Total Synthesis of Neohomohalichondrin B

The total synthesis of neohomohalichondrin B has been achieved using a de novo sequence that enabled a highly convergent pathway to access the C38-C55 thioester fragment. The highlights of this synthesis include: (i) a tandem base-induced hydrolysis and rearrangement to access the C47-C50 tetrahydrofuran, and (ii) a Ni(I)/Ni(II)-mediated ketone coupling and acid-catalyzed cyclization sequence to access the C44 spiroketal and complete carbon framework of the left half fragment. The total synthesis of neohomohalichondrin B was completed following coupling of the left half thioester with a C1-C37 macrolactone iodide, according to our method for the unified synthesis of halichondrins. This synthetic strategy may facilitate an improved method to prepare other members of the halichondrin family, and analogues thereof.