Toward a Synthesis of Hirsutellone B by the Concept of Double Cyclization

This account describes a strategy for directly forming three of the six rings found in the polyketide natural product hirsutellone B via a novel cyclization cascade. The key step in our approach comprises two transformations: a large-ring-forming, nucleophilic capture of a transient acylketene and an intramolecular Diels–Alder reaction, both of which occur in tandem through thermolyses of appropriately functionalized, polyunsaturated dioxinones. These thermally induced “double cyclization” cascades generate three new bonds, four contiguous stereocenters, and a significant fraction of the polycyclic architecture of hirsutellone B. The advanced macrolactam and macrolactone intermediates that were synthesized by this process possess key features of the hirsutellone framework, including the stereochemically dense decahydro­fluorene core and the strained <i>para</i>-cyclophane ring. However, attempts to complete the carbon skeleton of hirsutellone B via transannular carbon–carbon bond formation were undermined by competitive O-alkylation reactions. This account also documents how we adapted to this undesired outcome through an evaluation of several distinct strategies for synthesis, as well as our eventual achievement of a formal total synthesis of hirsutellone B

Cascade Reaction of Donor–Acceptor Cyclopropanes: Mechanistic Studies on Cycloadditions with Nitrosoarenes and <i>cis</i>-Diazenes

Tandem ring opening, elimination, and cycloaddition of donor–acceptor cyclopropanes were observed in Yb­(OTf)₃-catalyzed cycloaddition with nitrosoarenes. The reaction results in formation of tetrahydro-1,2-oxazine instead of the normal cycloadduct isoxazolidine via in situ nitrone formation. A similar cascade sequence was observed with <i>cis</i>-diazines. Mechanistic studies on this unique transformation offer an entirely new approach for reaction design with donor–acceptor cyclopropanes