A formal total synthesis of (+)-apicularen A: base-induced conversion of apicularen-derived intermediates into salicylihalamide-like products

Abstract

A synthesis of apicularen precursor (−)-6 in 18 steps from D-glucal is reported. As (+)-6 has been converted into the potent, naturally occurring salicylate anti-cancer agent, (−)-apicularen A in 8 steps, this study constitutes a formal total synthesis of (+)-apicularen A. Key steps in the synthetic route include: (i) useful D-glucal elaboration processes, (ii) organometallic displacements at carbohydrate C-6 triflates using Knochel-type and related functionalised, aromatic Grignard reagents, (iii) stereoselective allyltrimethylsilane–acetal reactions generating C-allyl systems, (iv) stereocontrolled aldehyde allylation processes from both substrate and reagent, and (v) a novel Keck-type macrolactonisation. In addition, preliminary studies are reported in which a procedure has been devised to convert apicularen-derived intermediates into salicylihalamide-like products.