Refoldable Foldamers: Global Conformational Switching by Deletion or Insertion of a Single Hydrogen Bond

Abstract Small changes in the structure of a foldamer may lead to gross changes in conformational preference. We show that the simple insertion or deletion of a single hydrogen bond by changes in pH or by photochemical deprotection is sufficient to refold a helical oligomer, interconverting M and P screw‐sense preference. As a consequence of the switch, information may be transmitted to a remote catalytic site, selectively directing the formation of either of two enantiomeric products by a reaction involving 1,22‐remote intermolecular asymmetric induction.


General Experimental and Materials
All reactions were carried out in oven-dried glassware under an atmosphere of nitrogen using standard anhydrous techniques. All reagents were obtained from commercially available sources and used without further purification, or where indicated prepared internally. Air-and moisturesensitive liquids and solutions were transferred via syringe or stainless steel cannula. Reactions performed at 0 °C were done so using an ice bath. Anhydrous dichloromethane and tetrahydrofuran were obtained by distillation from calcium hydride, and sodium wire with a benzophenone indicator, respectively. Other anhydrous reaction solvents were obtained from standard anhydrous solvent engineering system. Petrol (or PE) refers to the fraction of light petroleum ether boiling between 40 and 65 °C. Triethylamine was stored over potassium hydroxide. All products were dried on a rotary evaporator followed by connection to a high vacuum system to remove any residual solvent. Flash chromatography was performed on silica gel (Merck 60H, 40-60 nm, 230-300 mesh). Analytical thin layer chromatography was performed on aluminium backed silica (60 F254) plates.

Instrumentation
All 1 H and 13 C nuclear magnetic resonance spectra were obtained using Bruker AVANCE 400, 500 or 800 MHz spectrometers. Chemical shifts are quoted in parts per million (ppm), and coupling constants (J) are quoted in Hz to the nearest 0.5 Hz. 1 H-NMR spectra were referenced to the residual deuterated solvent peak (CDCl3 7.27; CD3OD 3.31; THF-d8 1.73 ppm) and 13 C-NMR were referenced to the carbon resonance of the solvent (CDCl3 77.00; CD3OD 49.05; THF-d8 25.37 ppm). Multiplicities are denoted as s (singlet), d (doublet), t (triplet), q (quartet), spt (septet) and m (multiplet) or denoted as br (broad), or some combination of these, where appropriate. Where 1 H-NMR spectra were run in CD3OD exchangeable protons (NH, OH) are reported only where observed. Assignments were made using DEPT-135, 2D 1 H-COSY and HMQC experiments.
Infra-red spectra were recorded on an ATi Perkin Elmer Spectrum RX1 FT-IR spectrometer. Only absorption maxima (λmax) of interest are reported and quoted in wavenumbers (cm -1 ). Low and high resolution mass spectra were recorded by staff at the University of Manchester. Electrospray (ES) spectra were recorded on a Waters Platform II and high resolution mass spectra (HRMS) were recorded on a Thermo Finnigan MAT95XP and are accurate to ±0.001 Da. Melting points were determined on a GallenKamp apparatus and are uncorrected. Optical rotation measurements were taken on an AA-100 polarimeter at 20 °C with the solvent and concentration (g/100 mL) stated. Circular Dichroism (CD) measurements were performed at 20 °C on a JASCO J-815 spectropolarimeter, using a 1 mm cell with the solvent and concentration stated, where applicable. Analytical HPLC analysis was performed on a Hewlett-Packard series 1050 system, using the column and eluent stated, with UV detection at 254, 230 and 210 nm.

Experimental Procedures
Methods for the synthesis of N3Aib4OH, HAib4OtBu, Z-GlyAib4O t Bu, 1 Z-Aib*Aib4OH and Z-L-AlaNH t Bu 2 have been previously reported.
General procedure B: synthesis of thiourea catalysts from non-commercially available isothiocyanates To a stirred solution of primary amine in anhydrous THF (10 mL/mmol) was added sequentially thiophosgene (1.2 equiv.) and DIPEA (2.4 equiv.) and the mixture stirred at room temperature for 2.5 h. The solvents were removed and the residue purified by flash column chromatography. The corresponding isothiocyanate was added as a solution in THF (20 mL/mmol) to a flame-dried RB flask charged with HAib4-L-AlaNH t Bu or HGlyAib4-L-AlaNH t Bu (1.0 equiv.). The reaction was heated at reflux for 3-5 d, the solvents removed and the residue purified directly by flash column chromatography.
General procedure C: synthesis of thiourea catalysts from commercially available isothiocyanates To a stirred solution of HAib4-L-AlaNH t Bu or HGlyAib4-L-AlaNH t Bu in anhydrous THF (20 mL/mmol) was added isothiocyanate (1.2 equiv.) and the reaction heated at reflux for 3-5 d. The solvents were removed and the residue purified directly by flash column chromatography.