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Acc Chem Res. 2019 Jan 15;52(1):199-215. doi: 10.1021/acs.accounts.8b00473. Epub 2018 Dec 11.

Peptide-Based Catalysts Reach the Outer Sphere through Remote Desymmetrization and Atroposelectivity.

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Department of Chemistry , Yale University , P.O. Box 208107, New Haven , Connecticut 06520-8107 , United States.


Nature's catalytic machinery has provided endless inspiration for chemists. While the enzymatic ideal has yet to be fully realized, the field has made tremendous strides toward synthetic, small-molecule catalysts for a wide array of transformations, often drawing upon biological concepts in their design. One strategy that has been particularly influenced by enzymology is peptide catalysis, wherein oligopeptides are implemented as chiral catalysts in synthetically relevant reactions. The fundamental goal has been to mimic enzymatic active sites by taking advantage of secondary structures that allow for multifunctional activation of substrates within a framework of significantly reduced molecular complexity. Our group has now been studying peptide-based catalysis for over two decades. At the outset, there were many reasons to be concerned that general contributions might not be possible. Precedents existed, including the Juliá-Colonna epoxidations mediated by helical oligopeptides, among others. However, we sought to explore whether peptide catalysts could find broad applications in organic synthesis despite what was expected to be their principal liability: conformational flexibility. Over time, we have been able to identify peptidic catalysts for a variety of site- and enantioselective transformations ranging from hydroxyl group and arene functionalizations to redox and C-C bond forming reactions. The peptides often exhibited excellent catalytic activities, in many cases enabling never-before-seen patterns of selectivity. Recent studies even suggest that, in certain situations, the conformational flexibility of these catalysts may be advantageous for asymmetric induction. In the course of our studies, opportunities to employ peptide-based catalysis to solve long-standing and stereochemically intriguing problems in asymmetric synthesis presented themselves. For example, we have found that peptides provide exceptional enantiotopic group differentiation in catalytic desymmetrization reactions. Early results with symmetrical polyol substrates, such as myo-inositols and glycerols, eventually spurred the development of remote desymmetrizations of diarylmethanes, in which the enantiotopic groups are separated from the prochiral center by ∼6 Å and from one another by nearly 1 nm. Various hydroxyl group functionalizations and electrophilic brominations, as well as C-C, C-O, and C-N cross-coupling reactions using peptidic ligands on copper(I) have now been developed within this reaction archetype. Additionally, the preponderance of axially chiral, atropisomeric compounds as ligands, organocatalysts, and pharmacophores encouraged us to employ peptides as atroposelective catalysts. We have developed peptide-catalyzed brominations of pharmaceutically relevant biaryl, non-biaryl, and hetero-biaryl atropisomers that take advantage of dynamic kinetic resolution schemes. These projects have vastly expanded the reach of our original hypotheses and raised new questions about peptide-based catalysts and the extent to which they might mimic enzymes. Herein, we recount the development and optimization of these stereochemically complex reactions, with a particular focus on structural and mechanistic aspects of the peptide-based catalysts that make them well-suited for their respective functions. The ability of these peptides to address important yet fundamentally challenging issues in asymmetric catalysis, combined with their modularity and ease-of-synthesis, make them primed for future use in organic synthesis.

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