posted on 2021-11-04, 16:36authored byDaniel Zell, Cian Kingston, Janis Jermaks, Sleight R. Smith, Natalie Seeger, Jana Wassmer, Lauren E. Sirois, Chong Han, Haiming Zhang, Matthew S. Sigman, Francis Gosselin
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.