generality of this approach, it has been underutilized as a
strategy in peptidomimetic design.
Scheme 1
Often, the biological activity of a peptide is dependent on
three consecutive amino acid residues, such as the well-
known RGD triad.5 Utilization of an Aca-linking strategy
for the mimicry of such compounds would require the tether
to mimic a third amino acid residue by incorporating an
amino acid side-chain equivalent onto itself. Two obvious
positions for side-chain substitution are at C-2 and C-6 of
the Aca chain, as pictured in Figure 1. In this Letter, we
describe the synthesis of two Gly-Gly mimics containing a
monosubstituted Aca linker representing an additional
phenylalanine moiety (1 and 2, Figure 1). The choice of Gly-
Gly as the central dipeptide was made to permit examination
of the conformational tendencies of the linkers in the absence
of a conformationally demanding dipeptide unit. In earlier
work,4 it had been established that a 3-methyl-substituted
Aca chain occupied type II â-turn space to a surprising
degree as determined by CD spectroscopy. However, the
position of the methyl group in that compound did not
correspond to that of a side chain in a naturally occurring
â-turn.
We envisioned using methods that would be widely
applicable to a variety of proteinogenic side-chain types with
modest modifications. While the final stages in the syntheses
followed standard peptide-coupling protocols, the synthesis
of the 2-benzyl-substituted linker was accomplished using
an oxazolidinone-mediated asymmetric alkylation reaction
as the key step (Scheme 1).6 Thus, 6-bromohexanoyl chloride
was coupled to the standard Evans chiral auxiliary to form
3. After displacement of the bromide with NaN3, deproto-
nation and alkylation with benzyl bromide afforded 5 (73%,
g98% de). Following the removal of the chiral auxiliary,7
the azido acid was coupled to the N-terminus of glycylglycine
ethyl ester to afford a seco-tripeptide. The azide moiety was
then directly reduced8 to afford Boc-protected amine 7b. This
step proved convenient inasmuch as attempted direct reduc-
tions to the unprotected amine proved problematic, possibly
due to catalyst poisoning by the product. Ester hydrolysis,
Boc deprotection, and cyclization with diethyl cyanophos-
phonate (DECP) resulted in the formation of 1. No racem-
ization was evident by chiral HPLC examination of azide
7a (Chiralcel OD-H column, 7% EtOH/hexane) using a
racemic mixture as the standard.
The synthesis of the Aca tether bearing a C-6 benzyl
substituent utilized a chiral pool approach (Scheme 2).
Elongation of the carbon chain of Boc-L-phenylalanal9 was
effected by Wittig reaction with [3-(ethoxycarbonyl)propyl]-
Scheme 2
(3) (a) Deslauriers, R.; Leach, S. J.; Maxfield, F. R.; Minasian, E.;
McQuie, J. R.; Meinwald, Y. C.; Ne´methy, G.; Pottle, M. S.; Rae, I. D.;
Scheraga, H. A.; Stimson, E. R.; Van Nispen, J. W. Proc. Natl. Acad. Sci.
U.S.A. 1979, 76, 2512-2514. (b) Ne´methy, G.; McQuie, J. R.; Pottle, M.
S.; Scheraga, H. A. Macromolecules 1981, 14, 975-985. (c) Deslauriers,
R.; Evans, D. J.; Leach, S. J.; Meinwald, Y. C.; Minasian, E.; Ne´methy,
G.; Rae, I. D.; Scheraga, H. A.; Somorjai, R. L.; Stimson, E. R.; Van Nispen,
J. W.; Woody, R. W. Macromolecules 1981, 14, 985-996. (d) Maxfield,
F. R.; Bandekar, J.; Krimm, S.; Evans, D. J.; Leach, S. J.; Ne´methy, G.;
Scheraga, H. A. Macromolecules 1981, 14, 997-1003. (e) Bandekar, J.;
Evans, D. J.; Krimm, S.; Leach, S. J.; Lee, S.; McQuie, J. R.; Minasian,
E.; Ne´methy, G.; Pottle, M. S.; Scheraga, H. A.; Stimson, E. R.; Woody,
R. W. Int. J. Pept. Protein Res. 1982, 19, 187-205. (f) Perczel, A.; Fasman,
G. D. Protein Sci. 1992, 1, 378-395. (g) Perczel, A.; Hollo´si, M.; Sa´ndor,
P.; Fasman, G. D. Int. J. Pept. Protein Res. 1993, 41, 223-236.
(4) Kitagawa, O.; Vander Velde, D.; Dutta, D.; Morton, M.; Takusagawa,
F.; Aube´, J. J. Am. Chem. Soc. 1995, 117, 5169-5178.
(5) (a) Ojima, I.; Chakravarty, S.; Dong, Q. Bioorg. Med. Chem. 1995,
3, 337-360. (b) Samanen, J. Ann. Rep. Med. Chem. 1996, 31, 91-99.
(6) Evans, D. A. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic: Orlando, 1984; Vol. 3, pp 2-110.
(7) Li, Z.-H.; Bulychev, A.; Kotra, L. P.; Massiva, I.; Mobashery, S. J.
Am. Chem. Soc. 1998, 120, 13003-13007.
(8) Kotsuke, H.; Ohishi, T.; Araki, T. Tetrahedron Lett. 1997, 38, 2129-
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Org. Lett., Vol. 2, No. 12, 2000