Alkylative Desymmetrization as Symmetry-Inspired Unified Strategy for the Enantioselective Synthesis of (–)-[5]-Ladderanoic Acid and Unnatural Inverse-[3]-ladderanol

The unique architecture of naturally occurring ladderane phospholipids has inspired innovation in strategies for their chemical synthesis. 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. We earlier applied our previously developed alkylative desymmetrization reaction to the enantioselective total synthesis of [3]-ladderanol. We have now adapted the same reaction 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 hexacyclic meso-cyclohexenedione through organocatalytic desymmetrization, followed by a ring-deconstructive formal one-carbon deletion, which transformed cyclobutane-fused α-alkylated cyclohexenediones into 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 flexibility of this strategy facilitated the synthesis of inverse-[3]-ladderanol – an unnatural structural isomer of [3]-ladderanol and paved avenues to its other such isomers. Preliminary bio-physical studies hinted at the rationale for a plausible evolutionary exclusion of inverse- [3]-ladderanol by nature.