Atroposelective Synthesis of Hindered Amides - Exploration of Synthetic Peptide Catalysts -
Final Report Abstract
Over the course of the funding period of this Walter Benjamin fellowship, new methods for the synthesis of chiral molecules with uncommon stereochemical properties were developed, using synthetic peptide catalysts. This work can be devided into two parts, where in both parts the amid functional group plays a central role in the conceptual development of the project. The first part of the herein described endeavor focussed on the design of novel catalysts for the atroposelective formation of rotationally hindered amides. The importance of chirality in the context of the medicinal application of drug molecules is well-established, in particular since the thalidomide scandal in the 1960’s. In this context, the amid functional group – which is found in most small drug molecules – can exhibit a special form of chirality: atropisomerism. The drug telenzepine is a classic example of a rotationally hindered amid and the 500-fold higher activity of the (+)-enantiomer towards muscarnic receptors compared to the (–)-enantiomer highlights the importance of the stereochemical properties of drug candidates in medicinal applications. Using telenzepine as a blueprint and inspired by traditional peptide coupling reagents, this work developed model systems which aimed to generate enantioenriched telenzepine derivatives through atroposelective coupling of the central amid bond. A variety of catalytic systems was investigated, including the utilization of novel active alcohol catalysts, unreported Brønsted acid catalysts, as well as alternative atroposelective oxidation processes. The second part of the presented research aimed to develop an asymmetric aromatic Finkelstein reaction for the desymmetrization of diarylmethines. In this reaction regime, a stereocenter was generated 5 Å removed from the center of reaction, by means of copper- catalyzed replacement of a bromide by an iodide substituent. The utilization of a guanidinylated synthetic peptide ligand in combination with the tailored placement of amid anchors in the substrate enabled a highly enantioselective reaction. Employment of traditional transition metal catalyzed cross-coupling reactions, the prepared aryl-iodides were transformed into otherwise difficult-to-access diarlymethines in highly chemoselective reactions under retention of the stereoinformation. Merger of experimental and computational tools for analysis identified steric parameters and conformational effects that are key to high enantioselectivity in this desymmetrization reaction.
Publications
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An Asymmetric Aromatic Finkelstein Reaction: A Platform for Remote Diarylmethane Desymmetrization.
Morack, Tobias; Myers, Tyler; Karas, Lucas; Hardy, Melissa; Mercado, Brandon; Sigman, Matthew & Miller, Scott
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An Asymmetric Aromatic Finkelstein Reaction: A Platform for Remote Diarylmethane Desymmetrization. Journal of the American Chemical Society, 145(41), 22322-22328.
Morack, Tobias; Myers, Tyler E.; Karas, Lucas J.; Hardy, Melissa A.; Mercado, Brandon Q.; Sigman, Matthew S. & Miller, Scott J.
