Breaking symmetry to generate asymmetry, commonly termed as desymmetrization, is a remarkably powerful strategy for building molecular complexity. Successful implementation of this strategy holds the potential to forge multiple stereogenic centers in a single step. In fact, stereocenters can also be created away from the reaction site.
During the past few years, we have developed a number of organocatalytic enantioselective desymmetrization reactions including formal C(sp²)-H alkylations and de novo construction of arenes and heteroarenes. To demonstrate the usefulness of these fascinating transformations, we applied them to the enantioselective synthesis of one of the structurally most unusual class of natural products, namely ladderane phospholipids. Thus, the application of C(sp²)-H alkylative desymmetrization of meso-enediones led to the direct installation of the eight-carbon alkyl chain and construction of the entire core structure of [3]-ladderanol. Simple functional group transformation was sufficient to achieve [3]-ladderanol in just four steps. In contrast, the enantioselective synthesis of [5]-ladderanoic acid posed a more serious challenge due to the presence of the alkylated cyclobutane scaffold. This structural feature precluded the direct access of this core through our alkylative desymmetrization reaction. We eventually devised a deconstructive carbon deletion approach to achieve [5]-ladderanoic acid, while still using alkylative desymmetrization as the key enantiodetermining step.
In addition to natural ladderanes, we have devised an efficient approach to their unnatural analogues such as benzo-[3]-ladderanol. In this case, we applied our newly developed desymmetrizing de novo arene construction reaction.
The topic of this talk will be primarily confined to a few of these enantioselective desymmetrization reactions and their applications for the synthesis of complex targets.

Sayan Ray

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