A Ring-Deconstructive Carbon-Deletion Approach to the Enantioselective Total Synthesis of [5]-Ladderanoic Acid

The unique architecture of naturally occurring ladderane phospholipids has inspired innovation in strategies for their chemical synthesis and biosynthetic hypotheses. Despite the emergence of a few independent synthetic routes to both their known components, i.e., (+)-[3]-ladderanol and (-)-[5]-ladderanoic acid, a unified strategy for their enantioselective syntheses is yet to be documented. In 2022, we reported an enantioselective total synthesis of [3]-ladderanol using an alkylative desymmetrization reaction, developed in our lab. We have now adapted this desymmetrization strategy for the enantioselective total synthesis of [5]-ladderanoic acid by leveraging the symmetry of its pentacyclododecane skeleton. Our synthetic strategy relies on the installation of a five-carbon linear alkyl chain to the hexacyclic <i>meso</i>-cyclohexenedione through organocatalytic alkylative desymmetrization, followed by a ring-deconstructive formal one-carbon deletion, which transformed cyclobutane-fused α-alkyl cyclohexenediones to alkylated cyclobutanes. This is not only the first time an organocatalytic reaction is applied to the enantioselective synthesis of [5]-ladderanoic acid but also the first example of the application of a symmetry-inspired unified enantioinduction strategy for accessing both these targets. The versatility and modularity of this strategy facilitated the synthesis of <i>inverse</i>-[3]-ladderanol, an unnatural structural isomer of [3]-ladderanol, and paved avenues to its other such isomers. In this context, we proposed a hypothesis for the biosynthetic conversion of (-)-[5]-ladderanoic acid to (+)-[3]-ladderanol through reductive ring rupture. Preliminary biophysical studies hinted at a plausible evolutionary exclusion of <i>inverse</i>-[3]-ladderanol by nature.