Rational molecular design and EPC synthesis of a type VI β-turn inducing peptide mimetic

Article abstract of DOI:10.1002/1521-3773(20010917)40:18<3361::AID-ANIE3361>3.0.CO;2-9

A fruitful combination of molecular dynamics based design and modern synthetic reactions led to a conformatively rigidized cis-peptidyl proline surrogate (see picture). NMR spectroscopic experiments clearly show the existance of type VIa β-turn properties

Full text of DOI:10.1002/1521-3773(20010917)40:18<3361::AID-ANIE3361>3.0.CO;2-9

COMMUNICATIONS
pressure. The red solid residue was extracted with hexane (300 mL) and
filtered. The volume of the filtrate was reduced to 100 mL and cooled to
graphic data (excluding structure factors) for the structures reported
in this paper have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication no. CCDC-160613.
Copies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax: (‡44)1223-
336-033; e-mail: deposit@ccdc.cam.ac.uk).
�
208C. Two crops of dark red crystals were collected by filtration. Yield:
1
1
1.6 g (65%). M.p. 192 ± 1948C; H NMR (C
6
D
6
, 308C): d ˆ 29.7 (4H,
n
1/2 ˆ 110 Hz), 9.5 (36H, n1/2 ˆ 12 Hz), � 19.4 (18H, n1/2 ˆ 7 Hz); elemental
analysis (%) calcd for C34
H
58Cl
2
U: C 52.7, H 7.48; found: C 52.6, H 7.55; EI
‡
MS: m/z: 774 [M ]; the parent ion isotopic cluster was simulated: (calcd.%,
[10] T. R. Mohs, G. P. A. Yap, A. L. Rheingold, E. A. Maatta, Inorg. Chem.
1995, 34, 9.
obsvd.%): 774 (100, 100), 775 (38, 39), 776 (71, 71), 777 (25, 25), 778 (14,
1
4), 779 (5, 4).
[11] J. B. Strong, G. P. A. Yap, R. Ostrander, L. M. Liable-Sands, A. L.
Rheingold, R. Thouvenot, P. Gouzerh, E. A. Maatta, J. Am. Chem.
Soc. 2000, 122, 639.
2
8
: THF (30 mL) was added to a mixture of KC (140 mg, 1.04 mmol) and 1
(
400 mg, 0.52 mmol). A dark green color was generated immediately in the
[
[
12] G. K. Johnson, E. O. Schlemper, J. Am. Chem. Soc. 1978, 100, 3645.
13] A. Müller, F. Peters, M. T. Pope, D. Gatteschi, Chem. Rev. 1998, 98,
solution upon the addition of solvent. The mixture was stirred for 2 h, after
which a solution of pyridine N-oxide (100 mg, 1.05 mmol) in THF (25 mL)
was added. The dark green color of the solution immediately turned dark
reddish brown. The reaction mixture was stirred for 12 h, after which the
solvent was removed under vacuum and the residue extracted with toluene
and filtered through Celite. Dark reddish brown crystals of 2 were obtained
from a cold (� 308C) concentrated toluene solution. Yield: 275 mg (54%);
2
39.
[
[
14] M. S. Grigorꢁev, N. A. Baturin, A. A. Bessonov, N. N. Krot, Radio-
chemistry 1995, 37, 12.
15] I. A. Charushnikova, V. P. Perminov, S. B. Katser, Radiochemistry
1
995, 37, 454.
�
1
[16] M. P. Wilkerson, C. J. Burns, H. J. Dewey, J. M. Martin, D. E. Morris,
IR(Nujol): nÄ ˆ 690, 710 cm (U�O); elemental analysis (%) calcd for
R. T. Paine, B. L. Scott, Inorg. Chem. 2000, 39, 5277.
109 156 4 13 6
C H N O U : C 41.45, H 4.98, N 1.77; found: C 41.91, H 5.40, N 1.53.
[17] E. V. Dehmlow, C. Bollmann, Z. Naturforsch. B 1993, 48, 457.
The magnetization of crystalline powdered samples of 2 was recorded
between 5 ± 300 K at 0.1 T with a SQUID magnetometer (Quantum
Design). Values of the magnetic susceptibility were corrected for the
�
6
3
� 1
underlying diamagnetic increment (cdia ˆ � 1660  10 cm mol ) by using
tabulated Pascal constants and the effect of the blank sample holder
(
gelatine capsule/quartz wool).
Cyclic voltammetric studies were conducted by using a Perkin ± Elmer
Princeton Applied Research Corporation (PARC) Model 263 potentiostat
under computer control using M270 software. Samples were run in 0.1m
tetrabutylammonium hexafluorophosphate solution in tetrahydrofuran at a
platinum working electrode with a silver wire quasi-reference electrode in
either a PARC microcell in the glove box or in a Schlenk cell. Measured
potentials were calibrated by using the ferrocene/ferrocenium couple
Rational Molecular Design and EPC Synthesis
of a Type VI b-Turn Inducing Peptide
Mimetic**
Tobias Hoffmann, Harald Lanig,* Reiner Waibel, and
Peter Gmeiner*
(
E
1/2 ꢀ 0.55 V vs. NHE).
Received: April 23, 2001 [Z16983]
Besides the specific role of proline for the structure of
proteins, experimental and simulation studies indicate that
proline-containing sequence motives can act as molecular
hinges, swivels, and switches and, thus, are involved in
biological signaling processes.[ Furthermore, cis/trans-prolyl
isomerization that can be catalyzed by rotamase enzymes is
critical for the folding process.[ Recently, pseudoprolines
inducing a cis-peptide bond were introduced into the V3 loop
of GP120 of HIV-1, which suggests that a trans/cis isomer-
ization resulting in formation of a type VI b-turn conforma-
tion plays a crucial role in the infection process.[ Thus, the
creation of type VI b-turn model systems is of interest for the
discovery of molecular probes to gain detailed insight into the
intermolecular interaction processes. Using appropriate con-
[
1] M. T. Pope, Heteropoly and Isopoly Oxometalates, Springer, Berlin,
983.
2] V. W. Day, W. G. Klemperer, Science 1985, 228, 4699.
1
[
[
[
[
[
[
1]
3] Chem. Rev. 1998, 98, 3 ± 271.
4] W. N. Lipscomb, Inorg. Chem. 1965, 4, 132.
2]
5] G. Marcu, M. Rusu, D. Rusu, J. Radioanal. Nucl. Chem. 1999, 242, 119.
6] K.-C. Kim, M. T. Pope, J. Am. Chem. Soc. 1999, 121, 8512.
7] P. G. Allen, J. J. Bucher, D. L. Clark, N. M. Edelstein, S. A. Ekberg,
J. W. Gohdes, E. A. Hudson, N. Koltsoyannis, W. W. Lukens, P. N.
Neu, P. D. Palmer, T. Reich, D. K. Shuh, C. D. Tait, B. D. Zwick, Inorg.
Chem. 1995, 34, 4797.
3]
[
8] B. J. Warner, B. L. Scott, C. J. Burns, Angew. Chem. 1998, 110, 1005;
Angew. Chem. Int. Ed. 1998, 37, 959.
[
9] Crystallographic details for 2: a dark red crystal (0.12 Â 0.08 Â
0
.04 mm) was mounted from Paratone N oil onto a glass fiber and
immediately placed on a Bruker P4/CCD/PC diffractometer. A
hemisphere of data was collected by using a combination of f and w
scans, with 30 second frame exposures and 0.38 frame widths. A total
of 14413 reflections (� 14 ꢁ h ꢁ 15, � 20 ꢁ k ꢁ 20, 0 ꢁ l ꢁ 28) were
collected at Tˆ 203(2) K in the q range of 1.49 ± 23.328 of which 14413
were unique (Rint ˆ 0.0000); MoKa radiation (l ˆ 0.71073 Š). The
structure was solved by using direct methods and difference Fourier
techniques (SMART Version 4.210, Bruker Analytical X-ray Systems,
Inc., 1996). All non-hydrogen anisotropic temperature factors were
restrained by using the ISOR option, and hydrogen atoms were placed
in calculated (dC�H ˆ 0.96 Š for methyl, 0.93 Š for methyl) positions.
The residual peak and hole electron density was 1.770 and
[
*] Prof. Dr. P. Gmeiner, Dipl.-Chem. T. Hoffmann, Dr. R. Waibel
Department of Medicinal Chemistry
Emil Fischer Center, Friedrich-Alexander-University
Schuhstrasse 19, 91052 Erlangen (Germany)
Fax : (‡49)9131-85-22585
E-mail: gmeiner@pharmazie.uni-erlangen.de
Dr. H. Lanig
Computer Chemistry Center
Friedrich-Alexander-University
Nägelsbachstrasse 25, 91052 Erlangen (Germany)
Fax : (‡49)9131-85-26565
1.791 eŠ 3 . The absorption coefficient was 7.641 mm . The least-
�
� 1
�
E-mail: lanig@chemie.uni-erlangen.de
squares refinement converged normally with residuals of R1 ˆ 0.0686
2
[**] This work was supported by the BMBFand the Fonds der Chemischen
(
I > 2s(I)), wR2 ˆ 0.1610, and GOF ˆ 1.152 (F ); C109
136 4 13 6
H N O U ,
Å
Industrie. EPC ˆ enantiomerically pure compound.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
space group P1 (no. 2), triclinic a ˆ 13.8298(7), b ˆ 18.681(1), c ˆ
2
6
5.335(2) Š, a ˆ 80.118(1), b ˆ 76.867(1), g ˆ 72.803(1)8, Vˆ
3
� 3
050.9(6) Š , Z ˆ 2, F(000) ˆ 2916,
1
calcd ˆ 1.733 gcm . Crystallo-
Angew. Chem. Int. Ed. 2001, 40, No. 18
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4018-3361 $ 17.50+.50/0
3361

COMMUNICATIONS
formational restraints, bicyclic cis-peptidyl proline surrogates
were investigated with low yielding and nonselective multi-
dilution technique was employed for the conversion of the
diene 5c into the bicyclic azocine 4c. 10 mol% of the catalyst
was chosen to initiate the metathesis reaction and a second
[
4, 5]
step reaction sequences.
Stimulated by a recently de-
[
6]
[12]
scribed Molecular Dynamic (MD) study, we herein present
the design of a lactam-bridged type VIa b-turn mimetic (1).
NMR spectroscopy based conformational analysis and a
practical and efficient EPC synthesis of a model peptide
surrogate by the self-reproduction of chirality methodology of
portion of catalyst (2 mol%) was added after 24 h. Gratify-
ingly, the desired cyclization took place without any detect-
able oligomerization products, although complete conversion
could not be achieved.
To decide which ring size and configuration is most
promising in terms of possible intramolecular hydrogen-bond
interactions, we performed MD simulations on the different
target structures A ± F shown in Scheme 3. All calculations
[
7]
Seebach et al. and Grubbsꢁ ring-closing olefin metathesis
RCM) are also reported (Scheme 1).
[
8]
(
Scheme 1.
Following the above strategy, we approached to the a-
alkylproline derivative 3 by employing the concept of self-
[
7]
reproduction of chirality which was recently re-investigated
[
9]
by Wang and Germanas (Scheme 2). Thus, diastereocon-
Scheme 3.
were performed in the gas phase with no continuum model or
explicit solvent molecules present, using the AM1 Hamilto-
nian implemented in the semiempirical program package
VAMP7.0.[ After heating the system to 400 K, 1200 geo-
metries were sampled at constant temperature resulting in a
total data-acquisition time of 120 ps. The integration time step
was 1 fs, the coupling constant to the heat bath 40 fs. The
ability to form a hydrogen bond was rated by a time-
dependent plot of the two possible donor± acceptor inter-
actions, which lead either to a type VIa, or, by reorientation
of the C- and N-termini by rotation about the torsion angles
Y3 and F2 (see Scheme 1), respectively, to a type VIb turn,
13]
i‡2
i‡1
which involve CO and NH . Classification of the b-turn
type was done by time-dependent analysis of the dihedral
angles Y3 and F2, in accord with the data published by
Robinson.[
Scheme 2. a) CCl
3
CH(OH)
2
, C
6
H
6
, 808C; b) lithium diisopropylamide
; d) 5a:
, 08C !RT, 5b: X ˆ OH, n ˆ 1, 5c: X ˆ OH,
iBu, THF; e) [Ru], CH Cl
(
LDA), allyl bromide, THF, � 788C; c) HCl, MeOH, NaHCO
3
X ˆ Cl, n ˆ 0, CH
2 2 3
Cl , NEt
14]
n ˆ 2, 4-methyl morpholine (NMM), ClCO
2
2
2
(
Cy ˆ cyclohexyl).
For the six-membered lactams, the cis-isomer A allows the
formation of both possible hydrogen bonds. However, for the
chosen simulation conditions, no distinct turn pattern can be
assigned. For the trans-isomer B, the formation of a hydrogen
bond is geometrically not possible. Expanding the ring by one
methylene unit leads to the fused azacycloheptenones C and
D. According to the MD simulations, the increased flexibility
resulted in a growing tendency of the trans-isomer D to form a
type VIa2 interaction pattern. Nevertheless, the mean NH ´´´
OC distance of 4.6 Š is too large for a stable hydrogen bond.
Similar to A, the homologue C is able to form both hydrogen-
bonding interactions. During the simulations, a type VIa1
pattern was established several times, but, in spite of the
corresponding hydrogen-bond interaction, no typical VIb
motif was observed. The fused eight-membered lactams E and
trolled C-alkylation of the bicyclic proline derivative 2a
furnished the N,O-acetal 2b which was transformed into a-
allylproline ester 3 by treatment with one equivalent of HCl in
methanol. To evaluate the scope of our synthetic concept, we
tried to prepare differently sized bicyclic model lactams of
type 4. Thus, the RCM precursors 5a ± c were synthesized by
N-acylation of the proline derivative 3. The subsequent RCM
experiments were performed using the ruthenium-based
[
10]
catalyst I
in refluxing CH Cl which proved to be the
2 2
solvent of choice. The dienes 5a, b underwent clean con-
version to furnish the 5,6- and 5,7-fused unsaturated bicyclic
lactams 4a, b in 91 and 75% yield, respectively. To minimize
competing intermolecular oligomerization processes,[11] a high
3362
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4018-3362 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2001, 40, No. 18

COMMUNICATIONS
F exhibited the most interesting behavior. For the cis-isomer
E a hydrogen bond between the amide carbonyl and the
carbamate NH was observed, however, the flexibility within
the molecule allowed switching to a type VIa-like hydrogen-
bond interaction (this occurred several times during the
simulation). Moreover, the trans-isomer F formed only one
hydrogen-bonding pattern, a type VIa2 subtype (Y3 ˆ 08
and F2 ˆ � 1208) of the b-VI turn family (Figure 1a). As a
charges at the boundary between the solute and the contin-
uum (water, dielectric constant ˆ 78.4) and therefore repre-
sents the dielectric properties of the bulk molecules. Both
series of simulations show the same principal behavior. As a
general effect, structural fluctuations are damped by the
environment, which leads to a more meaningful interpretation
of the data.
To experimentally verify our MD simulation prediction of
type VIa b-turn inducing properties for the bicyclic peptido-
mimetic F, the RCM precursor 6 was prepared starting from
tert-butoxycarbonyl (Boc) protected (S)-allylglycine and the
a-allylproline 3 (Scheme 4). Subsequently, Ru-catalyzed ring-
closure of the protected dipeptide 6 led to formation of the
Scheme 4. a) (S)-N-Boc-2-amino-4-pentenoic acid, NMM, ClCO
THF; b) 7 mol% [Ru], CH Cl 408C; c) LiOH, dioxane/H O; d) BnNH
Cl , 1-hydroxy-
2
iBu,
2
2
2
2
(
1
Bn ˆ benzyl), N,N'-dicyclohexyl carbodiimide (DCC), CH
2
2
H-benzotriazole (HOBt); e) HCl/diethyl ether.
Figure 1. a) Plot of the dihedral angles Y3 and F2 calculated from the
eight-membered azacycle 7 in 57% yield. To improve the
120 ps semiempirical MD simulation (AM1, 400 K) of compound F. Note
that the mean values come close to the ideal angles of a type VIa2 turn
efficiency of the reaction we tried the highly active N-hetero-
cyclic carbene-coordinated catalyst II. Actually, the meta-
[14]
(
Y3 ˆ 08 and F2 ˆ � 1208).
No conformational interchange can be
[16]
observed. b) Representative example of a conformation extracted from the
trajectory. The dihedral angles Y3 ˆ 238 and F2 ˆ � 1028 result in a NH ´´´
OC distance of 2.3 Š for this non-equilibrium conformation.
thesis reaction proceeded smoothly with only 7 mol% of
catalyst to yield the bicyclic olefin 7 in 88% (12 h, reflux).
Finally, hydrolysis of the ester function and DCC coupling to
benzylamine as a representative NH-providing unit gave the
target model peptide 8 that could be readily transformed into
the primary amine 9.
representative geometrical example, a snapshot taken from
the MD simulation of compound F is shown (Figure 1b). The
conformational behavior is independent from the starting
geometry of the simulation. Beginning with a geometry-
optimized type VIb turn, the conformation of the molecule
switches to a stable VIa2 motif after a few picoseconds of data
acquisition.
Comparison of all six simulations strongly supports the
assumption that the lactam-bridged peptide surrogate F
should be most suitable for the formation of a hydrogen-
bonding pattern leading to a successful type VIa b-turn
mimetic.
Conformational analysis of the lactam-bridged peptidomi-
metic 8 is mainly based on NMR spectroscopy, particularly on
coupling constants, NOEs, and variable temperature (VT)
measurements. A strong NOE was detected between H-7a
and H-3 indicating the transannular proximity of these two
protons in a boat conformation of the eight-membered lactam
ring. In combination with a detailed analysis of the proton
couplings further strong NOEs between the amide N-H and
H-3 and the carbamate N-H and H-4a, respectively, were
diagnostic for a type VIa b-turn conformation adopted by the
lactam 8. Clearly the fused ring system is fixed in a stable
conformation which forces the substituents at C-3 and C-8
into an orientation able to form a hydrogen bond between the
amide NH and the carbamate CˆO as predicted by the MD
To account for solvent effects which may influence the
conformational preferences of peptide-like structures, we
repeated the calculations applying the COSMO approach of
[
15]
Klamt and Schüürmann. This technique describes quantum
mechanically the macroscopic environment by polarization
calculations. The presence of an intramolecular hydrogen
Angew. Chem. Int. Ed. 2001, 40, No. 18
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4018-3363 $ 17.50+.50/0
3363

COMMUNICATIONS
bond, indicated by the comparatively downfield shift (d ˆ
Atomic Force Microscope Studies on
Condensation of Plasmid DNA with
Functionalized Fullerenes**
8
.11) of the amide N�H resonance was unambiguously
demonstrated by comparison of the amide N�H shifts in the
spectra (in CDCl ) of the carbamate 8 and the amine 9 when
3
�
H appeared significantly shifted
Hiroyuki Isobe, Sho Sugiyama, Ken-ichi Fukui,
Yasuhiro Iwasawa, and Eiichi Nakamura*
the signal of the amide N
upfield (Dd ˆ 1.61) after removal of the Boc unit. Besides the
main conformational population, VT NMR experiments
which showed a significant chemical-shift change (Dd/DTˆ
A recent paper reported the first example of the use of a
carbon cluster as a vector to deliver DNA into mammalian
cells.[ Thus, mixed with the tailor-made tetraminofullerene
�
1
�
5.2 ppbK ) gave evidence for a temperature dependant
coexistence of non-hydrogen bonded conformations, cor-
roborated by NOEs between H-3 and the carbamate N-H at
1, 2]
[17]
1, a plasmid DNA forms micrometer-sized fullerene ± DNA
particles as observed by optical microscope, which, after
elevated temperature (330 K, CDCl ). The FT-infrared (IR)
3
�
1
spectrum displayed an extensive absorption at 3350 cm
characteristic for a hydrogen bonded amide and an absorption
HMe2N
+
�
1
MeH
at 3405 cm also indicating the coexistence of a solvent-
exposed amide.
N
O
H
O
H
+
+
NMeH
O
Et
HMe2N
In conclusion, a highly efficient proline-based type VI b-
turn mimetic was designed employing the results of molecular
dynamics simulation. EPC synthesis involving Seebachꢁs self-
reproduction of chirality methodology and Grubbsꢁ ring-
closing olefin metathesis gave access to the novel molecular
scaffold.
O
O
+
O
H
HMeN +
+
1
2
NMe2H
Received: March 12, 2001
Revised: June 26, 2001 [Z16752]
incubation with the target cells, became located inside the
cytoplasm as phagocytes. Expression of the encoded gene
took place over several days, indicating that the plasmid DNA
was released into the cytoplasm without being damaged by
the fullerene complexation. Although these biological experi-
ments demonstrated the ability of the fullerene 1 to condense
and release DNA, the molecular nature of such reversible
DNA condensation remained unclear. We report herein the
results of atomic force microscope (AFM) studies[ that
provided molecular-level information on the DNA condensa-
tion/release processes induced by fullerene vesicles.[ When
used in a small quantity, the fullerene 1 condenses a single
plasmid DNA into a 1 ± DNA complex. Upon further addition
of 1, many single-molecule DNA condensates gather together
to form the micrometer-sized fullerene ± DNA particles
observed previously by optical microscopy. Release of the
DNA molecules from these large particles was achieved
experimentally by removal of the fullerene through CHCl3
extraction.
[
[
[
1] M. S. P. Sansom, H. Weinstein, Trends Pharmacol. Sci. 2000, 21, 445 ±
51.
2] S. Fischer, R. L. Dunbrack, Jr., M. Karplus, J. Am. Chem. Soc. 1994,
16, 11931 ± 11937.
3] A. Wittelsberger, M. Keller, L. Scarpellino, L. Patiny, H. Acha-Orbea,
M. Mutter, Angew. Chem. 2000, 112, 1153 ± 1156; Angew. Chem. Int.
Ed. 2000, 39, 1111 ± 1115.
4] D. Gramberg, C. Weber, R. Beeli, J. Inglis, C. Bruns, J. A. Robinson,
Helv. Chim. Acta 1995, 78, 1588 ± 1606.
5] K. Kim, J. P. Germanas, J. Org. Chem. 1997, 62, 2847 ± 2852.
6] G. Müller, G. Hessler, H. Y. Decornez, Angew. Chem. 2000, 112, 926 ±
28; Angew. Chem. Int. Ed. 2000, 39, 894 ± 896.
7] D. Seebach, M. Boes, R. Naef, W. B. Schweizer, J. Am.Chem. Soc.
983, 105, 5390 ± 5398.
8] a) R. H. Grubbs, S. Chang, Tetrahedron 1998, 54, 4413 ± 4450; b) M.
Schuster, S. Blechert, Angew. Chem. 1997, 109, 2124 ± 2144; Angew.
Chem. Int. Ed. Engl. 1997, 36, 2036 ± 2055; c) A. Fürstner, Angew.
Chem. 2000, 112, 3140 ± 3172; Angew. Chem. Int. Ed. 2000, 39, 3012 ±
4
1
3]
4]
[
[
[
9
[
[
1
3
043.
The interactions between the fullerene 1 and DNA were
probed for 4 kbp supercoiled plasmid DNA (pBR322). Thus,
we added an increasing amount of 1 to a pH 7.6 buffer solution
of pBR322 and plotted the amount of the DNA mobile on the
gel against the reagent/base pair ratio (R). As shown in
Figure 1 (solid line), there was observed precipitous decrease
[
9] H. Wang, J. P. Germanas, Synlett 1999, 7, 33 ± 36.
[
[
10] P. Schwab, R. H. Grubbs, J. W. Ziller, J. Am. Chem. Soc. 1996, 118,
00 ± 110.
1
11] a) ªAlkene Metathesis in Organic Synthesisº: A. Fürstner, Top.
Organomet. Chem. 1998, 1, 37 ± 72; b) E. L. Dias, S. T. Nguyen,
R. H. Grubbs, J. Am. Chem. Soc. 1997, 118, 3887 ± 3897.
12] M. Ulman, R. H. Grubbs, J. Org. Chem. 1999, 64, 7202 ± 7207.
13] T. Clark, A. Alex, B. Beck, J. Chandrasekar, P. Gedeck, A. Horn, M.
Hutter, B. Martin, G. Rauhut, W. Sauer, T. Schindler, T. Steinke,
Programme Package VAMP7.0, Oxford Molecular Group Plc.,
Oxford, 1998.
[
[
[*] Prof. Dr. E. Nakamura, Dr. H. Isobe, S. Sugiyama, Dr. K.-i. Fukui,
Prof. Dr. Y. Iwasawa
Department of Chemistry
The University of Tokyo
[
[
14] J. A. Robinson, Synlett 2000, 4, 429 ± 441.
15] A. Klamt, G. Schüürmann, J. Chem. Soc. Perkin Trans. 2 1993, 799 ±
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax : (‡81)3-5800-6889
8
05.
16] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1, 953 ±
56.
E-mail: nakamura@chem.s.u-tokyo.ac.jp
[
[
[
**] This research was supported by Grant-in-Aid for Specially Promoted
Research from Ministry of Education, Culture, Sports, Science, and
Technology.
9
17] a) L. Belvisi, C. Gennari, A. Mielgo, D. Potenza, C. Scolastico, Eur. J.
Org. Chem. 1999, 389 ± 400; b) E. S. Stevens, N. Sugawara, C. M.
Bonora, C. Toniolo, J. Am. Chem. Soc. 1980, 102, 7048 ± 7050; c) K.
Weber, U. Ohnmacht, P. Gmeiner, J. Org. Chem. 2000, 65, 7406 ± 7416.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
3364
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4018-3364 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2001, 40, No. 18