Electronics of Para and Meta-Substituted Phenolic Esters for Selective Acylations of Amines

250715

Department of Chemistry, Biochemistry & Physics
Investigation Into the Electronics of Para and Meta-Substituted Phenolic Esters for Selective Acylations of Amines

Esterase-cleavable prodrugs can generally be used to overcome poor pharmacokinetic properties as they can remain stable in the gastrointestinal tract until bioconverted into their active form by enzymes. This has been applied to mycophenolic acid (MPA), an immunosuppressant commonly used to prevent organ transplant rejection, for the preparation of mycophenolate mofetil (MMF), an FDA-approved ester prodrug derivative that enhances the bioavailability of MPA by around 90%. However, literature-reported synthetic pathways of MMF require multi-step syntheses and the usage of early-stage protections and hazardous catalysts such as thionyl chloride. Moreover, as the largest drain of atoms in large-scale chemical processes is not the reagents but rather the solvents, multi-step syntheses that require intermediary chromatographic purifications are economically and environmentally unsustainable on the industrial scale. To resolve this, we screen conditions to synthesize mono-siloxy MPA and install the mofetil substituent through single-pot esterification, averting the need for intermediary purification. We optimized a telescoped monosilylation, Shiina esterification, and HCl-mediated desilylation to provide MMF in a chromatography-free operation directly from MPA. By reducing the amount of solvent and hazardous reagents required in synthesizing MMF, we aim for optimized synthetic feasibility, allowing for maximized efficiency on industrial scales, thus increasing the accessibility of MMF for organ transplant patients. We envision this will provide an expedient synthesis for analogs of MPA.
RESEARCHERS: Abhinav Chalasani, Mission San Jose High School ‘26; Navya Sathish, Cupertino High School ‘26
ADVISOR: Njoo Lab Synthesis | Physical Organic Chemistry | Catalysis | Chemical Biology | Spectroscopy | Medicinal Chemistry
KEYWORDS: Mycophenolic Acid | Mycophenolate Mofetil | Esterification | Immunosuppressants | IMPDH Inhibition | One-Flask Synthesis | Shiina Esterification