Total Synthesis of Iheyamine A via the Cyanide-Catalyzed Imino-Stetter Reaction

Abstract

The total synthesis of iheyamine A from readily available ethyl 2-aminocinnamate and 5-methoxyindole-2-carboxaldehyde is described. The cyanide-catalyzed imino-Stetter reaction of an aldimine derived from ethyl 2-aminocinnamate and 5-methoxyindole-2-carboxaldehyde provided the desired unsymmetrical 2,2′-bisindole-3-acetic acid derivative. The subsequent introduction of an amino group at the C-3′ position, followed by the formation of the azepine ring, completed the total synthesis of iheyamine A.

A Stereodivergent Strategy for Total Syntheses of Antirhine Alkaloids

“…The acetoacetonate moiety in compound 8 could be introduced by the reaction of ethyl acetoacetate with intermediate 5 bearing a basic tetracyclic indoloquinolizidine core. Indoloquinolizidinium 5 could be prepared by the C-ring formation from 2-(2-pyridinyl)­indole-3-acetic acid derivative 9 , which could be synthesized via the cyanide-catalyzed imino-Stetter reaction − of 2-aminocinnamic acid derivative 3 and pyridine-2-carboxaldehyde derivative 4 .…”

Cyanide Anions as Nucleophilic Catalysts in Organic Synthesis

“…These intermediates could be further processed to related alkaloids arcyriaflavin A (81, four steps from 79), 87 calothrixin B (82, five steps from 79), 87 and iheyamine A (83, five steps from 80). 88 Imine formation from ,-unsaturated aldehydes leads to 2-vinylindole derivatives. 89 An example is the transformation of imine 84 to vinylindole 85, a precursor for the synthesis of (+)-goniomitine (86) (55% over three steps from compound 85, Scheme 22).…”

“…These intermediates could be further processed to related alkaloids arcyriaflavin A (81, four steps from 79), 87 calothrixin B (82, five steps from 79), 87 and iheyamine A (83, five steps from 80). 88…”

Asymmetric Total Synthesis of Iheyamine B

“…The unique structural features and beneficial biological activities of iheyamine B, along with its very low isolation yield from the natural resource, have prompted the chemical community to develop a total synthesis of this natural product. Although the total synthesis of iheyamine A has been previously reported, − there have been no reports on the total synthesis of iheyamine B presumably because of the absence of an appropriate protocol to construct the azepine scaffold bearing vicinal 2-oxopropyl subunits with a trans -configuration. As iheyamines A and B are isolated from the same source in nature and possess structural similarities, it was envisioned that iheyamines A and B may be synthesized from the same intermediate in their biosynthetic pathway.…”