Selective Oxidation of Disparate Functional Groups Mediated by a Common Aspartic Acid-Based Peptide Catalyst Platform

ConspectusAs drug molecules become increasingly complex, the need to develop new or improved strategies for the efficient and selective synthesis and editing of bioactive compounds grows. Inspired by the high selectivity and fast rates exhibited in many enzymatic reactions to assemble complex natural products, our group and others have developed peptide-based catalysts to mediate synthetically relevant transformations that can be orthogonal, or akin to, native enzymatic reactivity. Peptide catalysts offer several useful features, such as modularity, ease of synthesis, and often enhanced compatibility with synthetic reaction conditions.In one intriguing area, our group has employed the proteinogenic amino acid aspartic acid (Asp) as a catalytic residue embedded within short peptide sequences to selectively introduce a singular oxygen atom into increasingly complex scaffolds, which might constitute a type of single atom editing. Our strategy has involved the development of an aspartic acid/peracid catalytic shuttle, a mechanism that, to our knowledge, has not yet been documented in enzymes.Our foray into Asp-catalyzed oxidation began with the discovery of a peptide sequence to impart enantioselectivity in the epoxidation of minimal olefins. This platform was then extended to include nucleophilic Baeyer-Villiger oxidations and electrophilic <i>N</i>- and <i>S</i>-atom oxidations. Of note, these reactions all use hydrogen peroxide as the stoichiometric oxidant; the appended peptide sequence dictates the selectivity on a per-reaction-type basis. Lead peptides for each transformation were identified using both combinatorial and rational design approaches, and mechanistic studies were used to guide our development along the way or to elucidate modes of action after the fact. In all cases, selectivity was achieved through critical noncovalent interactions between the substrate and peptide catalyst.We have always endeavored to test these catalysts in increasingly complex settings, facing difficult challenges in chemo-, site-, and stereoselectivity in a variety of molecular scaffolds. In a particularly forward-looking example, Asp-peptides were used to perform late-stage molecular editing of geldanamycin, a quintessentially complex and bioactive natural product. Asp-peptides have now also been used to edit the three-dimensional structure of loratadine, the active ingredient in Claritin, to generate helically chiral <i>N</i>-oxide analogues with chemo- and stereoselectivity. In the case of both geldanamycin and loratadine, the oxidized bioactive analogues underwent biological testing, providing insight into the development of future medicinally relevant molecules. Taken together, this Account details the power of Asp-catalysts to address challenges in asymmetric catalysis while also contributing to the need for rapid access to drug analogues.