Rapid Total Synthesis of Iheyamine A via a Pictet–Spengler/Redox-Mediated Cyclization Cascade

Abstract

The Pictet−Spengler reaction between tryptamine and (5-methoxy-2-nitrophenyl)-glyoxal in hot AcOH could trigger a redox-mediated cyclization and reduction sequence to form iheyamine A in 52% yield. Note pubs.acs.org/joc

Recent Progress Toward Total Syntheses of Iheyamines A and B

“…The first strategy is based on a potential biomimetic approach to the naturally occurring heterocyclic ring system (Scheme 1a). [5,8,[10][11][12] This approach involves the reaction of tryptamine 3 and 5-methoxyisatin 4 affording spirooxindole 5. Subsequent CÀ C bond migration from the C18 atom to the C11 atom allows the construction of the azepine scaffold leading to the total synthesis of iheyamine A (1).…”

“…The first strategy is based on a potential biomimetic approach to the naturally occurring heterocyclic ring system (Scheme 1a) [5,8,10–12] . This approach involves the reaction of tryptamine 3 and 5‐methoxyisatin 4 affording spirooxindole 5 .…”

“…Very recently, another total synthesis of iheyamine A ( 1 ) was reported by the Liu group from tryptamine 3 and 5‐methoxy‐2‐nitrophenylglyoxal 70 via redox‐mediated cascade cyclization (Scheme 13). [12] The authors expected that the Pictet‐Spengler reaction between tryptamine 3 and glyoxal derivative 70 would afford the tetrahydrocarboline derivative 71 . Subsequent intramolecular hydride transfer from the α‐methide of the amine moiety to the nitro group would produce compound 72 carrying both the corresponding imine and hydroxyamine moieties.…”

“…In 2016, Sperry and coworkers reported the first total synthesis of iheyamine A (1), utilizing an acidcatalyzed cross-Mannich-type reaction as the key reaction to construct an unsymmetrical 2,2'-bisindole scaffold. [6] Since the first total synthesis, six total syntheses of iheyamine A (1) [7][8][9][10][11][12] and two total syntheses of iheyamine B (2) [11,13] have been reported, highlighting the importance of these natural products in the synthetic chemistry community. Despite these recent publications on the total syntheses of these natural products, no reviews have been published on the total syntheses of these natural products.…”