Conformational Studies of Phe-Rich Foldamers by VCD Spectroscopy and ab Initio Calculations

Abstract

Employing VCD spectroscopy, we demonstrate that the structural behavior of the oligomers Boc-(L-Phe-L-Oxd)(n)-OBn is similar from n = 2 to n = 6; ab initio calculations for the n = 1 case provide physical insight into the conformational properties. Further information is gained by IR, (1)H NMR, and ECD spectroscopies. ECD spectra suggest the presence of different conformations between n = 1 on one side and longer chain foldamers on the other side. VCD and absorption IR spectra in methanol solutions can be interpreted as indicative of a PPII structure. In the case of Boc-L-Phe-L-Oxd-OBn, VCD spectra in CCl(4) and detailed DFT computational analysis allow one to demonstrate that the most populated conformers exhibit backbone dihedral angles similar to those of a PPII geometry. This is a remarkable outcome, as we had previously demonstrated that the Boc-(L-Ala-D-Oxd)(n)-OBn series folds in a β-band ribbon spiral that is a subtype of the 3(10) helix.

Solid‐State Properties and Vibrational Circular Dichroism Spectroscopy in Solution of Hybrid Foldamers Stereoisomeric Mixtures

“…In Figure 5, we show a comparison of the three calculated VCD with the three observed VCD spectra. From these calculations and from previous results, [4] we note that, although for standard peptides the amide I band owing to the backbone carbonyl stretching is below ñ = 1700 cm…”

“…Routine NMR spectra were recorded with a Varian Inova 400 spectrometer at 400 ( Boc-(l-Phe-l-Oxd) 2 -OBn (1): For synthetic details and characterization data, see ref. [4].…”

“…Boc-l-Phe-l-Oxd-d-Phe-l-Oxd-OBn (2): A mixture of H-l-Phe-lOxd-OBn·TFA (1 mmol) [4] and Et 3 N (3 mmol, 0.44 mL) in dry acetonitrile (10 mL) was added at room temperature to a stirred solution of Boc-l-Phe-d-Oxd-OH (1 mmol, 0.39 g) [13] and HATU (1 mmol, 0.38 g) in dry acetonitrile (10 mL) under an inert atmosphere. The solution was stirred for 40 min under an inert atmosphere, then acetonitrile was removed under reduced pressure and replaced with ethyl acetate.…”

“…[3] Recently, we described the synthesis and conformational analysis of the foldamers Boc-(l-Phe-l-Oxd) n -OBn (n = 1-6; Boc = tert-butyloxycarbonyl; l-Oxd = trans-(4S,5R)-4-carboxy 5-methyloxazolidin-2-one; Bn = benzyloxycarbonyl). [4] The synthesis was performed by conventional methods in solution and conformational analysis was performed by means of IR, 1 H NMR, electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) spectroscopy; ab initio calculations in the case of n = 1 provided a physical insight into the conformational properties.…”

“…VCD and absorption IR spectra in CCl 4 could be interpreted as indicative of a polyproline II (PPII) structure in the case of short Boc-l-Phe-l-Oxd-OBn because detailed DFT computational analysis allowed us to demonstrate that the most populated conformers exhibited backbone dihedral angles similar to those of a PPII geometry. The conformational Upon slow evaporation of a 1:1 diastereoisomeric mixture of Boc-(l-Phe-l-Oxd) 2 -OBn (1; Boc = tert-butyloxycarbonyl; lOxd = trans-(4S,5R)-4-carboxy 5-methyloxazolidin-2-one, Bn = benzyloxycarbonyl) and Boc-l-Phe-l-Oxd-d-Phe-l-Oxd-OBn (2) in methyl tert-butyl ether, single crystals suitable for an X-ray diffraction study were obtained.…”