the aqueous solubility of these compounds for applications in
biological systems is underway.
We thank The University of Oxford for funding (ST), and
Dr Martin Smith (University of Oxford), and Dr Ian Jones
(Yale University) for helpful discussions.
Fig. 5 Single crystal X-ray structure of 11.
Notes and references
z Forming the same product via nucleophilic substitution of 1-fluoro-
3-nitrobenzene proved unsuccessful.
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Fig. 6 Selected region of a NOESY spectrum of 16 (pyridine-d5,
0.01 mmolꢁ1, see (ESIw) for a larger version).
mechanism might operate in binding a putative protein target
(Fig. 6). A molecular mechanics calculation14 of dihedral angle
energy plots for trimer 16 indicated preferred angles of
ꢁ179.31 and 01 for the angle shown in blue (C10–C7) and
+172.91 and ꢁ101 for the angle in shown in red (C16–C12,
Scheme 2, see ESIw for full plots); and thus a coplanar
arrangement of rings. Applying the same method for groups
larger than methyl, e.g. isopropyl as a mimic of the valine
side-chain, does not significantly increase the rotational barrier,
auguring well for incorporation of groups to mimic other amino
acid side-chains.
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15 Molecular graphics and analyses were performed with the UCSF
Chimera package: National Center for Research Resources grant
2P41RR001081, National Institute of General Medical Sciences
grant 9P41GM103311; E. F. Pettersen, T. D. Goddard,
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In summary, we have designed a route to a non-peptidic
scaffold capable of reproducing a recognition domain of a
peptide b-strand. As proof-of-principle we synthesised a mimic
of three alanine residues in the i, i + 2 and i + 4 positions.
Solid and solution phase studies, alongside modelling, demon-
strate that the desired conformation, in which the side-chains
are presented in the same fashion as those of the natural
peptide, is readily accessible. The synthesis is modular and
scalable allowing facile incorporation of a range of amino acid
side-chains and extension to longer oligomers. Work to improve
17 Not shown, see (ESIw) compound 6.
18 A racemic synthesis of 5 from (ꢀ)-alaninol was also followed
(see ESIw). The configuration of the chiral centre was arbitrarily
assigned (S); CCDC # 873486.
19 CCDC # 873487.
c
9836 Chem. Commun., 2012, 48, 9834–9836
This journal is The Royal Society of Chemistry 2012