A Process Chemistry Benchmark for sp²–sp³ Cross Couplings

Abstract

As sp2–sp3 disconnections gain acceptance in the medicinal chemist’s toolbox, an increasing number of potential drug candidates containing this motif are moving into the pharmaceutical development pipeline. This raises a new set of questions and challenges around the novel, direct methodologies available for forging these bonds. These questions gain further importance in the context of process chemistry, where the focus is the development of scalable processes that enable the large-scale delivery of clinical supplies. In this paper, we describe our efforts to apply a wide variety of standard, photo-, and electrochemical sp2–sp3 cross-coupling methods to a pharmaceutically relevant intermediate and optimize each through a combination of high throughput and mechanistically guided experimentation. With data regarding the performance, benefits, and limitations of these novel methods, we evaluate them against a more traditional two-step palladium-catalyzed process. This work reveals trends and similarities between these sp2–sp3 bond-forming methods and suggests a path forward for further refinements.

Controlling Ni redox states by dynamic ligand exchange for electroreductive Csp3–Csp2 coupling

“…A dvances in Ni-based catalysis have enabled new C-C bond-forming methodologies that directly couple two C electrophiles in a net-reductive process without the need to preform a nucleophilic coupling partner (1)(2)(3)(4). The ubiquity of simple organohalides or other C electrophiles has caused Ni-catalyzed cross-electrophile coupling (XEC) to become one of the most common strategies for C-C coupling in industry, particularly to form C(sp 3 )-C(sp 2 ) bonds (5)(6)(7)(8)(9)(10)(11). Although chemical (3), photoredox (12), and electrochemical (13) approaches have been developed to deliver the reducing equivalents needed for XEC, all three reductive strategies are limited to couplings of similar classes of alkyl and aryl halides.…”

In-Situ Bromination Enables Formal Cross-Electrophile Coupling of Alcohols with Aryl and Alkenyl Halides

“…As noted above, the ability to directly use alcohols in cross-electrophile coupling reactions without extra steps will be of particular advantage in the generation of small libraries in medicinal chemistry. , To explore this application, we coupled all combinations of 12 aryl halide cores with 8 alcohols on 10 μmol scale in a 96-well plate using three ligand regimes (dtbbpy only, 1:1 dtbbpy/ L1 , and L1 only). All reagents except Mn were dosed using liquid handling and standard multichannel pipettes.…”

“…Cross-coupling reactions to form C­(sp 3 )–C­(sp 2 ) bonds are increasingly important for the synthesis of structurally diverse molecules in medicinal chemistry and natural product synthesis . In medicinal chemistry, small-scale high-throughput experimentation is now routine to allow rapid synthesis of focused libraries to explore structure–activity relationships (SAR) and optimize lead compounds while preserving valuable material .…”

Tunable and Practical Homogeneous Organic Reductants for Cross-Electrophile Coupling

“…The problems associated with heterogeneous reductants have led researchers to explore alternative electron sources in both XEC and other related transition metal-mediated reactions. 11 Two potentially attractive solutions are to facilitate reduction events through photocatalytic 12 or electrochemical methods. 13 Both of these strategies allow for tuning of the reduction potential and have led to advances in XEC, such as improved substrate scopes, extensions to new substrates, and the use of XEC in flow chemistry.…”

“…The problems associated with heterogeneous reductants have led researchers to explore alternative electron sources in both XEC and other related transition metal-mediated reactions . Two potentially attractive solutions are to facilitate reduction events through photocatalytic or electrochemical methods .…”