Total Synthesis of Peniterphenyls A and E.

Our previously discovered marine natural products, peniterphenyls A and E, exhibit superior anti-herpes simplex virus 1/2 (HSV 1/2) activity, probably via interference with virus adsorption and membrane fusion to host cells. Their clear mechanism mode still remains unresolved due to its limited availability from nature. This study establishes their first site-selective chemical total syntheses, affording peniterphenyls A and E in overall yields of 4.5% (over thirteen steps) and 2.3% (over twelve steps), respectively. A nucleophilic aromatic substitution (SNAr) between compounds 4 and 5, and a direct C(sp2)-H/C(sp2)-H oxidative coupling using the Pd(TFA)2/AgOAc catalyst system with a pivaloyl directing group conveniently furnishes the dibenzofuran core with good efficiency. Steric hindrance and substituent directing effects of arene govern the high site-selectivity of the Pd-catalyzed C(sp2)-H activation during furan formation. Featuring readily available materials and straightforward operations, this synthetic route provides convenient access to these bioactive natural products for further study.