The synthetic alkyl-lysophospholipid (ALP) Edelfosine has garnered attention due to its potent in vivo activity, oral administration route, and synergistic effects with other therapies. Its development as a preclinical candidate, however, is constrained by challenges associated with the economical, large-scale preparation of the enantiopure compound. Herein, we describe the development of a novel synthetic route that provides enantiopure (S)-Edelfosine in a scalable manner, amenable to industrial implementation. Through several iterations, we achieve synthetic improvements via a more convergent assembly of the substituted glycerol portion of the title compounds. By exploiting a chiral benzylglycidyl ether as the key synthon, we demonstrate the successful four-step, formal, and total syntheses of (S)- and (R)-Edelfosine respectively─the shortest demonstrably scalable routes of their kind. Finally, we establish phenyl trimethylammonium iodide as a suitable green alternative to carcinogenic iodomethane in this context. Our streamlined chiral pool approach thus furnishes a significant improvement in the synthetic accessibility of optically pure Edelfosine and paves the way for the parallel development of both medicinally relevant ALP enantiomers.
