Stereochemistry and Total Synthesis of Neonorhalichondrin B

The first total synthesis of neonorhalichondrin B has been completed and the previously undetermined left half sidechain stereochemistry has been elucidated. This was achieved by the initial preparation of a series of stereoisomeric models, leading to a tentative assignment of 49R, 51S, 52S. We then synthesized neonorhalichondrin B incorporating this stereochemistry, confirming our proposed assignment. Highlights of our synthetic sequence include the use of a novel Cu-mediated ketone coupling to prepare the C44 spiroketal, and a Ni(I)/Ni(II)-catalyzed ketone coupling for the final disconnection.