Stereochemical Elucidation of Neohomohalichondrin B (aka Halistatin 3)

Halistatin 3 and neohomohalichondrin B are members of the halichondrin class of natural products, isolated and characterized independently, albeit without full stereochemical assignment. Here, we determine the absolute stereochemistry of these compounds, confirming they are structurally identical. This study involved the initial preparation of a series of stereoisomeric models for comparison with the left half of these natural products, leading to a proposed assignment of 50S,51R,54R for their left half side chain. Next, we prepared a synthetic compound incorporating this revised stereochemistry. Finally, we present two strands of evidence that this compound was structurally identical to the natural products: (i) NMR comparison showed excellent agreement with the reported data for both halistatin 3 and neohomohalichondrin B, and (ii) HPLC comparison confirmed that our revised stereochemistry was identical to an authentic sample of isolated halistatin 3.