Breaking symmetry – organocatalytic enantioselective synthesis of natural and unnatural ladderanes /

Includes bibliographical references

PhD;2024;Organic Chemistry

Architecturally unique compounds produced by nature have remained a source of inspiration for organic chemists. Ladderane phospholipids (such as [5][3]PC and [3][3]PC), isolated in the year 2002 from anaerobic ammonium oxidizing (anammox) bacteria, revealed such never-seen-before structural features in nature. These lipids are composed of either (+)-[3]-ladderanol or a mixture of (+)-[3]-ladderanol and (–)-[5]-ladderanoic acid. The presence of such lipids in the membrane of anammoxosome helps in maintaining a pH gradient across the membrane that drives ATP synthesis. Breaking symmetry to generate asymmetry, commonly termed as desymmetrization, is a remarkably powerful strategy for building molecular complexity. Despite efforts by three independent research groups – Corey, Burns, and Brown – to synthesize both (+)-[3]-ladderanol and (–)-[5]-ladderanoic acid, a unified strategy to target both of these compounds has yet to be documented. This talk outlines a novel desymmetrization approach to both [3]-ladderanol and [5]-ladderanoic acid by breaking the symmetry of the tetracyclo- and pentacyclododecane skeleton respectively, by introducing a linear alkyl chain in a one-pot two-step operation, under a sequential combination of a chiral tertiary aminosquaramide and an achiral tertiary aminourea as catalysts. This approach also offers flexibility in synthesizing unnatural enantiomers and structurally modified variants of ladderanes. Apart from natural ladderanes, we have also developed an efficient strategy for enantioselective synthesis of unnatural benzo-analogue of [3]-ladderanol – this time through a desymmetrizing de novo arene ring construction. During this study, an intricate regioselectivity issue was encountered, which was resolved through alkoxy-directed dienamine catalysis. Preliminary studies revealed that the membrane formed using this unnatural benzo-analogue of [3]-ladderanol displayed lower proton permeability compared to a membrane assembled using [3]-ladderanol.