Products Cited in Publications Worldwide Catalytic asymmetric synthesis of meta benzene isosteres

Catalytic asymmetric synthesis of meta benzene isosteres

Zhang, Mingkai; Chapman, Matthew; Sarode, Bhagyesh R; Xiong, Bingcong; Liang, Hao; Chen, James K; Weerapana, Eranthie; Morken, James P

DOI: PMID:

Abstract

Although aromatic rings are common elements in pharmaceutically active compounds, the presence of these motifs brings several liabilities with respect to the developability of a drug1. Nonoptimal potency, metabolic stability, solubility and lipophilicity in pharmaceutical compounds can be improved by replacing aromatic rings with non-aromatic isosteric motifs2. Moreover, whereas aromatic rings are planar and lack three-dimensionality, the binding pockets of most pharmaceutical targets are chiral. Thus, the stereochemical confguration of the isosteric replacements may ofer an added opportunity to improve the afnity of derived ligands for target receptors. A notable impediment to this approach is the lack of simple and scalable catalytic enantioselective syntheses of candidate isosteres from readily available precursors. Here we present a previously unknown palladium-catalysed reaction that converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes and we show that the shape of these nortricyclanes makes them plausible isosteres for metadisubstituted aromatic rings. With chiral catalysts, the Pd-catalysed reaction can be accomplished in an enantioselective fashion and subsequent transformation of the boron group provides access to a broad array of structures. We also show that the incorporation of nortricyclanes into pharmaceutical motifs can result in improved biophysical properties along with stereochemistry-dependent activity. We anticipate that these features, coupled with the simple, inexpensive synthesis of the functionalized nortricyclane scafold, will render this platform a useful foundation for the assembly of new biologically active agents.

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Bis(pinacolato)diborane

A24796073183-34-398%

Bis(pinacolato)diborane

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