This tutorial review provides an introduction to metathesis reactions between carbonyls and olefins or alkynes and their application in natural product synthesis.
Some of the simplest and most powerful carbon-carbon bond forming strategies take advantage of readily accessible ubiquitous motifs: carbonyls and olefins. Here we report a fundamentally distinct mode of reactivity between carbonyls and olefins that differs from established acid-catalyzed carbonyl-ene, Prins, and carbonyl-olefin metathesis reaction paths. A range of epsilon, zeta-unsaturated ketones undergo Brønsted acid–catalyzed intramolecular cyclization to provide tetrahydrofluorene products via the formation of two new carbon-carbon bonds. Theoretical calculations and accompanying mechanistic studies suggest that this carbocyclization reaction proceeds through the intermediacy of a transient oxetane formed by oxygen atom transfer. The complex polycyclic frameworks in this product class appear as common substructures in organic materials, bioactive natural products, and recently developed pharmaceuticals.
New drugs introduced to the market are privileged structures
that
have affinities for biological targets implicated in human diseases
and conditions. These new chemical entities (NCEs), particularly small
molecules and antibody–drug conjugates (ADCs), provide insight
into molecular recognition and simultaneously function as leads for
the design of future medicines. This Review is part of a continuing
series presenting the most likely process-scale synthetic approaches
to 44 new chemical entities approved for the first time anywhere in
the world during 2020.
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