Disulfide-Bridged Peptides That Mediate Enantioselective Cycloadditions through Thiyl Radical Catalysis

Abstract

An enantioselective vinylcyclopropane ring-opening/cycloaddition cascade is described. The active thiyl radical catalysts are generated in situ via UV light-promoted homolysis of cystine-based dimers. Amide-functionalization of the peptide at the 4-proline position is essential for effective asymmetric induction. Stereochemical communication is dependent on steric interactions with this substituent that are enforced by H-bonding to the peptide backbone.

Scheme 1

Polar and radical cysteine catalysts in biology and synthesis

Scheme 2. Peptide optimization studies^a

^aReactions were performed on a 0.05 mmol scale and were quenched by exposure to air. Conversions, diastereomeric ratios, and enantiomeric excesses were determined by CSP-HPLC (254 nm, uncorrected). Ar = 4-CF₃Ph.

Scheme 3. Breadth of olefin coupling partners^a

^aReactions were performed on a 0.1 mmol scale and were quenched by exposure to air. Isolated yield of a mixture of trans and cis diastereomers. Diastereomeric ratios determined by ¹H NMR, enantiomeric ratios determined by CSP-HPLC (254 nm, uncorrected). Average of 2 separate experiments. Ar = 4-CF₃Ph. ^c10 mol % catalyst. ^dDiastereomeric ratio reported after purification, crude dr 80:20 (trans:cis)