Unified, Efficient, and Scalable Synthesis of Halichondrins: Zirconium/Nickel‐Mediated One‐Pot Ketone Synthesis as the Final Coupling Reaction

Unified, efficient, and scalable syntheses of the halichondrin natural products are reported. A newly developed Zr/Ni‐mediated one‐pot ketone synthesis was used to couple the two halves of the final product at a late stage in the synthesis. With the use of a slight excess of the left halves, the desired ketones were isolated in yields of 80–90 %. The halichondrins were obtained from these ketones in two steps, namely desilylation and [5,5]‐spiroketal formation. The new synthetic route was effective for the total synthesis of all members in the homohalichondrin subgroup. The scalability of this process was demonstrated with halichondrin B; 150 mg of halichondrin B (68 % overall yield) were obtained from 200 mg of the right‐half precursor.