Convergent Synthesis of Methyl Peracetyl Hikosaminide Enabled by Intermolecular Radical Addition to Aldehyde

Abstract Methyl peracetyl hikosaminide, a degradation product of the anthelmintic hikizimycin, comprises a linear carbon chain bearing 10 oxygen-substituted and 1 nitrogen-substituted functional groups. In 2017, we constructed this synthetically challenging structure through a novel radical–radical cross-coupling of two hexose-derived α-alkoxyacyl tellurides. Although the single coupling generated the adduct with 10 contiguous stereocenters, the yield remained modest due to insufficient chemo- and stereoselectivities. To enhance coupling efficiency, we designed an alternative convergent strategy featuring intermolecular radical addition to an aldehyde as the key reaction. The obtained adduct was successfully converted into methyl peracetyl hikosaminide in 4 steps, enabling a higher-yielding, expeditious synthesis of the target molecule. This improved strategy provided the chemical foundation for our successful total synthesis of hikizimycin in 2020.