Enantioselective Synthesis of a Unique, Folded Α/Γ Oligomeric Peptide Incorporating cis-Γ-Aminobutyrolactone Acetic Acid (ABAA) Units

Abstract

We report here a new asymmetric approach that provides γ-amino acids bearing a cis-butyrolactone constraint at the Cβ–Cγ bond, leading to a tetrapeptide based on alternating cis-γ-aminobutyrolactone acetic acid (ABAA) and L-leucine, starting from a singly epoxidized cyclohexene. To synthesize the constrained cis-γ-butyrolactone amino acid unit 4, a relay consisting of (R,R)-Salen complex-catalyzed ring-opening desymmetrization of cyclohexene monoepoxide, followed by oxidative cleavage and reductive transformations, was employed. Both stereocenters of the γ-amino acid backbone were generated from achiral precursors in a single process with high diastereo- and enantioselectivity. Further, corresponding peptides 6 and 10 were synthesized by stepwise fragment condensation using HOBt/HBTU as the coupling agent. Solution-phase peptide coupling with L-leucine resulted in the dipeptide cis-γ-butyrolactone-L-leucine (6), with its absolute crystal structure determined by single-crystal X-ray diffraction. At the same time, tetrapeptide 10 was synthesized from the TFA salt of Boc-protected dipeptide 7 and Boc-protected dipeptide acid 8. Tetrapeptide 10 exhibited a specific helical conformation as determined by density functional theory and molecular dynamics simulations. Based on their geometric structure, hydrogen-bonding N–H⋯O interactions and N–H⋯O bond-angle interactions, foldamer 10 induced an angle-helical conformation.