A computer algorithm to discover iterative sequences of organic reactions

Abstract

Iterative syntheses comprise sequences of organic reactions in which the substrate molecules grow with each iteration and the functional groups, which enable the growth step, are regenerated to allow sustained cycling. Typically, iterative sequences can be automated, for example, as in the transformative examples of the robotized syntheses of peptides, oligonucleotides, polysaccharides and even some natural products. However, iterations are not easy to identify—in particular, for sequences with cycles more complex than protection and deprotection steps. Indeed, the number of catalogued examples is in the tens to maybe a hundred. Here, a computer algorithm using a comprehensive knowledge base of individual reactions constructs and evaluates myriads of putative, but chemically plausible, sequences and discovers an unprecedented number of iterative sequences. Some of these iterations are validated by experiment and result in the synthesis of motifs commonly found in natural products. This computer-driven discovery expands the pool of iterative sequences that may be automated in the future.