Scalable Total Syntheses of (-)-Hapalindole U and (+)-Ambiguine H

The Stigonemataceae family of cyanobacteria produces a class of biogenetically related indole natural products that include hapalindoles and ambiguines. In this full account, a practical route to the tetracyclic hapalindole family is presented by way of an eight-step, enantiospecific, protecting-group-free total synthesis of (-)-hapalindole U that features an oxidative indole-enolate coupling. With gram-scale access to hapalindole U, the first total synthesis of an ambiguine alkaloid, (+)-ambiguine H, was completed via an isonitrile-assisted prenylation of an indole followed by a photofragmentation cascade.