Unravelling Information-Rich Chemical Synthesis Experiments with Computational Metabolomics: Identification of Reactivity Patterns for Baldwin and Whitehead “Manzamine Alkaloids” Biosynthesis Scenario

A key bottleneck in the study of biosynthetic pathways for complex natural products is identifying the appropriate mechanisms and conditions to assemble intricated skeletons, especially when no genomic or proteomic data are available. In this regard, a chemoinformatic exploration of highly textured knowledge generated by chemical synthesis experiments can address this issue and become part of a general method for the analysis of information-rich high-throughput experiments of multicomponent reactions. Starting from a bio-inspired experimental design, we have applied a combined screening and selection approach, leveraging reaction conditions and synthetic probe-informed molecular networking workflow. This procedure quickly pinpointed relevant bio-inspired reaction conditions that may follow Baldwin and Whitehead renowned hypothesis for the biosynthesis of Manzamine-type alkaloids. A model for keramaphidin B, collapsing a multi–step synthesis into a one-pot reaction, was devised for this purpose providing important information in terms of biosynthesis.