Asymmetric Synthesis of 1,4-Oxachalcogenanes

Morpholines and piperazines are heterocycles found in numerous drugs^1,2. Given their pharmacological potential, we are interested in exploring their bioisosteres by synthesizing structurally related variations. Introducing heteroatoms such as sulfur allows for the formation of 1,4-oxathianes and thiomorpholines, which may alter pharmacological properties³. However, 1,4-Oxathiane is a heterocyclic system still underexplored in medicinal chemistry. Due to the limited literature on the enantioselective synthesis of these structures, we are developing a methodology that may also enable similar modifications with Se and Te variations.  Based on the methodologies previously described for the formation of α-substituted α,β-N-Tosylaziridines^4,5, we are utilizing these species as bis-electrophiles in reactions with 2-mercaptoethanol acting as bis-nucleophile, leading to a cyclic hemiacetal bearing a tetrasubstituted stereocenter. A subsequent oxidation allowed the isolation of the desired heterocycle. The enantioselective cyclization, followed by the regioselective and stereospecific aziridine ring-opening, is expected to ensure the enantiopurity of the product.