applications because they show higher stability in vivo and
do not bind to the active site of proteolytic enzymes. We
were particularly attracted to heterocyclic backbone mod-
ified macrocyclic sugar based β-peptides because they
possess greater conformational flexibility to form flat ring
structures, an important condition for intermolecular
H-bond directed self-assembly, and also because the pep-
tide main chain can provide an opportunity to alter and
fine-tune the chemical properties of peptide nanotubes.
Synthesis of cyclo-tri-β-peptides having a 14-helix archi-
tecture from the amide oligomer of a cis-furanoid sugar
amino acid7 encouraged us to synthesize a 1,4-linked
triazole backbone containing a hybrid triazol/amide
macrocycle from triazole-amide oligomers of cis-furanoid
sugar triazole amino acids basically for two reasons: (a) the
1,4-triazole linkage serves as a trans peptide bond isostere
in terms of planarity, polarity, and hydrogen bond donat-
ing as well as accepting capacities;8aꢀc (b) separation of the
triazole and amide by a two carbon unit permits it to adopt
a chair-like conformation effectively so that the triazole
ring can also participate in noncovalent interaction during
the nanotube formation. Our study highlights that repla-
cing the amide bond in a cyclo-β-peptide witha 1,4-triazole
linkage leads to a conformation resembling the D-,L-R-
amino acid based cyclic peptides5b in the orientation of the
amide groups but the mode of self-assembly is distinctly
different. Both parallel and antiparallel β-sheet intermole-
cular hydrogen bondingsexist inthe triazole/amidemacro-
cycle with identical chirality throughout the backbone
unlike the alternatingly chiral cyclic D-,L-R-peptides (only
antiparallel β-sheet intermolecular hydrogen bonding).
The basic intermediate for the solution phase synthesis9
of the peptide macrocycle 9 is the 1,2,3-triazole di-β-
peptide isostere 5, readily synthesized from N-Cbz pro-
tected cis-furanoid homopropargyl sugar amine 49,10 from
protected sugar amine 2 and cis-furanoid azido ester 37a
derived from diacetone glucose 1 via Cu(I) catalyzed azide
alkyne cycloaddition.11a,b The intermediate dimeric Cbz
protected triazole amino ester was converted to two dif-
ferent intermediates: the free amino ester 7 by hydrogena-
tion and the Cbz protected amino acid 6 by LiOH H2O
treatment. After coupling the two intermediates by stan-
3
dard protocol (using EDC HCl and HOBt), the ester
3
group was hydrolyzed again by LiOH H2O to obtain the
3
tetramer Cbz protected amino acid 8. Activation of the
linear tetramer acid 8 by pentafluorophenol and subse-
quent hydrogenation via in situ cyclization gave the final
triazole/amide macrocyclecompound 9 which waspurified
by preparative HPLC (Scheme 1).
Scheme 1. Preparation of Compound 9
1H NMR spectra of 9 in polar and nonpolar solvents
(DMSO, CCl4ꢀCDCl3, MeOH) are well-defined, reflect-
ing a high degree of C2 symmetry. The observed coupling
constant JNH,CβH(S2) is approximately 3.6 Hz, implying a
pseudo positive j angle (i.e., ∼þ60), which is generally
accessible with the D-R-amino acid residues;6 the value
observed in typical cyclo-β-peptides is nearly 8.5 Hz.7a,b
The low intensity of ROE cross peaks of the triazole ring
proton with the C(β) proton of sugar S1 and C(R) proton
of sugar S2 (Figure 1) definitely indicates a pseudo trans
configuration, which is normally observed with L-R-amino
Figure 1. (a and b) Two rotamers of the pseudo cyclic β-peptide
9; (c and d) two sugar derived components of that peptide.
(7) (a) Jagannadh, B.; Reddy, M. S.; Lohitha Rao, C.; Prabhakar,
A.; Jagadeesh, B.; Chandrasekhar, S. Chem. Commun. 2006, 4847.
(b) Fujimura, F.; Fukuda, M.; Sugiyama, J.; Morita, T.; Kimura, S.
Org. Biomol. Chem. 2006, 4, 1896.
(8) (a) Angell, Yu L.; Burgess, K. Chem. Soc. Rev. 2007, 36, 1674.
(b) Angelo, N.; Arora, P. S. J. Am. Chem. Soc. 2005, 127, 17134. (c) Brik,
A.; Alexandratos, J.; Lin, Y. C.; Elder, J. H.; Olson, A. J.; Wlodawer, A.;
Goodsell, D. S.; Wong, C. H. ChemBioChem 2005, 6, 1167.
(9) See Supporting Information.
(10) (a) Hauske, J. R.; Dorff, P.; Julin, S.; Martinelli, G.; Bussolari, J.
Tetrahedron Lett. 1992, 33, 3715. (b) Ohira, S. Synth. Commun. 1989, 19,
561.
(11) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 2596. (b) Tornøe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
Org. Lett., Vol. 13, No. 20, 2011
5513