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Models for Peptide Receptors.

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The specific applications for which these materials are suitable will be shown by future developments.
German version: Angew. Chem. 1993, 105, 887
[l] In this article the term (photo)luminescence is used exclusively; that is. no
distinction is made between fluorescence and phosphorescence.
[2] a) L. T. Canham, Appl. Phys. Lett. 1990, 57, 1046; b) A. Richter, P. Steiner, F. Kozlowski, W. Lang, IEEE Elerrron Device Lett. 1991, 12, 691; c) N.
Koshida, H. Koyama, Appl. Phys. Lett. 1992,60,347; d) V. Petrova-Koch,
A. Kux, F. Muller, T. Muschik, F. Koch, V. Lehmann, Muter. Res. Soc.
Symp. Proc. 1992, 283, in press.
[3] A. Uhlir. Be// Syst. Tech. J. 1956, 35, 333.
[4] a) V. Lehmann. H. Cerva. Muter. Res. SOL..
Svmp. Proc. 1992,256.2; bj V.
Lehmann. B. Jobst, T. Muschik. A. Kux, V. Petrova-Koch, Jpn. J Appl.
PIijs.. 1993, 32. 23.
[5] V. Lehmann. U. Gosele, Appl. Phys. Lett. 1991, 58, 856.
161 a) R. T. Collins, M. A. Tischler. J. H. Stathis. ibid. 1992, 61, 1649; b) J.
Christen, V. Petrova-Koch, V. Lehmann, T Muschik, A. Kux, M. Grundmann. D. Blomberg, 21st ICPS, Berjmg, Augwt 1992, c ) F. Koch, V.
Petrova-Koch, T. Muschik. A. Nikolov, V. Gavrilenko. Muter. Res. Sot..
Symp. Proc. 1992, 283, 191.
[7] S. Y Ren, J. D. Dow, Phjs. Rre. B ’ Condens. Mutter 1992, 45, 6492.
[8] a) S. Prokes, 0. J. Glembocki, V. M. Bermudez, R. Kaplan. L. E. Friedersdorf, P. C. Searson. Phys. Rev. B . Condens. Mutter 1992, 45. 1378.
b) M. S. Braiidt. H. D . Fuchs, M. Stutzmann, J. Weber. M. Cardonga,
Solid State Commun. 1992, H i , 307.
[9] a)V. Petrova-Koch, T. Muschik, A. Kux, B. K . Meyer. E Koch, V. Lehmann, Appl. P h w Lett. 1992.61,943; b) T. Muschik. V. Petrova-Koch. V.
Lehmann, B. K . Meyer, F. Koch. unpublished results; c) M. Ruckschloss,
B. Landkammer, 0. Ambacher, S. Vepiek, Muter. Res. Sur. Svmp. Proc.
1992,283. 65. d) K. A. Littau, P. J. Szajowski. A. J. Miiller, A. R. Kortan,
L. E. Brus, J. Plrys. Chem. 1993, 97. 1224; e ) P . D. Calcott. K . J. Nash,
L. T. Canham, M. J. Kane, D. Brumhead. J. Phys. Cond. Mutter 1993, 5.
L 91, f ) G. S. Hiyashi, Y. Y. Chabal. G. W. Trucks, K. Raghavachari. Appl.
Phys. Lett. 1990, 56, 656.
[lo] a) H Linke, P. Omling. B. K . Meyer. V. Petrova-Koch, T. Muschik, V.
Lehmann. Muter. Res. Soc. Symp. Pror. 1992, 283. 251 ; b) M. S. Brandt.
M. Stutzmann. Appl. Phys. Lett. 1992, 61. 2569.
[ l l ] V, Gavrilenko. P. Vogl, F. Koch. Muter. Res. Soc. Sjmp. Proc. 1992, 283,
431.
1121 a ) A . Kux, F. Miiller, F. Koch, Muter Res. Sot.. S w p . Proc. 1992, 283,
31 1 ; b) C. Pickering. M . I. J. Bealoe, D. J. Robbins, P. J. Pearson, R. Greef,
J. Phvs. C . Solid State Phys. 1984, 17, 6535; c j M. Stutzmann. J. Weber,
M. S. Brandt. H. D. Fuchs, M. Rosenbauer, P. Deak, A. Hopner, A.
Breitschwerdt, DPG-Friihjuhrsber.. Regensburg, 1992; d) A. V. Adrianov.
P. I. Kovalev, V. B. Shuman. I. D. Yaroshetskii, JETPLett. 1992,56,236;
e) V. Petrova-Koch, T. Muschik, D. I. Kovalev. F. Koch. V. Lehmann,
Muter. Re.7. Soc. Symp. Proc. 1992, 283, 179.
1131 S. B. Zhang. Chin-Yuyeh. A. Zunger, Materials Research Society meeting
in Boston. December 1992, conference abstracts.
[14] a) F. Wohler. Liebigs Ann. Chem. 1863, 117. 264; b) 0. Henigschmid,
Monutsh. Chem. 1909,30. 509; c) H. Kautsky. Z. Anorg. Allg. Chem. 1921,
/ 1 7 . 209: d) Kolloid-Z. 1943, 102, 1 ; e j A. Weiss. G. Beil. H. Meyer. 2.
Nuturforsch. B 1980, 35. 25-30. f) E. Hengge. Chem. Ber. 1962, 95, 645,
648. g) E. Hengge. K. Pretzer, ibid. 1963. 96. 470.
[15] D. Deak, M. Rosenbauer. M. Stutzmann, J. Weber. M. S. Brandt, Phys.
Rev Lett. 1992. 6 9 , 2531
[16] ”Siloxene” samples luminesce typically in the spectral range of 700740 nm; the position of the emission maximum is a function of the pronounced substituent effects a s well as of the preparation process. In the
work from Weiss et al. [14e]. in particular, the intercalation of solvent
molecules between the layers is studied.
[17] H. Franz. V. Petrova-Koch. T. Muschik, V. Lehmann, J. Peisl, Muter. Re.\.
Soc. S.rmp. Pror. 1992. 283. 133.
[18] R. West in Comprehensive Orgunomcruilrc Chemi.stry (Eds.: G. Wilkrnson,
F. G. A. Stone, E. W. Abel). Pergamon, 1982.
[19] J. Michl, J. W. Downing. T. Karatsu, A. J. McKinley. G. Poggi,G. Wallraff.
R. D. Miller, Pure Appl. Chem. 1988, 60. 959.
Models for Peptide Receptors
By Hans-Jorg Schneider*
The development of selective host compounds for reversible binding of peptides is one of the most interesting
fields in biomimetic chemistry. The topic is of importance for
the understanding of molecular recognition mechanisms including those in proteins, for analytical methods, which incorporate sensor technology, and for the preparation of stereochemically pure peptides. The efficient preparation of
peptides with a completely or partially “nonnatural” configuration”’ is a particularly attractive research area in medicinal chemistry because of the enormous diversity of biological activity of inany oligopeptides. The therapeutically
important stability of peptides against proteases, which
often degrade the peptides, administered, for instance, as
antibiotics, before they reach their target, can be significantly improved by the introduction of o-amino acids instead of
L-amino acids.
I n view of this importance and of the early success of the
“chiral resolution machine” of Cram et al.,I2] which uses
crown ethers containing bisnaphthyl units to separate amino
acids, it is somewhat surprising that the selective complexation of peptides by organic host compounds has not yet been
attempted on a very broad scale. The major noncovalent
interactions for peptides have been analyzed by D. H.
Williams et al. for the example of natural host vanomycin
(1),[31
which binds the carboxylate terminus of Ala-Ala sequences of a peptidoglycan precursor compound (highlighted in boldface superimposed on the structural formula of 1).
A model limited predominantly to the carboxylate binding
niche of this antibiotic was obtained by HamiIton et aI.I4] in
the form of compound 2; the NMR spectrum of this model
compound shows that a proton is transferred from bound
HO OH
2
[*] Prof. H.-J. Schneider
Fachrichtung Organische Chemie der Universitdt
D-W-6600 Saarbriicken 11 (FRG)
Telefax: Int. code + (681)302-4105
848
(T) VCH Verlug.~gesell.rchufimbH, W-6940 Weinheim, 1993
H0
‘
0570-0833/9310606-0848$ 10.00+ ,2510
I
Angex. Chem. Int. Ed. Engl. 1993, 32, No. 6
carboxylic acids (e.g., the cyanoacetic acid superimposed on
the structural formula of 2) to its dimethylamino terminus.
Rebek et al. have developed systems like 3 from Kemp’s
acid and diaminonaphthalenes or para-phenylenediamine as
spacer between the converging diimidelactam units. The energy difference for the binding of enantiomers of rigid diketopiperazines in systems with 2,6-dimethylnaphthalene as
spacer can be up to 2.5 kcalmol-’,[5a1 but for more flexible
peptides (e.g.. with para-phenylenamine as spacer) this reduces to about 0.5 kcalmolThe association constants
in chloroform are maximally K = 4700 M - ; in general they
are smaller for imides than for a m i d e ~ . [ ~For
” ] normal amide
groupings, the analysis of a large number of supramolecular
associations in chloroform as solvent yields-in the absence
of additional effects-a
common binding energy of
(1.2 + 0.2) kcalmol-’ or K 10 M - ’ for each hydrogen
bond formed.16]
H
’
Bn
I
\
0
3
CH,Ph
6
5
Most recently Still et al. have made a further breakthrough with the polycyclic receptor 7,[*’] which not only
displays similar enantioselectivities also for N-acylated and
Boc-protected peptides, but also can be synthesized surprisingly easily: The condensation of Boc-protected (R,R)-1,2diaminocyclohexane (H,B) with pentafluorophenyl esters of
trimesic acid (A(OH),) (Scheme 1) gives a 39% yield of the
desired cyclooligomer 7; even the treatment of the commercially available free diamine H,B with trimesic acid trichloride ACI, affords in one step a yield of 13O/O that is still very
acceptable when compared with many macrocyclizations !
The bonding energies show a preference for L configurations,
Crown ethers bearing amino acids as substituents were
also used for the binding of peptides. Thus, according to
ZiniE et aL1’], the “lariate” ether 4 serves as “symporter” for
the simultaneous binding of a potassium ion and a dipeptide
carboxylate: for transport, enantiomer ratios sym,/sym, of
1.6 (for amino acid derivatives) are achieved. NMR measurements also show anisochronism, but binding constants
for the associates have not yet been determined.
n
CO
u
4
oc
4
7
co
A
C. Still et aI.[’l of Columbia University, New York, have
been most intensely involved with the development of
macrocyclic host compounds for the enantioselective complexation of peptides. Whereas the mono- and semicyclic
receptors employed earlier, like 5 (X = SO,),18a1still show
only relatively modest preferences of up to 80% ee between
peptidic ammonium ions, not only because of their high
conformational flexibility, AAG values of over 3 kcalmol-’
have already been accomplished with the basketlike tricyclic
model 6 (X = S).t8b1
The host 6 binds Boc-protected peptides
with the small NHMe end groups close to its phenyl rings.
The L isomer is consistently preferentially bound; at the
Same time the host discriminates between side chains Of *la*
Val, and Leu, for instance.
Angew. Chi,m. Int. Ed. Engl. 1993. 32. N o . 6
0 VCH
0::
0
CONH,,,,
H
Scheme 1. Top: Structural formula andschematic representation of7: bottom:
7 with peptide guest (arrow).
VerlagsgesellschafimbH. W-6940 Weinheim, 1993
0570-0833i93i0606-0849 S 10.00 f .25/0
849
which increases with the size of the side chain, for example,
from 1.9 for Gly through 3.5 for Ala to 5.0 for Val (in each
case in kcal mol - for the relevant N-acyl-NHMe-dipeptide
in chloroform). One explanation for this could be that the
side chain contributes significantly to the binding through
van der Waals forces with the host’s phenyl rings-on this
subject, see the analyses of the binding of 1 by Williams et
al.[3c1-0r that the solvent molecule (chloroform) no longer
finds space in the cavity next to, for example, the small
glycine residue. The geometries of the complex were consistent with the results of force field simulations, and supported
experimentally by the upfield shifts A6 of the protons that
are in contact with the host’s phenyl rings, which are induced
by the ring current (e.g., A6 = 2.5 for the valine methyl proton).
The possible applications of host compounds that are easy
to synthesize, capable of immobilization, and able to separate peptides with over 99 % ee are apparent. In what direction should future research go? Extension to larger peptides
is desirable-although the system 7 binds even tripeptides
very efficiently, the application of synthetic large-cavity
complexes will probably reach a limit set by preparative considerations. The differentiation of the peptide termini, that is
the direction of the sequence, might be achieved by the introduction of terminal anionic and/or cationic groups into the
receptor. For preparative applications, receptors that can
also be used on a larger scale for the separation of
diastereomers would be welcomed. More difficult is the
development of compounds that also function in aqueous
medium. The rational design of new synthetic peptide receptors and antibiotics from them, as well as the efforts to understand biological systems will necessitate the increased application of physical and calculational methods. Finally the
implementation of signalling functions-in the simplest case
chromophoric elements-is a crucial step to turn the promising systems into actual receptors in the biological sense and
to make them applicable for sensor technology.
German version: Angew. Chem. 1993, 105, 890
[I] See, for example, G. Jung, A. G. Beck-Sickinger, Angew. Chem. 1992, 104,
375; Anger/. Chem. Inl. Ed. Engl. 1992, 31, 367.
[2] D. J. Cram, J. M. Cram, Acc. Chem. Res. 1978, 11, 8,
[3] a) D. H. Williams, J. P. Waltho, Pure Appl. Chem. 1989, 61, 5 8 5 ;
b) Biochem. Pharmacol. 1988,37, 133; c) D. H. Williams, J. P. L. Cox, A. J.
Doig, M. Gardner, U. Gerhard, P. T. Kaye, A. R. Lal, I. A. Nicholls, C. J.
Salter, R. C. Mitchell, J. Am. Chem. SOC.1991, 1f3, 7020, and references
therein.
[4] A. D. Hamilton, N. Pant, A. V. Muehldorf, Pure Appl. Chem. 1988,60,533;
N. Pant, A. D. Hamilton, J. Am. Chem. SOC.1988, ff0,2002.
(51 a) K . 3 . Jeong, A. V. Muehldorf, J. Rebek, Jr., J. Am. Chem. SOC.1990,112,
6144; b) M. Famulok, K.-S. Jeong, G. Deslongchamps, J. Rehek, Jr.,
Angew. Chem. 1991, 103, 880; Angew. Chem. Int. Ed. Engl. 1991, 30, 858;
c ) K.-S. Jeong, T. Tjivikuva, A. Muehldorf, G. Deslongchamps, M. Famulok, J. Rebek, Jr., J. Am. Chem. SOC.1991, 113,201; W L. Jorgensen, D. L.
Severance, ibid. 1991, 113, 209.
[6] H.-J. Schneider, R. K. Juneja, S . Simova, Chem. Ber. 1989, f22, 1211.
(71 a) M. ZiniE, L. Frkanec, V. SkariC, J. Trafton, G. W Gokel, SupramoL
Chem. 1992, f , 4 7 ; b) J. Chem. SOC.Chem. Commun. 1990, 1726.
(81 a) G. Li. W C. Still, J. Org. Chem. 1991, 56, 6964; b) J.-I. Hong, S. K.
Namgoong, A. Bernardi, W. C. Still, J. Am. Chem. SOC.1991, 113, 5111;
c) S. S. Yoon, W C. Still, ibid. 1993, 115, 823.
Tantalum(v) Phosphinidene Complexes as Phospha-Wittig Reagents**
By Philip P. Power*
The report by Schrock et al.[’] describing the synthesis of
tantalum phosphinidene complexes and their behavior as
phospha-Wittig (or phosphinidene transfer) reagents will
undoubtedly have a major impact in several areas of inorganic and organometallic chemistry. The title compounds,
which have the formula 1, R = Ph, cyclo-C,H, ,(Cy), or tBu,
are the first stable examples of electron-rich (or nucleophilic)
phosphinidene complexes. In this manner, they are
analogous to the Schrock-type carbenes,r21and distinct from
[(N,N)Ta=PR]
1
[*I
. . Prof. P. P. Power
[“‘I
850
Department of Chemistry, University of California
Davis, CA 95616 (USA)
Telefax: Int. code + (916)752-8995
The tern phosphinidene is used here instead of the less common IUPAC
term A’-phosphandiyl.
0 VCH Verlagsgesellschaft mbH, W-6940 Weinheim, 1993
the transient phosphinidene complexes of low-valent transition metals.[31The latter species contain an electrophilic
phosphorus center and are thus analogous to the Fischer
carbene complexes, which contain an electrophilic carbon
center.[41Stable phosphinidene transition metal complexes
were originally reported by Lappert et al. in 1987,[5,61but
these and subsequent reports[’**I employed large groups
such as 2,4,6-tBu3C,H, at the phosphorus center to ensure
stability. In contrast, the new tantalum phosphinidene complexes 1 are stable with much smaller substituents at phosphorus such as Ph, Cy, and tBu. In these tantalum complexes
the stability has been ascribed to the use of the amido N,N
ligand. This trinegative, tetradentate amido ligand has enabled the isolation of some remarkable trigonal monopyramidal metal complexes with empty apical coordination
sites.[g1When bound to tantalum, the ligand forms a protective pocket owing to the “upright” orientation of the three
R,Si substituents, yet, the ligand also permits access to the
tantalum atom through the clefts between the arms of N,N
ligand. In addition, access to the phosphorus atom is possibk owing to the relatively Small organic substituents. Furthermore, the thermal stability of the complexes is such that
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Angew. Chem. Int. Ed. Engl. 1993, 32, No. 6
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