Chiral Sulfoxide-Induced Single Turn Peptide α-Helicity

Inducing α-helicity through side-chain cross-linking is a strategy that has been pursued to improve peptide conformational rigidity and bio-availability. Here we describe the preparation of small peptides tethered to chiral sulfoxide-containing macrocyclic rings. Furthermore, a study of structure-activity relationships (SARs) disclosed properties with respect to ring size, sulfur position, oxidation state, and stereochemistry that show a propensity to induce α-helicity. Supporting data include circular dichroism spectroscopy (CD), NMR spectroscopy, and a single crystal X-ray structure for one such stabilized peptide. Finally, theoretical studies are presented to elucidate the effect of chiral sulfoxides in inducing backbone α-helicity.

2) H2N-Ala-Ala-Ala-Xn-Resin (0.1 mmol) was dissolved in anhydrous DMF (10 mL) at ambient temperature, and swelled for 20 min. N-Acetyl-L-cysteine ( 98mg, 0.3 mmol, 3.0 equiv) and DMAP (26 mg, 0.1 mmol, 1.0 equiv) was added, and the reaction was degassed, UV irradiated for 1 h with stirring. After photo reaction, the resin was washed with DCM for three times and then with methanol to shrink the resin. The resin was dried under a steam of argon gas for 1 hour.
3) The dried peptide-containing resin was placed in a polypropylene container with a screw cap, then cleavage cocktail (2.0 mL, TFA/TIS/EDT/H2O 94/1/2.5/2.5) was added and the container was sealed tightly with screw cap. The container was gently agitated on an orbital shaker in the fume hood for 2 h. The TFA cocktail was removed with by evaporation under a steam of argon gas in the fume hood, and the residue was precipitated with cold diethyl ether 3×3 ml.
4) The precipitate was dried and dissolved in 100 mL dry DMF, and then HATU (115 mg, 0.3 mmol) and DIEA (82 uL, 0.5 mmol) were added at 0 °C. The mixture was stirred overnight and then concentrated in vacuo. The residue was dissolved in H2O and purified on HPLC.
General procedure B. Thiolether linker was constructed through on-resin cyclization.
The resin was washed with DMF and DCM for three times, and then shrink with methanol. The resin was dried with a steam of argon gas for 1 h.
3) The dried peptide-containing resin was placed in a polypropylene container with a screw cap, then cleavage cocktail (2.0 mL, TFA/TIS/EDT/H2O 94/1/2.5/2.5) was added and the container was sealed tightly with screw cap. The container was gently agitated on an orbital shaker in the fume hood for 2 h. The TFA cocktail was removed by evaporation under a steam of argon gas in the fume hood, and the residue was precipitated with cold diethyl ether 3×3 ml. The residue was dissolved in H2O/acetonitrile 1:1 and purified on HPLC or used directly in the oxidation procedure.
General procedure C. This procedure was the same with General procedure A except for that Rink amide resin and N-Acetyl-L-cysteine were change to CTC resin and L-Cysteinamide monohydrochloride.