Catalytic Enantioselective Synthesis of Cyclobutenes from Alkynes and Alkenyl Derivatives

Discovery
of enantioselective catalytic reactions for the preparation
of chiral compounds from readily available precursors, using scalable
and environmentally benign chemistry, can greatly impact their design,
synthesis, and eventually manufacture on scale. Functionalized cyclobutanes
and cyclobutenes are important structural motifs seen in many bioactive
natural products and pharmaceutically relevant small molecules. They
are also useful precursors for other classes of organic compounds
such as other cycloalkane derivatives, heterocyclic compounds, stereodefined
1,3-dienes, and ligands for catalytic asymmetric synthesis. The simplest
approach to make cyclobutenes is through an enantioselective [2 +
2]-cycloaddition between an alkyne and an alkenyl derivative, a reaction
which has a long history. Yet known reactions of this class that give
acceptable enantioselectivities are of very narrow scope and are strictly
limited to activated alkynes and highly reactive alkenes. Here, we
disclose a broadly applicable enantioselective [2 + 2]-cycloaddition
between wide variety of alkynes and alkenyl derivatives, two of the
most abundant classes of organic precursors. The key cycloaddition
reaction employs catalysts derived from readily synthesized ligands
and an earth-abundant metal, cobalt. Over 50 different cyclobutenes
with enantioselectivities in the range of 86–97% ee are documented.
With the diverse functional groups present in these compounds, further
diastereoselective transformations are easily envisaged for synthesis
of highly functionalized cyclobutanes and cyclobutenes. Some of the
novel observations made during these studies including a key role
of a cationic Co­(I)-intermediate, ligand and counterion effects on
the reactions, can be expected to have broad implications in homogeneous
catalysis beyond the highly valuable synthetic intermediates that
are accessible by this route.