Tweezers with different bite: Increasing the affinity of synthetic receptors by varying the hinge part

Article abstract of DOI:10.1002/(SICI)1521-3773(19980803)37:13/14<1846::AID-ANIE1846>3.0.CO;2-E

With preservation of selectivity, the hinge part of tweezerlike synthetic receptor molecules can be varied to achieve a higher affinity. The synthetic peptidosulfonamide receptor (below left; R = Disperse Red 1) with the bis(aminomethyl)benzoic acid hinge selectively bound the tripeptide shown below on the right (K(a) = 4100 M^-1). Combination of a diversity in the hinge part with that present in the tweezer arms will provide access to large and diverse synthetic receptor libraries.

Full text of DOI:10.1002/(SICI)1521-3773(19980803)37:13/14<1846::AID-ANIE1846>3.0.CO;2-E

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altered substitution on ring D of 3 in the Pr form, whereas in
the Pfr form the chromophore ± protein interactions discrim-
inate between the substitution patterns of 1 and 3. There
remains the question of whether this selectivity of the
chromophore ± protein interactions reflects either steric and/
or electronic effects (see Figure 2).
Tweezers with Different Bite: Increasing the
Affinity of Synthetic Receptors by Varying the
Hinge Part**
Dennis W. P. M. Löwik, M. David Weingarten,
Matthias Broekema, Arwin J. Brouwer, W. Clark Still,
and Rob M. J. Liskamp*
Received: December 30, 1997 [Z11303IE]
German version: Angew. Chem. 1998, 110, 1943 ± 1946
Despite the tremendous progress in the design and syn-
thesis of receptor molecules with predicted binding proper-
ties, it remains a difficult task to design a molecule capable of
binding to a particular ligand. Therefore, recent efforts have
turned to the more ªbiomimetic approachº of combinatorial
chemistry for the generation of libraries of synthetic receptors
capable of binding certain desired ligands. The approach is
inspired by natureꢁs very own combinatorial approach so
clearly demonstrated by the immune system.
Based on the successful concept of ªtweezerlikeº two
armed synthetic receptors,[1] we have developed synthetic
receptors consisting of peptidosulfonamide peptidomimet-
ics.[2] We would like to prepare libraries of tweezerlike
receptors that can be screened for their binding affinity
to a variety of ligands, peptides, other biomolecules (for
example, those that are present on pathogenic organisms),
drugs, and signaling molecules. Although our present syn-
thetic receptor showed a remarkable binding selectivity,[2] to
have further possible applications its binding affinity with
ligands had to be increased. We now describe the results of
incorporating less flexible ªhingesº in tweezerlike synthetic
receptors.
Keywords: chromophores ´ photochromism ´ phytochrome
´ tetrapyrroles ´ UV/Vis spectroscopy
[1] a) K. Schaffner, S. E. Braslavsky, A. R. Holzwarth in Frontiers in
Supramolecular Organic Chemistry and Photochemistry (Eds.: H.-J.
Schneider, H. Dürr), VCH, Weinheim, 1991, p. 421; b) W. Rüdiger, F.
Thümmler, Angew. Chem. 1991, 103, 1242; Angew. Chem. Int. Ed.
Engl. 1991, 30, 1216; c) S. E. Braslavsky, W. Gärtner, K. Schaffner,
Plant Cell Environ. 1997, 20, 700.
[2] Photomorphogenesis in Plants (Eds.: R. E. Kendrick, G. H. M.
Kronenberg), 2nd ed., Kluwer Academic, Dordrecht, 1994.
[3] a) J. A. Wahleithner, L. Li, J. C. Lagarias, Proc. Natl. Acad. Sci. USA
1991, 88, 10387; b) L. Deforce, M. Furuya, P.-S. Song, Biochemistry
1993, 32, 14165; c) T. Kunkel, K.-I. Tomizawa, R. Kern, N.-H. Chua, E.
Schäfer, Eur. J. Biochem. 1993, 215, 587; d) W. Gärtner, C. Hill, K.
Worm, S. E. Braslavsky, K. Schaffner, ibid. 1996, 236, 978; e) P.
Schmidt, U. H. Westphal, K. Worm, S. E. Braslavsky, W. Gärtner, K.
Schaffner, J. Photochem. Photobiol. B 1996, 34, 73; f) A. Ruddat, P.
Schmidt, C. Gatz, S. E. Braslavsky, W. Gärtner, K. Schaffner,
Biochemistry 1997, 36, 103; g) C. Kneip, D. Mozley, P. Hildebrandt,
W. Gärtner, S. E. Braslavsky, K. Schaffner, FEBS Letters 1997, 414, 23.
[4] J. Cornejo, S. I. Beale, M. J. Terry, J. C. Lagarias, J. Biol. Chem. 1992,
267, 14790.
Our present ªtweezerlikeº synthetic receptors consist of
three different parts (Scheme 1): A hinge to which the
tweezer arms are attached; a dye or a solid-phase bead
attached to this hinge; and two binding arms, which at present
consist of peptidosulfonamide peptidomimetics. Based on the
original hinge in tweezer 1, hinges in tweezers 2 ± 6 were
selected to gradually vary the flexibility and interchain
distance, or both, between the amino nitrogen atoms.
The route for the preparation of the tweezerlike synthetic
receptors is exemplified by the preparation of tweezers 2 and
5 in Schemes 2 and 3. The bis(aminomethyl)benzoic acid
hinge present in receptor 2 was synthesized from 3,5-
dimethylbenzoic acid (7).[3] We took advantage from the fact
[5] Dimethyl ester 2 was synthesized for the first time by Gossauer and
coworkers.[6]
[6] J.-P. Weller, A. Gossauer, Chem. Ber. 1980, 113, 1603.
[7] See also: B. Knipp, K. Kneip, J. Matysik, W. Gärtner, P. Hildebrandt,
S. E. Braslavsky, K. Schaffner, Chem. Eur. J. 1997, 3, 263.
[8] a) A. Gossauer, W. Hirsch, Justus Liebigs Ann. Chem. 1974, 1496; b) A.
Gossauer, R.-P. Hinze, J. Org. Chem. 1978, 43, 283.
[9] L. Li, J. C. Lagarias, J. Biol. Chem. 1992, 267, 19204.
[10] M. A. Drinan, T. D. Lash, J. Heterocycl. Chem. 1994, 31, 255.
[11] K. Kohori, M. Hashimoto, H. Kinoshita, K. Inomata, Bull. Chem. Soc.
Jpn. 1994, 67, 3088.
[12] N. Ono, H. Katayama, S. Nisyiyama, T. Ogawa, J. Heterocycl. Chem.
1994, 31, 707.
[13] J. E. Bishop, J. F. OꢁConnell, H. Rapoport, J. Org. Chem. 1991, 56,
5079.
[14] K. Ichimura, S. Ichikawa, K. Iamamata, Bull. Chem. Soc. Jpn. 1976, 49,
1157.
[15] P. Manitto, D. Monti, J. Chem. Soc. Chem. Commun. 1980, 178.
[16] The signal groups for the substitution pattern on ring D in 2 and 4 also
correspond with the related signals from the dimethyl esters of
biliverdin IXa and XIIIa: H. Lehner, S. E. Braslavsky, K. Schaffner,
Justus Liebigs Ann. Chem. 1978, 1990.
[*] Prof. Dr. R. M. J. Liskamp, D. W. P. M. Löwik, M. Broekema,
A. J. Brouwer
Department of Medicinal Chemistry
Utrecht Institute for Pharmaceutical Sciences
Utrecht University
[17] D. Mozley, A. Remberg, W. Gärtner, Photochem. Photobiol. 1997, 66,
710.
P.O. Box 80082, NL-3508 TB Utrecht (The Netherlands)
Fax : (‡ 31)30-253-6655
[18] Pr and Pfr represent the thermally stable forms in the phytochrome
photocycle, which absorb red (r) and far-red (fr) light, respectively.
[19] Correspondingly shifted absorption values are also found when
phytochrome is reconstituted from recombinant oat apoprotein with
native phytochromobilin (1), which is isolable from algae in small
amounts and only with difficulties. This successful reproduction of
phytochrome reconstitution based on native 1 minimizes the risk of
artifacts that might have arisen in reconstitution employing the now
readily available synthetic 1.
E-mail: r.m.j.liskamp@far.ruu.nl
Dr. M. D. Weingarten, Prof. Dr. W. C. Still
Department of Chemistry
Columbia University, New York, NY 10027 (USA)
Fax : (‡ 1)212-854-5429
E-mail: clark@still3.chem.columbia.edu
[**] These investigations were supported in part (D.W.P.M.L. and A.J.B.)
by The Netherlands Foundation for Chemical Research (SON) with
financial aid from The Netherlands Technology foundation. Support
from NATO (921326) is gratefully acknowledged.
[20] C. Kratky, H. Falk, K. Grubmayr, U. Zrunek, Monatsh. Chem. 1985,
116, 761.
1846
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Boc protecting groups in 16
were removed and introduction
of the peptidosulfonamide arms
by the sulfonyl chloride ap-
proach completed the synthesis
of 5.
In synthetic receptor 3 the
commercially available diami-
nobenzoic acid hinge was used.
The carbazole hinge present in
tweezer 4 was prepared accord-
ing to Rebek et al.[9] The choice
for the preorganized tweezer
hinge present in receptor 6 was
inspired by the work of Die-
derich et al.[10] and this hinge
was obtained after reduction
and attachment of the dye
part.[11]
The thus obtained receptors
1 ± 6 were screened for binding
against a 24389 ( ˆ 293) mem-
ber encoded sidechain-depro-
tected tripeptide library on
TentaGel (AA3 AA2 AA1
N(H) TentaGel).[12] The bead-
supported tripeptide library
was equilibrated in a chloro-
form solution of the receptor
(Figure 1).[13] Immediately it
can be seen that receptors 2, 3,
and 4 showed an increased
binding affinity, since the con-
centration for binding of these
receptors to the beads was low-
er than the concentration for
binding of the original receptor
(Table 1). The binding by the
pyrrolidine receptor 5 is com-
parable to that of the original
receptor 1, and clearly two
tweezer arms are needed for a
Scheme 1. Structures of tweezerlike synthetic receptor: R ˆ Disperse Red 1; the hinge parts are shown in the
[12]
frames; AA1±3
.
significant binding, since the
that some monobrominated product 10 always occurred on
bromination of 8 by using 10 for the preparation of the so-
called amputated tweezer containing only one arm (2a, see
above). After removal of the Boc protective groups in 11, the
peptidosulfonamide arms were introduced through the sul-
fonyl chloride approach.[4] Saponification of the methyl ester
followed by coupling to Disperse Red 1 (DispR) completed
the synthesis of the intensely blood-red synthetic receptor 2.
The amputated receptor 2a was prepared analogously
(Scheme 2).
The pyrrolidine hinge[5] in tweezer 5 was prepared form L-
tartaric acid (Scheme 3). The pyrrolidine diol 14 was prepared
according to Nagel et al.[6] This diol was converted into the
diazide,[7] then reduced, and the resulting amino groups
protected to afford 15. The dye was attached to a spacer group
by hydrogenolysis of the benzyl group.[8] Subsequently, the
ªamputatedº receptor having one arm (2a) does not give rise
to an appreciable binding even at a concentration of 425mm.
At first glance the absence of any binding whatsoever by
receptor 6 was surprising. However, we reasoned that
repulsion between the lone pairs on the oxygen atoms of the
sulfonamide groups attached to the diazobicyclonane system
might disfavor the chair± chair shape and as a consequence
favor the formation of a boat ± chair conformation and lead to
the opening of the tweezerlike structure.[14]
After 72 h equilibration the colored beads were separated
and decoded by photolytic release of the molecular tags, as
monitored by electron-capture gas chromatography (EC-
GC).[15] The number of beads which were decoded for each
synthetic receptor are shown in Table 1. This table also shows
the consensus sequences bound by each receptor, the
frequencies with which they were found among the decoded
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Scheme 2. Synthesis of the receptors 2 (with the bis(aminomethyl)benzoic
acid hinge) and the amputated tweezer 2a; NBS ˆ N-bromosuccinimide,
AIBN ˆ azobisisobutyronitrile, Boc ˆ tert-butoxycarbonyl, NMM ˆ N-
methylmorpholine, DIC ˆ diisopropylcarbodimide, DMAP ˆ N,N-dime-
thylaminopyridine, R ˆ Disperse Red.
Scheme 3. Synthesis of the receptors 5 with the pyrrolidine hinge; Bn ˆ
benzyl, HOBt ˆ 1-hydroxybenzotriazole, DEAD ˆ diethylazodicarboxy-
late, R ˆ Disperse Red.
Figure 1. Photographs of the screening assays of tweezer receptors 1, 2, 3,
and 5 for binding to the bead-supported tripeptide library.
beads, and the frequency of their occurrence in the bead-
supported tripeptide library.
Practically all consensus sequences of all tweezers show the
presence of an acidic amino acid residue mostly occurring at
position AA3. AA2 is almost invariably a polar amino acid
residue (Asn and very often His). Like the earlier described
synthetic receptor 1, both the diamino receptor 3 and the
pyrrolidine receptor 5 show some degree of diastereoselec-
tivity since l-Glu d-His or d-Glu l-His are found, but not
the corresponding diastereomeric sequences l-Glu l-His or
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Table 1. Binding selectivity of receptors 1 ± 6 for tripeptides in a 24389 ( ˆ 293)
member encoded sidechain-deprotected tripeptide library on TentaGel (AA3-
AA2 AA1 N(H) TentaGel).
was observed on using the more rigid tweezer 3, a
receptor that has less space between the peptidosulfo-
namide arms. This tweezer, like the previous tweezer 2,
also improved the binding affinity of similar tripeptides,
for example l-Glu d-His l-Val, which bound to the
original tweezer 1. Although a coloring of the tripeptide
containing beads comparable to that with the benzyl
tweezer 2 took place upon incubation with a concen-
tration of the carbazole tweezer 4, none of the beads
were dark orange or red. Therefore, the binding affinity
was considered not be significantly enhanced relative to
the original receptor 1. Apparently, despite the rigid
character of the carbazole hinge the distance between
the arms is too large for a clear increase in the binding
affinity. The pyrrolidine hinge seemed a very attractive
one with respect to rigidity and chirality, and the
selectivity of binding of the tweezer containing this
hinge was very high. In 95% of the decoded beads the
sequence l/d-Glu d/l-His Xxx was found. Moreover
l-Glu d-His Xxx and d-Glu l-His Xxx were found,
but not the corresponding diastereomeric sequences l-
Glu l-His Xxx or d-Glu d-His Xxx (Table 1).
However, the binding affinity was a little disappointing.
Apparently, the tweezer arms point too far away
from each other for a significant increase of binding to
occur.
Recep- Equilibri-
Decoded
beads
Consensus sequence
AA3 AA2 AA1
Found
Library
tor
um con-
frequen- member
cy [%][a] frequen-
cy [%][b]
centration number
[mm]
1[e]
2
70
40
34
28
l/d-Ala-d/l-Asp-l/d-Xxx[d] 50
0.1
0.3
6.9
0.2
0.2
0.07
l-Glu d-His/Asn Xxx
20
61
32
21
21
100
64
70
27
61
63
56
38
95
26
Glu Xxx Xxx[c]
l/d-Glu d/l-His Xxx[d]
l/d-Glu Xxx l/d-Val
Gly Asn/His Asp/Glu
Glu/Asp Xxx Xxx
Glu Xxx Xxx
2a
3
425
20
3
33
14
6.9
6.9
6.9
0.2
6.9
6.9
0.2
0.2
0.02
Xxx His Xxx
Xxx Xxx Asp
l/d-Glu d/l-His Xxx[d]
Glu Xxx Xxx
4
40
16
Xxx His Xxx
l/d-Glu d/l-His Xxx[d]
l/d-Glu d/l-His Xxx
l/d-Glu d/l-His Phe[d]
none
5
6
80
19
500
none
[a] Only consensus sequences found in ꢀ20% of the beads are listed here.
[b] Frequency with which these are actually present in the tripeptide library. [c] No
prefix l- or d- indicates no preference for either enantiomer by the synthetic
receptor. [d] The prefixes l- and d- placed in this manner indicate that, for example,
l-Glu-d-His-Xxx and d-Glu-l-His-Xxx are found but not l-Glu-l-His-Xxx or d-
Glu-d-His-Xxx. [e] See reference [2].
Table 2. Binding affinity of receptors 1 ± 6 for peptides, which were synthesized
according to the sequences found by decoding.
d-Glu d-His. This diastereoselectivity is also shown,
albeit less clearly, by the other two receptors 2 and 4
that were capable of recognizing the Glu-His sequence.
As was the case with the original receptor 1, most
variability is found in the amino acid residue that is
nearest to the polymer support (AA1). However, in the
original receptor 1 this is predominantly a polar amino
acid residue while in the receptors 2 and 3 (which
contain less flexible hinges than the hinge of 1) and in
the carbazole receptor 4 the distribution of polar to
nonpolar amino acids in AA1 is about equal whereas in
the pyrrolidine-based receptor 5 there is a shift to an
apolar amino acid for AA1.
1
Recep- Resynthesized peptide
tor
Screening Binding
Ka
DG [kJmol
]
1
[c]
affinity[a] affinity[b] [m
]
1
2
3
d-Ala l-Asp d-Ser
l-Glu d-Asn l-Val
d-Ala l-Asp d-Ser
l-Glu d-Asn l-Val
d-Ala l-Asp d-Ser
l-Glu d-Asn l-Val
l-Glu d-His l-Val
Gly l-His l-Asp
Gly l-His l-Asp
d-Ala l-Asp d-Ser
l-Glu d-His l-Val
‡
‡‡
‡
320
95
4100
1680
14.2
11.2
20.5
18.3
‡
[f]
‡‡‡
‡‡‡
‡‡
‡
‡‡‡
[e]
760
16.4
[e]
[d]
[d]
‡‡
‡‡
‡‡‡
‡‡‡
‡
210
13.2
[d]
[d]
[d]
[d]
4
5
‡
[e]
‡‡
‡‡
ꢁ 40
ꢁ
9
10.8
‡‡‡
80
Although the trends are clear and we seem to be on
our way towards realizing our main aim with an increase
in the binding affinity, binding of the peptide sequences
determined by decoding the beads had to be verified by
binding experiments with these peptides obtained by
independent synthesis and determination of some
representative binding constants.
[a] As determined from incubation with the bead-supported tripeptide library:
‡‡‡ red beads; ‡ ‡ dark orange to red beads;‡ dark orange beads. [b] By incubation
in chloroform of the resynthesized peptide on the bead with the colored receptor.
[c] As derived from UV measurements, the error is Æ 10%, with the exception of
1
4100m
:
Æ 5% and 210 and 40m 1, each Æ 15%. [d] Not determined. [e] Not
found. [f] Not found, however the related sequence d-Ala l-Asp d-Thr was found.
Based on the sequences found from the decoding
experiments we selected the indicated sequences for resyn-
thesis (Table 2). Several binding constants were determined.
Indeed, the binding affinity of the sequence d-Ala l-Asp d-
Ser that bound with high selectivity to the original receptor 1
was increased more than tenfold (from 330 to 4100m 1) with
synthetic receptor 2. An increasing affinity was also observed
with the sequence l-Glu d-Asn l-Val that bound with a
lower affinity to the original receptor (95m 1) but that bound
In conclusion, we have shown that by varying the hinge part
of tweezerlike synthetic receptor molecules it is possible to
increase the binding affinity of tripeptides significantly while
maintaining the selectivity. The availability of a variety of
hinges or scaffolds and building blocks inspired by ªnatural
diversityº will provide access to all sorts of required libraries
capable of binding compounds other than peptides.
1
to tweezer 2 with a respectable affinity of Ka ˆ 1680m . A
Received: January 2, 1998 [Z11316IE]
German version: Angew. Chem. 1998, 110, 1947 ± 1950
twofold increase in binding affinity of d-Ala l-Asp d-Ser
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Keywords: combinatorial chemistry ´ peptides ´ peptidomi-
metics ´ receptors ´ sulfonamides
A Spontaneous Fragmentation: From the
Criegee Zwitterion to Coarctate Möbius
Aromaticity**
Christian Berger, Christian Bresler, Ulrich Dilger,
Daniel Geuenich, Rainer Herges,* Herbert Röttele,
and Gerhard Schröder*
[1] S. C. Zimmerman, W. Wu, Z. Zeng, J. Am. Chem. Soc. 1991, 113, 196 ±
201; R. Boyce, G. Li, H. P. Nestler, T. Suenaga, W. C. Still, ibid. 1994,
116, 7955 ± 7956; S. R. Labrenz, J. W. Kelly, ibid. 1995, 117, 1655 ±
1656; Y. Cheng, T. Suenaga, W. C. Still, ibid. 1996, 118, 1813 ± 1814;
H. Wennemers, S. S. Yoon, W. C. Still, J. Org. Chem. 1995, 60, 1108 ±
1109; C. Gennari, H. P. Nestler, B. Salom, W. C. Still, Angew. Chem.
1995, 107, 1894 ± 1896; Angew. Chem. Int. Ed. Engl. 1995, 34, 1765 ±
1768.
Dedicated to Professor William von E. Doering
on the occasion of his 80th birthday
Coarctate reactions[1] are defined as those in which two
bonds are simultaneously formed and broken at one or more
atoms. Like the pericyclic reactions, they form an independent
and coherent class of concerted reactions. Rules are available
for predicting the stereochemical course of coarctate reac-
tions,[1] similar to the Woodward ± Hoffmann rules for peri-
cyclic reactions. We now describe an unusual fragmentation
reaction which is in accordance with these stereochemical
rules and for which such a coarctate transition state was
confirmed by theoretical calculations.
[2] D. W. P. M. Löwik, S. J. E. Mulders, Y. Cheng, Y. Shao, R. M. J.
Liskamp, Tetrahedron Lett. 1996, 37, 8253 ± 8256.
[3] K. Kurz, M. G. Göbel, Helv. Chim. Acta 1996, 79, 1967 ± 1979.
[4] D. B. A. de Bont, G. H. Dijkstra, J. A. J. den Hartog, R. M. J. Liskamp,
Bioorg. Med. Chem. Lett. 1996, 6, 3035 ± 3040.
[5] This hinge was successfully applied in the synthetic receptors of Still
et al. see for example a) S. S. Yoon, W. C. Still, Tetrahedron 1995, 51,
567 ± 578; b) Y. Shao, W. C. Still, J. Org. Chem. 1996, 62, 6086 ± 6087;
c) Z. Pan, W. C Still, Tetrahedron Lett. 1996, 37, 8699 ± 8702; d) M.
Torneiro, W. C. Still Tetrahedron 1997, 53, 8739 ± 8750.
[6] U. Nagel, E. Kinzel, J. Andrade, G. Prescher, Chem. Ber. 1986, 119,
3326 ± 3343.
Tropone ethylene acetal (1) is in equilibrium with the
norcaradiene derivative 1a. Above 1008C 1 undergoes
[7] J. Skarzewski, A. Gupta, Tetrahedron Assym. 1997, 8, 1861 ± 1867.
[8] See reference [5a].
[9] R. J. Pieters, I. Huc, J. Rebek, Jr., Chem. Eur. J. 1995, 1, 183 ±
192.
1
sigmatropic rearrangements (Ea ˆ 23.9 kcalmol ).[2] More-
over, above 1108C 1 decomposes via 1a to give carbon
[10] F. Diederich, D. R. Carnanague, Helv. Chim. Acta 1994, 77, 800 ± 818.
[11] It was difficult to functionalize the hindered secondary hydroxy
function in the diazabicyclononane part of the ligands with a suitable
anchor molecule to which the dye had to be attached. Ultimately, the
use of methyl p-bromomethylbenzoate in the presence of potassium
hydride and 18-crown-6 furnished the hinge part of 6.
[12] AA1±3: Gly, d- and l-Ala, d- and l-Val, d- and l-Leu, d- and l-Phe, d-
and l-Pro, d- and l-Ser, d- and l-Thr, d- and l-Asn, d- and l-Gln, d-
and l-Asp, d- and l-Glu, d- and l-His, d- and l-Lys, d- and
l-Arg.
1
dioxide, benzene, and ethene (Ea ˆ 31.6 kcalmol ).[2] The
fragmentation of 1a was interpreted as a chelotropic cyclo-
reversion to give benzene and 2-carbena-1,3-dioxolane. The
authors speculate that the decomposition of the 2-carbena-
1,3-dioxolane and the chelotropic cycloreversion might be
part of a single concerted step.[2] The parent structural
element in the fragmentation of 1a is the 4,7-dioxaspiro[2.4]-
heptane 2. If a C ± O bond in 2 is replaced by a O ± O bond (3),
[13] We attempted to reach a concentration of the receptor slightly lower
than that required for binding approximately 1% of the library beads.
These concentrations are listed in Table 1.
[14] A bissulfonamide derivative of the diazabicyclonane system gave rise
to a chair ± boat shape, whereas a bistrifluoroacetyl derivative gave
rise to a chair± chair shape: P. H. McCabe, N. J. Milne, G. A. Sim, J.
Chem. Soc. Chem. Commun. 1985, 625 ± 626
[15] M. H. J. Ohlmeyer, R. N. Swanson, L. W. Dillard, J. C. Reader, G.
Asouline, R. Kobayashi, M. Wigler, W. C. Still, Proc. Natl. Acad. Sci.
USA 1993, 90, 10922 ± 10926.
[*] Prof. Dr. R. Herges, Dipl.-Chem. D. Geuenich
Institut für Organische Chemie der Technischen Universität
Hagenring 30, D-38106 Braunschweig (Germany)
Fax: (‡49)531-391-5388
E-mail: r.herges@tu-bs.de
Prof. Dr. G. Schröder, Dr. C. Berger, Dipl.-Chem. C. Bresler,
Dr. U. Dilger, Dr. H. Röttele
Institut für Organische Chemie der Universität
Kaiserstrasse 12, D-76128 Karlsruhe (Germany)
Fax: (‡49)721-608-4825
[**] We grateful to Prof. H. J. Schäfer and Dipl.-Chem. M. Letzel,
Universität Münster, for help with the Kolbe electrolysis during the
synthesis of 22.
1850
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3713-1850 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1998, 37, No. 13/14