Symmetry Breaking Routes to Natural and Unnatural Ladderanes

Breaking symmetry to generate asymmetry, commonly termed 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 alkylation¹ and de novo construction of (hetero)arenes. ² We subsequently applied these reactions to the enantioselective synthesis complex targets. 

Naturally occurring ladderane phospholipids represent a class of targets, which provided us with the motivation to develop some of these enantioselective desymmetrization reactions. This talk will focus on the application of our desymmetrizing C(sp²)‒H alkylation reaction to [3]- ladderanol, ³ [5]-ladderanoic⁴ acid as well as their unnatural analogues in an effort to unravel their biosynthetic hypothesis. In addition, our recent work on the enantioselective synthesis of an unnatural benzo-analogue of [3]-ladderanol through the application of our newly developed alkoxy-directed dienamine catalysis⁵ will also be discussed.

References: 

1. (a) Manna, M. S.; Mukherjee, S. J. Am. Chem. Soc. 2015, 137, 130. (b) Sarkar, R.; Mukherjee, S. Org. Lett. 2016, 18, 6160. (c) Mallojjala, S. C.; Sarkar, R.; Karugu, R. W.; Manna, M. S.; Ray, S.; Mukherjee, S.; Hirschi, J. S. J. Am. Chem. Soc. 2022, 144, 17399.
2. (a) Ghosh, B.; Harariya, M. S.; Mukherjee, S. Angew. Chem. Int. Ed. 2022, 61, e202204523. (b) Ghosh, B.; Balhara, R.; Jindal, G.; Mukherjee, S. Angew. Chem. Int. Ed. 2021, 60, 9086.
3. Ray, S.; Mondal, S.; Mukherjee, S. Angew. Chem. Int. Ed. 2022, 61, e202201584.
4. Ray, S.; Das, S.; Behera, D.; Biswas, P.; Tarafdar, P. K.; Mukherjee, S. ChemRxiv, 2025, DOI: 10.26434/chemrxiv-2025-gmdmv
5. Ray, S.; Behera, D.; Harariya, M. S.; Das, S.; Tarafdar, P. K.; Mukherjee, S. J. Am. Chem. Soc. 2025, 147, 2523.