molecule 2,8 and the X-ray crystal structure shows that the
cyclopropylic strain effectively works to restrict the
conformation.
Figure 1. Diagram of the cyclopropylic strain, and the X-ray
crystal structures of 1 and 2.
We hypothesized that peptidomimetics with 3D struc-
tural diversity could be developed using the cyclopropylic
strain. We first designed the tetrapeptide-mimetic scaffolds
derived from the structures of 1 and 2, which comprise
eight stereoisomers IꢀIV and ent-Iꢀent-IV in Figure 2. In
each stereoisomer, the backbone (indicated in red) is not
only restricted into the “trans” or “cis” configuration by
the cyclopropane ring itself, but is also further constrained
to the “folded” or “extended” form due to the cyclo-
propylic strain, depending on the stereochemistry of C10.
Accordingly, the “cis-folded” (I) and “trans-extended”
(IV) scaffolds mimic the β-turns and β-strands of the
tetrapeptides, respectively, while the “trans-folded” (II)
and “cis-extended” (III) scaffolds mimic the conforma-
tions halfway between the β-turns and β-strands. In addi-
tion, the absolute 3D positioning of the side-chain
functional groups in each of the scaffolds IꢀIV differs
from those of the enantiomeric scaffolds ent-Iꢀent-IV
(up-series vs down-series, based on the direction of the
cyclopropane ring), which would be effective for searching
a broad chemical space to determine the bioactive con-
formation, thereby identifying nonpeptidic leads.
Figure 2. Designed tetrapeptide-mimetic scaffolds.
activities;9 therefore, we designed peptidomimetics 3ꢀ6
and ent-3ꢀent-6 (Figure 3) by allocating the functional
groups corresponding to the core tetrapeptide sequence
side chains into RiꢀRiþ3. The 2-naphthyl moiety (Nap)
was used as bioisostere for the indole ring of Trp.9c
To demonstrate the utility of the cyclopropylic strain-
based peptidomimetics with 3D structural diversity,
we identified nonpeptidic melanocortin receptor (MCR)
ligands. The common core sequence His-Phe-Arg-Trp
in endogenous MCR ligands is essential for their biological
Figure 3. Designed MCR ligands.
In the previous synthesis of 1 and 2, corresponding to the
scaffolds ent-I and IV, respectively, both the stereochem-
istry and functional groups introduced were limited. This
study, however, required a common procedure for synthe-
sizing all eight scaffolds IꢀIV and ent-Iꢀent-IV stereose-
lectively, where the side-chain substituents RiꢀRiþ3 must be
potentially replaceable. Our general synthetic scheme is
shown in Scheme 1. We planned to prepare both the trans-
and cis-type mimetics from known chiral cyclopropane deri-
vative 7 or ent-7, which are readily prepared in high optical
purity from (R)- or (S)-epichlorohydrin, respectively.10 The
Riþ2 and Riþ3 moieties, respectively, would be regioselectively
introduced into the two ester moieties of 7 (ent-7).
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