A synthetic approach to palmerolides via Negishi cross coupling. The challenge of the C15–C16 bond formation

The esterification of fragment C1–C8 (2) with fragment C16–C23 (3) to give iodo derivative 4, followed by a Pd-catalysed coupling with a C9–C15 fragment (7 or 8), may provide a common precursor of most palmerolides. Ligands and reaction conditions were exhaustively examined to perform the C15–C16 bond formation via Negishi reaction. With simple models, pre-activated Pd–Xantphos and Pd–DPEphos complexes were the most efficient catalysts at RT. Zincation of the C9–C15 fragment (8) and cross coupling with 4 required 3 equiv of t-BuLi, 10 mol % of Pd–Xantphos and 60 °C.