Total Synthesis of Aplydactone by a Conformationally Controlled C−H Functionalization

Abstract

A concise, protecting-group-free total synthesis of the unusual brominated sesquiterpene aplydactone is described. Our synthesis features a [2+2] photocycloaddition, a Wolff ring contraction, an unusual remote C-H functionalization to establish the highly strained tetracyclic core, and a hydrogen-atom transfer (HAT) reaction to access the bromine-containing stereocenter. A finely tuned conformation of the α-diazoketone precursor is the key for the success of the late-stage transannular C-H insertion to deliver a bridged six-membered ring and a quaternary stereocenter (C6) between two quaternary carbon atoms (C1 and C7).

Recent advances in the total synthesis of cyclobutane-containing natural products

“…In 2017, the Zhang group developed an alternative synthetic route to this molecule, in which the [2]-ladderane core was also installed readily by the same ring-contraction strategy at the early stage. 84 Remarkably, the two fused four-membered scaffolds remained intact in continuous ring contraction courses, providing a new perspective on the inherent ring strain in cyclobutanes.…”

Preparation and Synthetic Applications of Five-to-Seven-Membered Cyclic α-Diazo Monocarbonyl Compounds

“…As the acidity of the methylene group in the α-position to the carbonyl group is relatively low, the diazo transfer reaction requires fairly forceful conditions, which would lead to the other methylene group also being affected in the reaction. Therefore, to achieve a selective mono transfer of the diazo function, the ketones are preliminarily activated by formylation, and only such a monoformylated substrate is subjected to deformylative diazo transfer conditions [ 6 , 7 , 8 , 9 ]. This is illustrated by the preparation of mono-diazo bicyclic ketone derivative 1 ( Scheme 1 ).…”

Gold Catalysis Enabling Furan-Fused Cyclobutenes as a Platform toward Cross Cycloadditions

“…Polyheterocycles with a cyclobutane functionality at the fused junction are important structural motif in many natural products (I, II, III) and also behave as a new glycoluril diether, one kind of supramolecular precursors (IV) with a wide dihedral angle on the concave face (Scheme A). Classical procedures, such as [2π+2π]-photocycloaddition, ring-expansion of cyclopropane, nucleophilic ring-closure, transition-metal catalyzed cyclization, and so on, have been developed for the construction of cyclobutane-containing architecturally complex molecules.…”