Dihydrobenzofurans
and indolines are important constituents
of
pharmaceuticals. Herein, we describe a novel strategy for their construction
in which the aromatic ring is createdde novothrough
an inverse-electron demand Diels–Alder reaction and cheletropic
extrusion sequence of a 2-halothiophene-1,1-dioxide with an enol ether/enamide,
followed by aromatization. Unusually, the aromatization process proved
to be highly challenging, but it was discovered that treatment of
the halocyclohexadienes with a base effected an α-elimination–aromatization
reaction. Mechanistic investigation of this step using deuterium-labeling
studies indicated the intermediacy of a carbene which undergoes a
1,2-hydrogen shift and subsequent aromatization. The methodology was
applied to a modular and stereoselective total synthesis of the antiplatelet
drug beraprost in only 8 steps from a key enal-lactone. This lactone
provided the core of beraprost to which both its sidechains could
be appended through a 1,4-conjugate addition process (lower ω-sidechain),
followed byde novoconstruction of beraprost’s
dihydrobenzofuran (upper α-sidechain) using our newly developed
methodology. Additionally, we have demonstrated the breadth of our
newly established protocol in the synthesis of functionalized indolines,
which occurred with high levels of regiocontrol. According to density-functional
theory (DFT) calculations, the high selectivity originates from attractive
London dispersion interactions in the TS of the Diels–Alder
reaction.