Oxygen-rich conformationally restricted 3D building blocks are valuable tools for medicinal chemistry. Decreased lipophilicity of fragments brought by those blocks empowers those to be implemented into the drug scaffold, increasing both target affinity and bioavailability, compared to the carbon analogs. Our search for methods of functionalization of α-ketoester alkylation led to an interesting result. Cyclic α-ketoesters, alkylated with dibromoethane produced first C-alkylated product and later O-annulated compounds. Further expansion and optimization with this procedure led to the multigram scale (> 200 g from 1 synthetic run) method for the synthesis of bicyclic fused tetrahydrofurans with various sizes and natures of the adjacent rings.<br/>Formed [3+3] annulated product exhibits highly reactive vinyl alcohol moiety, which converts to the corresponding cyclic hemi- or mixed acetals immediately under solvolytic conditions. We demonstrated the series of starting β-ketoesters based on cyclohexane, cycloheptane, 4-oxopiperidine, and 4-oxotetrahydro-2H-pyran that can be subjected to the current reaction. All of those can interconvert into the corresponding cycles on the multigram scale.<br/>Consequently, we have shown that those bicyclic compounds can undergo typical functional group interconversions (FGI), e.g. hydrolysis to an acid, reductions to aldehyde or ethanol, and moreover, aminations via the Curtius rearrangement and amide reduction.<br/>Current blocks can significantly impact the lead optimization approaches via increasing the toolbox of synthetic chemists.

Cyclic β-ketoesters as precursors for bicyclic tetrahydrofurans

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