Leveraging the Persistent Radical Effect in the Synthesis of trans-2,3-Diaryl Dihydrobenzofurans.

A simple method for accessing trans-2,3-diaryl dihydrobenzofurans is reported. This approach leverages the equilibrium between quinone methide dimers and their persistent radicals. This equilibrium is disrupted by phenols that yield comparatively transient phenoxyl radicals, leading to cross-coupling between the persistent and transient radicals. The resultant quinone methides with pendant phenols rapidly cyclize to form dihydrobenzofurans (DHBs). This putative biomimetic access to dihydrobenzofurans provides superb functional group tolerance and a unified approach for the synthesis of resveratrol-based natural products.

Evolution towards green radical generation in total synthesis.

The use of radicals as intermediates in total synthesis has evolved since their initial use in the latter half of the twentieth century. Radical generation from metal hydride methodologies has shifted to "greener" techniques including catalytic metal-mediated systems, electrochemical and photoredox-mediated processes. This review will focus on these classical and contemporary methods for radical generation and their applications in recent total syntheses.

Propargylglycine-based antimicrobial compounds are targets of TolC-dependent efflux systems in Escherichia coli.

A library of novel l-propargylglycine-based compounds were designed and synthesized with the goal of inhibiting the growth of Gram-negative bacteria by targeting LpxC, a highly conserved Gram-negative enzyme which performs an essential step in the lipid A biosynthetic pathway. These compounds were designed with and without a nucleoside and had varying tail structures, which modulate their lipophilicity. The synthetic scheme was improved compared to previous methods: a methyl ester intermediate was converted to a hydroxamic acid, which obviated the need for a THP protecting group and improved the yields and purity of the final compounds. Antimicrobial activity was observed for non-nucleoside compounds containing a phenyl propargyl ether tail (5) or a biphenyl tail (6). An MIC of 16 µg/mL was achieved for 6 in Escherichia coli, but inhibition was only possible in the absence of TolC-mediated efflux. Compound 5 had an initial MIC >160 µg/mL in E. coli. Enhancing outer membrane permeability or eliminating efflux reduced the MIC modestly to 100 µg/mL and 80 µg/mL, respectively. These results highlight the importance of hydrophobicity of this class of compounds in developing LpxC inhibitors, as well as the design challenge of avoiding multidrug efflux activity.