Enantioselective Synthesis of (2S,3S)-epi-Oxetin and Its Incorporation into Conformationally Constrained Pyrrolidinyl PNA with an Oxetane Backbone

Fmoc-protected (2S,3S)-epi-oxetin was synthesized from (E)-4-(benzyloxy)but-2-enal via enantioselective organocatalytic epoxidation, epoxide ring opening with azide, alcohol activation and ring closure, followed by functional-group manipulation in eight steps with 12 % overall yield and 94 % ee. The amino acid was used as a building block for a new conformationally constrained pyrrolidinyl PNA with an oxetane-containing backbone. The unexpected sensitivity of the oxetane backbone posed considerable synthetic challenges under standard Fmoc-solid-phase peptide synthesis conditions, and a mechanism for acid-catalyzed degradation was proposed. In addition, the DNA- and RNA-binding properties of the oxetane PNA were investigated. The presence of an oxetane ring decreased the stability of the PNA⋅DNA and PNA⋅RNA duplexes when compared to PNA with a cyclobutane-containing backbone, which could be explained by the flattening of the oxetane ring, leading to a suboptimal torsional angle.