A C3-symmetric molecular scaffold for the construction of large receptors

Article abstract of DOI:10.1039/b406335j

A novel C₃-symmetric scaffold has been efficiently synthesized exhibiting the property that variable receptor arms can be easily attached by simple alkylation reactions; the utility of the scaffold as a skeleton for large receptors has been exa

Full text of DOI:10.1039/b406335j

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A C3-symmetric molecular scaffold for the construction of large
receptors
Gebhard Haberhauer,* Thomas Oeser and Frank Rominger
Organisch-Chemisches Institut, Universita¨t Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg,
Germany. E-mail: gebhard.haberhauer@urz.uni-heidelberg.de; Fax: 149 (0) 6221 544205
Received (in Cambridge, UK) 28th April 2004, Accepted 29th June 2004
First published as an Advance Article on the web 6th August 2004
A novel C3-symmetric scaffold has been efficiently synthesized
case of the three-down conformation, making them more suitable
for the inclusion of substrates. The synthetic pathway to platform 1
is shown in Scheme 2. As starting material we used Cbz-protected
L-valine (3) which was activated as mixed anhydride using isobutyl
chloroformate and coupled to the keto ester 4 at 225 uC.4 The
resulting amidoketone 5 was condensed to the imidazole 6 with
ammonium trifluoroacetate which was formed in situ from
methanolic ammonia and trifluoroacetic acid in refluxing xylenes
with azeotropic removal of water. Saponification of the methyl
ester of imidazole 6 without racemization at the a-C-atom of the
L-valine-based moiety failed. To overcome this problem, we
replaced the Cbz-group by the Boc-group and protected the NH of
the imidazole ring with a benzyl group. The methyl esters of the
resulting benzyl imidazoles 7a,b can be simply saponified by using
aqueous NaOH providing the corresponding carbocyclic acids in
95% yield. Subsequent removal of the benzyl group at the
imidazole ring by hydrogenolysis followed by amine deprotection
using trifluoroacetic acid gave the amino acid 8. Several methods
for a one-pot trimerization of the imidazole 8 were examined. The
most advantageous route proved to be the activation of the acid
group with pentafluorophenyl diphenylphosphinate (FDPP) in the
presence of an excess of Hu¨nig’s base in acetonitrile under high
dilution conditions (0.05 M) at room temperature. This method
provided scaffold 1 in a satisfactory yield (35%).
exhibiting the property that variable receptor arms can be
easily attached by simple alkylation reactions; the utility of
the scaffold as a skeleton for large receptors has been
examined with
a corresponding tris(bipyridyl) derivative
toward phloroglucinol.
The use of receptor molecules with pre-organized ligands for the
effective binding of guest molecules is well documented.1 A suitable
pre-organization of functional groups and conformational con-
straint can be achieved by controlling the stereochemistry through
steric hindrance of the substituents around a rigid platform. For
example, the exceptional stereochemical characteristic of hexasub-
stituted benzene derivatives is leading many chemists to use such
persubstituted systems as platforms for the construction of rather
small receptor systems.2
In this paper, we wish to report the synthesis of the C3-symmetric
molecular scaffold 1 which can be easily transformed into enlarged
receptors 2 using standard alkylation conditions (Scheme 1).3{ The
advantage of this concept is that starting from a single scaffold (1),
a variety of large three-armed receptors (2) can be synthesized in
a simple manner by attaching three pre-formed receptor arms
(RCH2Br) to platform 1. Due to steric repulsion between the
isopropyl groups and the arms, the preferred conformation of 2
should be the three-down conformation, i.e. all three arms are
oriented opposite to the isopropyl groups of the adjacent a-C-
atoms. Furthermore, the isopropyl groups of the a-C-atoms in 1
and 2 guarantee that the azole moieties of the macrocycle do not
form a single plane but have a cone-like structure.4 This deviation
from planarity should result in the three arms (R) of 2 being
substantially equidistant without divergence to each other in the
Scheme 2 Synthesis of scaffold 1. Reagents and conditions: (i) ClCOOi-Bu,
NMM, THF, 225 uC, 80%; (ii) NH3, TFA, xylenes, reflux, 72%;
(iii) Boc2O, H2, Pd(OH)2, THF, 95%; (iv) BnBr, K2CO3, CH3CN, reflux
2h, 51% for 7a, 32% for 7b; (v) 2 M NaOH, MeOH–dioxane, 95%; (vi) H2,
Pd(OH)2, MeOH; (vii) TFA, DCM, 90% (two steps); (viii) FDPP,
i-Pr2NEt, CH3CN, rt, 35%.
Scheme 1 Transformation of C3-symmetric scaffold 1 into the three-armed
platforms 2.
2 0 4 4
C h e m . C o m m u n . , 2 0 0 4 , 2 0 4 4 – 2 0 4 5
T h i s j o u r n a l i s ß T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Fig. 1 Crystal structures of (a) the three-armed receptor 2a with dichloromethane guest, (b) the free receptor 2e with acetonitrile guest and (c) the complex of
receptor 2e with phloroglucinol and dichloromethane; all hydrogen atoms and some representations of disordered dichloromethane have been omitted for
clarity. In the case of (b) a second independent molecule with some disorder is omitted as well as the acetonitrile of solvation. In all cases the receptors show
threefold crystallographic symmetry.
To determine the preferred stereochemical orientation of the
arms of platforms 2, we performed a conformational search for 2a
Notes and references
{ Synthesis of platforms 2: To a solution of 1 (0.20 mmol) in acetonitrile
(30 ml) were added K2CO3 (1.50 mmol) and RCH2Br (0.75 mmol) at room
temperature and the mixture was stirred at reflux for 8 h. Solvent was
evaporated and the residue was dissolved in AcOEt, extracted with water
and brine, dried over MgSO4 and concentrated in vacuo. Purification was
accomplished by chromatography on silica gel (DCM–AcOEt–MeOH, 75 :
25 : 3) to yield 2 (45–85%) as white solids.
by molecular mechanics calculations with Monte Carlo minimiza-
tion procedures, using the MM2* force field as implemented in the
MacroModel program.5 As was expected, the low-energy con-
formation of 2a is the three-down conformation. The lowest-energy
two-down–one-up conformation is calculated to be 4.4 kJ mol21
higher in energy. For further stereochemical investigations, we
examined the solid-state structures of 2a and 2e. The obtained
X-ray structures confirmed in both cases that the three-down
conformation was preferred and the arms were almost equidistant
to each other (Fig. 1).{ In platform 2a, which was crystallized from
methylene chloride, the shortest distance between two phenyl arms
{ Crystal data: for C48H57N9O3?CH2Cl2 (2a): M ~ 892.95, hexagonal,
˚
space group P63, Z ~ 2, a ~ 13.5462(4), b ~ 13.5462(4), c ~ 14.8813(9) A,
3
V ~ 2364.9(2) A , r ~ 1.254 g cm23, T ~ 100(2) K, hmax ~ 25.68u,
˚
radiation Mo Ka, l ~ 0.71073 A, m ~ 0.19 mm21, 20642 reflections
˚
measured, 3014 unique (Rint ~ 0.042), 2989 observed (I w 2s(I)), R1(F) ~
0.126, wR(F2) ~ 0.253.{ For C63H69N15O3?2*CH3CN (2e): M ~ 1166.44,
trigonal (rhombohedral axes), space group R3, Z ~ 2, a ~ 22.2326(1),
˚
is about 8 A resulting in the formation of a cavity enclosing a
solvent molecule. The distance and the orientation of the bipyridyl
arms in 2e, which was crystallized from acetonitrile, are essentially
the same as in 2a.
˚
b ~ 22.2326(1), c ~ 22.2326(1) A, a ~ 36.035(1), b ~ 36.035(1), c ~
3
36.035(1)u, V ~ 3401.81(3) A , r ~ 1.139 g cm23, T ~ 200(2) K, hmax
~
˚
21.93u, radiation Mo Ka, l ~ 0.71073 A, m ~ 0.07 mm21, 21493
reflections measured, 5458 unique (Rint ~ 0.0546), 4296 observed
(I w 2s(I)), R1(F) ~ 0.069, wR(F2) ~ 0.168.{ For C63H69N15O3?
C6H6O3?2*CH2Cl2 (complex 2e and phloroglucinol): M ~ 1380.29,
trigonal (hexagonal axes), space group R3, Z ~ 3, a ~ 12.9951(5),
˚
In order to prove the utility of the platforms 2 as large receptors,
we examined the behaviour of 2e toward phloroglucinol. Like
comparable tris(bipyridyl) cages reported by other groups,6 2e was
found to solubilise phloroglucinol in dichloromethane and
chloroform. Unfortunately, due to the insolubility of this guest
molecule in CDCl3, it was impracticable to determine the stability
constant of the formed complex by NMR titration. However, in a
CDCl3 solution containing 10% acetonitrile, which is known to
lower substantially binding constants for hydroxy-substituted
benzenes,7 the NMR titration resulted in a binding constant of
680 ¡ 85 M21. Furthermore, we were able to grow single crystals
of this complex from CD2Cl2 (Fig. 1).{ The three bipyridyl arms
take hold of the pholoroglucinol by forming three hydrogen
bridges. These hydrogen bridges are formed exclusively by the
nitrogen atoms of the pyridyl rings remotest from the scaffold.
From the X-ray structure it cannot be deduced whether the
nitrogen atoms of the pyridyl rings neighbouring the scaffold point
into the interior of the receptor or to the exterior. The cavity
between the phloroglucinol and the platform is filled with solvent
molecules. To the best of our knowledge, receptor 2e is the first
non-cage receptor which is able to encapsulate phloroglucinol.
Moreover, this is the first X-ray structure of an encapsulated
phloroglucinol.
3
23
,
˚
˚
b ~ 12.9951(5), c ~ 40.694(3) A, V ~ 5951.5(6) A , r ~ 1.155 g cm
˚
T ~ 100(2) K, hmax ~ 28.27u, radiation Mo Ka, l ~ 0.71073 A, m ~
0.20 mm21, 20311 reflections measured, 6464 unique (Rint ~ 0.0323), 6003
observed (I w 2s(I)), R1(F) ~ 0.073, wR(F2) ~ 0.199. CCDC 239318–
239320. See http://www.rsc.org/suppdata/cc/b4/b406335j/ for crystallo-
graphic data in .cif format.
1 J.-M. Lehn, Supramolecular Chemistry: Concepts and Perspectives, VCH,
Weinheim, 1995.
2 For some recent examples see: B. J. Postnikova and E. V. Anslyn,
Tetrahedron Lett., 2004, 45, 501; S.-G. Kim, K.-H. Kim, Y. K. Kim,
S. K. Shin and K. H. Ahn, J. Am. Chem. Soc., 2003, 125, 13819;
G. Hennrich and E. V. Anslyn, Chem.–Eur. J., 2002, 8, 2218.
3 For recent examples of C3-symmetric platforms see: S. Kubik, J. Am.
Chem. Soc., 1999, 121, 5846; S. R. Waldvogel, R. Fro¨hlich and
C. A. Schalley, Angew. Chem., Int. Ed., 2000, 39, 2472.
4 G. Haberhauer and F. Rominger, Tetrahedron Lett., 2002, 43, 6335.
5 MacroModel: F. Mohamadi, N. G. J. Richards, W. C. Guida,
R. Kiskamp, M. Lipton, C. Caufield, G. Chang, T. Hendrickson and
W. C. Still, J. Comput. Chem., 1990, 112, 440; MM2: N. L. Allinger, J. Am.
Chem. Soc., 1977, 99, 8127; Monte Carlo (MCMM): G. Chang,
W. C. Guida and W. C. Still, J. Am. Chem. Soc., 1989, 111, 4379.
6 I. M. Atkinson, A. R. Carroll, R. J. A. Janssen, L. F. Lindoy,
O. A. Matthews and G. V. Meehan, J. Chem. Soc., Perkin Trans. 1, 1997,
295; F. Ebmeyer and F. Vo¨gtle, Angew. Chem., Int. Ed. Engl., 1989, 28, 79.
7 C. F. Martens, R. J. M. Klein Gebbink, M. C. Feiters and R. J. M. Nolte,
J. Am. Chem. Soc., 1994, 116, 5667.
Finally, the versatility of the present approach to large receptor
synthesis should be emphasised. The ready availability of platform
1 will allow us to produce a series of three-armed receptors suitable
for binding other selected guests.
We thank the Deutsche Forschungsgemeinschaft for support
and Dr Andreea Schuster for assistance.
C h e m . C o m m u n . , 2 0 0 4 , 2 0 4 4 – 2 0 4 5
2 0 4 5