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

ABSTRACT

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.