25 (p, Boc
CH3), 19.2 (p, Val CH3), 19.1 (p, Val CH3), 17.4 (p, Val CH3), 17.3
DCM (50 mL) a solution of hexachloroethane (4.735 g, 20.0 mmol)
and triphenylphosphane (2.885 g, 11.0 mmol) in DCM (50 mL)
was added followed by triethylamine (10.12 g, 100 mmol) in DCM
(25 mL) at room temperature. After completion of addition the
mixture was stirred for a week. The volatiles were then removed
at reduced pressure leaving a viscous, tacky material, which was
subjected to column chromatography on silica gel (DCM/EtOAc,
95:5Ǟ75:25) to give 2.775 g (52.0%) of 15a as a white solid. TLC:
Rf = 0.80 (DCM/EtOAc, 3:1, silica). 1H NMR (300 MHz, CDCl3):
δ = 7.87 (dd, 3JH,H = 5.5, 4JH,H = 3.1 Hz, 2 H; PhtN CH-2,5), 7.75
(p, Val CH ) ppm. IR (KBr): ν = 3420, 2969, 1722, 1500, 1468,
˜
3
4
3
(dd, JH,H = 5.5, JH,H = 3.1 Hz, 2 H; PhtN CH-3,4), 7.46 (dd,
1416, 1392, 1261, 1166, 1111, 948, 716, 698, 531 cm–1. UV/Vis
(MeOH, c = 0.0069 mg/mL): λmax (log ε) = 219 (4.76), 239 (4.08),
279 (3.65) nm. ESI-HRMS: m/z calcd. for [C29H34N3O8]+ 552.2340,
found 552.2316.
4
3JH,H = 7.6, JH,H = 1.6 Hz, 2 H; Bn CH-3,5), 7.38–7.31 (m, 3 H,
2
Bn CH-2,4,6), 5.43 (d, JH,H = 12.3 Hz, 1 H; Bn CH2), 5.38 (d,
3
2JH,H = 12.3 Hz, 1 H; Bn CH2), 5.26 (d, JH,H = 9.4 Hz, 1 H; Boc
2
2
NH), 5.24 (d, JH,H = 16.4 Hz, 1 H; PhtNCH2), 5.17 (d, JH,H
=
3
3
16.4 Hz, 1 H; PhtNCH2), 4.69 (dd, JH,H = 9.1, JH,H = 5.8 Hz, 1
H; Val α-CH), 2.14–2.03 (m, 1 H, Val β-CH), 1.38 (s, 9 H, Boc
Amido Ketone 14b: In a round-bottomed flask equipped with a
mechanical stirrer Z--Val-OH (15.08 g, 60.0 mmol) was dissolved
in dry DCM (300 mL) and N-methylmorpholine (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 60 min keto amine 13 (23.33 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 warmed up to
room temperature in further 2 h resulting in a thick suspension.
The white solid was filtered off and the filtrate was evaporated to
dryness. The remaining solids were merged and washed on a funnel
sequentially with water (1ϫ300 mL), 1  HCl (2ϫ150 mL) and
water (1ϫ300 mL) then dried in vacuo. The crude product was
recrystallized from EtOH/iPrOH to yield 30.85 g (87.8%) of 14b as
CH3), 0.84 (d, JH,H = 6.8 Hz, 6 H; Val CH3) ppm. 13C NMR
3
(75 MHz, CDCl3): δ = 167.1 (q, 2 PhtN CO), 163.4 (q, oxazole C-
5), 161.2 (q, CO2Bn), 155.3 (q, oxazole C-2), 151.9 (q, Boc CO),
135.4 (q, oxazole C-4), 134.3 (t, PhtN CH-3,4), 131.8 (q, Bn C-1),
128.81 (q, PhtN C-1,6), 128.59 (t, Bn CH-2,6), 128.57 (t, Bn CH-
3,5), 128.39 (t, Bn CH-4), 123.6 (t, PhtN CH-2,5), 79.9 (q, Boc
C(CH3)3), 67.1 (s, Bn CH2), 54.0 (t, Val α-CH), 32.9 (t, Val β-CH),
32.9 (s, PhtNCH2), 28.2 (p, Boc CH3), 18.5 (p, Val CH3), 17.7 (p,
Val CH ) ppm. IR (KBr): ν = 3395, 2972, 1775, 1718, 1616, 1499,
˜
3
1468, 1456, 1421, 1392, 1367, 1248, 1172, 1115, 1068, 941, 753,
715, 699, 530 cm–1. UV/Vis (CH2Cl2, c = 0.077 mg/mL): λmax (log
ε) = 294 (3.33) nm. ESI-HRMS: m/z calcd. for [C29H32N3O7]+
534.2235, found 534.2242.
Oxazole 15b: To a solution of 14b (5.856 g, 10.0 mmol) in dry
a 1:1 mixture of two diastereomers as a white powder. TLC: Rf =
0.62 (DCM/EtOAc, 3:1, silica). H NMR (500 MHz, CDCl3): δ = and triphenylphosphane (2.885 g, 11.0 mmol) in DCM (50 mL)
DCM (50 mL) a solution of hexachloroethane (4.735 g, 20.0 mmol)
1
7.87–7.83 (2 dd, 2 H; PhtN CH-2,5), 7.74–7.72 (2 dd, 2 H; PhtN
CH-3,4), 7.40–7.32 (m, 10 H, Z and Bn CH-2,3,4,5,6), 7.21–7.19
was added followed by triethylamine (10.12 g, 100 mmol) in DCM
(25 mL) at room temperature. After completion of addition the
mixture was stirred for two weeks. The volatiles were then removed
at reduced pressure leaving a viscous, tacky material, which was
3
3
(2 d, JH,H = 5.6 Hz, 1 H; amide NH), 5.53–5.49 (2 d, JH,H
=
3
7.8 Hz, 1 H; NHCHCO2Bn), 5.44–5.40 (2 d, JH,H = 9.6 Hz, 1 H;
Z NH), 5.31–5.25 (4 d, 2 H; Z CH2), 5.12–5.04 (4 d, 2 H; subjected to column chromatography on silica gel (DCM/EtOAc,
2
CO2CH2Ph), 4.85 (d, JH,H = 18.2 Hz, 0.5 H; PhtNCH2), 4.84 (d,
95:5Ǟ75:25) to give 4.297 g (75.7%) of 15b as a white solid. TLC:
2JH,H = 18.2 Hz, 0.5 H; PhtNCH2), 4.75 (d, JH,H = 18.2 Hz, 0.5 Rf = 0.77 (DCM/EtOAc, 3:1, silica). 1H NMR (300 MHz, CDCl3):
2
2384
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2375–2387

Oxazole Cyclopeptides for Chirality Transfer
δ = 7.86 (dd, 3JH,H = 5.5, 4JH,H = 3.1 Hz, 2 H; PhtN CH-2,5), 7.74 C-5), 161.9 (q, 2 PhtN CO), 158.4 (q, CO2H), 152.7 (q, oxazole C-
3
4
(dd, JH,H = 5.5, JH,H = 3.1 Hz, 2 H; PhtN CH-3,4), 7.48–7.44
2), 134.7 (q, oxazole C-4), 131.3 (t, PhtN CH-3,4), 129.0 (q, PhtN
C-1,6), 123.3 (t, PhtN CH-2,5), 52.6 (t, Val α-CH), 32.7 (t, Val β-
CH), 30.5 (s, PhtNCH2), 18.4 (p, Val CH3), 17.0 (p, Val CH3) ppm.
(m, 2 H), 7.39–7.28 (m, 8 H), 5.53 (d, 3JH,H = 9.4 Hz, 1 H; Z NH),
2
5.40 (s, 2 H, Bn CH2), 5.24 (d, JH,H = 16.2 Hz, 1 H; PhtNCH2),
5.17 (d, 2JH,H = 16.2 Hz, 1 H; PhtNCH2), 5.08 (d, 2JH,H = 12.3 Hz,
IR (KBr): ν = 3420, 2967, 1775, 1718, 1613, 1511, 1468, 1421, 1394,
˜
2
1 H; Z CH2), 5.03 (d, JH,H = 12.3 Hz, 1 H; Z CH2), 4.77 (dd,
1245, 1190, 1118, 1068, 941, 828, 793, 715, 648, 607, 531 cm–1. UV/
3JH,H = 9.3, JH,H = 5.9 Hz, 1 H; Val α-CH), 2.17–2.06 (m, 1 H,
Vis (MeOH, c = 0.060 mg/mL): λmax (log ε) = 220 (4.63), 240 (4.18),
3
Val β-CH), 0.86 (d, 3JH,H = 6.8 Hz, 6 H; Val CH3) ppm. 13C NMR 290 (4.29) nm. ESI-HRMS: m/z calcd. for [C17H18N3O5]+ 344.1241,
(75 MHz, CDCl3): δ = 167.1 (q, 2 PhtN CO), 163.0 (q, oxazole C- found 344.1269.
5), 161.1 (q, CO2Bn), 155.9 (q, oxazole C-2), 152.0 (q, Z CO), 136.1
Scaffolds 17 and 18: To a solution of the free amino acid 16
(q, oxazole C-4), 135.3 (q, Bn C-1), 134.3 (t, PhtN CH-3,4), 131.8
(1.717 g, 5.0 mmol) in dry DMF (125 mL) were added PyBOP
(q, Z C-1), 128.8 (q, PhtN C-1,6), 128.62 (t, Bn CH-2,6), 128.57 (t,
(3.903 g, 7.5 mmol) and iPr2NEt (4.201 g, 32.5 mmol) under argon
Z CH-2,6), 128.5 (t, Bn CH-3,5), 128.4 (t, Z CH-3,5), 128.1 (t, Bn
atmosphere at 0 to 5 °C. After 15 min the cooling bath was re-
CH-4), 128.0 (t, Z CH-4), 123.6 (t, PhtN CH-2,5), 67.1 (s, Z CH2),
moved and stirring was continued at room temperature for further
67.0 (s, Bn CH2), 54.6 (t, Val α-CH), 32.9 (s, PhtNCH2), 32.85 (t,
72 h. The solvent was then evaporated in vacuo, and purification
Val β-CH), 18.5 (p, Val CH3), 17.8 (p, Val CH3) ppm. UV/Vis
of the product was performed by flash chromatography on silica
(MeOH, c = 0.0049 mg/mL): λmax (log ε) = 215 (4.59), 238 (sh,
gel (DCM/EtOAc/MeOH, 75:25:0Ǟ75:25:3) to yield 0.514 g
4.18), 297 (2.96) nm. ESI-HRMS: m/z calcd. for [C32H30N3O7]+
(31.6%) of oxazole trimer 17 and 0.182 g (11.2%) of oxazole tetra-
568.2078, found 568.2074.
mer 18 as white powders.
Oxazolecarboxylic Acid 22: Oxazole 15a (2.668 g, 5.0 mmol) in
methanol (50 mL) was hydrogenated at room temperature and at-
mospheric pressure using Pearlman’s catalyst (0.050 g, 20%
1
Data for 17: TLC: Rf = 0.50 (DCM/EtOAc, 3:1, silica). H NMR
3
(500 MHz, CDCl3): δ = 8.09 (d, JH,H = 7.9 Hz, 1 H; amide NH),
7.83 (dd, JH,H = 5.5, JH,H = 3.1 Hz, 2 H, 2 H; PhtN CH-2,5),
3
4
Pd(OH)2 on charcoal). The reaction was monitored by TLC, and
on completion (3 h) the catalyst was filtered off and washed with
several portions of methanol. The filtrate was then evaporated and
dried in vacuo to obtain 2.171 g (97.9%) of the free acid 22 as a
white solid. 1H NMR (300 MHz, CDCl3): δ = 8.70 (br. s, 1 H;
3
4
7.71 (dd, JH,H = 5.5, JH,H = 3.1 Hz, 2 H; PhtN CH-3,4), 5.34 (d,
2JH,H = 16.3 Hz, 1 H; PhtNCH2), 5.21 (d, JH,H = 16.3 Hz, 1 H;
2
3
3
PhtNCH2), 4.99 (dd, JH,H = 7.9, JH,H = 5.0 Hz, 1 H; Val α-CH),
3
2.27–2.18 (m, 1 H, Val β-CH), 0.94 (d, JH,H = 6.9 Hz, 3 H, Val
CH3), 0.92 (d, JH,H = 6.9 Hz, 3 H, Val CH3) ppm. 13C NMR
3
4
CO2H), 7.87 (dd, 3JH,H = 5.2, JH,H = 3.1 Hz, 2 H; PhtN CH-2,5),
(125 MHz, CDCl3): δ = 167.0 (q, 2 PhtN CO), 161.8 (q, oxazole
C-2), 159.8 (q, CONH), 149.3 (q, oxazole C-5), 134.1 (t, PhtN CH-
3,4), 131.8 (q, PhtN C-1,6), 130.0 (q, oxazole C-4), 123.5 (t, PhtN
CH-2,5), 52.9 (t, Val α-CH), 33.4 (t, Val β-CH), 32.4 (s, PhtNCH2),
3
4
7.74 (dd, JH,H = 5.2, JH,H = 3.1 Hz, 2 H; PhtN CH-3,4), 6.17 (d,
3JH,H = 9.5 Hz, 1 H; Boc NH), 5.28 (s, 2 H, PhtNCH2), 4.71 (dd,
3JH,H = 9.5, JH,H = 6.3 Hz, 1 H; Val α-CH), 2.18–2.03 (m, 1 H,
3
3
Val β-CH), 1.37 (s, 9 H, Boc CH3), 0.86 (t, JH,H = 6.8 Hz, 6 H;
18.2 (p, Val CH ), 18.1 (p, Val CH ) ppm. IR (KBr): ν = 3390,
˜
3
3
Val CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.1 (q, 2 PhtN
CO), 164.5 (q, oxazole C-5), 163.8 (q, CO2H), 155.7 (q, oxazole C-
2), 152.9 (q, Boc CO), 134.3 (t, PhtN CH-3,4), 131.8 (q, PhtN C-
1,6), 128.3 (q, oxazole C-4), 123.6 (t, PhtN CH-2,5), 79.8 (q, Boc
C(CH3)3), 54.3 (t, Val α-CH), 32.9 (s, PhtNCH2), 32.8 (t, Val β-
CH), 28.2 (p, Boc CH3), 18.6 (p, Val CH3), 18.0 (p, Val CH3) ppm.
2966, 2933, 2876, 1776, 1722, 1683, 1637, 1576, 1524, 1468, 1423,
1391, 1197, 1087, 943, 903, 787, 753, 714, 611, 531 cm–1. UV/Vis
(MeOH, c = 0.0034 mg/mL): λmax (log ε) = 220 (5.189), 294 (3.790)
nm. CD (MeOH, c = 0.0034 mg/mL): λ (∆ε [dm3 ml–1 cm–1]) = 201
(+16.4), 211 (0.0), 220 (–31.2) nm. ESI-HRMS: m/z calcd. for
[C51H46N9O12]+ 976.3260, found 976.3293.
IR (KBr): ν = 3387, 2973, 2935, 1776, 1726, 1617, 1514, 1468, 1420,
˜
1393, 1368, 1307, 1247, 1171, 1116, 1070, 1015, 941, 715, 530 cm–1.
UV/Vis (CH2Cl2, c = 0.072 mg/mL): λmax (log ε) = 240 (4.259),
296 (3.22) nm. ESI-HRMS: m/z calcd. for [C22H26N3O7]+ 444.1765,
found 444.1773.
Data for 18: This compound contained even after several chroma-
tographic purifications traces of 17. TLC: Rf = 0.47 (DCM/EtOAc,
3:1, silica). 1H NMR (500 MHz, CDCl3): δ = 7.83 (dd, 3JH,H = 5.5,
4JH,H = 3.1 Hz, 2 H, 2 H; PhtN CH-2,5), 7.71 (dd, JH,H = 5.5,
3
4JH,H = 3.1 Hz, 2 H; PhtN CH-3,4), 7.25 (d, JH,H = 9.8 Hz, 1 H;
3
3
3
Oxazolecarboxylic Acid Hydrochloride Salt 16. Preparation from
15b: To a solution of 15b (2.838 g, 5.0 mmol) in MeOH (87.5 mL)
2  aqueous HCl (12.5 mL, 25.0 mmol) and Pd/C catalyst (5%,
0.050 g) were added, and the mixture was stirred under hydrogen
atmosphere (105 Pa) at room temperature for 6 h. On completion
the catalyst was removed through filtration and evaporation of the
filtrate afforded 1.889 g (99.5%) of the hydrochloride salt 16 as a
white powder.
amide NH), 5.25 (s, 2 H, PhtNCH2), 5.13 (dd, JH,H = 9.8, JH,H
= 7.6 Hz, 1 H; Val α-CH), 2.27–2.17 (m, 1 H, Val β-CH), 0.96 (d,
3JH,H = 6.8 Hz, 3 H; Val CH3), 0.88 (d, JH,H = 6.8 Hz, 3 H; Val
3
CH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 167.1 (q, 2 PhtN
CO), 161.8 (q, oxazole C-2), 160.1 (q, CONH), 149.5 (q, oxazole
C-5), 134.1 (t, PhtN CH-3,4), 131.8 (q, PhtN C-1,6), 130.2 (q, ox-
azole C-4), 123.5 (t, PhtN CH-2,5), 51.4 (t, Val α-CH), 33.1 (t, Val
β-CH), 32.8 (s, PhtNCH2), 18.6 (p, Val CH3), 18.4 (p, Val CH3)
ppm. ESI-HRMS: m/z calcd. for [C68H60N12O16]+ 1301.4323,
found 1301.4394.
Preparation from 22: To a solution of HCl in EtOAc (15%, 30 mL)
oxazole carboxylic acid 22 (2.217 g, 5.0 mmol) was added, and the
mixture was stirred for 2 h at ambient temperature. The volatiles
were then removed in vacuo to provide 1.862 g (98.1%) of the hy-
drochloride salt 16 as a white powder, which was used in the next
step without further purification. 1H NMR (300 MHz, [D6]-
Scaffold 19: To a solution of 17 (0.195 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 mix-
ture was stirred for further 24 h. The resulting suspension was con-
centrated and dried in vacuo, then covered with DCM (50 mL)
followed by the addition of benzyl chloroformate (0.341 g,
DMSO): δ = 8.98 (br. s, 4 H; CO2H und NH3+), 7.94–7.86 (m, 4
3
H, PhtN CH-2,3,4,5), 5.20 (s, 2 H, PhtNCH2), 4.36 (d, JH,H
=
6.0 Hz, 1 H; Val α-CH), 2.28–2.16 (m, 1 H, Val β-CH), 0.91 (d, 2.0 mmol) and Et3N (0.304 g, 3.0 mmol). After stirring at room
3
3JH,H = 6.8 Hz, 3 H; Val CH3), 0.77 (d, JH,H = 6.8 Hz, 3 H; Val temperature for 6 h the mixture was concentrated and the residue
CH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 166.9 (q, oxazole
was subjected to column chromatography on silica gel (DCM/
Eur. J. Org. Chem. 2008, 2375–2387
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2385

Á. Pintér, G. Haberhauer
FULL PAPER
1
EtOAc/MeOH, 75:25:0Ǟ75:25:5) to yield 0.112 g (57.0%) of 19 0.070 g (quant.) of 1. H NMR (500 MHz, [D4]MeOH): δ = 8.54
as a colorless glassy solid. TLC: Rf = 0.67 (DCM/EtOAc/MeOH,
(d, 3JH,H = 7.9 Hz, 1 H; amide NH), 5.24–5.21 (m 1 H; Val α-CH),
4.60 (s, 2 H, CH2NH3+), 2.45–2.38 (m, 1 H, Val β-CH), 1.09 (d,
1
3
75:25:3, silica). H NMR (500 MHz, CDCl3): δ = 8.15 (d, JH,H
=
3
7.9 Hz, 1 H; CONH), 7.35–7.29 (m, 5 H, Ph CH-2,3,4,5,6), 6.34
3JH,H = 6.9 Hz, 3 H; Val CH3), 1.06 (d, JH,H = 6.9 Hz, 3 H; Val
(br. t, 1 H; ZNHCH2), 5.14 (d, 2JH,H = 12.2 Hz, 1 H; Z CH2), 5.09 CH3) ppm. 13C NMR (125 MHz, [D4]MeOH): δ = 164.4 (q, ox-
2
(d, JH,H = 12.2 Hz, 1 H; Z CH2), 5.08 (d, 1 H, Val α-CH), 4.74–
azole C-2), 161.7 (q, CONH), 149.6 (q, oxazole C-5), 133.2 (q, ox-
2
3
4.69 (dd, JH,H = 16.5, JH,H = 6.3 Hz, 1 H; ZNHCH2), 4.71–4.66
azole C-4), 54.7 (t, Val α-CH), 34.9 (s, CH2NH3+), 34.8 (t, Val β-
2
3
(dd, JH,H = 16.5, JH,H = 6.0 Hz, 1 H; ZNHCH2), 2.34–2.24 (m, CH), 18.9 (p, Val CH ), 18.5 (p, Val CH ) ppm. IR (KBr): ν =
˜
3
3
3
1 H, Val β-CH), 1.03 (d, JH,H = 6.7 Hz, 3 H; Val CH3), 0.99 (d,
3438, 3380, 2967, 2877, 2607, 1661, 1579, 1540, 1474, 1446, 1410,
3JH,H = 6.7 Hz, 3 H; Val CH3) ppm. 13C NMR (125 MHz, CDCl3): 1373, 1326, 1295, 1275, 1252, 1216, 1200, 1160, 1128, 1079, 1021,
δ = 161.4 (q, oxazole C-2), 160.5 (q, CONH), 156.3 (q, Z CO), 982, 939, 902, 822, 784, 775, 725, 644, 614 cm–1. UV/Vis (MeOH,
153.3 (q, oxazole C-5), 136.3 (q, Ph C-1), 129.8 (q, oxazole C-4),
c = 0.0053 mg/mL): λmax (log ε) = 221 (4.661) nm. CD (MeOH, c
128.41 (t, Ph CH-3,4,5), 128.05 (t, Ph CH-2,6), 66.9 (s, Z CH2), = 0.0053 mg/mL): λ (∆ε [dm3 mol–1 cm–1]) = 208 (+24.2), 218 (0.0),
53.0 (t, Val α-CH), 36.0 (s, ZNHCH2), 33.4 (t, Val β-CH), 18.36 (t, 232 (–48.6) nm. ESI-HRMS: m/z calcd. for [C27H40N9O6]+
Val CH3), 18.15 (t, Val CH3) ppm. UV/Vis (MeOH, c = 0.0099 mg/
mL): λmax [nm] (log ε) = 210 (4.792), 225 (4.687), 286 (3.196) nm.
CD (MeOH, c = 0.0099 mg/mL): λ [nm] (∆ε [dm3 ml–1 cm–1]) =
208 (+15.4), 217 (0.0), 231 (–35.2) nm. ESI-HRMS: m/z calcd. for
[C51H58N9O12]+ 988.4199, found 988.3919.
586.3096, found 586.3077.
Ligand 4: To a slurry of NaH (0.019 g, 0.48 mmol) in dry THF
(2 mL) a solution of 2 (0.024 g, 0.04 mmol) in THF (6 mL)
was added then stirred for 60 minutes at room temperature
under Argon. 5-Bromomethyl-5Ј-methyl-2,2Ј-bipyridine (0.042 g,
0.16 mmol) was added and the mixture was refluxed overnight. Sol-
vent was evaporated and the remaining solid was subjected to col-
umn chromatography on alumina (Brockmann IV, neutral) using
NH/EtOAc, 50:50Ǟ10:90 to yield 0.015 g (33.0%) of 4 as a white
solid. TLC: Rf = 0.47 (NH/EtOAc, 30:70; Al2O3). 1H NMR
(500 MHz, CDCl3): δ = 8.59 (s, 1 H, Bipy CH-6), 8.47 (s, 1 H, Bipy
Scaffold 20: To a solution of 17 (0.195 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 mix-
ture was stirred for further 24 h. The resulting suspension was co-
oled to 0 to 5 °C, and a solution of di-tert-butyl dicarbonate
(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 3 h. Then solvents were evaporated in vacuo,
and column chromatography of the residue on silica gel (DCM/
EtOAc/MeOH, 75:25:0Ǟ75:25:4) yielded 0.164 g (92.3%) of 20 as
a colorless solid. TLC: Rf = 0.70 (DCM/EtOAc/MeOH, 75:25:3,
3
3
CH-6Ј), 8.31 (d, JH,H = 8.1 Hz, 1 H; Bipy CH-3), 8.23 (d, JH,H
3
= 8.1 Hz, 1 H; Bipy CH-3Ј), 8.19 (d, JH,H = 7.9 Hz, 1 H; amide
3
3
NH), 7.78 (d, JH,H = 8.1 Hz, 1 H; Bipy CH-4), 7.59 (d, JH,H
=
3
3
8.1 Hz, 1 H; Bipy CH-4Ј), 5.13 (dd, JH,H = 7.8, JH,H = 4.8 Hz, 1
H; Val α-CH), 5.01 (s, 2 H, CH2OCH2Bipy), 4.68 (s, 2 H,
CH2OCH2Bipy), 2.39–2.33 (m, 1 H, Val β-CH), 2.38 (s, 3 H, Bi-
1
3
silica). H NMR (500 MHz, CDCl3): δ = 8.14 (d, JH,H = 7.9 Hz,
3
3
3
1 H; CONH), 5.82 (br. s, 1 H; BocNHCH2), 5.03 (dd, JH,H = 7.9,
pyCH3), 1.07 (d, JH,H = 6.9 Hz, 3 H; Val CH3), 1.03 (d, JH,H
=
3JH,H = 4.7 Hz, 1 H; Val α-CH), 4.63 (dd, JH,H = 16.4, JH,H
=
2
3
6.9 Hz, 3 H; Val CH3) ppm. 13C NMR (125 MHz, CDCl3): δ =
162.6 (q, oxazole C-2), 160.0 (q, CONH), 155.8 (q, Bipy C-2), 153.2
(q, Bipy C-2Ј), 151.7 (q, oxazole C-5), 149.5 (t, Bipy CH-6Ј), 148.5
(t, Bipy CH-6), 137.5 (t, Bipy CH-4Ј), 136.4 (t, Bipy CH-4), 133.5
(q, Bipy C-5Ј), 132.8 (q, Bipy C-5), 131.4 (q, oxazole C-4), 120.6
(t, Bipy CH-3Ј), 120.5 (t, Bipy CH-3), 70.3 (s, CH2OCH2Bipy), 61.5
(s, CH2OCH2Bipy), 53.2 (t, Val α-CH), 33.6 (t, Val β-CH), 18.45
(p, BipyCH3), 18.33 (p, 2 Val CH3) ppm. UV/Vis (MeOH/H2O, 1:1,
c = 0.0114 mg/mL): λmax (log ε) = 236 (5.06), 274 (sh, 4.77), 292
(4.98), 300 (sh, 4.91) nm. CD (MeOH/H2O, 1:1, c = 0.0114 mg/
mL): λ (∆ε [dm3 mol–1 cm–1]) = 218 (0), 235 (–125.9), 253 (0), 263
(+22.2), 285 (0), 295 (–7.3), 302 (0), 318 (+76.3) nm. ESI-HRMS:
m/z calcd. for [C63H67N12O9]+ 1135.5148, found 1135.5112.
2
3
6.6 Hz, 1 H; BocNHCH2), 4.55 (dd, JH,H = 16.4, JH,H = 5.7 Hz,
1 H; BocNHCH2), 2.33–2.26 (m, 1 H, Val β-CH), 1.38 (s, 9 H, Boc
3
3
C(CH3)3), 1.02 (d, JH,H = 6.9 Hz, 3 H; Val CH3), 0.97 (d, JH,H
= 6.9 Hz, 3 H; Val CH3) ppm. 13C NMR (125 MHz, CDCl3): δ =
161.20 (q, oxazole C-2), 160.4 (q, CONH), 155.5 (q, Boc CO), 153.7
(q, oxazole C-5), 129.6 (q, oxazole C-4), 79.7 (q, Boc C(CH3)3),
53.0 (t, Val α-CH), 35.4 (s, BocNHCH2), 33.4 (t, Val β-CH), 28.2
(p, Boc C(CH3)3), 18.2 (t, 2 Val CH3) ppm. UV/Vis (MeOH, c =
0.0116 mg/mL): λmax (log ε) = 223 (4.545), 297 (2.608) nm. CD
(MeOH, c = 0.0116 mg/mL): λ (∆ε [dm3 mol–1 cm–1]) = 207 (+13.3),
217 (0.0), 231 (–28.9) nm. ESI-HRMS: m/z calcd. for
[C42H64N9O12]+ 886.4669, found 886.4682.
Scaffold 1. Preparation from 17: To a solution of 17 (0.098 g,
0.10 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 re-
sulting suspension was concentrated and dried in vacuo, then
treated with 2  HCl (50 mL) and insoluble phthalylhydrazide was
filtered off. The filtrate was extracted with DCM (3ϫ50 mL), then
evaporated and dried in vacuo to yield 0.056 g (80.6%) of 1.
UV-Absorption and CD-Spectrophotometric Titrations: For the UV-
absorption and CD-spectrophotometric titrations stock solutions
of the ligand (10–3  in MeOH) and of the metal salts (10–3–10–2

in MeOH or H2O) were prepared. Automatized titrations were per-
formed at 20 °C using 1-cm-path-length quartz cuvettes. To a li-
gand solution (2.500 mL; cligand = 10–5  in MeOH/H2O (1:1),
using TRIS/HCl buffer (0.10 /0.02 ) at pH = 8.90) in the cuvette
a ligand-metal solution (up to 0.500 mL; cligand = 10–5 , cmetal ion
= 2ϫ10–4 to 5ϫ10–4 , using TRIS/HCl buffer (0.10 /0.02 ) at
pH = 8.90) was added in discrete steps by the titration accessory
and after appropriate mixing time (3–10 min) spectra were re-
corded.
Preparation from 19: Platform 19 (0.099 g, 0.10 mmol) was dis-
solved in MeOH (40 mL), then treated with 2  HCl (10 mL) and
palladium on charcoal catalyst (20%; 0.050 g) was added. The mix-
ture was hydrogenated at atmospheric pressure for 4 h, then filtered
and evaporated to give 0.061 g (87.8%) of 1.
A continuous titration experiment for Job-plot analysis was per-
formed with ligand and metal salt solutions of same concentration
(2ϫ10–5 ) keeping the total volume constant by removing the
same volume of titrated solution from the cuvette before each ad-
dition of the titrant.
Preparation from 20: Scaffold 20 (0.089 g, 0.10 mmol) was treated
with HCl/EtOAc solution (15%, 30 mL) at room temperature for
2 h. Volatiles were then removed in a rotary evaporator and the
resulting white solid was exhaustively dried in vacuo to afford
2386
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2375–2387

Oxazole Cyclopeptides for Chirality Transfer
ESI-HRMS data for the complexes 4·M2+
4·Zn2+ m/z calcd. for [C63H66N12O964Zn]2+ 599.2178, found
599.2233.
4·Cu2+
598.7217.
4·Co2+
596.7243.
4·Ni2+ m/z calcd. for [C63H67N12O958Ni]2+ 596.2209, found
:
Anslyn, Chem. Eur. J. 2002, 8, 2218; i) J. Bitta, S. Kubik, Org.
Lett. 2001, 3, 2637; j) R. D. Ionescu, T. Frejd, Chem. Commun.
2001, 1088; k) G. R. L. Cousins, R. L. E. Furlan, Y.-F. Ng, J. E.
Redman, J. K. M. Sanders, Angew. Chem. Int. Ed. 2001, 40,
423; l) D. Q. McDonald, W. C. Still, J. Am. Chem. Soc. 1996,
118, 2073.
:
:
m/z calcd. for [C63H67N12O963Cu]2+ 598.7180, found
m/z calcd. for [C63H66N12O959Co]2+ 596.7198, found
[5]
[6]
a) D. Moon, S. Kang, J. Park, K. Lee, R. P. John, H. Won,
G. H. Seong, Y. S. Kim, G. H. Kim, H. Rhee, M. S. Lah, J.
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Supporting Information (see also the footnote on the first page of
this article): Schematic representation of the four different con-
formers P1, P2, M1, and M2 of the 4·Zn2+ complex.
For reviews on the isolation, structure and synthesis of the Lis-
soclinum cyclic peptides see: a) P. Wipf, in Alkaloids: Chemical
and Biological Perspectives (Ed.: S. W. Pelletier), Elsevier, Am-
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Acknowledgments
[7]
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This work was generously supported by the Deutsche Forschungs-
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helpful discussions.
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Published Online: March 27, 2008
Eur. J. Org. Chem. 2008, 2375–2387
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2387