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

A unified, efficient, and scalable synthesis of the halichondrin class of natural products was reported. The newly developed Zr/Ni-mediated one-pot ketone synthesis was used to couple right halves with left halves, where Cp2ZrCl2 with Zn or Mn played a crucial role to accelerate the coupling reaction and, at the same time, suppress by-product formation. With use of a slight excess of the left halves, the desired ketones were isolated in 80~90% yields. Halichondrins were obtained from these ketones basically in two operations, i.e., desilylation and [5,5]-spiroketal formation. For the members in the halichondrins-A and -C sub-groups, however, an additional step was required to remove the protecting group at the polycycle, whereas for the members in the norhalichondrin sub-group, an additional step was used to hydrolyze the methyl ester at C53. The new synthetic route was successfully applied for a total synthesis of all the members in the homohalichondrin sub-group as well.