Enabling Deoxygenative C(sp²)-C(sp³) Cross-Coupling for Parallel Medicinal Chemistry

Abstract

Herein we report the development of an automated deoxygenative C(sp 2 )-C(sp 3 ) coupling of aryl bromide with alcohols to enable parallel medicinal chemistry. Alcohols are among the most diverse and abundant building blocks, but their usage as alkyl precursors has been limited. Although metallaphotoredox deoxygenative coupling is becoming a promising strategy to form C(sp 2 )-C(sp 3 ) bond, the reaction setup limits its widespread application in library synthesis. To achieve high throughput and consistency, an automated workflow involving solid-dosing and liquid-handling robots has been developed. We have successfully demonstrated this high-throughput protocol is robust and consistent across three automation platforms. Furthermore, guided by cheminformatic analysis, we examined alcohols with comprehensive chemical space coverage and established a meaningful scope for medicinal chemistry applications. By accessing the rich diversity of alcohols, this automated protocol has the potential to substantially increase the impact of C(sp 2 )-C(sp 3 ) cross-coupling in drug discovery.

Unlocking Tertiary Acids for Metallaphotoredox C(sp2)–C(sp3) Decarboxylative Cross-Couplings

“…In recent years, there has been significant expansion in the number and variety of methods for the formation of C­(sp 2 )–C­(sp 3 ) bonds using transition metal-catalyzed cross-coupling . A major driver for the development of new C­(sp 2 )–C­(sp 3 ) bond-forming reactions is their high interest to medicinal chemists . The products of such reactions have a higher fraction of sp 3 carbon atoms (Fsp 3 ) than those of more traditional cross-couplings, and higher Fsp 3 has been correlated with improved physicochemical properties and increased “drug-likeness” .…”

At the Speed of Light: The Systematic Implementation of Photoredox Cross-Coupling Reactions for Medicinal Chemistry Research

“…These collaborations can leverage the “know-how” and innovation of academia and the state-of-art facilities, capabilities, and synthetic problems from industry to result in synthetic methods where the product is greater than the sum of its parts. Industrial teams have also helped to advance this field and examples include recent studies on method validation for both medicinal chemistry and process chemistry applications. ,,, Finally, with the fast adoption of photoredox cross-couplings in medicinal chemistry projects, the necessity of large-scale syntheses utilizing this chemistry for drug candidates, or their intermediates, will be inevitable. Some aspects revolving around scalability remain to be addressed, despite the great progress that has been made in this area.…”

“…The most recently published of the four transformations evaluated in this study was the deoxygenative coupling, first shown by MacMillan and co-workers in 2021 . This transformation was rapidly adopted internally for analogue synthesis, and on the basis of recent reports, other pharmaceutical companies have embraced this method, too . The major disadvantage of this protocol compared to the others is the requirement of a two-step process: activation of the alcohol using a benzoxazolium N -heterocyclic carbene (NHC) reagent followed by a nickel/photoredox-catalyzed cross-coupling of the activated alcohol with an aryl halide substrate.…”

“…The necessity for multiple steps, and particularly the required filtration following alcohol activation, can increase the barrier of difficulty for parallel library synthesis. Nevertheless, this represents a challenge that can be addressed using automation . Furthermore, the MacMillan group’s guide for reaction condition selection mitigates the need for HTE in most instances .…”

“…This can be further explored by conducting R-group decompositions on the alkyl monomers present in the data set to obtain their corresponding alkyl functional groups. Chemical space analysis of the R-groups was conducted using tSNE clustering to reduce the dimensionality of the multidimensional feature space into a two-dimensional representation of the R-group chemical space (Figure C). ,, Highlighting the top three functional handles that were used in libraries to install the R-groups, namely BF 3 K salts, halides, or alcohols, shows the more limited/similar chemical space reached by using BF 3 K salt monomers in the data set. Meanwhile, halides and alcohols exhibited much broader coverage of the R-group chemical space, owing to the much wider commercial availability of structurally and functionally diverse building blocks.…”