Progress toward a biomimetic synthesis of pegaharmaline A

Efforts towards a biomimetic synthesis of the alkaloid pegaharmaline A began with attempted validation of the putative biosynthesis described in the isolation report. The reaction between vasicinone-derived pyrroloquinazoline 1 and tryptamines 2 and 9 proceeded under aqueous conditions at ambient temperature, forming the 1,6,10-triazaspiro[4.5]dec-7-anes 7 and 8. Alternative pyrroloquinazoline precursors were subsequently investigated; the reaction between dehydrodimethylisovasicinone (10) and tryptamine (9) led to the ring-opened product 13 that could not be converted into pegaharmaline A scaffold under Bischler-Napieralski conditions. The Pictet-Spengler reaction between a model isovasicinone (22) and tryptamine (9) was successful, but the resulting tetrahydro-β-carboline could not be converted into the natural product. These studies suggest an alternative biosynthetic pathway is potentially operating, while structural revision of the natural product cannot be ruled out at this time. As vasicinones and tryptamines are widely distributed throughout Nature, the novel scaffolds reported herein may be undiscovered natural products.