Development of an Asymmetric Synthesis of a Chiral Quaternary FLAP Inhibitor

A practical
sequence involving a noncryogenic stereospecific boronate
rearrangement followed by a robust formylation with an in situ generated
DCM anion has been developed for the asymmetric construction of an
all-carbon quaternary stereogenic center of a FLAP inhibitor. The
key boronate rearrangement was rendered noncryogenic and robust by
using LDA as the base and instituting an in situ trapping of the unstable
lithiated benzylic carbamate with the boronic ester. A similar strategy
was implemented for the DCM formylation reaction. It was found that
the 1,2-boronate rearrangement for the formylation reaction could
be temperature-controlled, thus preventing overaddition of the DCM
anion and rendering the process reproducible. The robust stereospecific
boronate rearrangement and formylation were utilized for the practical
asymmetric synthesis of a chiral quaternary FLAP inhibitor.