The desymmetrization of
endo-norborn-5-ene-2,3-dicarboxylic anhydride (5)
by proline derivatives
is used to prepare peptides and pseudopeptides incorporating an
endo-(2S,3R)-2-amino-3-carboxynorborn-5-ene (1) residue. The peptides contain a
single conformationally constrained β-amino
acid residue, while the pseudopeptides also contain a urea linkage and
two peptide chains running
in parallel directions. The key step in the synthesis is a Curtius
rearrangement on the amido
acids 6a,b to generate an isocyanate that is then directly
reacted with suitably protected amino
acids and peptides to give the peptides and pseudopeptides. The
synthesis of the peptide analogue
4 is also described; in this compound, the two peptide
chains run parallel to one another, and the
stereochemistry of the norbornene unit within compound 4 was
determined by X-ray analysis of
the related peptide analogue 23.
The synthesis of pseudopeptides
1
−
3 and peptide 4 were
reported in the accompanying article.
X-ray analysis of pseudopeptide 1 showed it to adopt a
solid state conformation in which the Pro-Phe-Phe chain formed two consecutive β-turns, stabilized by hydrogen
bonding between the Phe
NH's and the norbornene carbonyls. However, NMR, IR, and CD
studies showed that in CDCl3,
CH2Cl2, and CH3CN
solution, pseudopeptide 1 does not adopt a preferred
conformation. A longer
pseudopeptide 2 was found to exist in two different
conformations in CDCl3 solution. The
major
conformer adopts a structure in which both tripeptide chains form a
single β-turn which is stabilized
by the formation of a hydrogen bond between the C-terminal
amino acid NH and one of the
norbornene carbonyls. In the minor conformer, however, the
Pro-Phe-Phe chain forms two β-turns,
analogous to the X-ray structure of pseudopeptide 1.
The introduction of a urea unit into one of
the peptide chains, as in pseudopeptide 3, offsets the atom
positions so as to allow interchain
hydrogen bonding, and the 3
J(α-CH−NH)
coupling constants and NOE's suggest that in
CDCl3
pseudopeptide 3 adopts a parallel β-sheet conformation.
The parallel β-sheet is stabilized by the
formation of two intramolecular hydrogen bonds involving the NH's of
the Ala and Val residues.
Finally, peptide 4, which incorporates a
conformationally constrained β-amino acid, was
determined
by NMR techniques to form an antiparallel β-sheet (also referred to
as a β-ladder or β-hairpin). A
series of model peptides lacking the norbornene unit were also
prepared, and in each case NMR
and IR techniques showed that the model peptides did not form well
defined conformations
containing intramolecular hydrogen bonds.
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