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Tertiary Aliphatic Amides: Polyprolines and Peptoids

The helix is ubiquitous in the secondary structure of a-peptides and their b- and g-homologs (see Chapters 2 and 5). In regular helices formed from secondary a- or b-peptides (Figs. 1.12a and b), intrachain C=O-H-N hydrogen bonding between nonadjacent residues is essential to folding: for example, between C=O; and N-H;+4 for an a-helix (3.613-helix); between C=O; and N-H;+3 for a 310-helix in a-polypeptides; and between N-H; and C=O;+2 and for a 314-helix in b-polypeptides. Intuitively, it might be imagined that upon converting these secondary amides to tertiary aliphatic amides, the resulting loss of hydrogen bond donors may result in the inability of an oligomeric strand to adopt a well-defined folded conformation. This is, however, not the case. Oligomers of the naturally occurring amino acid proline also adopt helical conformations despite the fact that proline is a secondary amine and that its oligomers are tertiary amides unable to form intramolecular hydrogen bonds (Fig. 1.12c). For an a-helix, the f,

Fig. 1.12 Repeat units of (a) a-polypeptides; (b) b-polypeptides; (c) polyproline; (d) peptoids (poly(N-substituted glycine)); and (e) N-methylated polypeptides.

C torsion angle distribution (Fig. 1.12a) in the Ramachandran plot lies near (—63°, —42°) [123]. The Ramachandran plot of polyproline is quite distinct because the ring structure of the pyrrolidine ring is constrained. The f, c distribution is centered approximately at —75°, 145° for the left-handed polyproline type II helix, which is stable in aqueous medium and which contains all-trans tertiary amides (o = 180°), and at —70°, 160° for the right-handed polyproline type I helix which contains all-cis tertiary amides (o = 0°) (Fig. 1.13) [123].

The polyproline type II helix is found in both folded and unfolded peptides and plays important roles in biological signal transduction, transcription, cell motility, and immune responses [125-127]. The triple helix of collagen consists of three intertwined polyproline type II helices. It is still unclear why the polyproline

Fig. 1.13 Crystal structures at the same scale of: (a) a left-handed polyproline type II helix (top view and side view); and (b) a pentameric peptoid helix [124] (side chains have been replaced by balls in the left-hand view.

type II helix is intrinsically so stable despite the absence of strong intramolecular interactions. In addition to the rigidity imparted by the pyrrolidine ring which sets the f angle, solvent and stereoelectronic effects apparently determine the preferred c values. For example, a (possibly cooperative) stabilizing n ! p* interaction between O;_i and Chas been shown to play a substantial role in stabilizing the polyproline type II helix [125]. Substituents in position 4 of the pyrrolidine ring modulate the ring conformation which in turn enhance or inhibit the n ! p * interaction and the preference for a trans over cis amide conformation, thus defining the balance between type II and type I helices [125].

Peptoids (N-substituted glycine derivatives; Fig. 1.12d) have many similarities to polyprolines, including their inability to form intrachain hydrogen bonds and the possibility to form cis tertiary amide backbone linkages [128]. However, like polyprolines, peptoids do fold into helical structures based on conformational preferences of the backbone chain, side-chain-backbone steric repulsions, and dipole-dipole repulsions between main-chain amide carbonyl electrons [129]. Peptoids with as few as five residues have been shown to form reversible and cooperative stable helical structures in both aqueous and organic solvents [128,

130]. Note that the peptoid backbone is achiral and the chirality of the secondary structure (helix screw sense) is governed by the chirality of the side chains [130]. An X-ray crystal structure of an (S)-N-(1-cyclohexylethyl)glycine pentamer reported by Wu et al. shows a left-handed helix with similar torsional angles (f, c, and o) as the polyproline type I helix (Fig. 1.13) [124]. Ramachandran plots indicate a greater conformational diversity for peptoids compared with peptides, which is believed to be related to the lack of substitution on the a-carbon (which is achiral) and the absence of an amide N-H capable of hydrogen bonding [129,

131]. Nevertheless, peptoids have a great potential for biological applications (see Chapter 8).

Another family of tertiary aliphatic amides are poly-N-methylated peptides (Fig. 1.12e) which have been described as ''more congested peptoid-like molecules'' [70]. In this case, an extended b-strand conformation rather than a helical conformation is adopted. In fact, X-ray crystallography of (N-Me-L-Ala)6 and all-N-Me-(Ser(OBz)-Val-Ala-Ser(OBz)-Val-Ala) indicates that the b-strand conformations of poly-N-methylated peptides retain an ability to form hydrogen bonds with a-peptide b-strands through their carbonyl groups.

Other classes of foldamers related to peptoids and polyprolines include some b-peptide derivatives containing cyclic tertiary amide linkages that can be broadly classified as cyclic b-peptoids (Fig. 1.14). By controlling all the torsion angles of the backbone, Lee et al. [132] have designed a completely non-hydrogen-bonded helical pseudopeptide composed of amide linked oxanipecotic acid units (Fig. 1.14a). In this work, circular dichroism was used to show that an oxanipecotic acid tetramer adopts a non-hydrogen-bonded helical structure more efficiently than the nipecotic tetramer (Fig. 1.14b) [133]. The symmetric chemical environment adjacent to the nitrogen atom in the piperidine ring of nipecotic acid makes the cis and trans conformation of the amide linkage equivalent whereas this is not the case in oxanipecotic acid.

Fig. 1.14 Oxanipecotic acid oligomers (a), nipecotic acid oligomers (b), 2,2-disubstituted pyrrolidine-4-carboxylic acid oligomers (c), benzyl (4S,5R)-5-methyl-2-oxo-1,3-oxazolidine-4-carboxylate oligomers (d), and pyroglutamic acid oligomers (e).

Using NMR structural analysis and circular dichroism, Huck et al. have studied 2,2-disubstituted pyrrolidine-4-carboxylic acid oligomers (Fig. 1.14c) that fold into helical structures without intramolecular backbone hydrogen bonding [134]. The preferred cis conformation of the backbone amide linkage in this foldamer is reminiscent of the cis conformation of the backbone in polyproline I helices.

Homo-oligomers of benzyl (4S,5R)-5-methyl-2-oxo-1,3-oxazolidine-4-carboxylate (n = 2-5; Fig. 1.14d) adopt polyproline type Il-like helical conformations. Once again, the torsion angle, f, is restricted by the cycle to values between —50 to —80° while the c and o torsion angles are both trans (140-160° and 180°, respectively). However, in contrast to the polyproline II helix, this helical conformation is stabilized by intramolecular a-C-Hi, 2-oxo-1,3-oxazolidine O=Ci+1 hydrogen bonds [135]. Similar stabilization by intramolecular C-H---O=C hydrogen bonding was observed for homo-oligomers of pyroglutamic acid (n = 2-4; Fig. 1.14e) [136].

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