Convergent Total Synthesis of Hikizimycin Enabled by Intermolecular Radical Addition to Aldehyde
Haruka Fujino, Takumi Fukuda, Masanori Nagatomo, Masayuki Inoue
Abstract
Hikizimycin (1), which exhibits powerful anthelmintic activity, has the most densely functionalized structure among nucleoside antibiotics. A central 4-amino-4-deoxyundecose of 1 possesses 10 contiguous stereocenters on a C1–C11 linear chain and is decorated with a cytosine base at C1 and a 3-amino-3-deoxyglucose at C6-OH. These distinctive structural features of 1 make it an extremely challenging target for de novo construction. Herein, we report a convergent total synthesis of 1 from four known components: 3-azide-3-deoxyglucose derivative 4, bis-TMS-cytosine 5, d-mannose 9, and d-galactose derivative 10. We first designed and devised a novel radical coupling reaction between multiply hydroxylated aldehydes and α-alkoxyacyl tellurides. The generality and efficiency of this process was demonstrated by the coupling of 7c and 8, which were readily accessible from two hexoses, 9 and 10, respectively. Et3B and O2 rapidly induced decarbonylative radical formation from α-alkoxyacyl telluride 8, and intermolecular addition of the generated α-alkoxy radical to aldehyde 7c yielded 4-amino-4-deoxyundecose 6-α with installation of the desired C5,6-stereocenters. Subsequent attachments of the cytosine with 5 and of the 3-azide-3-deoxyglucose with 4 were realized through selective activation of the C1-acetal and selective deprotection of the C6-hydroxy group. Finally, the 3 amino and 10 hydroxy groups were liberated in a single step to deliver the target 1. Thus, the combination of the newly developed radical-coupling and protective-group strategies minimized the functional group manipulations and thereby enabled the synthesis of 1 from 10 in only 17 steps. The present total synthesis demonstrates the versatility of intermolecular radical addition to aldehyde for the first time and offers a new strategic design for multistep target-oriented syntheses of various nucleoside antibiotics and other bioactive natural products.