# Cyclic Octamer Petroids: Simplified Isosters of Bioactive Fungal Cyclodepsipeptides
## 2 Results and Discussion  
### Chemistry and Conformational Studies  
The syntheses of cyclic octamer peptoids **5**-**8** began with the solid-phase \"submonomer\" construction of linear precursors **9**-**12** (Table 1) [5]. \(N\),\(N\)'-disopropylcarbodiimide-induced bromoacetic acid condensations were alternated with amine substitutions until formation of the desired linear oligomeric amides. Detachment from the acid-labile solid support in the presence of hexafluorooisopropanol yielded octamers in acceptable to good yields and decent purities (Table 1). \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Sequence 1 [FOOTNOTE:1]Footnote 1: \(N\)Val = \(N\)-(isopropyl)glycine; \(N\)Leu = \(N\)-(isobutyl)glycine; \(N\)Phe = \(N\)-(benzyl)glycine; \(N\)Ala = \(N\)-(methyl)glycine; \(N\)Am = \(N\)-(pentyl)glycine; \(N\)Ala = \(N\)-(pentyl)glycine; \(N\)Ala = \(N\)-(pentyl)glycine; \\ \hline H-[\(N\)Val-\(N\)Leu]\({}_{4}\)-OH (**9**) & 867.5 [M + H]\({}^{+}\) & 100\% & 82\% \\ H-[\(N\)Phe-\(N\)Leu-\(N\)Ala-\(N\)Leu]\({}_{2}\)-OH (**10**) & 908.2 [M + H]\({}^{+}\) & 49\% & 92\% \\ H-[\(N\)Phe-\(N\)Leu]\({}_{4}\)-OH (**11**) & 1059.6 [M + H]\({}^{+}\) & 89\% & 71\% \\ H-[\(N\)Nam-\(N\)Ala]\({}_{4}\)-OH (**12**) & 811.5 [M + H]\({}^{+}\) & 100\% & 83\% \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Solid-phase synthesis of linear peptoids **9**–**12**: sequences, mass data (ESI/MS), chemical yields and purity. Figure 1: Natural octamer cyclic depsipeptides (OCDs) mycotoxins **(1–4)** and cyclic peptoid congeners **(5–8)** synthesized in the present paper. Head-to-tail cyclisations of crude linear peptoids **9-12** were performed in high dilution conditions (3.0 mM concentration) in the presence of HATU as the coupling agent [26]. Cyclic compounds were purified from traces of unreacted/oligomerized linear peptoids through precipitation from hot acetonitrile (in the case of **5** and **7**) or reverse-phase column chromatography (oligomers **6** and **8**). Cyclic oligoamides **5-8** were isolated as white amorphous solids (purity > 98%, HPLC analysis). Despite their large size, the mycotoxins' congeners showed good conformational stabilities (\({}^{1}\)H NMR analysis, Figure 2). In particular, cyclopeptoids with \(\beta\)-branched \(N\)-side chains (**5-7**) exhibited single dominant conformers (>85%, \({}^{1}\)H NMR analysis, Figure 2a-c), while \(N\)-methyl/amyl substituted **8** displayed multiple conformations in slow equilibrium on the NMR time scale (Figure 2d). Conformational interconversion barriers have been quantified by variable-temperature (VT) \({}^{1}\)H NMR experiments for conformationally homogeneous **5-7**. Coalescence temperatures were experimentally determined to be 110 \({}^{\circ}\)C (C\({}_{2}\)D\({}_{2}\)Cl\({}_{4}\), \(\Delta\)G\({}^{\ddagger}\) = 17.4 \(\pm\) 0.9 kcal/mol, 300 MHz), 90 \({}^{\circ}\)C (C\({}_{2}\)D\({}_{2}\)Cl\({}_{4}\), \(\Delta\)G\({}^{\ddagger}\) = 16.4 \(\pm\) 0.8 kcal/mol, 300 MHz) for cyclopeptidoids **5**, **6** and **7**, respectively. No conformational stability studies have been reported for octamer cyclodepispeptides in that, in most of the deuterated solvents, bassianolide [14], PF1022A [15; 27] and verticilide A1 [28] are present as complex mixtures of conformers in slow equilibrium on the NMR time scale. 2D homonuclear (COSY) and heteronuclear (HMQC, HMBC) experiments allowed assignment of the \({}^{1}\)H/\({}^{13}\)C resonances for cyclic peptoids **5-7**, suggesting formation of \(C_{2}\)-symmetric _ccttcctt_ species for **5** and **7** (half of the signals were present in the NMR spectra, as previously reported for octamer peptoids [29; 30; 31; 32; 33; 34]) and a \(C_{1}\)-symmetric species for **6**. Peptoid bond geometries have been documented by \({}^{1}\)H NMR chemical shifts values.