Total Synthesis of Halistatins 1 and 2.

The first total synthesis of halistatins 1 and 2 has been completed using Cr-mediated coupling reactions for the C11/C12, C17/C18, and C19/C20 bond formation. For the C11/C12 bond formation, a stoichiometric Ni/Cr-mediated reaction is used to couple an α-quaternary aldehyde with a vinyl iodide. The solubilized Cr-reagent, prepared from CrCl2 and a sulfonamide ligand, allows one to perform the coupling with ∼1 equiv of Cr-reagent. Catalytic, asymmetric Co/Cr-mediated iodoallylation is adopted to incorporate the requisite C17-C19 functionality in a stereoselective manner. Asymmetric Ni/Cr-mediated coupling is used to form the C19/C20 bond effectively. Through this study, it has been found that the stereoselectivity of [5,5]-spiroketalization dramatically depends on solvents; p-toluenesulfonic acid (PTSA) in 1:1 methanol-water gave a >20:1 stereoselectivity favoring the natural series. This condition is also effective to isomerize C38-epi-halichondrins into C38 natural halichondrins.