Convergent Total Synthesis of Hikizimycin Enabled by Intermolecular Radical Addition to Aldehyde

Abstract

Hikizimycin (<b>1</b>), which exhibits powerful anthelmintic activity, has the most densely functionalized structure among nucleoside antibiotics. A central 4-amino-4-deoxyundecose of <b>1</b> 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 <b>1</b> make it an extremely challenging target for de novo construction. Herein, we report a convergent total synthesis of <b>1</b> from four known components: 3-azide-3-deoxyglucose derivative <b>4</b>, bis-TMS-cytosine <b>5</b>, d-mannose <b>9</b>, and d-galactose derivative <b>10</b>. 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 <b>7c</b> and <b>8</b>, which were readily accessible from two hexoses, <b>9</b> and <b>10</b>, respectively. Et₃B and O₂ rapidly induced decarbonylative radical formation from α-alkoxyacyl telluride <b>8</b>, and intermolecular addition of the generated α-alkoxy radical to aldehyde <b>7c</b> yielded 4-amino-4-deoxyundecose <b>6-α</b> with installation of the desired C5,6-stereocenters. Subsequent attachments of the cytosine with <b>5</b> and of the 3-azide-3-deoxyglucose with <b>4</b> 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 <b>1</b>. Thus, the combination of the newly developed radical-coupling and protective-group strategies minimized the functional group manipulations and thereby enabled the synthesis of <b>1</b> from <b>10</b> 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.