# Cyclic Octamer Petroids: Simplified Isosters of Bioactive Fungal Cyclodepsipeptides
## 2 Results and Discussion
### Complexation Studies  
The biological action of CDPs is often associated to the formation of metal complexes [18; 19; 20]. We therefore tested the metal chelating attitudes of cyclic peptoids **5-8** in the presence of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl)]borate (NaTFPB, [12]) in CDCl\({}_{3}\) solutions (\({}^{1}\)H NMR analysis, Figure 6). In all the performed experiments the presence of two equivalents of Na\({}^{+}\) cation induced formation of highly symmetric metalated species in slow equilibrium with the corresponding free hosts on the NMR time scale. Addition of one equivalent of NaTFPB showed the formation of a mixture of multiple complexes in slow equilibrium on the NMR time scale. Two equivalent of cationic guest established the formation of single detectable, highly symmetric, complexes. The relatively low chemical shift values observed for the \(N\)Ala (2.85 ppm in [**6**:2 Na]\({}^{2+}\); 2.88 ppm in [**8**:2 Na]\({}^{2+}\)) and \(N\)Val (3.96 ppm in [**5**:2 Na]\({}^{2+}\)) C\(\alpha\)H resonances; the small \(\Delta\)S evidenced for the diastereotopic -N-CH\({}_{2}\)-CH(CH\({}_{3}\))\({}_{2}\) protons of \(N\)Leu (0.22 in [**5**:2 Na]\({}^{2+}\); 0.30 in [**6**:2 Na]\({}^{2+}\)), -N-CH\({}_{2}\)-Ph protons of \(N\)Phe (0.48 in [**6**:2 Na]\({}^{2+}\); 0.51 in [**7**:2 Na]\({}^{2+}\)) and -N-CH\({}_{2}\)-(CH\({}_{2}\))\({}_{3}\)-CH\({}_{3}\) protons of \(N\)Nam (0.23 in [**8**:2 Na]\({}^{2+}\)) residues suggested, for all the cyclic octamers, _all-trans_ peptoid junctions [36]. The host/guest ratio (calculated integrating the signals of the host/guest complex respect to those of dissolved guest, NaTFPB) remained constant during all the titration experiments and documented a 1:2 macrocycle/Na\({}^{+}\)_ratio_ for all the synthesized complexes. The apparent association constants were therefore calculated for the formation of the [**5**-**8**:2 Na]\({}^{2+}\) species by \({}^{1}\)H NMR (1.0 mM, CDCl\({}_{3}\)) [37; 38] showing similar values for all the bimetallic adducts (K\({}_{a}\): [**5**:2 Na]\({}^{2+}\): 1.9\(\cdot\)10\({}^{7}\) M\({}^{-2}\), [**6**:2 Na]\({}^{2+}\): 7.2\(\cdot\)10\({}^{6}\) M\({}^{-2}\), [**7**:2 Na]\({}^{2+}\): 1.9\(\cdot\)10\({}^{6}\) M\({}^{-2}\), [**8**:2 Na]\({}^{2+}\): 1.3\(\cdot\)10\({}^{7}\) M\({}^{-2}\)). VT \({}^{1}\)H NMR experiments indicated no sign of coalescence up to 110 \({}^{\circ}\)C (C\({}_{2}\)D\({}_{2}\)Cl\({}_{4}\), 600 MHz). The efficient ion-dipole interactions between the carbonyl groups and the sodium cation increases the conformational stabilities of the macrorings. Also, the Na\({}^{+}\)-complexes were present as couples of enantiomorphous cyclooligomers (Figure 7). In particular, cyclic peptoids [**5c**:2 Na]\({}^{2+}\) and [**5d**:2 Na]\({}^{2+}\), showing alternating side chains, are \(C_{4}\)-symmetric conformational enantiomers; macrorings [**6a**:2 Na]\({}^{2+}\) and [**6b**:2 Na]\({}^{2+}\) are \(C_{2}\)-symmetric species and **7** and **8** (not reported), with alternating side chains, form couples of \(C_{4}\)-symmetric conformational enantiomers. Figure 5: \({}^{1}\)H NMR spectra resulting from the quantitative step-wise addition of [PERSON]’s alcohol to the 5.0 mM solution in CDCl\({}_{3}\) (600 MHz). Red asterisks denote split signals. Figure 6: \({}^{1}\)H NMR spectra showing [5-8 2 Na]\({}^{2+}\) complexes and general structure of the highly symmetric _all-trans_ core conformer. Residual solvent peaks are labelled with a red asterisk. H\({}_{2}\)O and further CDCl\({}_{3}\) impurities are labelled with a black asterisk. 1.0 mM host solutions in the presence of 2.0 equivalents of NaTFPB in CDCl\({}_{3}\) (400 MHz). Formation of conformational enantiomers in rigid octamer cyclopeptoids as free hosts or complexes represents a crucial factor to predict/interpret their biological action. It should be noted that the presence of enantiomorphous species is not detrimental to the biological activity only when the biological target is not chiroselective (as in the case of the cell membrane) [39].