Enantioselective Total Synthesis of (–)-Ambiguine

Key words

Friedel–Crafts reaction - [4+3] cycloaddition - ambiguine P - hapalindole alkaloids

Significance

Isolated from the cultured cyanobacterium Fischerella ambigua in 2010, ambiguine P belongs to the hapalindole alkaloid family. The pentacyclic natural product contains a seven-membered ring and an embedded indole, which pose significant synthetic challenges. The authors report an enantioselective total synthesis of the target employing a stepwise [4+3]-cycloaddition strategy.

Comment

Ketone B, accessible from limonene (A), was transformed into enol ether D in four steps. A net [4+3] cycloaddition of this diene with indole E and subsequent intramolecular Friedel–Crafts reaction installed the target’s pentacyclic core. Functional group manipulations furnished diene I, which was transformed into the natural product by NBS-mediated regioselective oxidation.