Scheme 1.

Synthesis of the lipophilic 4-N-alkanoyl gemcitabine derivatives.

Reagents and conditions: (a) R′(CH₂)_nCOOH/NMM/HOBt/EDCI/DMF/DMSO/60 °C/overnight; (b) (i) TMSCl/Pyr/CH₃CN, 0 °C/2.5 h, (ii) BrCH₂CH₂(CH₂)₈COOH/CDI/CH₃CN/65 °C/overnight; (c) BrCH₂CH₂(CH₂)₈COOH/ClCOOEt/Et₃N/DMF (d) (Boc)₂O/KOH/1,4-dioxane; (e) BrCH₂CH₂(CH₂)₈COCl/NaHCO₃/CH₂Cl₂; (f) DAST/CH₂Cl₂; (g) TFA