Stereoselective Synthesis of the C27–C35 Eribulin Fragment and Its Utilization in Building Structurally Diverse Macrocycles

Abstract

A practical and scalable stereoselective synthesis of the western substituted tetrahydrofuran ring C27–C35 fragment of eribulin was developed by using (2S,3S)-tartaric acid as a cheap starting material that was converted into an intermediate through a stereoselective vinylation­ and cross-metathesis as the key steps. A regio- and stereo­selective intramolecular oxy-Michael cyclization or an iodocyclization reaction finally provided the required western tetrahydrofuran ring fragment and its related isomeric analogues. These key fragments were further utilized in obtaining several types of macrocyclic derivatives for exploration of their biological properties. The simplicity of our present approach has the potential to be considered for large-scale syntheses of key fragments of eribulin and related analogues.