Repurposing amine and carboxylic acid building blocks with an automatable esterification reaction

Abstract

We present a robust deaminative esterification reaction between an alkyl pyridinium salt and carboxylic acid, as complement to the venerable amide coupling. The scope of this reaction is further demonstrated with a robot-assisted library synthesis.

Exploring the combinatorial explosion of amine–acid reaction space via graph editing

“…To affirm the experimental viability of our theoretical work, our lab is seeking out reaction conditions leading to unconventional amine–acid couplings 74 . We have previously reported sp 2 amine–acid coupling 76 , sp 3 – sp 3 C–C coupling 78 , sp 3 – sp 3 C–O coupling 77 , and sp 3 – sp 2 C–C coupling 75 , and here demonstrate an additional transformation, where activated benzylamine ( 49 ) and benzoic acid ( 50 ) couple to form alcohol 51 (Fig. 7 ).…”

“…Meanwhile, the sp 3 – sp 3 C–O coupling motif 43 and sp 3 – sp 3 C–N coupling 40 are the most abundant in structures containing only carbon and oxygen, and carbon and nitrogen respectively. Together, these findings suggest that these three transformations could be valuable in drug discovery and natural product synthesis, among which we have recently reported C–C coupling 74 , 75 and C–O coupling 76 , 77 . The most abundant substructures with C, N and O atoms contain fragments of the amide bond ( 46, 47 ), which once more underscores the prevalence of the amide coupling in drug discovery, but also opportunities in accessing complementary chemical space with amine–acid couplings that do not produce the amide, yet preserve C, N and O atoms.…”

Rapid planning and analysis of high-throughput experiment arrays for reaction discovery

“…General phactor™ workflow for general use and to recreate the chemistry reported in this and other manuscripts [52][53][54][55][56][57] The workflow for phactor™ contains six stages: Settings, Factors, Chemicals, Analysis, and Report (Fig. 5).…”

“…Regardless of instrumentation or throughput, all results are stored in the same format, facilitating analysis of results across multiple experiments. Reaction discovery and library synthesis campaigns utilizing standard 24-, 96-, 384-and 1536-well experiments are described in detail [52][53][54][55][56][57] .…”

“…Phactor™ facilitates the discovery of new reactivity. Our lab is broadly interested in amine-acid coupling reactions 52,53,[55][56][57] and particularly amine-acid C-C coupling reactions 55,57 . Diverse chemistries discovered with the aid of phactor™ are shown in Fig.…”