Synthesis of a Polycyclic Halichondrin C1–C14 Fragment via Intermolecular Oxy-Michael/Trans-Ketalization

Syntheses of a crystalline polycyclic halichondrin C1–C14 building block starting from a d-gulono-1,4-lactone-derived intermediate in the current Halaven manufacturing process are described. Key features of the syntheses include an acid-catalyzed tandem intermolecular oxy-Michael/intramolecular trans-ketalization reaction and stereoselective Kishi reductions.