Biomimetically Inspired, One-Step Synthesis of Exotine A and Exotine B

Abstract

The one-step syntheses of exotine A and exotine B, which comprise the unusual coumarin-cyclohepta[b]indole ring system, have been achieved via the biomimetically inspired combination of indole, prenal, and either trans-dehydroosthol or gleinadiene. This facile threecomponent reaction delivered a mixture (17:1) of exotine A and 11′-epiexotine A in a 43% yield from trans-dehydroosthol and a mixture (4:1) of exotine B and 11′-epi-exotine B in a 50% yield from gleinadiene. Some mechanistic aspects of this process were explored, and spectral evidence for 3,3′-spiroindolenine intermediates was obtained. Moreover, a skeletal isomer of exotine A that likely originates from a 1,2-alkyl rearrangement of a protonated 3,3′-spiroindolenine was isolated and characterized by Xray crystallography. These findings not only provide experimental support for Jiang's proposed biosynthesis of exotine A and exotine B but also foreshadow the existence of other exotine-derived natural products having isomeric frameworks. Exploratory attempts to induce an enantioselective 3CR using a chiral phosphoric acid were unsuccessful.

An Update on Cyclohepta[b]indoles

“…In 2020, Lepovitz and Martin published a total synthesis of racemic exotines A ((�)-57) and B ((�)-58) by (4 + 3) cycloaddition of an in situ formed allyl indolyl carbenium ion. [28] Inspired by the possible biosynthetic pathway proposed by Jiang et al in 2015, [29] they developed a one-pot procedure using indole (56), prenal (55) and an appropriately substituted coumarin derivative 54 in the presence of p-TsOH•H 2 O to obtain (�)-57 or (�)-58 (Figure 18).…”