Self-assembling α,γ-cyclic peptides that generate cavities with tunable properties

The design and synthesis of self-assembling cyclic peptides with tunable cavity properties is described, allowing the incorporation of guests with different features.


Computational methods 54
Scheme 2SI: Synthesis of the N-methylated Ahf using Fukuyama´s method for the preparation of the fully protected amino acid 2. Removal of Nosyl group and coupling with Boc-D-Leu-OH provide the dipeptide 4, the basic component used in the synthesis of CP4. Figure 1SI: Top: Structure of CP2 and model of the tetrahydrofurane conformations, in which the amide proton is hydrogen bonded to its own carbonyl group, showing the perpendicular orientation between the Hα and the Hβ and between the H and the Hβ. Bottom: 1 H NMR spectrum of CP2 (20 mM, CDCl3, 298 K); in the inset, an extension of the spectral region between 5.4 and 3.6 ppm should be shown, where the vicinal protons α-Ahf and β-Ahf appear as singlets, which suggests their perpendicular orientation.

Figure 8SI
: DFT Optimized structures of bis(methyl picolinate) silver(I) complexes with higher (less stable) energies compared to those presented in the main part of the manuscript. The energies of these conformations are about 11, 5, 13 and 18 kcal/mol (from left to right) less stable than those corresponding to the conformers presented there. The silver ion is in gray whereas the two picolinates are highlighted in orange.

Figure 9SI:
Top and lateral views of the DFT optimized structures for the anti-eclipsed, clockwise and counter-clockwise alternating dimers, respectively. All the hydrogens, except those from the backbone and those from the pyridines, have been removed for clarity. The side chains were changed to methyl groups to reduce the number of possible conformers.
Analytical thin-layer chromatography was performed on E. Merck silica gel 60 F254 plates.
Compounds, which were not UV active, were visualized by dipping the plates in a nynhidrin solution and heating. Silica gel flash chromatography was performed using E. Merck silica gel (type 60SDS, 230-400 mesh). Solvent mixtures for chromatography are reported as v/v ratios.
HPLC purification was carried out on a HITACHI D-7000 using a Phenomenex Luna 5µ Silica 100 Angstroms column with CH2Cl2/MeOH gradients between 96:4 and 87:13. 1 H NMR spectra were recorded on Varian Inova 500 MHz, Varian Mercury 300 MHz or Bruker DPX 250 MHz spectrometers. Chemical shifts (δ) were reported in parts per million (ppm) relative to tetramethylsilane (δ = 0.00 ppm) or by the deuterated solvent. 1 H NMR splitting patterns are designated as singlet (s), doublet (d), triplet (t), or quartet (q). All first-order splitting patterns were assigned on the basis of the appearance of the multiplet. Splitting patterns that could not be easily interpreted are designated as multiplet (m) or broad (br          The crystal structure was deposited at the Cambridge Crystallographic Data Centre, and the data was assigned to the following deposition number: CCDC 1400134.

Computational methods:
The starting geometries of the cyclic peptides investigated in this work were constructed from  Number