Aspects of Peptidomimetics - Peptide and Protein Design for Biopharmaceutical Applications - page 59

The synthesis and application of 1-aminocycloalkanecarboxylic acids
has been reviewed up to 2000 [47], with an update up to 2007 [48], and
those of the enantiomerically pure Phe analogues - c n Phe ( n ¼ 3-6) - were
also reviewed recently [49]. Asymmetric synthesis methods and efficient
resolution on a cellulose-derived stationary phase have been reported.
Next to c n analogues of the aromatic amino acids Phe, Tyr, Trp and His
[26], various other substituted cycloalkane analogues have been prepared
[50], such as: R ¼ OH ( n ¼ 3, 4) [51-55], R ¼ CH 3 ( n ¼ 1, 2, 4)
[54,56,57], R ¼ iPr ( n ¼ 2, 3) [57,58], R ¼ PhCH 2 CH 2 ,(1 0 )Nal,
p-ClPh ( n ¼ 1) [59]. Studies on model dipeptides RCO-Pro-c n Phe-
NHR 0 revealed the influence of the side-chain orientation on the con-
formation of the backbone modulating the b-turn preferences. Whereas
the cyclopropane analogues (ACCs or r -amino acids) have been used in
peptide chemistry for many years [60] and were shown to result in an
increased metabolic stability [28,29], the application potential of the
other analogues remains largely to be explored [49]. Enkephalin analo-
gues containing a c 5 Serorc 6 Ser residue at the 2-position were shown to
be more potent than the native peptide, with subnanomolar affinities for
the d-receptors [53,61].
In contrast to the 1-aminocycloalkane carboxylic acid analogues
discussed above, little has been reported on the synthesis and use of the
2,4-methano analogues (Figure 3.10). Racemic methano analogues of
Arg, Lys, Orn, Thr and Val were incorporated into the tuftsin sequence.
Some analogues were considerably more active than the parent peptide,
and showed high resistance to enzymatic degradation [62]. Asymmetric
syntheses of cis - and trans -2,4-methanoVal and Leu were reported, as
well as syntheses of the achiral 2,4-methanoPro, and of some of its chiral
homologues [56,57,63].
In a similar fashion, the b-carbon of an amino acid can be tethered
to the a-nitrogen, leading to 3-substituted cyclic iminoacids, which can
be considered chimeras of amino acids and azetidine, proline or pipecolic
acid (Figure 3.11). Similarly, linking C g to the a-nitrogen leads to
4-substituted proline or pipecolic acid analogues, in which there is an
additional constraint of w 2 .
3-substituted azetidine-2-carbocyclic analogues bearing side chains
of Phe, 1-Nal, Leu, Val, Glu, Lys, Arg and Nle have been reported, but
applications in bioactive peptides are lacking [50,64,65]. Various meth-
ods for the preparation of enantiomerically pure 3-substituted prolines
as amino acid-proline chimeras or prolino amino acids have been
reported, leading to chimeras of Asp [66], Arg [67-69], Lys, Glu, Gln,
homoSer [69], Phe, homoPhe [70] and Tyr [69,71,72]. These amino