The Enantioselective Synthesis of Eburnamonine, Eucophylline, and 16′‐epi‐Leucophyllidine

• Published in: Angewandte Chemie International Edition 2021-08, Vol.60 (33), p.17957-17962
• Main Authors: Reimann, Christopher E., Ngamnithiporn, Aurapat, Hayashida, Kohei, Saito, Daisuke, Korch, Katerina M., Stoltz, Brian M.
• Format: Article
• Language: English
• Subjects: alkaloids; Alkylation; Amides; Azabicyclo Compounds - chemical synthesis; Azabicyclo Compounds - chemistry; Chemical synthesis; convergence; cross-coupling; divergence; Enantiomers; Hemispheres; Hydrogenation; Indole Alkaloids - chemical synthesis; Indole Alkaloids - chemistry; Molecular Structure; Palladium; Phenols; Quinoline; Stereoisomerism; total synthesis; Vinca Alkaloids - chemical synthesis; Vinca Alkaloids - chemistry
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202106184

A synthetic approach to the heterodimeric bisindole alkaloid leucophyllidine is disclosed herein. An enantioenriched lactam building block, synthesized through palladium‐catalyzed asymmetric allylic alkylation, served as the precursor to both hemispheres. The eburnamonine‐derived fragment was synthesized through a Bischler–Napieralski/hydrogenation approach, while the eucophylline‐derived fragment was synthesized by Friedländer quinoline synthesis and two sequential C−H functionalization steps. A convergent Stille coupling and phenol‐directed hydrogenation united the two monomeric fragments to afford 16′‐epi‐leucophyllidine in 21 steps from commercial material. A “convergent–divergent” strategy was used to synthesize the dimeric natural product leucophyllidine. An enantioenriched lactam building block was advanced in a divergent fashion to complete syntheses of both eburnamonine and eucophylline in 10 and 16 steps, respectively. A convergent cross‐coupling and hydrogenation sequence was then employed to afford 16′‐epi‐leucophyllidine (see scheme).