Syntheses and structures of imidazole analogues of Lissoclinum cyclopeptides

Article abstract of DOI:10.1002/ejoc.200300207

The syntheses of the cyclic peptides 3-7, which contain imidazole units in their backbones and resemble naturally occurring marine cyclopeptides such as westiellamide and ascidiacyclamide, are described. Structural investigations on the trimer 3 reveal a molecular triangle conformation with all lone pairs of the imidazole nitrogen atoms and the hydrogen atoms of the secondary amides directed to the center of the macrocycle. The structures of the tetramers 4 and 6 display distorted molecular square conformations with the heterocycles (4) and the αCH groups (6) placed at the comers of the rectangle, respectively. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).

Full text of DOI:10.1002/ejoc.200300207

FULL PAPER
Syntheses and Structures of Imidazole Analogues of Lissoclinum Cyclopeptides
Gebhard Haberhauer*[a] and Frank Rominger[a]
Keywords: Amino acids / Cyclization / Imidazoles / Natural products / Peptidomimetics
The syntheses of the cyclic peptides 3−7, which contain im-
idazole units in their backbones and resemble naturally oc-
curring marine cyclopeptides such as westiellamide and asci-
diacyclamide, are described. Structural investigations on the
trimer 3 reveal a molecular triangle conformation with all
lone pairs of the imidazole nitrogen atoms and the hydrogen
atoms of the secondary amides directed to the center of the
macrocycle. The structures of the tetramers 4 and 6 display
distorted molecular square conformations with the hetero-
cycles (4) and the αCH groups (6) placed at the corners of
the rectangle, respectively.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
structural elements in basic active sites of enzymes.[11] How-
ever, no cyclopeptides containing imidazole units in the
scaffold have yet been isolated from nature. This may be
due to the fact that the diaminopropanoic acid (Dap), for-
mally the amino analogue of serine, rarely occurs in natural
sources.[12] This prompted us to synthesize the peptides 3Ϫ7
(Figure 1), which contain imidazole units in their back-
bones and resemble naturally occurring marine cyclopep-
tides such as westiellamide and ascidiacyclamide, and also
A wide variety of unusual cyclopeptide alkaloids have
been isolated from marine sources in recent years.[1] These
compounds have usually been identified as secondary
metabolites of algae, fungi, and primitive marine organisms,
possessing various biological activities, including cytotox-
icity, antibacterial activities, and antiviral activities.[2] Ex-
amples of their ability to overcome multidrug resistance or
to act as antineoplastic agents have been found.[3] The Lis-
soclinum class of cyclic peptides, such as westiellamide (1)[4]
or ascidiacyclamide (2),[5] belongs to these alkaloids and is
characterized by an alternating sequence of oxazole, thia-
zole, oxazoline, and thiazoline moieties with hydrophobic
standard amino acid residues.[6] These five-membered het-
erocyclic rings result from condensation of serine, thre-
onine, and cysteine side chains with the preceding carbonyl
groups in a peptide sequence. The unique macrocyclic het-
erocyclic scaffolds in Lissoclinum cyclopeptides have
prompted the speculation that they may function in vivo
as metal complexation and transport agents.[7] Evidence for
metal complexation properties of Lissoclinum cyclopeptide
alkaloids has been obtained by metal ion binding studies to
westiellamide, patellamides, and ascidiacyclamide.[8] Ad-
ditionally, intensive investigations concerning the appli-
cation of properties resulting from this particularly rigid
structure have been conducted.[9]
The imidazole unit, as part of the side chain of histidine,
plays a major role in the biological functions of many pep-
tides and proteins. Imidazoles, for example, are well known
as ligands in many metalloenzymes (e.g. metalloprote-
ases),[10] and due to their basicity, have proven to be key
[a]
Organisch-Chemisches Institut der Universität Heidelberg,
Universität Heidelberg,
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax: (internat.) ϩ 49-(0)6221/544205
E-mail: gebhard.haberhauer@urz.uni-heidelberg.de
Figure 1. Lissoclinum cyclopeptides and their imidazole analogues
Eur. J. Org. Chem. 2003, 3209Ϫ3218
DOI: 10.1002/ejoc.200300207
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3209

G. Haberhauer, F. Rominger
FULL PAPER
to investigate the structure modifications caused by the in-
troduction of these imidazole moieties.
Removal of the Boc group of 11 with HCl in ethyl acetate
provided the hydrochloride 14, which was coupled to the
free acid building block 12 by use of 1-(3-dimethylaminop-
ropyl)-3-ethylcarbodiimide hydrochloride (EDCI)[17] and
Results and Discussion
benzotriazol-1-yloxytris(pyrrolidino)phosphonium
hexa-
fluorophosphate (PyBOP)[18] as activation reagents. How-
ever, both routes resulted in low yields of the desired prod-
uct 15, often accompanied by large amounts of undesired
side products. The use of diphenyl phosphorazidate
(DPPA)[19] in the presence of Hünig’s base in acetonitrile
proved superior, finally providing 15 in 70% yield. The pro-
tected linear dimer 15 was successively subjected to methyl
and Boc deprotection to give the corresponding free amino
acid, which was dimerized by FDPP activation in aceto-
nitrile to afford the tetramer 5 in 44% yield. Overall, the
yield of this route is 29% starting from imidazole 11.
Another route for a stepwise preparation of the 24-mem-
bered cyclooctapeptide 5 is summarized in Scheme 3. Here,
the protected linear tetramer 18 was synthesized by coup-
ling of the dimeric modules 16 and 17 with DPPA and
Hünig’s base in acetonitrile. After basic and acidic protec-
tive group cleavages, macrolactamization with FDPP as
coupling reagent gave the desired cyclic peptide 5 in 45%
yield. The overall yield amounts to 18% starting from the
monomeric module 11. From comparison of the three syn-
thetic routes to the tetramer 5, it is evident that the cyclodi-
merization (Scheme 2) is the most convenient.
Synthesis
A straightforward synthesis for the 18-membered cyclo-
hexapeptide 3 and the 24-membered cyclooctapeptide 5 is
summarized in Scheme 1.[13] It started with the activation
of the Boc-protected valine 8 as a mixed anhydride by treat-
ment with isobutyl chloroformate and coupling to the keto
ester 9[14] at Ϫ20 °C. The resulting amidoketone 10 was
transformed into the imidazole 11 with methylamine in the
presence of acetic acid in refluxing xylenes with azeotropic
removal of water.[15] Deprotection of the carboxyl residue
by saponification and removal of the Boc group with HCl
in ethyl acetate afforded the amino acid 13. The one-pot
macrocyclization of the imidazole 13 was carried out
through pentafluorophenyl diphenylphosphinate (FDPP)[16]
activation and addition of Hünig’s base in acetonitrile, and
yielded the trimer 3 in 35% yield and the tetrameric com-
pound 5 in 10% yield.
Scheme 1
Because of the difficulties occurring during the separ-
ation of the tetramer 5 from the trimer 3, we also elaborated
alternative synthetic routes, which provided the tetramer 5
in significantly increased yields and in higher purity. An
appropriate way is presented in Scheme 2.
Scheme 3
We therefore also chose the cyclodimerization route for
the syntheses of the C2-symmetric cyclooctapeptides 6 and
7 (Scheme 4). The amidoketone 10 was transformed either
into the oxazole module 19 or into the thiazole module 20
by use of PPh3 in the presence of CCl4 and Et3N[20] or
Lawesson’s reagent,[21] respectively. After acid cleavage of
Scheme 2
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Eur. J. Org. Chem. 2003, 3209Ϫ3218

Syntheses and Structures of Imidazole Analogues of Lissoclinum Cyclopeptides
FULL PAPER
the Boc group, the resulting hydrochlorides 21 and 22 were
coupled to the imidazole acid 12 with DPPA and Hünig’s
base in acetonitrile to afford the dimers 23 and 24 in 65%
and 60% yields, respectively. Protective groups were re-
moved from the carboxylic acid and amino termini and the
dimeric modules were subjected to cyclization by FDPP ac-
tivation in the presence of Hünig’s base in acetonitrile. After
two days, the reaction mixtures were worked up and the
macrocycles 6 and 7 could be isolated in 35% and 56%
yields, respectively.
Scheme 5
(Scheme 5).[26] Condensation of oxazoline acid 27 with hy-
drochloride salt 28 with the aid of DPPA in the presence of
Hünig’s base in acetonitrile gave the dimer 29 in 68% yield.
Removal of the Z group and the benzyl ester in 29 was
achieved by catalytic hydrogenation with Pd(OH)2 in meth-
anol. The final cyclodimerization step was successfully im-
plemented by treatment of the crude amino acid with FDPP
and Hünig’s base in acetonitrile. Isolation of the product
afforded the desired macrocycle 4 in 30% yield.
Scheme 4. i) PPh3, Et3N, CCl4, 86% for 19; Lawesson’s reagent,
75% for 20. ii) HCl/EtOAc, quant. iii) 12, DPPA, iPr2NEt, 65% for
23, 60% for 24. iv) 2  NaOH. v) HCl/EtOAc. vi) FDPP, iPr2NEt,
CH3CN, 35% for 6, 56% for 7
A challenging aspect in the preparation of the macrocycle
4 is the presence of trans-4,5-disubstituted oxazoline, which
turned out to be an acid-sensitive and readily opened moi-
ety, in the peptide backbone (Scheme 5).[22] For this reason,
in earlier works on peptide macrocycles the oxazoline ring-
closure was delayed until the final step.[23] Additionally, pre-
liminary studies in our lab have shown that the oxazoline
moiety is not stable under the reaction and workup con-
ditions necessary for the cleavage of a methyl ester at an
imidazole ring. However, there are particular cases in which
the preconstructed oxazoline was employed successfully.[24]
We chose to follow this strategy, since we expected that the
incorporation of a further rigid moiety (the oxazoline) into
the tetrapeptide sequence of 29 in addition to the presence
of the imidazole ring should significantly facilitate the ring-
closure process through backbone bending. Moreover, as
protecting groups in 29 we decided to use the Z group for
the amine and the benzyl ester for the acid, since both
should be removable under non-acidic conditions. The -
valine-derived imidazole 32 (Scheme 6) was prepared in the
same way as its enantiomer (11, Scheme 1). Transesterifi-
cation of the methyl ester 32 to the benzyl ester 34 was
accomplished by saponification with sodium hydroxide and
Scheme 6
Structural Investigations
The NMR spectra (1H, 13C) for the 18-membered peptide
subsequent alkylation with benzyl bromide and DBU (1,8- 3 and the 24-membered peptide 5 indicate that they are C3-
diazabicyclo[5.4.0.]undec-7-ene)[25] in acetonitrile. The and C4-symmetric, respectively. The 1H NMR spectra for 3
benzyl ester 34 was then subjected to amine deprotection and 5 are similar, although the doublets of the amide NH
with HCl in ethyl acetate, providing the hydrochloride salt resonances in 3 are shifted about δ ϭ 0.8 ppm further
28 in essentially quantitative yield. The oxazoline 27 was downfield than those in 5, suggesting that the interaction
obtained as follows, by the procedure reported by Wipf between the lone pairs of the imidazole nitrogen and the
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G. Haberhauer, F. Rominger
FULL PAPER
Figure 2. Molecular structures of 3, 6, and 4: top view (upper row) and side view (lower row); all hydrogen atoms have been omitted
for clarity
hydrogen of the secondary amides are probably stronger in macrocycle plane, respectively. The distances between the
3 than in 5. The vicinal 3JNHCH values of 8.9 Hz and 9.1 Hz opposite heterocycles amount to 6.3 A for the imidazoles
˚
˚
for 3 and 5, respectively, correspond to dihedral angles of and 7.8 A for the oxazoles. The -valine side chains are in
160° Ͻ θ Ͻ 180° in both macrocycles.[27]
pseudoaxial orientation and are all directed from the same
In the case of 3 we were able to obtain single crystals by face of the macrocycle. The NHαCH dihedral angles of the
crystallization from acetone (Figure 2).[13] The 18-mem- amide linkages in 6 are between 164° and 173°, which is in
bered peptide 3 adopts a molecular triangle conformation agreement with the values determined by H NMR spec-
1
in the solid state. As in the case of the X-ray analyses of troscopy.
the closely related westiellamide[4] (1) and nostocylamide,[28]
The macrocycle 4 shows NMR spectra consistent with
there are no intra- or intermolecular hydrogen bonds, their a C2-symmetric structure in solution. The vicinal coupling
formation being prevented by the disposition of the peptide constants (3JNHCH) amount to 8.7 Hz and 9.9 Hz. It is
NH groups into the center of the ring and peptide carbonyl known that thiazole- and oxazoline-containing cyclic octa-
functions toward the outside of the ring. The valine side peptide patellamides, which resemble the octapeptide 4 re-
chains of 3 all lie on the same face of the molecule and garding the oxidation states of the azoles and configura-
adopt axial positions. Unlike in the structures of westiella- tions of the adjacent side chains, exist in one of two confor-
mide and nostocylamide, the azole moieties of the macrocy- mations (square and folded forms) depending on the side
cle 3 do not form a single plane but have a cone-like struc- chains present in the molecule.[29] However, it became ap-
ture, their deviation from the coplanar structure amounting parent that the values of the vicinal coupling constants
to about 33°. The NHαCH dihedral angles of the three am- (3JNHCH) are not an appropriate means for distinguishing
ide linkages in 3 were found to be between 168 and 173°, the two conformers of symmetric patellamides.[30] Accord-
which is consistent with the values determined by 1H ingly, the observed NMR spectroscopic data are not suf-
NMR spectroscopy.
ficient for unambiguous determination of the conformation
The NMR spectra of 6 and 7 indicate that they are C2- of 4 in solution. X-ray diffraction analysis of a single crystal
symmetric. The values for the NH amide resonances (δ ϭ of 4 revealed that two crystallographically independent
7.32 ppm and 7.65 ppm for 6; δ ϭ 7.65 ppm and 7.92 ppm molecules of 4 exist in the asymmetric unit, and their con-
3
for 7) and for the vicinal coupling JNHCH (9.9 Hz and formations are similar to each other. Therefore, only one
9.0 Hz for 6; 9.2 Hz and 9.1 Hz for 7) are similar to those molecule is shown in Figure 2. The macrocycle displays a
of the tetramer 5 (δ ϭ 7.53 ppm; 9.1 Hz), thus suggesting molecular square or saddle-shaped conformation in which
that all three 24-membered peptides adopt similar confor- the imidazole and oxazoline rings are separated from each
mations in solution. Single crystals of 6 could be obtained other and located at the corners of the backbone ring. The
by crystallization from dichloromethane/petroleum ether at valine side chains are in pseudoaxial orientation, the -val-
room temperature. Tetramer 6 displays a distorted molecu- ine groups adjacent to the imidazole ring and the -valine
lar square conformation with the αCH groups placed at the groups adjacent to the oxazoline ring protruding over and
corners of the rectangle (Figure 2). The imidazole and the under the ring chain, respectively. These features are similar
oxazole moieties are tilted about 70° and 15° out of the to the square form of ascidiacyclamide.[31]
3212
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Eur. J. Org. Chem. 2003, 3209Ϫ3218

Syntheses and Structures of Imidazole Analogues of Lissoclinum Cyclopeptides
FULL PAPER
45.0 mmol) was added, and the solution was cooled to Ϫ25 °C.
Isobutyl chloroformate (5.91 mL, 45.0 mmol) was added while the
reaction mixture was maintained at Ϫ25 °C. After 35 min, amino
ketone 9 (7.54 g, 45.0 mmol) followed by a second equivalent of
NMM (4.95 mL, 45.0 mmol) were added at Ϫ25 °C. Stirring was
continued for 20 h while the mixture was warmed to room tempera-
ture. The solvent was evaporated and the residue was dissolved in
EtOAc, and then washed with water and brine. The organic layer
was dried with MgSO4 and concentrated in vacuo. Purification was
accomplished by chromatography on silica gel (petroleum ether/
ethyl acetate, 1:1) to yield 7 (12.71 g; 85%) as a white solid; m.p.
Conclusion
In conclusion, we have demonstrated that the preparation
of 18- and 24-membered cyclic peptides containing imidaz-
ole moieties in their backbones can be achieved in satisfac-
tory yields in few steps. The observed structures resemble
corresponding naturally occurring marine cyclopeptides
such as westiellamide and ascidiacyclamide. This means
that the modification of the structures caused by the ex-
change of oxazoline or thiazoline moieties by imidazole
rings is minimal. Future studies will aim at determining
how the imidazole unit influences further properties of the
macrocycles, such as metal complexation and biological ac-
tivity.
1
3
109Ϫ112 °C. H NMR (300 MHz, CDCl3): δ ϭ 0.91 (d, JH,H
ϭ
6.9 Hz, 3 H, CHMe2), 0.92 (d, 3JH,H ϭ 6.9 Hz, 3 H, CHMe2), 0.97
3
(d, JH,H ϭ 6.8 Hz, 6 H, CHMe2), 1.43 (s, 9 H, CMe3), 1.44 (s, 9
H, CMe3), 2.24Ϫ2.11 (m, 2 H, CHMe2), 2.38 (s, 6 H, COMe), 3.80
(s, 6 H, CO2Me), 4.06 (m, 2 H, CHCONH), 5.02 (m, 2 H, NHCO2),
5.23 (m, 2 H, CHCO2Me), 7.06 (d, 3JH,H ϭ 6.1 Hz, 1 H, NH), 7.13
3
(d, JH,H ϭ 6.0 Hz, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 17.3, 17.5, 19.1, 19.2, 27.9, 28.0, 28.3, 30.7, 30.9, 53.2, 53.3,
59.5, 62.86, 62.90, 80.2, 155.7, 166.25, 166.33, 171.4, 197.92,
197.99 ppm. IR (KBr): ν˜ ϭ 3440, 3323, 2959, 2873, 1751, 1727,
1687, 1656, 1524 cmϪ1. FAB-HRMS: m/z calcd. for C15H27N2O6
[MHϩ] 331.1869, found 331.1864. C15H26N2O6 (330.38): calcd. C
54.53, H 7.93, N 8.48; found C 54.54, H 7.92, N 8.45.
Experimental Section
General Remarks: Amino ketone 9[14] and oxazoline 27[26] were pre-
pared by reported procedures. All chemicals were reagent grade
and used as purchased. All moisture-sensitive reactions were per-
formed under argon in distilled dry solvents. Reactions were moni-
tored by TLC analysis with silica gel 60 F254 thin layer plates. Flash
chromatography was carried out on silica gel 60 (230Ϫ400 mesh).
Melting points were determined in capillary tubes and are uncor-
Methyl 2-[(S)-1-tert-Butoxycarbonylamino-2-methylpropyl]-1,5-di-
methyl-1H-imidazole-4-carboxylate (11): Acetic acid (13 mL) and
MeNH2 in MeOH (8 , 13 mL, 105 mmol) were added at room
temperature to a solution of 10 (11.56 g, 35.0 mmol) in xylenes
(220 mL). The solution was stirred at 150 °C with azeotropic re-
moval of water for 3.5 h and then cooled down to room tempera-
ture. MeNH2 in MeOH (8 , 5 mL, 40.0 mmol) and acetic acid
(10 mL) were added and the mixture was stirred at reflux with
azeotropic removal of water for 5 h. The solution was cooled, the
solvent was concentrated, and the residue was purified by chroma-
tography on silica gel (petroleum ether/ethyl acetate, 1:1) to provide
11 (8.58 g, 75%) as a white solid and in Ͼ 96% ee as determined
by HPLC analysis [Chiralpak AD-H, hexane/iso-propanol, 90:10,
0.5 mL/min, t(minor) ϭ 9.8 min, t(major) ϭ 12.8 min); m.p. 130
1
rected. H and 13C NMR spectra were measured with Bruker WH
300, Avance 300, and Avance 500 instruments. All chemical shifts
(δ) are given in ppm relative to TMS. The spectra were referenced
to deuterated solvents indicated in brackets in the analytical data.
HRMS spectra were recorded with a JEOL JMS-700 instrument.
IR spectra were measured with a Bruker Vector 22 FT-IR spec-
trometer. Elemental microanalyses were performed by the micro-
analytical laboratory of the University of Heidelberg.
Abbreviations: Boc: tert-butoxycarbonyl; FDPP: pentafluorophenyl
diphenylphosphinate; DBU: 1,8-diazabicyclo[5.4.0.]undec-7-ene;
DCM: dichloromethane; DMF: N,N-dimethylformamide; DPPA:
diphenylphosphoryl azide; NMM: N-methylmorpholine; THF:
tetrahydrofuran; Z: benzyloxycarbonyl.
1
3
°C. H NMR (300 MHz, CDCl3): δ ϭ 0.81 (d, JH,H ϭ 6.7 Hz, 3
3
H, CHMe2), 0.99 (d, JH,H ϭ 6.7 Hz, 3 H, CHMe2), 1.38 (s, 9 H,
CMe3), 2.15Ϫ2.27 (m, 1 H, CHMe2), 2.51 (s, 3 H, CHetMe), 3.54
(s, 3 H, NMe), 3.86 (s, 3 H, CO2Me), 4.51 (m, 1 H, CHCHet), 5.32
General Procedure for the Cleavage of the Methyl Ester Group: The
protected compound (1 equiv.) was dissolved in methanol/dioxane
(10:7, 0.08 ), followed by slow addition of 2  NaOH solution
(10 equiv.) at 0 °C. Stirring was continued until TLC showed the
consumption of all starting material, and then brine, 1  HCl solu-
tion, and DCM were added. The aqueous phase was repeatedly
extracted with DCM; the organic layers were combined, dried with
MgSO4, and concentrated in vacuo to give the acid compound,
which was used in the next step without further purification.
3
(d, JH,H ϭ 9.5 Hz, 1 H, NHCO2) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 10.2, 18.5, 19.6, 28.3, 30.3, 33.2, 51.4, 52.2, 79.5,
127.6, 135.9, 148.4, 155.7, 164.3 ppm. IR (KBr): ν˜ ϭ 3447, 3341,
2968, 1694, 1678, 1573, 1525 cmϪ1. FAB-HRMS: m/z calcd. for
C16H27N3O4Na [MNaϩ] 348.1899, found 348.1904. C16H27N3O4
(325.40): calcd. C 59.06, H 8.36, N 12.91; found C 58.86, H 8.37,
N 12.71.
N-Boc-Protected Aminoimidazolecarboxylic Acid 12: Compound 11
(4.88 g, 15.0 mmol) was converted into 12 as described above in the
general procedure for the cleavage of the methyl ester group. Yield:
General Procedure for the Cleavage of the Boc Group: The Boc-
protected compound (1 equiv.) was dissolved in ethyl acetate (0.1
) and the solution was cooled to 0 °C. HCl in EtOAc (10 ml/
mmol starting material) was added at that temperature. The ice
bath was removed after 30 min and stirring was continued at room
temperature for two hours. The mixture was concentrated in vacuo
to provide a quantitative yield of the hydrochloride, which was used
in the next step without further purification.
1
4.44 g (95%); m.p. 99Ϫ102 °C. H NMR (300 MHz, CDCl3): δ ϭ
3
3
0.76 (d, JH,H ϭ 6.6 Hz, 3 H, CHMe2), 1.12 (d, JH,H ϭ 6.4 Hz, 3
H, CHMe2), 1.39 (s, 9 H, CMe3), 2.48Ϫ2.62 (m, 1 H, CHMe2),
2.59 (s, 3 H, CHetMe), 3.70 (s, 3 H, NMe), 4.54 (m, 1 H, CHCHet),
7.40 (s, 1 H, NHCO2) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 9.9,
19.5, 19.6, 28.3, 31.1, 32.5, 52.8, 79.5, 125.7, 135.2, 148.9, 156.4,
163.5 ppm. IR (KBr): ν˜ ϭ 3431, 2973, 1704, 1635, 1511 cmϪ1
Methyl
amino}-3-oxobutanoate (10): (S)-BocϪValϪOH (8; 9.78 g, 312.1918. C15H25N3O4·(H2O) (329.39): calcd. C 54.69, H 8.26, N
.
2-{[(S)-2-(tert-Butoxycarbonylamino)-3-methylbutanoyl]- FAB-HRMS: m/z calcd. for C15H26N3O4 [MHϩ] 312.1923, found
45.0 mmol) was dissolved in THF (250 mL), NMM (4.95 mL,
www.eurjoc.org
12.76; found C 54.95, H 7.95, N 12.43.
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G. Haberhauer, F. Rominger
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Hydrochloride of Aminoimidazole-carboxylic Acid 13: Compound
12 (2.80 g, 9.00 mmol) was converted into 13 as described above in
procedure for the cleavage of the methyl ester group. Yield: 770 mg
(95%); m.p. 204 °C. 1H NMR (300 MHz, [D6]acetone): δ ϭ 0.90
3
3
the general procedure for the cleavage of the Boc group. Yield:
(d, JH,H ϭ 6.7 Hz, 3 H, CHMe2), 0.95 (d, JH,H ϭ 6.8 Hz, 3 H,
1
3
3
quantitative; m.p. 182 °C. H NMR (300 MHz, [D6]DMSO): δ ϭ CHMe2), 1.10 (d, JH,H ϭ 6.5 Hz, 3 H, CHMe2), 1.21 (d, JH,H
ϭ
3
3
0.80 (d, JH,H ϭ 6.7 Hz, 3 H, CHMe2), 1.06 (d, JH,H ϭ 6.6 Hz, 3 6.6 Hz, 3 H, CHMe2), 1.39 (s, 9 H, CMe3), 2.62 (s, 3 H, CHetMe),
H, CHMe2), 2.39Ϫ2.48 (m, 1 H, CHMe2), 2.51 (s, 3 H, CHetMe), 2.65 (s, 3 H, CHetMe), 2.75Ϫ2.52 (m, 2 H, CHMe2), 3.94 (s, 3 H,
3
3.73 (s, 3 H, NMe), 4.58 (m, 1 H, CHCHet), 9.16 (s, 3 H, NH3),
11.17Ϫ12.16 (s,
NMe), 3.99 (s, 3 H, NMe), 4.89 (d, JH,H ϭ 9.2, 1 H, CHCHet),
3
1
H, CO2H) ppm. 13C NMR (75 MHz, 5.24 (d, JH,H ϭ 9. 6 Hz, 1 H, CHCHet) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ ϭ 9.7, 18.1, 18.7, 31.3, 31.8, 50.6, 124.0, 136.9, [D6]acetone): δ ϭ 10.81, 10.84, 20.2, 20.5, 20.6, 21.1, 29.5, 32.8,
143.5, 161.8 ppm. IR (KBr): ν˜ ϭ 3431, 2968, 1995, 1722, 1632, 33.5, 33.7, 34.1, 54.1, 54.3, 81.2, 123.5, 124.1, 138.3, 139.1, 148.8,
1510 cmϪ1. FAB-HRMS: m/z calcd. for C10H18N3O2 [MHϩ]
212.1399, found 212.1370.
149.6, 157.5, 160.6, 161.8 ppm. IR (KBr): ν˜ ϭ 3429, 2970, 1711,
1664, 1636, 1511 cmϪ1. FAB-HRMS: m/z calcd. for C25H40N6O5
[MHϩ] 505.3138, found 505.3117.
Hydrochloride of Aminoimidazole Methyl Ester 14: Compound 11
(2.93 g, 9.00 mmol) was converted into 14 as described above in the
general procedure for the cleavage of the Boc group. Yield: quanti-
N-Boc-Protected Methyl Ester 18: iPr2NEt (233 mg, 1.80 mmol)
and DPPA (124 mg, 0.45 mmol) were added at room temperature
to acid 17 (151 mg, 0.30 mmol) and aminohydrochloride 16
(205 mg, 0.45 mmol) in acetonitrile (12 mL) and the mixture was
stirred at room temperature for 3 days. The solvent was evaporated
and the residue was dissolved in EtOAc, and then extracted with
water and brine, dried with MgSO4, and concentrated in vacuo.
The residue was then purified by chromatography on silica gel
(DCM/EtOAc/MeOH, 75:25:3) to provide 172 mg (63%) of 18 as
a white solid; m.p. 146 °C. 1H NMR (300 MHz, [D6]acetone): δ ϭ
1
tative; m.p. 67 °C. H NMR (300 MHz, [D6]DMSO): δ ϭ 0.80 (d,
3
3JH,H ϭ 6.8 Hz, 3 H, CHMe2), 1.00 (d, JH,H ϭ 6.7 Hz, 3 H,
CHMe2), 2.25Ϫ2.37 (m, 1 H, CHMe2), 2.49 (s, 3 H, CHetMe), 3.64
(s, 3 H, NMe), 3.76 (s, 3 H, CO2Me), 4.45 (m, 1 H, CHCHet), 8.85
(s, 3 H, NH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ ϭ 9.8,
18.0, 18.4, 31.0, 31.5, 50.7, 51.0, 125.5, 137.1, 143.9, 162.4 ppm. IR
(KBr): ν˜ ϭ 3432, 2963, 1733, 1633, 1511 cmϪ1. FAB-HRMS: m/z
calcd. for C11H20N3O2 [MHϩ] 226.1556, found 226.1565.
3
0.84 (d, JH,H ϭ 6.7 Hz, 3 H, CHMe2), 0.90Ϫ1.00 (m, 15 H,
N-Boc-Protected Methyl Ester 15: iPr2NEt (2.96 mL, 17.0 mmol)
and DPPA (1.63 mL, 7.50 mmol) were added at room temperature
to acid 12 (1.56 g, 5.00 mmol) and aminohydrochloride 14 (1.44 g,
5.50 mmol) in acetonitrile (50 mL), and the mixture was stirred at
room temperature for 4 days. The solvent was evaporated, and the
residue was dissolved in EtOAc, and then extracted with water and
brine, dried with MgSO4, and concentrated in vacuo. Flash chro-
matography on silica gel (DCM/EtOAc/MeOH, 75:25:2) gave 15
(1.82 g, 70%) as a white solid; m.p. 84 °C. 1H NMR (300 MHz,
[D6]acetone): δ ϭ 0.89 (m, 6 H, CHMe2), 1.02 (m, 6 H, CHMe2),
1.37 (s, 9 H, CMe3), 2.19Ϫ2.43 (m, 2 H, CHMe2), 2.51 (s, 3 H,
CHMe2), 1.04Ϫ1.08 (m, 6 H, CHMe2), 1.30 (s, 9 H, CMe3),
2.10Ϫ2.22 (m, 1 H, CHMe2), 2.34Ϫ2.50 (m, 3 H, CHMe2), 2.51 (s,
6 H, CHetMe), 2.52 (s, 3 H, CHetMe), 2.53 (s, 3 H, CHetMe), 3.56
(s, 3 H, NMe), 3.59 (s, 3 H, NMe), 3.62 (s, 3 H, NMe), 3.67 (s, 3
H, NMe), 3.68 (s, 3 H, CO2Me), 4.51 (m, 1 H, CHCHet), 4.95Ϫ5.08
3
(m, 3 H, CHCHet), 6.26 (d, JH,H ϭ 9.4 Hz, 1 H, NHCO2), 7.44
3
(m, 2 H, CONH), 7.58 (d, JH,H ϭ 9.7 Hz, 1 H, CONH) ppm. 13C
NMR (75 MHz, [D6]acetone): δ ϭ 10.69, 10.72, 10.75, 11.3, 19.9,
20.1, 20.2, 20.3, 21.1, 21.2, 21.39, 21.40, 29.5, 31.7, 31.4, 33.5, 33.7,
33.9, 34.2, 51.17, 51.28, 51.30, 51.8, 54.0, 79.9, 129.2, 130.8, 130.9,
131.6, 134.2, 134.4, 134.6, 137.8, 148.4, 148.5, 148.6, 149.9, 157.5,
CHetMe), 2.52 (s, 3 H, CHetMe), 3.59 (s, 3 H, NMe), 3.66 (s, 3 H,
164.81, 164.83, 165.9 ppm. IR (KBr): ν ϭ 3404, 2963, 2873, 1705,
1656, 1592, 1500 cmϪ1. FAB-HRMS: m/z calcd. for C46H73N12O7
[MHϩ] 905.5725, found 905.5724.
˜
NMe), 3.76 (s, 3 H, CO2Me), 4.54 (m, 1 H, CHCHet), 5.03 (m, 1
3
H, CHCHet), 6.32 (d, JH,H ϭ 9.0 Hz, 1 H, NHCO2), 7.52 (d,
3JH,H ϭ 9.7 Hz, 1 H, CONH) ppm. 13C NMR (75 MHz, [D6]ace-
tone): δ ϭ 10.7, 11.2, 19.9, 20.2, 21.05, 21.15, 29.5, 31.7, 34.1, 34.2,
51.2, 51.9, 54.0, 80.0, 129.1, 130.9, 134.2, 137.9, 148.7, 150.0, 157.5,
164.8, 165.9 ppm. IR (KBr): ν˜ ϭ 3404, 2965, 2873, 1705, 1653,
1592, 1506 cmϪ1. FAB-HRMS: m/z calcd. for C26H43N6O5 [MHϩ]
519.3295, found 519.3312. C26H42N6O5·(H2O)0.5 (527.66): calcd. C
59.18, H 8.21, N 15.93; found C 59.43, H 8.25, N 15.69.
Imidazole Trimer 3 and Imidazole Tetramer 5: iPr2NEt (0.84 mL,
4.80 mmol) and FDPP (922 mg, 2.40 mmol) were added at room
temperature to a suspension of 13 (396 mg, 1.60 mmol) in aceto-
nitrile (34 mL) and the mixture was stirred at room temperature for
3 days. The solvent was evaporated and the residue was dissolved in
EtOAc, then extracted with water and brine, dried with MgSO4,
and concentrated in vacuo. Flash chromatography on silica gel
(DCM/EtOAc/MeOH, 75:25:6) gave 3 (109 mg, 35%) as a white
solid, followed by 5 (39 mg, 10%) as a white solid.
Hydrochloride of Methyl Ester 16: Compound 15 (441 mg,
0.85 mmol) was converted into 16 as described above in the general
procedure for the cleavage of the Boc group. Yield: quantitative;
m.p. 198 °C. 1H NMR (300 MHz, [D6]DMSO): δ ϭ 0.80 (d,
Alternatively, 5 can be prepared as follows:
3
3JH,H ϭ 6.7 Hz, 3 H, CHMe2), 0.89 (d, JH,H ϭ 6.8 Hz, 3 H,
1) Dimer 15 (182 mg, 0.35 mmol) was successively subjected to
methyl and Boc deprotection to give the corresponding free amino
acid. iPr2NEt (0.24 mL, 1.40 mmol) and FDPP (211 mg,
0.55 mmol) were added at room temperature to the stirred solution
of this compound in acetonitrile (10 mL) and the mixture was
stirred at that temperature for 3 days. The solvent was evaporated,
and the residue was dissolved in EtOAc, and then extracted with
water and brine, dried with MgSO4, and concentrated in vacuo.
Purification was accomplished by chromatography on silica gel
(DCM/EtOAc/MeOH, 75:25:7) to yield 5 (59 mg, 44%) as a white
solid.
3
3
CHMe2), 0.98 (d, JH,H ϭ 6.8 Hz, 3 H, CHMe2), 1.06 (d, JH,H
ϭ
6.5 Hz, 3 H, CHMe2), 2.25Ϫ2.35 (m, 1 H, CHMe2), 2.43 (s, 3 H,
CHetMe), 2.39Ϫ2.47 (m, 1 H, CHMe2), 2.53 (s, 3 H, CHetMe), 3.56
(s, 3 H, NMe), 3.81 (s, 3 H, NMe), 3.83 (s, 3 H, CO2Me), 4.43 (m,
1 H, CHCHet), 5.07 (m, 1 H, CHCHet), 8.36 (m, 1 H, CONH), 8.71
(s, 3 H, NH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ ϭ 9.3, 9.6,
17.9, 18.1, 18.8, 19.2, 30.4, 31.2, 31.5, 31.7, 49.9, 51.0, 51.9, 128.1,
133.9, 137.3, 142.4, 148.3, 162.7, 166.1, 169.6 ppm. IR (KBr): ν˜ ϭ
3426, 2966, 2021, 1728, 1637, 1511 cmϪ1. FAB-HRMS: m/z calcd.
for C21H35N6O3 [MHϩ] 419.2771, found 419.2788.
N-Boc-Protected Amino Acid 17: Compound 15 (830 mg, 2) Tetramer 18 (72 mg, 0.08 mmol) was subjected successively to
1.60 mmol) was converted into 17 as described above in the general methyl and Boc deprotection to give the corresponding free amino
3214
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3209Ϫ3218

Syntheses and Structures of Imidazole Analogues of Lissoclinum Cyclopeptides
FULL PAPER
acid. iPr2NEt (65 mg, 0.50 mmol) and FDPP (58 mg, 0.15 mmol)
were added at room temperature to the stirred solution of this com-
pound in acetonitrile (10 mL) and the mixture was stirred for 24 h.
The solvent was evaporated, and the residue was dissolved in
EtOAc, extracted with water and brine, dried with MgSO4, and
concentrated in vacuo. Purification was accomplished by chroma-
synthesis of 15. Flash chromatography on silica gel (DCM/EtOAc/
MeOH,75:25:2) provided 23 (659 mg, 65%) as a solid; m.p. 57Ϫ59
°C. 1H NMR (300 MHz, [D6]acetone): δ ϭ 0.90 (d, 3JH,H ϭ 6.7 Hz,
3
3 H, CHMe2), 0.93 (d, JH,H ϭ 6.8 Hz, 3 H, CHMe2), 0.99 (d,
3
3JH,H ϭ 6.8 Hz, 3 H, CHMe2), 1.03 (d, JH,H ϭ 6.7 Hz, 3 H,
CHMe2), 1.39 (s, 9 H, CMe3), 2.20Ϫ2.34 (m, 2 H, CHMe2), 2.51
tography on silica gel (DCM/EtOAc/MeOH, 75:25:6) to yield 5 (s, 3 H, CHetMe), 2.59 (s, 3 H, CHetMe), 3.60 (s, 3 H, NMe), 3.82
(28 mg, 45%) as a white solid.
(s, 3 H, CO2Me), 4.57 (m, 1 H, CHCHet), 5.08 (m, 1 H, CHCHet),
3
3
6.30 (d, JH,H ϭ 9.1 Hz, 1 H, NHCO2), 7.66 (d, JH,H ϭ 9.2 Hz, 1
H, CONH) ppm. 13C NMR (75 MHz, [D6]acetone): δ ϭ 10.7, 13.0,
19.6, 19.9, 20.4, 21.1, 29.6, 31.4, 34.07, 34.15, 52.7, 53.3, 54.1, 80.1,
129.2, 130.9, 134.5, 148.7, 157.5, 157.9, 163.8, 164.2, 164.9 ppm.
IR (KBr): ν˜ ϭ 3406, 2965, 2874, 1713, 1665, 1621, 1592, 1503
cmϪ1. FAB-HRMS: m/z calcd. for C25H40N5O6 [MHϩ] 506.2979,
found 506.3007. C25H39N5O6·(H2O)1/3 (511.61): calcd. C 58.69, H
7.81, N 13.69; found C 59.01, H 7.83, N 13.39.
Data for 3: M.p. Ͼ 250 °C. [α]2D0 ϭ Ϫ114 (c ϭ 1.0, CHCl3). 1H
3
NMR (300 MHz, [D6]acetone): δ ϭ 0.95 (d, JH,H ϭ 6.7 Hz, 9 H,
3
CHMe2), 1.01 (d, JH,H ϭ 6.8 Hz, 9 H, CHMe2), 2.05Ϫ2.13 (m, 3
H, CHMe2), 2.52 (s, 9 H, CHetMe), 3.62 (s, 9 H, NMe), 5.14 (m, 3
H, CHCHet), 8.36 (d, 3JH,H ϭ 8.9 Hz, 3 H, CONH) ppm. 13C NMR
(75 MHz, [D6]acetone): δ ϭ 10.6, 19.0, 20.8, 31.7, 36.4, 51.1, 131.3,
134.0, 148.7, 164.6 ppm. IR (KBr): ν˜ ϭ 3385, 2963, 2874, 1661,
1595, 1510, 1465 cmϪ1. FAB-HRMS: m/z calcd. for C30H46N9O3
[MHϩ] 580.3724, found 580.3707. C30H45N9O3·(H2O)2/3 (591.75):
calcd. C 60.89, H 7.89, N 21.30; found C 61.15, H 7.92, N 20.92.
Imidazole؊Oxazole Tetramer 6: Dimer 23 (178 mg, 0.35 mmol) was
successively subjected to methyl and Boc deprotection to give the
corresponding free amino acid. iPr2NEt (0.24 mL, 1.40 mmol) and
FDPP (211 mg, 0.55 mmol) were added at room temperature to the
stirred solution of this compound in acetonitrile (10 mL), and the
mixture was stirred at that temperature for 2 days. The solvent was
evaporated and the residue was dissolved in EtOAc, extracted with
water and brine, dried with MgSO4, and concentrated in vacuo.
Purification was accomplished by chromatography on silica gel
(DCM/EtOAc/MeOH, 75:25:5) to yield 23 (46 mg, 35%) as a white
solid; m.p. 145 °C. [α]2D0 ϭ Ϫ153 (c ϭ 1.0, CHCl3). 1H NMR
1
Data for 5: M.p. 150Ϫ152 °C. [α]2D0 ϭ Ϫ185 (c ϭ 1.0, CHCl3). H
NMR (300 MHz, [D6]acetone): δ ϭ 0.87 (d, 3JH,H ϭ 6.6 Hz, 12 H,
3
CHMe2), 1.10 (d, JH,H ϭ 6.7 Hz, 12 H, CHMe2), 2.35Ϫ2.46 (m,
4 H, CHMe2), 2.47 (s, 12 H, CHetMe), 3.67 (s, 12 H, NMe), 4.90
(m, 4 H, CHCHet), 7.53 (d, 3JH,H ϭ 9.1 Hz, 4 H, CONH) ppm. 13
C
NMR (75 MHz, [D6]acetone): δ ϭ 10.7, 20.5, 21.0, 31.4, 34.2, 51.4,
131.1, 133.8, 149.3, 164.8 ppm. IR (KBr): ν˜ ϭ 3409, 2962, 2873,
1656, 1593, 1502 cmϪ1. FAB-HRMS: m/z calcd. for C40H61N12O4
[MHϩ] 773.4939, found 773.4896.
3
(300 MHz, [D6]acetone): δ ϭ 0.94 (d, JH,H ϭ 6.6 Hz, 6 H,
3
3
CHMe2), 0.95 (d, JH,H ϭ 6.7 Hz, 6 H, CHMe2), 1.00 (d, JH,H
ϭ
Methyl
methyloxazole-4-carboxylate
2-[(S)-1-(tert-Butoxycarbonylamino)-2-methylpropyl]-5-
(19): Triethylamine (6.75 mL,
3
6.8 Hz, 6 H, CHMe2), 1.11 (d, JH,H ϭ 6.7 Hz, 6 H, CHMe2),
2.17Ϫ2.31 (m, 2 H, CHMe2), 2.43 (s, 6 H, CHetMe), 2.48Ϫ2.61 (m,
2 H, CHMe2), 2.62 (s, 6 H, CHetMe), 3.58 (s, 6 H, NMe), 4.96Ϫ5.09
48.4 mmol) was added at 0 °C to a solution of amidoketone 10
(4.00 g, 12.1 mmol), triphenylphosphane (6.35 g, 24.2 mmol), and
CCl4 (2.36 mL, 24.2 mmol) in anhydrous DCM (150 mL). The ice
bath was removed after 10 min and the mixture was stirred at room
temperature for 5 days. The solvent was evaporated and purifi-
cation was accomplished by flash chromatography on silica gel
(petroleum ether/EtOAc, 3:1) to yield 19 (3.26 g, 86%) as a white
solid; m.p. 57 °C. 1H NMR (300 MHz, CDCl3): δ ϭ 0.89 (d,
3
(m, 4 H, CHCHet), 7.32 (d, JH,H ϭ 9.9 Hz, 2 H, CONH), 7.65 (d,
3JH,H ϭ 9.0 Hz, 2 H, CONH) ppm. 13C NMR (75 MHz, [D6]ace-
tone): δ ϭ 10.6, 12.6, 19.5, 20.2, 20.4, 21.3, 31.4, 33.4, 34.3, 51.2,
53.3, 130.5, 130.9, 134.9, 148.0, 154.6, 162.5, 164.2, 164.7 ppm. IR
(KBr): ν˜ ϭ 3414, 2963, 2930, 2874, 1668, 1638, 1594, 1515 cmϪ1
.
FAB-HRMS: m/z calcd. for C38H55N10O6 [MHϩ] 747.4306, found
3
3JH,H ϭ 6.8 Hz, 3 H, CHMe2), 0.90 (d, JH,H ϭ 6.7 Hz, 3 H,
747.4302.
CHMe2), 1.41 (s, 9 H, CMe3), 2.08Ϫ2.20 (m, 1 H, CHMe2), 2.59
Methyl 2-[(S)-1-tert-Butoxycarbonylamino-2-methylpropyl]-5-meth-
ylthiazole-4-carboxylate (20): Lawesson’s reagent (7.08 g,
17.5 mmol) was added at room temperature to a solution of amido
ketone 10 (3.87 g, 11.7 mmol) in anhydrous THF (120 mL). The
mixture was stirred at reflux for 8 h. The solvent was removed and
the residue was dissolved in EtOAc, washed with water, 1  HCl,
saturated NaHCO3 solution and brine, dried with MgSO4, and
concentrated in vacuo. Purification was accomplished by flash
chromatography on silica gel (petroleum ether/EtOAc: 3:1) to yield
20 (2.87 g, 75%) as a solid; m.p. 88 °C. 1H NMR (300 MHz,
(s, 3 H, CHetMe), 3.88 (s, 3 H, CO2Me), 4.71 (m, 1 H, CHCHet),
3
5.25 (d, JH,H ϭ 9.3 Hz, 1 H, NHCO2) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 11.9, 17.9, 18.7, 28.2, 32.8, 51.9, 54.1, 79.9, 127.2,
155.3, 156.2, 162.1, 162.7 ppm. IR (KBr): ν˜ ϭ 3399, 3346, 2969,
2933, 1720, 1621, 1580, 1521 cmϪ1. FAB-HRMS: m/z calcd. for
C15H25N2O5 [MHϩ] 313.1763, found 313.1782. C15H24N2O5
(312.36): calcd. C 57.68, H 7.74, N 8.97; found C 57.53, H 7.71,
N 8.87.
Hydrochloride of Aminooxazole Methyl Ester 21: Compound 19
(1.00 g, 3.20 mmol) was converted into 21 as described above in
the general procedure for the cleavage of the Boc group. Yield:
quantitative; m.p. 73Ϫ76 °C. 1H NMR (300 MHz, [D6]DMSO):
δ ϭ 0.85 (d, 3JH,H ϭ 6.8 Hz, 3 H, CHMe2), 1.00 (d, 3JH,H ϭ 6.8 Hz,
3 H, CHMe2), 2.23Ϫ2.36 (m, 1 H, CHMe2), 2.60 (s, 3 H, CHetMe),
3.81 (s, 3 H, CO2Me), 4.36 (m, 1 H, CHCHet), 9.02 (s, 3 H, NH3)
ppm. 13C NMR (75 MHz, [D6]DMSO): δ ϭ 11.7, 17.3, 18.5, 30.4,
51.6, 52.7, 126.7, 156.9, 157.5, 161.6 ppm. IR (film): ν˜ ϭ 3408,
2967, 2360, 2024, 1717, 1616, 1520 cmϪ1. FAB-HRMS: m/z calcd.
for C10H17N2O3 [MHϩ] 213.1239, found 213.1258.
3
CDCl3): δ ϭ 0.88 (d, JH,H ϭ 6.8 Hz, 3 H, CHMe2), 0.95 (d,
3JH,H ϭ 6.8 Hz, 3 H, CHMe2), 1.42 (s, 9 H, CMe3), 2.28Ϫ2.47 (m,
1 H, CHMe2), 2.71 (s, 3 H, CHetMe), 3.90 (s, 3 H, CO2Me), 4.78
3
(m, 1 H, CHCHet), 5.24 (d, JH,H ϭ 8.2 Hz, 1 H, NHCO2) ppm.
13C NMR (75 MHz, CDCl3): δ ϭ 13.1, 17.2, 19.4, 28.3, 33.0, 52.0,
57.8, 80.0, 140.9, 144.3, 155.3, 162.8, 168.5 ppm. IR (KBr): ν˜ ϭ
3434, 2971, 1715, 1638, 1510 cmϪ1. FAB-HRMS: m/z calcd. for
C15H25N2O4S [MHϩ] 329.1535, found 329.1519.
Hydrochloride of Aminothiazole Methyl Ester 22: Compound 20
(1.05 g, 3.20 mmol) was converted into 22 as described above in
N-Boc-Protected Methyl Ester 23: The procedure applied for the
coupling of acid 12 (623 mg, 2.00 mmol) to the hydrochloride 21 quantitative; m.p. 145 °C. H NMR (300 MHz, [D6]DMSO): δ ϭ
the general procedure for the cleavage of the Boc group. Yield:
1
3
3
(547 mg, 2.20 mmol) was the same as that used in the case of the
www.eurjoc.org
0.84 (d, JH,H ϭ 6.8 Hz, 3 H, CHMe2), 1.01 (d, JH,H ϭ 6.8 Hz, 3
Eur. J. Org. Chem. 2003, 3209Ϫ3218
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3215

G. Haberhauer, F. Rominger
FULL PAPER
H, CHMe2), 2.22Ϫ2.36 (m, 1 H, CHMe2), 2.72 (s, 3 H, CHetMe), Benzyl 2-[(R)-1-tert-Butoxycarbonylamino-2-methylpropyl]-1,5-di-
3.82 (s, 3 H, CO2Me), 4.50 (m, 1 H, CHCHet), 8.95 (s, 3 H, NH3) methylimidazole-4-carboxylate (34): DBU (0.94 mL, 6.30 mmol)
ppm. 13C NMR (75 MHz, [D6]DMSO): δ ϭ 12.6, 17.9, 18.6, 31.7, and BnBr (1.00 mL, 8.40 mmol) were added at room temperature
51.6, 56.3, 140.2, 145.8, 161.0, 161.9 ppm. IR (KBr): ν˜ ϭ 3435,
2963, 2572, 2021, 1718, 1698, 1598 cmϪ1. FAB-HRMS: m/z calcd.
for C10H17N2O2S [MHϩ] 229.1011, found 229.1019.
to a solution of 33 (1.96 g, 6.30 mmol) in acetonitrile and the mix-
ture was stirred at that temperature for 6 days. The solvent was
evaporated and the residue was dissolved in EtOAc, extracted with
water and brine, dried with MgSO4, and concentrated in vacuo.
Purification was accomplished by chromatography on silica gel
(petroleum ether/ethyl acetate, 2:1) to yield 34 (1.53 g, 60%) as a
white solid; m.p. 80 °C. 1H NMR (300 MHz, CDCl3): δ ϭ 0.83 (d,
N-Boc-Protected Methyl Ester 24: The procedure applied for the
coupling of acid 12 (623 mg, 2.00 mmol) to the hydrochloride 22
(582 mg, 2.20 mmol) was the same as that used in the case of the
synthesis of 15. Flash chromatography on silica gel (DCM/EtOAc/
MeOH, 75:25:2) provided 24 (629 mg, 60%) as a solid; m.p. 64Ϫ66
°C. 1H NMR (300 MHz, [D6]acetone): δ ϭ 0.91 (d, 3JH,H ϭ 6.8 Hz,
3 H, CHMe2), 0.97Ϫ1.04 (m, 9 H, CHMe2), 1.39 (s, 9 H, CMe3),
2.21Ϫ2.35 (m, 1 H, CHMe2), 2.41Ϫ2.51 (m, 1 H, CHMe2), 2.52 (s,
3 H, CHetMe), 2.70 (s, 3 H, CHetMe), 3.61 (s, 3 H, NMe), 3.84 (s,
3 H, CO2Me), 4.58 (m, 1 H, CHCHet), 5.12 (m, 1 H, CHCHet), 6.28
3
3JH,H ϭ 6.7 Hz, 3 H, CHMe2), 1.00 (d, JH,H ϭ 6.7 Hz, 3 H,
CHMe2), 1.40 (s, 9 H, CMe3), 2.16Ϫ2.29 (m, 1 H, CHMe2), 2.48
(s, 3 H, CHetMe), 3.53 (s, 3 H, NMe), 4.53 (m, 1 H, CHCHet),
5.34Ϫ5.41 (m, 3 H, NHCO2, PhCH2), 7.27Ϫ7.46 (m, 5 H, ArH)
ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 10.5, 18.5, 19.6, 28.3, 30.3,
33.2, 52.2, 65.7, 79.4, 127.7, 127.9, 128.1, 128.4, 135.8, 136.7, 148.5,
155.7, 163.7 ppm. IR (KBr): ν˜ ϭ 3340, 2966, 1700, 1572, 1521
cmϪ1. FAB-HRMS: m/z calcd. for C22H32N3O4 [MHϩ] 402.2393,
found 402.2390. C22H31N3O4 (401.50): calcd. C 65.81, H 7.78, N
10.47; found C 65.71, H 7.72, N 10.40.
3
3
(d, JH,H ϭ 9.2 Hz, 1 H, NHCO2), 7.78 (d, JH,H ϭ 9.1 Hz, 1 H,
CONH) ppm. 13C NMR (75 MHz, [D6]acetone): δ ϭ 10.7, 14.0,
19.1, 19.9, 21.0, 21.0, 29.6, 31.4, 34.1, 34.4, 52.8, 54.1, 57.2, 80.1,
130.8, 134.5, 143.0, 145.8, 148.7, 157.5, 164.5, 165.1, 170.2 ppm.
IR (KBr): ν˜ ϭ 3400, 2964, 2873, 1714, 1664, 1592, 1501 cmϪ1
.
Hydrochloride of Aminoimidazole Benzyl Ester 28: Compound 34
(0.88 g, 2.20 mmol) was converted into 28 as described above in
the general procedure for the cleavage of the Boc group. Yield:
FAB-HRMS: m/z calcd. for C25H40N5O5S [MHϩ] 522.2750, found
522.2753. C25H39N5O5S·(H2O)0.5 (530.68): calcd. C 56.58, H 7.60,
N 13.20; found C 56.76, H 7.47, N 13.10.
1
quantitative; m.p. 137 °C. H NMR (300 MHz, [D6]DMSO): δ ϭ
3
3
0.80 (d, JH,H ϭ 6.8 Hz, 3 H, CHMe2), 0.98 (d, JH,H ϭ 6.7 Hz, 3
H, CHMe2), 2.19Ϫ2.32 (m, 1 H, CHMe2), 2.49 (s, 3 H, CHetMe),
3.61 (s, 3 H, NMe), 4.41 (m, 1 H, CHCHet), 5.22Ϫ5.34 (m, 2 H,
PhCH2), 7.47Ϫ7.29 (m, 5 H, ArH), 8.69 (s, 3 H, NH3) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ ϭ 9.9, 18.1, 30.8, 31.5, 50.7, 65.1,
126.1, 128.0, 128.2, 128.4, 136.3, 137.4, 144.0, 162.3 ppm. IR
(KBr): ν˜ ϭ 3436, 2965, 2019, 1729, 1631, 1504 cmϪ1. FAB-HRMS:
m/z calcd. for C17H24N3O2 [MHϩ] 302.1869, found 302.1858.
Imidazole؊Thiazole Tetramer 7: The procedure applied for the
macrocyclization of 24 (157 mg, 0.30 mmol) to the tetramer 7 was
the same as that used in the case of the synthesis of 6. Flash chro-
matography on silica gel (DCM/EtOAc/MeOH, 75:25:3) provided
7 (66 mg, 56%) as a solid; m.p. 205Ϫ207 °C. [α]2D0 ϭ Ϫ138 (c ϭ
1.0, CHCl3). 1H NMR (300 MHz, [D6]acetone): δ ϭ 0.94 (d,
3
3JH,H ϭ 6.6 Hz, 6 H, CHMe2), 0.99 (d, JH,H ϭ 6.6 Hz, 6 H,
CHMe2), 1.08Ϫ1.13 (m, 12 H, CHMe2), 2.49 (s, 6 H, CHetMe),
2.40Ϫ2.55 (m, 4 H, CHMe2), 2.73 (s, 6 H, CHetMe), 3.67 (s, 6 H,
NMe), 4.95Ϫ5.10 (m, 4 H, CHCHet), 7.65 (d, 3JH,H ϭ 9.2 Hz, 2 H,
Z-Protected Aminoimidazole Benzyl Ester 29: The procedure ap-
plied for the coupling of acid 27 (350 mg, 1.90 mmol) to the hydro-
chloride 28 (642 mg, 1.90 mmol) was the same as that used in the
case of the synthesis of 15. Flash chromatography on silica gel
(DCM/EtOAc/MeOH, 75:25:2) provided 29 (802 mg, 68%) as a
solid; m.p. 153 °C. 1H NMR (500 MHz, CDCl3): δ ϭ 0.62 (d,
3
CONH), 7.92 (d, JH,H ϭ 9.1 Hz, 2 H, CONH) ppm. 13C NMR
(75 MHz, [D6]acetone): δ ϭ 10.7, 13.5, 20.0, 21.11, 21.13, 31.5,
33.8, 34.4, 51.9, 56.0, 130.9, 134.6, 142.5, 143.8, 148.4, 163.5, 164.5,
167.9 ppm. IR (KBr): ν˜ ϭ 3407, 2961, 2928, 2873, 1666, 1593,
1546, 1504 cmϪ1. FAB-HRMS: m/z calcd. for C38H55N10O4S2
[MHϩ] 779.3849, found 779.3880.
3
3JH,H ϭ 6.8 Hz, 3 H, CHMe2), 0.79 (d, JH,H ϭ 6.9 Hz, 3 H,
3
3
CHMe2), 0.83 (d, JH,H ϭ 6.6 Hz, 3 H, CHMe2), 1.03 (d, JH,H
ϭ
6.7 Hz, 3 H, CHMe2), 1.44 (d, J ϭ 6.3 Hz, 3 H, COxaHMe),
1.98Ϫ2.06 (m, 1 H, CHMe2), 2.34Ϫ2.42 (m, 1 H, CHMe2), 2.47 (s,
Methyl
2-[(R)-2-tert-Butoxycarbonylamino-3-methylbutanoylam-
3
3 H, CImiMe), 3.51 (s, 3 H, NMe), 4.17 (d, JH,H ϭ 7.0 Hz, 1 H,
ino]-3-oxobutanoate (31): The applied procedure, workup, and puri-
fication were the same as those used in the case of the synthesis of
10. The NMR and IR spectra were identical to those described for
10. FAB-HRMS: m/z calcd. for C15H27N2O6 [MHϩ] 331.1869,
found 331.1879. C15H26N2O6 (330.38): calcd. C 54.53, H 7.93, N
8.48; found C 54.38, H 7.87, N 8.44.
COxaHCO2Me), 4.36 (m, 1 H, COxaHMe), 4.69 (m, 1 H, CHCHet),
4.84 (m, 1 H, CHCHet), 5.07Ϫ5.18 (m, 2 H, PhCH2), 5.29Ϫ5.35
3
(m, 2 H, PhCH2), 5.62 (d, JH,H ϭ 9.0 Hz, 1 H, NHCO2),
7.20Ϫ7.45 (m, 11 H, CONH, ArH) ppm. 13C NMR (125 MHz,
CDCl3): δ ϭ 10.4, 16.9, 18.7, 18.9, 19.7, 21.8, 30.3, 31.3, 32.9, 50.5,
54.4, 65.7, 66.8, 74.1, 80.4, 127.8, 128.0, 128.3, 128.40, 128.42,
135.8, 136.5, 136.6, 147.5, 156.3, 163.5, 168.7, 170.9 ppm. IR
(KBr): ν˜ ϭ 3305, 3260, 2964, 1696, 1655, 1572, 1524 cmϪ1. FAB-
HRMS: m/z calcd. for C34H44N5O6 [MHϩ] 618.3292, found
618.3262. C34H43N5O6 (617.74): calcd. C 66.11, H 7.02, N 11.34;
found C 65.87, H 6.98, N 11.12.
Methyl 2-[(R)-1-tert-Butoxycarbonylamino-2-methylpropyl]-1,5-di-
methyl-1H-imidazole-4-carboxylate (32): The applied procedure,
workup and purification were the same as those used in the case
of the synthesis of 11. The NMR and IR spectra were identical to
those described for 11, and the enantiomeric purity of 32 was also
Ͼ 96% ee. FAB-HRMS: m/z calcd. for C16H28N3O4 [MHϩ]
326.2080, found 326.2068. C16H27N3O4 (325.40): calcd. C 59.06, H
8.36, N 12.91; found C 59.04, H 8.31, N 12.79.
Imidazole؊Oxazoline Tetramer 4: Palladium hydroxide (200 mg)
was added at room temperature to a solution of dimer 29 (297 mg,
0.48 mmol) in methanol. The mixture was stirred under H2 for
20 h, filtered, and concentrated in vacuo. The residue was dissolved
in acetonitrile (25 mL), iPr2NEt (0.35 mL, 2.00 mmol) and FDPP
(327 mg, 0.85 mmol) were added at room temperature, and the mix-
ture was stirred for 3 days. The solvent was evaporated, and the
residue was dissolved in EtOAc, extracted with water and brine,
N-Boc-Protected Amino Acid 33: The applied procedure and
workup were the same as those used in the case of the synthesis of
12. The NMR and IR spectra were identical to those described
for 12. FAB-HRMS: m/z calcd. for C15H26N3O4 [MHϩ] 312.1923,
found 312.1940.
3216
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3209Ϫ3218

Syntheses and Structures of Imidazole Analogues of Lissoclinum Cyclopeptides
FULL PAPER
dried with MgSO4, and concentrated in vacuo. Purification was
Acknowledgments
accomplished by chromatography on silica gel (DCM/EtOAc/
MeOH, 75:25:5) to yield 4 (55 mg, 30%) as a white solid; m.p. Ͼ
250 °C. [α]2D0 ϭ ϩ132 (c ϭ 1.0, CHCl3). 1H NMR (300 MHz,
This work was supported by the Deutsche Forschungsgemeinsch-
aft. The authors thank Professor Rolf Gleiter (University of Heid-
elberg) and Dr. Rolf Roers (Bayer AG) for helpful discussions.
3
CDCl3): δ ϭ 0.65 (d, JH,H ϭ 6.9 Hz, 6 H, CHMe2), 0.83 (d,
3
3JH,H ϭ 6.9 Hz, 6 H, CHMe2), 0.93 (d, JH,H ϭ 6.7 Hz, 6 H,
3
3
CHMe2), 1.04 (d, JH,H ϭ 6.7 Hz, 6 H, CHMe2), 1.44 (d, JH,H
ϭ
[1] [1a]
[1b]
6.3 Hz, 6 H, COxaHMe), 2.07Ϫ2.30 (m, 4 H, CHMe2), 2.54 (s, 6
H, CImiMe), 3.54 (s, 6 H, NMe), 4.23 (m, 2 H, COxaHCO),
4.78Ϫ4.86 (m, 4 H, CHCHet, COxaHMe), 5.03 (m, 2 H, CHCHet),
D. J. Faulkner, Nat. Prod. Rep. 1999, 16, 155Ϫ198.
G.
R. Pettit, Pure Appl. Chem. 1994, 66, 2271Ϫ2281. [1c] N. Fuset-
ani, S. Matsunoga, Chem. Rev. 1993, 93, 1793Ϫ1806.
[1d]
B. S.
[1e]
Davidson, Chem. Rev. 1993, 93, 1771Ϫ1791.
Chem. Rev. 1993, 93, 1699Ϫ1730.
M. J. Garson,
3
3
7.69 (d, JH,H ϭ 9.9 Hz, 2 H, CONH), 7.98 (d, JH,H ϭ 8.7 Hz, 2
H, CONH) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 9.8, 17.3, 18.4,
18.7, 19.1, 21.9, 30.2, 31.9, 33.9, 49.3, 51.5, 73.5, 80.8, 129.7, 132.3,
146.1, 163.4, 169.1, 170.7 ppm. IR (KBr): ν˜ ϭ 3397, 2964, 2930,
2874, 1672, 1652, 1592, 1511 cmϪ1. FAB-HRMS: m/z calcd. for
C38H59N10O6 [MHϩ] 751.4619, found 751.4609.
[2] [2a]
R. S. Roy, A. M. Gehring, J. C. Milne, P. J. Belshaw, C. T.
[2b]
Walsh, Nat. Prod. Rep. 1999, 16, 249Ϫ263.
P. Wipf, P. C.
Fritch, S. J. Geib, A. M. Sefler, J. Am. Chem. Soc. 1998, 120,
4105Ϫ4112. [2c] A. K. Todorova, F. Jüttner, A. Linden, T. Plüss,
[2d]
W. v. Philipsborn, J. Org. Chem. 1995, 60, 7891Ϫ7895.
M. Li, J. C. Milne, L. L. Madison, R. Koller, C. T. Walsh,
Y. -
[2e]
Science 1996, 274, 1188Ϫ1193.
M. P. Foster, G. P. Concep-
X-ray Crystallographic Study: Data were collected with a Bruker
Smart CCD-diffractometer at 200 K. Relevant crystal and data col-
lection parameters are given below. CCDC-207161 (4) and CCDC-
207162 (6) contain the supplementary crystallographic data for the
structures in this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC,
12 Union Road, Cambridge CB2 1EZ, UK; Fax: (internat.) ϩ44
1223 336033; E-mail: deposit@ccdc.cam.ac.uk).
´
cion, G. B. Caraan, C. M. Ireland, J. Org. Chem. 1992, 57,
6671Ϫ6675.
[3] [3a]
J. Ogino, R. E. Moore, G. M. L. Patterson, C. D. Smith, J.
Nat. Prod. 1996, 59, 581Ϫ586. [3b] C. N. Holzapfel, W. J. v. Zyl,
Tetrahedron 1990, 46, 649Ϫ660.
[4] [4a]
M. R. Prinsep, R. E. Moore, I. A. Levine, G. M. L. Pat-
terson, J. Nat. Prod. 1992, 55, 140Ϫ142. [4b] T. W. Hambley, C.
J. Hawkins, M. F. Lavin, A. v. d. Brenk, D. J. Watters, Tetra-
hedron 1992, 48, 341Ϫ348.
[5]
[6]
Crystal Data for 4: C38H58N10O6·(CHCl3)0.5·H2O, colorless crystal
(polyhedron), dimensions 0.43 ϫ 0.36 ϫ 0.19 mm3, crystal system
Y. Hamamoto, M. Endo, M. Nakagawa, T. Nakanishi, K. Mi-
zukawa, J. Chem. Soc., Chem. Commun. 1983, 323Ϫ324.
˚
For reviews on the isolation, structure, and synthesis of the
orthorhombic, space group P212121, Z ϭ 8, a ϭ 15.5026(3) A, b ϭ
[6a]
Lissoclinum cyclic peptides see:
Chemical and Biological Perspectives, (Ed.: S. W. Pelletier), El-
sevier, Amsterdam, 1998, vol 12., pp 187Ϫ228.
P. Wi pf, i n Alkaloids:
˚
3
˚
3
20.5167(3) A, c ϭ 27.5323(4) A, α ϭ 90°, β ϭ 90°, γ ϭ 90°, V ϭ
˚
8757.0(2) A , ρ ϭ 1.257 g/cm , T ϭ 200(2) K, 2θmax ϭ 21.48°,
[6b]
P. Wi p f,
˚
radiation Mo-Kα, λ ϭ 0.71073 A, 0.3° ω-scans, covering a whole
Chem. Rev. 1995, 95, 2115Ϫ2134.
sphere in reciprocal space, 54375 reflections measured, 10026 un-
ique (Rint ϭ 0.0446), 8665 observed [I Ͼ 2σ(I)], intensities were
corrected for Lorentz and polarization effects, an empirical absorp-
tion correction was applied by use of SADABS[32] based on the
[7]
J. P. Michael, G. Pattenden, Angew. Chem. Int. Ed. Engl. 1993,
32, 1Ϫ23; Angew. Chem. 1993, 105, 1Ϫ24.
[8] [8a]
P. V. Bernhardt, P. Comba, D. F. Fairlie, L. R. Gahan, G.
R. Hanson, L. Lötzbeyer, Chem. Eur. J. 2002, 8, 1527Ϫ1536.
[8b]
Laue symmetry of the reciprocal space, µ ϭ 0.17 mmϪ1, Tmin.
ϭ
R. M. Cusack, L. Grøndahl, G. Abbenante, D. P. Fairlie,
L. R. Gahan, G. R. Hanson, T. W. Hambley, J. Chem. Soc.,
0.93, Tmax. ϭ 0.97, structure solved by direct methods and refined
against F2 with a full-matrix, least-squares algorithm by use of the
SHELXTL-PLUS (5.10) software package,[33] 1042 parameters re-
fined, hydrogen atoms were treated by appropriate riding models,
Flack absolute structure parameter 0.0(3), goodness of fit 1.07 for
observed reflections, final residual values R(F) ϭ 0.055, wR(F2) ϭ
0.143 for observed reflections, residual electron density Ϫ0.45 to
[8c]
Perkin Trans. 2 2000, 323Ϫ331.
D. J. Freeman, G. Pat-
tenden, A. F. Drake, G. Siligardi, J. Chem. Soc., Perkin Trans.
[8d]
2 1998, 129Ϫ135.
A. L. v. d. Brenk, D. P. Fairlie, L. R.
Gahan, G. R. Hanson, T. W. Hambley, Inorg. Chem. 1996, 35,
[8e]
1095Ϫ1100.
P. Wipf, S. Venkatraman, C. P. Miller, S. J.
Geib, Angew. Chem. Int. Ed. Engl. 1994, 33, 1516Ϫ1518; An-
[8f]
gew. Chem. 1994, 106, 1554Ϫ1556.
A. L. v. d. Brenk, D. P.
Ϫ3
˚
0.62 e·A
.
Fairlie, G. R. Hanson, L. R. Gahan, C. J. Hawkins, A. Jones,
Inorg. Chem. 1994, 33, 2280Ϫ2289.
[9] [9a]
Y. Singh, M. J. Stoermer, A. J. Lucke, M. P. Glenn, D. P.
Crystal Data for 6: C38H54N10O6, colorless crystal (polyhedron),
dimensions 0.42 ϫ 0.27 ϫ 0.25 mm3, crystal system orthorhombic,
[9b]
Fairlie, Org. Lett. 2002, 4, 3367Ϫ3370.
Thompson, Tetrahedron Lett. 2002, 43, 2459Ϫ2461.
Singh, N. Sokolenko, M. J. Kelso, L. R. Gahan, G. Abbenante,
G. Pattenden, T.
[9c]
Y.
˚
˚
space group P212121, Z ϭ 4, a ϭ 12.7473(2) A, b ϭ 17.2917(3) A,
3
˚
˚
c ϭ 22.0819(3) A, α ϭ 90°, β ϭ 90°, γ ϭ 90°, V ϭ 4867.35(13) A ,
ρ ϭ 1.019 g/cm3, T ϭ 200(2) K, 2θmax ϭ 23.23°, radiation Mo-Kα,
[9d]
D. P. Fairlie, J. Am. Chem. Soc. 2001, 123, 333Ϫ334.
G.
[9e]
Pattenden, T. Thompson, Chem. Commun. 2001, 717Ϫ718.
˚
λ ϭ 0.71073 A, 0.3° Ω-scans, covering a whole sphere in reciprocal
G. Haberhauer, L. Somogyi, J. Rebek, Jr., Tetrahedron Lett.
[9f]
space, 35807 reflections measured, 6977 unique (Rint ϭ 0.0403),
5882 observed [I Ͼ 2σ(I)], intensities were corrected for Lorentz
and polarization effects, an empirical absorption correction was ap-
plied by use of SADABS[32] based on the Laue symmetry of the
reciprocal space, µ ϭ 0.07 mmϪ1, Tmin. ϭ 0.97, Tmax. ϭ 0.98, struc-
ture solved by direct methods and refined against F2 with a full-
matrix, least-squares algorithm by use of the SHELXTL-PLUS
(5.10) software package[33], 519 parameters refined, hydrogen atoms
were treated by appropriate riding models, Flack absolute structure
parameter 0.5(16), goodness of fit 1.06 for observed reflections,
final residual values R(F) ϭ 0.056, wR(F2) ϭ 0.153 for observed
2000, 41, 5013Ϫ5016.
D. Mink, S. Mecozzi, J. Rebek, Jr.,
Tetrahedron Lett. 1998, 39, 5709Ϫ5712.
[10] [10a] B. L. Vallee, D. S. Auld, Biochemistry 1990, 29, 5647Ϫ5659.
[10b]
B. L. Vallee, D. S. Auld, Proc. Natl. Acad. Sci. U. S. A.
1990, 87, 220Ϫ224. [10c] B. W. Matthews, Acc. Chem. Res. 1988,
21, 333Ϫ340.
[11] [11a]
[11b]
J. Rebek, Jr., Struct. Chem. 1990, 1, 129Ϫ131.
F. K.
Winkler, A. DЈArcy, W. Hunziker, Nature 1990, 343, 771Ϫ774.
[12] [12a]
F. Ikegami, I. Murakoshi, Phytochemistry 1994, 35,
[12b]
1089Ϫ1104.
58, 5176Ϫ5180.
G. Haberhauer, F. Rominger, Tetrahedron Lett. 2002, 43,
6335Ϫ6338.
M. Wang, S. J. Gould, J. Org. Chem. 1993,
[13]
Ϫ3
˚
reflections, residual electron density Ϫ0.20 to 0.49 e·A
.
Eur. J. Org. Chem. 2003, 3209Ϫ3218
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3217

G. Haberhauer, F. Rominger
FULL PAPER
[14]
J. Singh, T. D. Gordon, W. G. Earley, B. A. Morgan, Tetra-
Gleich, Angew. Chem. Int. Ed. Engl. 1985, 24, 569Ϫ570; Angew.
Chem. 1985, 97, 606Ϫ607.
N. Ono, T. Yamada, T. Saito, K. Tanaka, A. Kaji, Bull. Chem.
Soc., Jpn. 1978, 51, 2401Ϫ2404.
P. Wipf, C. P. Miller, J. Am. Chem. Soc. 1992, 114,
10975Ϫ10977.
G. N. Ramachandran, R. Chandrasekaran, K. D. Kopple, Bi-
opolymers 1971, 10, 2113Ϫ2131.
hedron Lett. 1993, 34, 211Ϫ214.
T. D. Gordon, J. Singh, P. E. Hansen, B. A. Morgan, Tetra-
[25]
[26]
[27]
[28]
[15]
hedron Lett. 1993, 34, 1901Ϫ1904.
[16]
S. Chen, J. Xu, Tetrahedron Lett. 1991, 32, 6711Ϫ6714.
[17] [17a]
J. C. Sheehan, P. A. Cruickshank, G. L. Boshart, J. Org.
[17b]
Chem. 1961, 26, 2525Ϫ2528.
J. C. Sheehan, J. Preston, P.
A. Cruickshank, J. Am. Chem. Soc. 1965, 87, 2492Ϫ2493.
J. Coste, D. Le-Nguyen, B. Castro, Tetrahedron Lett. 1990,
31, 205Ϫ208.
T. Shioiri, K. Ninomiya, S. Yamada, J. Am. Chem. Soc. 1972,
94, 6203Ϫ6205.
P. Wipf, C. P. Miller, J. Org. Chem. 1993, 58, 3604Ϫ3606.
K. Clausen, M. Thorsen, S.-O. Lawesson, J. Chem. Soc., Perkin
Trans. 1 1984, 785Ϫ798.
Y. Hamada, S. Kato, T. Shioiri, Tetrahedron Lett. 1985, 26,
3223Ϫ3226.
A. K. Todorova, F. Jüttner, A. Linden, T. Plüss, W. v. Phil-
ipsborn, J. Org. Chem. 1995, 60, 7891Ϫ7895.
[18]
[19]
[29] [29a] A. Asano, K. Minoura, T. Yamada, A. Numata, T. Ishida,
Y. Katsuya, Y. Mezaki, M. Sasaki, T. Taniguchi, M. Nakai, H.
Hasegawa, A. Terashima, M. Doi, J. Peptide Res. 2002, 60,
10Ϫ22. [29b] T. Ishida, Y. In, F. Shinozaki, M. Doi, D. Yamam-
oto, Y. Hamada, T. Shioiri, M. Kamigauchi, M. Sugiura, J.
Org. Chem. 1995, 60. 3944Ϫ3952.
[20]
[21]
[22]
[30]
B. F. Milne, L. A. Morris, M. Jaspars, G. S. Thompson, J.
Chem. Soc., Perkin Trans. 2 2002, 1076Ϫ1080.
[23] [23a]
[31] [31a]
C. Boden, G. Pattenden, Tetrahedron Lett. 1994, 35,
T. Ishida, M. Tanaka, M. Nabae, M. Inoue, J. Org. Chem.
[23b]
[31b]
8271Ϫ8274.
Lett. 1986, 27, 2653Ϫ2656.
Shioiri, Tetrahedron Lett. 1985, 26, 6501Ϫ6504.
ada, M. Shibata, T. Shioiri, Tetrahedron Lett. 1985, 26,
S. Kato, Y. Hamada, T. Shioiri, Tetrahedron
1988, 53, 107Ϫ112.
T. Ishida, M. Inoue, Y. Hamada, S.
Kato, T. Shioiri, J. Chem. Soc., Chem. Commun. 1987,
[23c]
Y. Hamada, M. Shibata, T.
[23d]
Y. Ham-
370Ϫ371.
[32]
[33]
Program SADABS V2.03 for absorption correction; G. M.
Sheldrick, Bruker Analytical X-ray-Division, Madison, Wis-
consin 2001.
[23e]
5159Ϫ5162.
Y. Hamada, M. Shibata, T. Shioiri, Tetra-
hedron Lett. 1985, 26, 5155Ϫ5158.
[24] [24a]
S. V. Downing, E. Aguilar, A. I. Meyers, J. Org. Chem.
Software package SHELXTL V5.10 for structure solution and
refinement; G. M. Sheldrick, Bruker Analytical X-ray-Div-
ision, Madison, Wisconsin, 1997.
[24b]
1999, 64, 826Ϫ831.
Lett. 1986, 27, 163Ϫ166.
Tetrahedron Lett. 1985, 26, 4367Ϫ4370.
U. Schmidt, H. Griesser, Tetrahedron
[24c]
U. Schmidt, R. Utz, P. Gleich,
[24d]
U. Schmidt, P.
Received April 1, 2003
3218
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3209Ϫ3218