ABSTRACT
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.
Subject(s)
5-Lipoxygenase-Activating Protein Inhibitors/chemical synthesis , Boron Compounds/chemistry , Carbamates/chemistry , 5-Lipoxygenase-Activating Protein Inhibitors/chemistry , Catalysis , Molecular Structure , StereoisomerismABSTRACT
A practical noncryogenic process for the Aggarwal stereospecific boronate rearrangement with chiral secondary benzylic carbamates has been developed. The use of LDA instead of sec-BuLi combined with an in situ trapping of the unstable lithiated carbamate was critical to success. Furthermore, this new process increased the substrate scope to include the versatile aryl iodide and bromide substrates. The methodology was applied to a diverse array of substrates and was demonstrated on multikilogram scale.
