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Glycylglycine RotaxanesЧThe Hydrogen Bond Directed Assembly of Synthetic Peptide Rotaxanes.

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z and p anomers (10190) of 2,3,4,6-aceto-1(2-bromoethoxy)-~-galactose
in 68%
yield (8.3 8). The purified fi anomer could be obtained by flash chromatography.
Stereochemical assignments were made by an X-ray crystal structure of the fi
anomer.
2,3,4,6-tetraacetyl-l-(2-bromoethoxy)-~-galactose
was treated with cyclene to produce the monosubstituted product. The acetate protecting groups were cleaved, and
the three carboxyhc acid substituents were added by reaction with bromoacetic acid
at pH 10.5. The product 4,7,10-tri(acetic acid)-l-(2-~-galactopyranosylethoxy)I ,4,7,1O-tetraazacyclododecanewas isolated by anion exchange fast performance
liquid chromatography (FPLC, detection at 218 nm) in 37% overall yield. Gd3+or
Tb” ions were incorporated into complexes, and these (EGad-Gd and EGad-Tb)
were purified by repeated collections on a reverse phase HPLC analytic C,, column
with waterlacetonitrile (0-10% gradient) as the eluent (fluorescence detection
= 274 nm and i,, = 315 nm) in 70% yield. The high resolution mass spectrum
of the isolated solid provided a parent molecular ion (M+Na )+, which exhibited
the correct exact mass and the predicted isotope ratios.
X-ray data for C,,H,,O,,Br: CAD-4 diffractometer; monoclinic, colorless plates,
space group F”2, (no. 4); a total of 5603 reflections measured, 2981 used for refinemen t .
Fluorescence experiments [5,6] with EGad: The decay rate (inversely proportional
to the lifetime) of the emission peak at 1.- = 545 nm (& = 460 nm) was measured
with a Hitachi f-4500 fluorescence spectrophotometer (2 s delay, 64 scans) in H,O,
50150 H,O/D,O, and D,O. An exponential curve fit (DeltaGraph 3, Delta Point
Inc., Monterey, CA) was used to determine the decay rates. The slope of the decay
rates versus D,O concentration was compared to the literature value of a slope of
0.2391q to obtain q.
In three identical inversion-recovery (IR-NMR) high resolution experiments
(Bruker AMX 500, 26°C) EGad(2 mM) was incubated with two different concentrations ofp-gal (1.7 p~ and 5.1 PM)heat-inactivated p-gal(l0 min at 80‘, 5.1 pM),
and EGad alone (2 mM) in phosphate buffer (25 mM, pH 7.3) at 37 “C. Minimal
enzyme concentrations were used to reduce potential interactions between the contrast agent and the enzyme. The solutions in a 40 pL round-bottomed NMR tube
insert (Wilmad glass) were placed into a 5 mm NMR tube containing CD,CI. Tl
measurements were made immediately following mixing and after complete cleavage of the galactopyranose (> 95 % after incubation for 7 days). The data was
processed with the program Felix (BIOSYM/Molecular Simulations, San Diego,
CA), and the peak heights were fitted to an exponentially rising curve in order to
obtain T , (regression: R>0.999).
Received: September 18, 1996 [Z9568IE]
German version: Angew. Chem. 1997,109,750-752
-
Keywords: analytical methods p-galactosidase
NMR spectroscopy
*
lanthanides
-
[I] R.Y Tsien, A C S Symp. Ser. 1993, 538, 130-146.
[2] H. E. Keller in Handbookof BiologicalConfocalMicroscopy,2nd ed. (Ed.: J. B.
Pawley), Plenum, New York, 1995, p. 111.
[3] R. W. Bowtell, J. C. Sharp, P. Mansfield, E. W. Hsu, N. Aiken, A. Horsman,
Mag. Res. in Med. 1995,33,790-794; C. T. Rofe, J. Vannoort, P. J. Back, P. T.
Callaghan, J. Mag. Res. Ser. B. 1995,108,125-136; Z.P.Liang, P. C. Lauterbur, IEEE Trans. Med. Imaging 1994,13,677-686; R. E. Jacobs, S . E. Fraser,
Science 1994, 263, 681; A. F. Mellin, G. P. Cofer, B. R. Smith, S . A. Suddarth, L. W Hedlund, G. A. Johnson, Mag. Reson. Med. 1994, 32, 199-205;
W. Kuhn, Angew. Chem. 1990,29, 1-19.
[4] I. Bertini, C. Luchinat, N M R of Paramagnetic Molecules in Biological Systems,
BenjaminICummings, 1986.
[5] S.H . Koenig, K. E. Kellar, Magn. Res. Med. 1995, 34, 227-233.
[6] V. Alexander, Chem. Rev. 1995,95,273-242; K. Kumar, C. A. Chang, M. F.
Tweedle, Inorg. Chem. 1993, 32, 587-593.
[7] L. S . Szczepaniak, A. Sargeson, I. I Creasei, R. J. Geue, M. F. Tweedle, R. G .
Bryant, Bioconjuagate 1992, 3, 27-31.
181 K. Kumar, M. F. Tweedle, Pure Appl. Chem. 1993, 65, 515-520.
191 S . I. Kang, R. S . Ranganathan, J. E. Emswiler, K. Kumar, J. Z. Gougoutas,
M. F. Malley, M. F. Tweedle, Inorg. Chem. 1993, 32, 2912-2918; S.Aime, M.
Botta, G. Ermondi, ibid. 1992, 31, 4291 -4299.
[lo] M. Li, P. R. Selvin, J Am. Chem. Soc. 1995, 117,8132-8138
[ll] W. D. Horrocks, D. R. Sudnick J Am. Chem. Sac. 1979, 101, 334-339.
[12] X. Zhang, C. A. Chang, H. G. Brittain, J. M. Garrison, J. M. Telser, M. F.
Tweedle, Inorg. Chem. 1992, 31, 5597-5600.
[13] The molar quantity related to these T , values is the relaxivity R . R values at
500 MHzweredeterminedforEGad(1800 mMs-’)andGad(2400mMs-imM
s - ’ ) and compared to that of a related species, D03a (2700 ~ M s - ’ ) .
[14] J. F Kayyem, R. M Kumar, S . E. Fraser, T. J. Meade, Chem. andBio. 1995.2,
615-620.
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VCH Verlagsgesellschaft mbH, 0.69451 Wernheim. 1997
Glycylglycine RotaxanesThe Hydrogen Bond Directed Assembly of
Synthetic Peptide Rotaxanes
David A. Leigh,* Aden Murphy, John P. Smart, and
Alexandra M. 2. Slawin
Although DNA displays a range of hydrogen bond assembled, topologically distinct architectures,[’ 41 only recently have
~ a t e n a t e d , [ ~ ’ ~and
’ ~ *r~~ ]t a x a n a t e d [ ~l o.-~ .
substructures been identified in polypeptides and proteins. Unnatural DNA knots and catenanes of tremendous complexity
can be
and are seen as promising forerunners
to new types of drug delivery systems, nanoscale mechanical
devices, and even “biochips”.[’6z‘’I Here we report that glycylglycine derivatives can be used as templates for the formation of
benzylic amide macrocycles through a five-molecule, hydrogen
bond directed “clipping” strategy to give peptido[2]rotaxanes in
yields as high as 62%. The four intercomponent hydrogen
bonds responsible for rotaxanation “live on” in nonpolar solvents such as chloroform and, in the case of pyridine-2,6-dicarbamidobenzyl macrocycles, in the solid state and in polar solvents such as dimethylsulfoxide and dimethylsulfoxide -water
mixtures. In the latter, the macrocycle forms an impenetrable
molecular sheath over part of the peptide backbone making it
inaccessible to external reagents as small as D,O.
Benzylic amide [2]catenanes such as 1 are a structurally
diverse family of catenanes most conveniently prepared by
the eight-molecule condensation of aromatic 1,3-dicarboxylic
acid dichlorides and benzylic diamines in nonpolar solvents.[’8*’9] If the reactions are carried out in the presence
of a suitably stoppered benzylic 1,3-diamide “thread” such
as 2 [2]rotaxanes such as 3 are also formed.[”] In both
cases the mechanism for the formation of the topologically
complex products appears to be primarily the directed assembly of the macrocycle around two transoid amide bonds (4,
Scheme 1).[”I Divergent hydrogen bonding sites in a similar
spatial arrangement occur in adjacent amino acid residues in
peptide chains, and therefore it seemed possible that these could
also carry the correct structural information (5 and 6) to template the cyclization of benzylic amide macrocycles to give
rotaxanes (Scheme 2).
To test this hypothesis the simplest dipeptide, glycylglycine,
was incorporated into a suitable thread. The commercially
available glycylglycine ethyl ester was N-acylated with diphenylacetyl chloride (Et,N, THF, 90 %) and then transesterified[221
at the carboxylate terminus with 2,2-diphenylethanol
((Bu,SnCl),O, toluene, A, 90 YO).Equimolar quantities of
isophthaloyl dichloride and p-xylylene diamine were slowly
added to a solution of the dipeptide thread in anhydrous CHCI,
(Scheme 2a). After five equivalents had been added, the thread
was no longer consumed. Filtration and washing with acid and
base left only three components in solution. These were separated by flash chromatography and identified in order of
elution as the peptido[2]rotaxane 8 (62% yield), the unrotaxanated thread 7,and [2]catenane 1.
[*I Dr. D.A. Leigh, A. Murphy, Dr. J. P. Smart
Department of Chemistry
University of Manchester Institute of Science and Technology
Sackville Street, Manchester M60 1QD (UK)
Fax: Int. code +(161)200-4539
e-mail: david.leigh@umist.ac.uk
A. M. 2. Slawin
Molecular Structure Laboratory, Department of Chemistry
University of Loughborough (UK)
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Scheme 1. a) The principle mechanism of formation of benzylic amide catenanes; b) the "clipping" strategy to benzylic amide rotaxanes. Vogtle et al. have described the
synthesis of amide rotaxanes by a route in which threading is achieved by complexation of an amide group (produced in situ) in the cavity of the macrocycle [35].
Scheme 2. The synthesis of peptidorotaxanes 8 and 9 by five-molecule,hydrogen bond directed assembly. Rotaxane 9 forms via intermediate 6 , in which four hydrogen bonds
form with the carbonyl groups of the dipeptide thread. Rotaxane 8 forms by two mechanisms: via an intermediate analogous to 6 , in which all four hydrogen bonds from
the cyclization precursor are exclusively to the carbonyl groups of the thread, and an intermediate such as 5 , in which the cyclization precursor forms three hydrogen bonds
to the two carbonyls of the dipeptide thread and a fourth hydrogen bond to an amide hydrogen atom in the thread.
Angew. Chem In1 Ed Engf 1997. 36, No 7
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The 'H NMR spectra of 7 and 8 in CDCI, are shown in
Figure 1 a and b. With the exception of the signals of the phenyl
stoppers and amide proton H,, all the resonances for the protons in the peptide thread are shifted to significantly higher field
Figure 1. 'H NMR spectra (300 MHz, CDCI,) of a) glycylglycine thread 7, b) peptido[2]rotaxane 8 (with the isophthaloyl macrocycle), and c) peptido[Z]rotaxane 9
(with the pyridyl macrocycle)
tra of both the thread and the rotaxane (Figure 2 a and b), and
peptide amide protons (H, and H,) are shielded equally by the
macrocycle. A beautifully diagnostic feature of the rotaxane in
both solvents is that the benzylic protons of the macrocycle (HE)
appear as an ABX system because the two sides of the macrocycle experience different environments ; one faces the N-terminus of the peptide, the other the C-terminus.
Figure 2 'H NMR spectra (300 MHz, [DJDMSO) of a) glycylglycme thread 7,
b) peptido[2]rotaxane 8 (with the isophthaloyl macrocycle), and c).peptido[2]rotaxane 9 (with the pyridyl macrocycle).
in the rotaxane because of the shielding effects of the aromatic
rings of the macrocyclic sheath. The greater shielding of the
protons near the N-terminal glycine residue (particularly H,
compared to He) and the 0.5 ppm downfield shift of H, (which
indicates that the deshielding effect of intramolecular hydrogen
bonding is larger than the shielding of the proton by the macrocyclic ring) is consistent with the predominant structure of 8 in
CDCI, being that shown in Scheme 2. This type of hydrogen
bonding motif, in which the macrocycle binds to both sides of a
single amide residue, is a familiar feature in the X-ray crystal
structures of benzylic amide catenaries."',
The macrocycle
bridges the two amide carbonyl groups rather than one amide
and the ester group, even though the hydrogen bonding sites are
the same distance apart, because the ester carbonyl is a poor
hydrogen bond acceptor.[241Pirouetting of the macrocycle
around the dipeptide thread is rapid on the NMR timescale at
room temperature, giving rise to the simple spectrum observed
for the macrocyclic component. Low-temperature NMR studies
in C,D,CI, give an energy barrier of 13.4 kcalmol-' for the
spinning process at 298 K, which corresponds to a rotation frequency of 820 s-'.
In [DJDMSO, a hydrogen bond accepting solvent, the hydrogen bonding networks between the rotaxane components are
broken and the macrocycle moves freely up and down the peptide chain. Under these circumstances the two glycine methylene
groups (H, and He), which are coincident in the 'HNMR spec-
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As in the synthesis of the original benzylic amide catenanes,[l91 replacing isophthaloyl chloride with pyridyl-2,6-dicarboxylic acid dichloride (Scheme 2 b) leads to interlocked
structures with differing hydrogen bonding motifs and dynamic
properties. The 'H NMR spectrum of the pyridyl rotaxane 9 in
CDC1, is shown in Figure 1c. The shifts in the signals of the
peptide thread in this rotaxane follow the same basic trends as
those of the isophthaloyl-derived system 8, but the macrocyclic
proton resonances are broader because of the slower pirouetting
of the pyridyl macrocycle (100 s-' at 298 K as opposed to
820 s-' for 8). Furthermore both signals for the amide protons
of the thread (H, and H,) are now shielded, suggesting that in
9, unlike 8, neither of these protons act as hydrogen bond
donors. Both observations are consistent with the establ i ~ h e d ~ strong
'~,~~
preference
~
of pyridine-2,6-dicarbamido
units to adopt a cisoid conformation, giving rise to the hydrogen
bond network for 9 depicted in Scheme 2.
Unlike the isophthaloyl rotaxane 8, the hydrogen bonding
network in 9 is maintained even in hydrogen bond accepting
solvents such as [D,]DMSO ('H NMR spectrum in Figure 2c)!
In contrast to 8, the chemical shifts of the protons near the
C-terminus (He, H,, and HJ of 9 are very similar to those
of the analogous protons in the uncomplexed thread 7 (Figure 2a), whereas H, and H, are shielded by 0.7 and 1.5 ppm,
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~~
respectively. The 2.5 ppm shielding of H, occurs because it is
encapsulated by the macrocycle and inaccessible to the hydrogen bond accepting solvent. Addition of D,O to the sample has
no effect upon the structure adopted by the rotaxane, and only
a single glycine amide proton, H,, undergoes deuterium exchange. Remarkably neither H, nor the macrocycle amide protons H,,,, which are buried inside the rotaxane structure, are
exchanged by the rapid rotation of the pyridyl macrocycle,
which requires momentary breaking of all four intercomponent
hydrogen bonds.[261This shielding of the peptide backbone
from external reagents augurs well for the use of rotaxanation to
protect higher peptides from chemical and enzymatic degradation.
Single crystals of 9 suitable for investigation by X-ray crystal10graphy[~~]
were obtained by slow evaporation of a solution of
the peptidorotaxane in ethanol. The hydrogen bonding motifs
and relative positions of the rotaxane components determined
for the solid state (Figure 3) are identical to those established for
thread 2 (28 and 0 % when isophthaloyl dichloride and 2,6pyridinedicarbonylchloride, respectively, are used). This reflects
the excellent complementarity of the hydrogen bonding sites in
the dipeptide template and the folded macrocycle precursors (5
and 6 , Scheme 2). The subsequent tying up of the amide groups
in intramolecular hydrogen bonds produces dramatic changes
in the way in which the individual rotaxane components interact
with their local environments-both peptidorotaxanes are more
than 20000 times more soluble in chloroform than the free
macrocycles. Physical properties and stabilities are also affected: the melting and decomposition point of the glycylglycine
thread 7 is 148"C, whereas the still-solid pyridyl rotaxane 9
decomposes at 230 "C.
The use of peptide-based drugs is currently complicated by
their in vivo susceptibility to degradation and often poor membrane-permeability. If the hydrogen bond directed syntheses
described here can be extrapolated to more complex peptides,
then temporary housing within a rotaxane superstructure could
simultaneously provide protection from hostile environments
(in a manner similar to that suggested for the use of dendrimers
as drug delivery systems[321),improved stability, and engineered
lipophilicity/solubility characteristics.
Experimental Section
General method for the preparation of peptide [2]rotaxanes: Dipeptide thread 7
(500 mg, 0.988 mmol) and triethylamine (1.60 g, 15.8 mmol) were dissolved in anhydrous chloroform and stirred vigorously whilst solutions of the amine (7.91 mmol)
in anhydrous chloroform (40 mL, stabilized with amylenes rather than ethanol [18])
and the acid chloride (7.91 mmol) in anhydrous chloroform (40 mL) were added to
the reaction mixture over 4 h by using motor-driven syringe pumps. The reaction
mixture was filtered, washed successively with 1 M HCI (3 x 100 mL) and 5 % sodium bicarbonate (3 x 100 mL) and concentrated to dryness under reduced pressure.
The resulting solid was subjected to column chromatography (silica gel, CHCI,/
EtOAc) to yield, in order of elution, the peptido[?]rotaxane (8 or 9), unconsumed
7, and [2]catenane.
Selected physical and spectroscopic data 8 : Yield 635 mg (62%); m.p. 219°C; " C
NMR (75 MHz, [DJDMSO): 6 = 38.90, 41.25, 43.11, 48.91, 56.10, 65.88, 125.80,
126.50, 126.64, 127.41, 128.12, 128.36, 128.42, 128.60, 130.19, 134.31, 136.93,
139.95, 140.87, 165.68, 168.76, 169.35, 170.25, 171.39; FAB-MS (mNBA matrix):
m / z : 1040 [(rotaxane H)'],
533 [(macrocycle + H)']; Anal. calcd. for
C,,H,,O,N,:
C 74.0, H 5.6. N 8.1, 0 12.3: found: C 73.9, H 5.7, N 7.8, 0 12.1.
Selected physical and spectroscopic data for 9 : Yield 350 mg (34%); m.p. 230°C
(decomp); "C N M R (75 MHz, CDCI,): 6 = 41.17, 42.16, 42.59, 49.72, 58.55,
68.16,125.60. 127.20, 127.46, 127.70,127.97, 128.37, 128.45,128.76, 129.03, 137.99,
139.01, 140.22, 149.35, 163.66, 169.02, 169.38, 171.32; FAB-MS (mNBA matrix):
m / z : 1042 [(rotaxane €I)+], 535 [(macrocycle H)']; Anal. calcd. for
C,,H,,O,N,: C 71.5, H 5.4, N 10.8, 0 12.3; found: C 71.8, H 5.65, N 10.4,O 12.0.
It is interesting to note that with both rotaxanes fragmentation in the mass spectrometer occurs across the macrocycle (to leave a charged species) and not the
thread despite its weak ester linkage. The macrocyclic sheath protects the peptide
from degradation even under the conditions of fast atom bombardment mass spectrometry.
+
Figure 3. Solid-state structure of the peptido[2]rotaxane 9 as determined by X-ray
crystallography. For clarity the carbon atoms of the macrocycle are blue and the
carbon atoms of the peptide thread are green; oxygen atoms are red, nitrogen atoms
purple, and hydrogen atoms white. Two water molecules ofcrystallization,which do
not form hydrogen bonds with the rotaxane, are not shown. Lengths of intramolecular hydrogen bonds (in A): N3-HN4 2.313, N3-HN8 2.282, N6-HN5 2.284.
N6-HN7 2.248, 0 2 - HN4 2.229, 02-HN8 2.306, 0 1 -HN5 2.090, 01-HN7
1.923; lengths ofintermolecular hydrogeii bond (in A): 05-HN1' = 2.71.
9 in solution. The macrocycle adopts a chairlike conformation
that completely encapsulates the N-terminal glycine residue. As
anticipated, bifurcated hydrogen bonds occur in the macrocycle
from each pyridyl nitrogen atom to the adjacent 1,3-diamide
protons and from each of these to the amide carbonyl groups of
the peptide thread. It is interesting to note that the hydrogen
bonds are orthogonal to the lone pairs of the peptide amide
carbonyl group, a motif previously seen in other hydrogen bond
assembled catenanes.[l'.
2 7 , "I
This illustrates the "soft" acceptor d i r e ~ t i o n a l i t y [ ~of~ the
- ~ ~NH
] . . . O=C hydrogen bonding in these systems. Although no intercomponent x-stacking
interactions are apparent in the rotaxane X-ray structure (nor
are they possible in the assembly mechanism which appears to
be solely a hydrogen bond driven process), C-H . . . x-arene
hydrogen bonds are evident between the acidic N-terminal
glycine methylene protons (H,) of the thread and the xylylene
rings of the macrocycle.
The yields of the peptide rotaxanes (62 and 34%) are significantly higher than those obtained with the benzylic 1,3-diamide
233
Angew. Chem. I n l . Ed Engl. 1997, 36, No. 7
'cVCH Edugspwllschuft
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Received: August 21, 1996 [Z9478IE]
German version: Angew. Chew 1997, 109, 752-756
Keywords: hydrogen bonds macrocycles * peptides * rotaxanes
* self-assembly
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Liebigs Ann. 1995, 739-743; b) F. Vogtle, R. Jager, M. Hindel, S. OttensHildebrandt, W Schmidt, Synthesis 1996,353-356; c ) F. Vogtle, R. Jager, M.
Hindel, S. Ottens-Hildebrandt, Pure Appl. Chem. 1996, 68, 225-232; d) F.
Vogtle, M. Hindel. R. Jager, S. Meier, G. Harder, Chem. Eur. .I1996, 2,
640-643; e) R. Jager, M. Handel, J. Harren, K. Rissanen, F. Vogtle, Liebigs
Ann. 1996, 1201-1207.
a) S. Ottens-Hildebrandt, S. Meier, W Schmidt, F. Vogtle, Angew. Chem.
1994,106,1818-1821; Angew'. Chem. Int. Ed. Engl. 1994,33,1767-1770; b) F.
Vogtle, T. Dunnwald, T. Schmidt, Acc. Chem. Res. 1996, 29, 451-460.
Mr = 1050.18, clear crystal of dimensions
Crystal data for 9: C,,H,,O,
0.15 x 0.2 x 0.66 mm, monoclinic, space group P2Jn (no. 14); a = 18.172(2),
b =16.874(4),
c =18.259(38) A;
= 92.34(1)",
V = 5594(1) A3,
pEalcd
= 1.247 g ~ m - Z
~=
, 4; 8950 reflections measured, 8645 unique. Diffractometer Rigaku AFC7S, 2tJ,,, =120.1", Cu,, radiation, 1 =IS4178 A,
T = 296 K. The structure was solved by direct methods (SIR92) [33] and subjected to least-squares refinement (TEXSAN [34]) to yield final residuals of
R = 0.061 and R , = 0.045 for 713 parameters. All hydrogen atoms were placed
in chemically reasonable positions. Crystallographic data (excluding structure
factors) for the structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication no.
CCDC-179-100060. Copies of the data can be obtained free of charge on
application to The Director, CCDC, 12 Union Road, Cambridge CBZIEZ,
UK (fax: Int. code +(1223)336-033; e-mail: deposit@chemcrys.cam.ac.uk).
A Convergent Synthesis of a
Carbohydrate-Containing Dendrimer**
Peter R. Ashton, Sue E. Boyd, Christopher L. Brown,
Narayanaswamy Jayaraman, and J. Fraser Stoddart*
Amongst the distinctive features of dendrimers are their
monodispersities, high molecular weights, and nanoscopic dimensions. With the rapidly growing interest in the synthesis of
dendrimers, we have witnessed the use of an increasingly diverse
range of building blocks for their construction."] The emergenceL2]of neoglycoconjugates in glycobiology as a powerful
means for studying carbohydrate-protein interactions offers
new opportunities for the identification of different classes of
neoglyco~ystems.[~]
In this respect, carbohydrate-containing
dendrimers, with their very precise and predetermined structural features for each of the carbohydrate units, are an important vehicle for the development of new and more efficient neoglycoconjugates. For example, it could be anticipated, with
good reason, that such carbohydrate-containing dendrimers
might elicit different biological responses from those exhibited
by carbohydrate clusters located on oligomeric or polymeric
backbones.[41
We recently described['] a highly convergent synthesis of
carbohydrate-containing dendrimers with complete structural
homogeneity. Here we report the preparation of even larger
dendritic carbohydrate derivatives employing two different, yet
closely related strategies. We encountered for the first time the
problem of incomplete dendrimer formation as a result of limited core reactivity. The dendrimersr6]possess 24 and 36 peripheral D-glucopyranosidic units on a structure containing two different branching points, excluding those emanating from the core
itself.
A schematic representation of the two strategies adopted in
the synthesis of two closely related "36-mers" by the convergent
approach is shown in Scheme 1 a. In strategy 1, it was anticipated that the reaction of six equivalents of a dendritic (6-mer)
wedge, containing six monosaccharide residues and a focal-reactive functionality, with one equivalent of a hexafunctional
core compound (6-acid core) would afford 36-mer-A by a socalled 6 x 6 reaction sequence. In strategy 2, the reaction between three equivalents of a dendritic (12-mer) wedge, with 12
monosaccharide residues on its periphery, and one equivalent of
a trifunctional core compound (3-acid core) was expected also
to result in a 36-mer, namely 36-mer-B, by a 12 x 3 reaction
sequence. The structural components of the dendrimers were
derived from 1) the amino-protected tris(hydroxymethy1)aminomethane (TRIS) as the glycosyl acceptor, 2) a suitably
protected 3,3'-glycinamido dipropionic acid for further branching, and 3) either the 3,3'-iminodipropionic acid extended hypercore synthon or a glycine extended core synthon, both based on
1,3,5-tricarbonyl benzene, as the ultimate core component of the
dendrimers.
First we synthesized the higher generation dendrimer by
amide bond coupling to the hexaacid hypercore Zc7] with the
6-mer wedge amine 1 [51 in the presence of 1,3-dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT) as cou[*IProf. J. F. Stoddart, P. R. Ashton, Dr. S. E. Boyd, Dr. C. L. Brown,
[**I
132
0 VCH Verlagsgesellschuft mbH, 0-69451 Weinheim. 1997
Dr. N. Jayaraman
School of Chemistry, University of Birmingham
Edgbaston, Birmingham, B152TT (UK)
Fax: Int. code +(121)414-3531
Synthetic Carbohydrate Dendrimers, Part 2. This research is supported by the
Engineering and Physical Sciences Research Council and the Biotechnology
and Biological Sciences Research Council. Part 1: ref. [ 5 ] .
0570-0833/97/3607-0732$17.50+ S0jO
Angew. Chem. Int. Ed. Engl. 1997, 36, No 7
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