Relay Approach: A Convergent Synthesis of Key Fragments en route to (+)-Neosorangicin A

Herein, we report the synthesis of the three key fragments of the macrolide antibiotic (+)-neosorangicin A, a compound exhibiting potent activity against multiple pathogens. The tetrahydropyran unit (THP) was prepared via stereocontrolled Brown crotylation, followed by hydroboration and epoxide-opening/cyclization steps. Subsequent coupling with the known dioxabicyclo[3.2.1]octane fragment (BCO) via Grubbs metathesis furnished the THP-BCO key intermediate on a gram scale. This intermediate was further transformed into an E-vinyl iodide for a late-stage Stille coupling with the dihydropyran fragment (DHP), incorporating a shortened side chain relative to (+)-sorangicin A and bearing a secondary alcohol. This fragment was synthesized via 1,2-addition to a dihydropyran-methyl ketone followed by dehydration. Subsequent functional group manipulations enabled access to a phosphonate intermediate, which was converted into a stannylated Z,Z-diene via Ando olefination. The Stille coupling between the THP-BCO and the DHP fragments provided the carbon skeleton of the natural product and was confirmed by a relay approach using isolated (+)-neosorangicin A. This work establishes a selective route to the key building blocks, providing a foundation for the convergent total synthesis of (+)-neosorangicin A and a proof of concept via a relay approach.