Late-stage functionalization and derivatization of complex biologically-active compounds and natural products can extend their usefulness as both biological probes and treatments against ever-evolving drug resistance. Toward this end, a simple amino alcohol-derived catalyst has been developed to site-selectively protect cis-1,2-diol configurations in both simple substrates and natural products (Sun, X.; Worthy, A. D.; Tan, K. L. Angew. Chem. Int. Ed. 2011, 50, 8167). The bifunctional catalyst is modular: substrate is recognized and bound to the catalyst through an in situ generated oxazolidinium, while the vicinal imidazole catalyzes the silylation through base catalysis of the alcohol; both regions are tethered by a stereogenic linker which provides selectivity. Poor reactivity of the original scaffolding catalyst with trans-1,2-diols prompted our combined computational and experimental study to redesign this catalyst. De novo design was achieved by building catalyst elements—imidazole and oxazolidine—around the model system transition state. These elements were tethered together with an alkane bridge containing stereodirecting groups to retain site-selectivity. Experimental test, verification and synthetic insights expanded the reactivity of this catalyst scaffold.

De novo catalyst design of scaffolding bifunctional catalysts for the site-selective functionalization of trans-1,2 diols

249th National Meeting (2015)

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