Stereoconvergent and -divergent Synthesis of Tetrasubstituted Alkenes by Nickel-Catalyzed Cross-Couplings

Abstract

We report the development of a method to diastereoselectively access tetrasubstituted alkenes via nickel-catalyzed Suzuki-Miyaura cross-couplings of enol tosylates and boronic acid esters. Either diastereomeric product was selectively accessed from a mixture of enol tosylate starting material diastereomers in a convergent reaction by judicious choice of the ligand and reaction conditions. A similar protocol also enabled a divergent synthesis of each product isomer from diastereomerically pure enol tosylates. Notably, high-throughput optimization of the monophosphine ligands was guided by chemical space analysis of the kraken library to ensure a diverse selection of ligands was examined. Stereoelectronic analysis of the results provided insight into the requirements for reactive and selective ligands in this transformation. The synthetic utility of the optimized catalytic system was then probed in the stereoselective synthesis of various tetrasubstituted alkenes, with yields up to 94% and diastereomeric ratios up to 99:1 Z/E and 93:7 E/Z observed. Moreover, a detailed computational analysis and experimental mechanistic studies provided key insights into the nature of the underlying isomerization process impacting selectivity in the cross-coupling. ASSOCIATED CONTENTThe Supporting Information is available free of charge at http://pubs.acs.org." Experimental procedures, characterization and spectral data for all new compounds.

A Comprehensive Discovery Platform for Organophosphorus Ligands for Catalysis

“…The kraken tool may enable informed catalyst design based on organophosphorus ligands, facilitate the optimization of reaction process parameters, inspire new ligand choices, and promote the synthesis of new organophosphorus compounds. The database and tools reported herein are currently being applied to enhance reaction optimization − and mechanistic workflows . The open-source nature of our codes, as well as the open database, is designed to be extended by others, and we welcome further contributions by the community.…”

Design and Application of a Screening Set for Monophosphine Ligands in Cross-Coupling

“…The specific workflow for the selection of a diverse molecule set adopted herein (Figure ) represents just an example of a more general procedure where different choices can be made at every step, depending on the application. Indeed, others have used similar procedures to generate diverse sets of molecules in unique contexts, ,,− including phosphorus ligand sets. ,− …”

Mechanistic Inference from Statistical Models at Different Data-Size Regimes

“…Beyond trend evaluation, another powerful visualization technique for the identification of mechanism breaks are cutoff values in scatter plots. To streamline this approach, one can use computational ligand libraries that function as repositories of molecular parameters covering a broad chemical space. − Pioneering work by the Fey group established libraries mostly specializing in phosphine ligands, motivated by their prevalence in cross-coupling reactions. ,,− , More recently, a new library of monodentate phosphines, extended by ML techniques, was reported by the Aspuru-Guzik and Sigman groups . The library is incorporated in an online platform named Kraken, and 200 descriptors are available for each ligand in the database.…”

“…Kraken has been used as the initial step in optimization campaigns, guiding the selection of ligands from different regions of the chemical space. These ligands have been evaluated using high-throughput experimentation (HTE) , and multiobjective optimization strategies . More recently, the Doyle and Sigman groups have demonstrated how the use of data available in Kraken can also drive new mechanistic discoveries .…”