Luminescent Crown Ether Amino Acids
SCHEME 1. Structures of Crown Ether Amino Acids (CEAA) 1 and 2 Used in This Work
SCHEME 2. Synthesis of a Luminescent Crown
were able to bind monophosphorylated peptides with bis-
[zinc(II)-dipicolamine]-based receptors. Another approach
based on metal ion coordination was achieved by Anslyn.20
They designed a tweezer-like receptor where a copper
terpyridine in the center binds to histidine. Additional
carboxylate groups stabilize the tweezer complex by
formation of salt bridges. Shea21 used polymer imprinted
complexes for the binding of His-containing small
peptides.22-,27
Ether Amino Acida
Although these approaches all show good binding and
recognition abilities, they are rather restricted as they
bear no functional groups which make an oligomerization
or combination with other recognition moieties simple
and straightforward. This report illustrates an approach
for receptor creation based on a building block system.
Our aim is to address ammonium ions within peptide
chains, which can be either N-terminal or in lysine side
chains. We chose crown ethers as recognition moiety.
The use of covalently linked crown ethers28 to create
function goes back to the seminal work of Gokel,29-31 who
employed such systems as artificial ion channels. As
simple crowns such as the 18-crown-6 are not connect-
able, our investigation centered on crown ether amino
acids.32 These should be easy to oligomerize or combine
with other recognition moieties with use of standard
peptide synthesis methods. Furthermore, a fluorescent
phthalic ester or phthalimide moiety was incorporated
as a luminescent probe for binding events.33 The combi-
a Reagents and conditions: (a) Tos(CH2O)3H, K2CO3, DMF,
60 °C, 79%. (b) TosCl, KOH, THF, H2O, 0 °C f RT, 95%.
(c) H2N(CH2)2NHBoc, K2CO3, KI, MeCN, H2O, 81 °C, 79%.
nation of a crown ether ammonium ion binding site with
phenolphthalein to create a sensory system for diamines
has been previously reported by Fuji et al.34 The hybrid
compound allows distinguishing between aliphatic di-
amines of various lengths, but the chemosensor cannot
be easily extended, modified, or combined with other
groups. To overcome such drawbacks, we synthesized
several different crown ether amino acids (CEAA) of
which compounds 1 and 2 (Scheme 1) proved to be the
most suitable for our purposes.
(19) Ojida, A.; Mito-oka, Y.; Sada, K.; Hamachi, I. J. Am. Chem.
Soc. 2004, 126, 2454-2463.
(20) Wright, A. T.; Anslyn, E. V. Org. Lett. 2004, 6, 1341-1344.
(21) Hart, B. R.; Shea, K. J. J. Am. Chem. Soc. 2001, 123, 2072-
2073.
Results and Discussion
Syntheses. The synthesis of 1 and 2 was straight-
forward starting with the phthalic diester (3) [or the
phthalimide (4) for the synthesis of 2, respectively; see
the Supporting Information for the structure]. Dialkyla-
tion with triethyleneglycol-monotosylate led to 5 followed
by treatment with tosyl chloride to give the ditosylated
6. Cyclization with N-Boc-ethyldiamine gave the desired
building block 1 in good yields (79%) (Scheme 2). CEAA
1 and 2 show different absorption and emission proper-
ties due to their different chromophors. Both absorption
and emission are shifted bathochromically in phthalimide
CEAA 2 with respect to 1. The phthalic ester CEAA 1
emits at about 390 nm, the phthalimide CEAA 2 at about
490 nm (Figure 1). Both CEAA 1 and 2 have been tested
for ammonium binding ability with n-butylammonium
chloride in methanol. Both show a mediocre binding
affinity but good enhancement of fluorescence intensity.
Although structurally quite similar, the two crown ethers
(22) For other types of artificial peptide-binding molecules, see:
Allott, C.; Adams, H.; Bernad, P. L.; Hunter, C. A.; Rotger, C.; Thomas,
J. A. Chem. Commun. 1998, 2449-2450.
(23) Borchardt, A.; Still, W. C. J. Am. Chem. Soc. 1994, 116, 7467-
7468.
(24) Use of diketopiperazine binding sites: Conza, M.; Wennemers,
H. J. Org. Chem. 2002, 67, 2696-2698.
(25) Dowden, J.; Edwards, P. D.; Flack, S. S.; Kilburn, J. D. Chem.
Eur. J. 1999, 5, 79-89.
(26) Yoon, S. S.; Still, W. C. J. Am. Chem. Soc. 1993, 115, 823-
824.
(27) Sun, S.; Fazal, Md. A.; Roy, B. C.; Mallik, S. Org. Lett. 2000, 2,
911-914.
(28) Gunning, P.; Benniston, A. C.; Peacock, R. D. Chem. Commun.
2004, 2226-2227.
(29) Gokel, G. W.; Murrilo, O. Acc. Chem. Res. 1996, 29, 425-432.
(30) Shabany, H.; Pajewski, R.; Abel, E.; Mukhopadhyay, A.; Gokel,
G. W. J. Heterocycl. Chem. 2001, 38, 1393-1400.
(31) Leevy, W. M.; Donato, G. M.; Ferdani, R.; Goldman, W. E.;
Schlesinger, P. H.; Gokel, G. W. J. Am. Chem. Soc. 2002, 124, 9022-
9023.
(32) Artificial amino acids with crown ether side chain functionality
have been previously described. Kotha, S.; Brahmachary, E. Ind. J.
Chem., B 2001, 40B, 1-4. Meillon, J.-C.; Voyer, N. Angew. Chem., Int.
Ed. Engl. 1997, 36, 967-969. Mazaleyrat, J.-P.; Gaucher, A.; Goubard,
Y.; Savrda, J.; Wakselman, M. Tetrahedron Lett. 1997, 38, 2091-2094.
(33) For other emitting crown ether derivatives, see: Collins, G. E.;
Choi, L.-S. Chem. Commun. 1997, 1135-1136.
(34) Sensory system for the visualization of the distance of amino
groups in R,ω-diamines: Fuji, K.; Tsubaki, K.; Tanaka, N.; Hayashi,
T.; Otsubo, T.; Kinoshita, T. J. Am. Chem. Soc. 1999, 121, 3807-3808.
J. Org. Chem, Vol. 70, No. 2, 2005 671