Amphotericin B (AmB) remains the gold-standard antifungal for invasive mycoses, yet its poor oral bioavailability limits it to intravenous administration. One promising strategy for developing a oral formulation of AmB is prodrugging the primary amine on the mycosamine ring to increase lipophilicity and improve gastrointestinal permeation. Here we report the design and initial synthetic exploration of a lipophilic C14 mycosamine-modified AmB prodrug (denoted AmB-O14). 1-Tetradecanol was converted to its N-hydroxysuccinimide carbonate with disuccinimidyl carbonate in anhydrous DMF (r.t., 16h). After sequential liquid-liquid extractions (0.1 M HCl/brine, sat. NaHCO3, brine) and drying, the activated ester was isolated in 83% yield. Coupling to AmB (600 mg, 0.65 mmol) in 2:1 DMF/DMSO, (r.t., 4h) selectively modified the C-3’ amine, yielding 486 mg crude C14 carbamate (0.42 mmol, 71% of theory). Analytical RP-HPLC (C18, isocratic 77% ACN/23% H2O + 0.2% acetic acid, 16 min) shows a 14 min retention-time shift relative to parent AmB, consistent with the predicted rise in hydrophobicity. Comprehensive 2D NMR assignment is under way; preliminary 1H data suggests downfield shifts for H-2’/H-3’, supporting carbamate formation, though full spectral assignments are not yet complete. These results validate mycosamine-directed lipophilic modification as a tractable synthetic entry point and provide a reproducible workflow for the planned library of lipophilic AmB prodrugs now in progress.
