Cascading Auto-oxidative Biproline Guanylations Form Optically Active Dispacamide Dimers and Permit an Eight-Step Synthesis of (−)-Ageliferin

Abstract

A nickel catalyzed synthesis of isomeric 3,3'-biproline esters is described. When those materials are doubly acylated with the acid chloride of pyrrole-2-carboxylic acid, they become susceptible to auto-oxidation in the presence of guanidine. Through proper staging of reaction conditions, it is possible to initiate two consecutive oxidative guanylations prior to in situ cycloisomerization to afford spirocyclic bis-glycocyamidines. This unique outcome reflects a cascade of no fewer than 10 reactions occurring sequentially in one flask. The chemistry provides rapid access to advanced intermediates useful for the preparation of complex, optically active pyrrole/imidazole alkaloids.

Synthesis of Antibiotics and Related Molecules

“…23 Inspired by Nature's dimerization and rearrangement of oroidin-type alkaloids, Harran and co-workers devised a cascading auto-oxidation of a biproline derivative in the presence of guanidine free-base that affords a key spirocyclic intermediate in their synthesis of (−)-ageliferin. 24 While much effort in the past two decades has focused on understanding the molecular transformations involved in the biosynthesis of natural products, more recently chemists have started to also focus on another type of organic chemistry in biology involving natural products: metabolism of natural products to generate derivatives that sometimes have completely different activities. Sometimes, these metabolic reactions are catalyzed by human enzymes and sometimes by enzymes produced by the microbiome.…”