Streamlined Synthesis of Dibekacin: RSM-Guided Process Refinement and DFT-Based Mechanistic Study

Starting from kanamycin B, the important 3′,4′-alkene intermediate is synthesized through selective N-Boc protection, regioselective 4″,6″-O-benzylidene acetalization and Garegg–Samuelsson reaction. Within the framework of response surface methodology (RSM), the central composite design (CCD) was used to systematically optimize the process parameters of the key step in the Garegg–Samuelsson reaction, aiming to improve the selectivity of the target product. Density functional theory (DFT) calculations, in conjunction with steric hindrance analysis (% Vbur), were applied to elucidate the pathways of impurity formation and site reactivity during the iodination–elimination step. A telescoped cascade deprotection and hydrogenation process ultimately yielded dibekacin (1) with an overall yield of 35.8% and a purity of 99.4%. The streamlined process eliminates the need for resin-based purification and significantly reduces the production cycle, thereby underscoring its strong industrial applicability.