Aspects of Peptidomimetics - Peptide and Protein Design for Biopharmaceutical Applications - page 57

A single b-methyl substitution does not constrain significantly the
(w 1 ,w 2 ) space of an aromatic amino acid. Generally, there is a small energy
preference of the gauche( ) rotamer for the erythro isomer (2 S ,3 S ) and of
the anti rotamer for the threo isomer (2 S ,3 R ), which can be rationalized
on the basis of steric interactions in the different rotamers (Figure 3.8).

CH 3

H R

H

CH 3

-HN CO- -HN

CO- -HN CO-

H

R

H H

H 2 N COOH R

CH 3 H 3 C

H H H

(2 S , 3 S )- β MePhe gauche(-) gauche(+) anti

H

CH 3

R

H

CH 3

-HN CO- -HN CO-

CO-

-HN

H

H 3 C

R CH 3 R

H 2 N COOH H H

H

H

H

anti

(2 S , 3 R )- β MePhe gauche(-) gauche(+)

Figure 3.8 Rotamers b-MePhe

Evidently, when the steric bulk of the b-substituent is increased, as in
the b-isopropyl derivatives, the stereochemical bias is more pronounced
[25,27]. A variety of other b-alkyl- and b-phenyl-substituted Phe, Tyr and
Trp analogues have been reported [31,35-37]. However, except for the
Dip residue [29], their use in bioactive peptides remains to be demon-
strated. A very strong effect is obtained when the b-methyl substitution in
Phe or Tyr is accompanied by methylation of the aromatic ring at the
2 0 ,6 0 -positions, leading to trimethylPhe (TMP) or trimethylTyr (TMT)
[38] (Figure 3.7). The incorporation of (2 S ,3 S )TMT in the opioid
sequences of DPDPE, deltorphin-I and TMT-Tic dipeptides, as well as
in a bicyclic oxytocin analogue, provided insight into the topographical
requirements for receptor recognition by these ligands [38-40].
New synthetic methods for the efficient preparation of this interesting
class of b-substituted amino acids continue to be developed [36,41].
The fluorenylglycine (Fgl) and 1-indanylglycine (Ing) structures
(Figure 3.9) do not only constrain w 1 ,butalsow 2 . The Ing isomers can be
use as conformational probes which constrain the w 1 angle depending on
the backbone conformation [28,29]. For a backbone with extended con-
formation, the (2 S ,3 S )-Ing prefers the anti, and the (2 S ,3 R )-Ing the
gauche( ) conformation, with w 2 þ 60 and 60, respectively. In a