Scheme 4.

Synthesis of tafluprost (5), tafluprost methyl ester (32) and tafluprost ethylamide (33) from phenylsulfone 16 and aldehyde 17. Reagents and conditions: (1) LDA, THF, −78 °C, 1 h; (2) Na/Hg, Na₂HPO₄, MeOH, 0 °C for 60 min, then 16 h at r.t.; (3) PPTS, CH₂Cl₂, MeOH, 3 h at r.t., 79% yield from 16; (4) TEA, DMAP, Ac₂O, CH₂Cl₂, 97% yield; (5) CAS, MeOH, CH₂Cl₂, 7 h at r.t., 82% yield; (6) DMP, NaHCO₃, CH₂Cl₂, 99% yield; (7) Deoxo-Fluor, CH₂Cl₂; 0 °C for 15 min, then reflux for 24 h, 78% yield; (8) K₂CO₃, MeOH, 24 h at r.t., 76% yield; (9) LiOH H₂O, MeOH, overnight, 98% yield; (10) i-PrI, DBU, acetone, 21 h at r.t., 83% yield; (11) EtNH₂, H₂O, 60 h at r.t.; 85% yield.