Intramolecular Suzuki–Miyaura Reaction for the Total Synthesis of Signal Peptidase Inhibitors, Arylomycins A 2 and B 2

Development of the total syntheses of arylomycins A 1 and B 2 is detailed. Key features of our approach include 1) formation of 14‐membered meta , meta ‐cyclophane by an intramolecular Suzuki–Miyaura reaction; 2) incorporation of N ‐Me‐4‐hydroxyphenylglycine into the cyclization precursor, which avoids the late‐stage low‐yielding N ‐methylation step; 3) segment coupling of a fully elaborated peptide side chain to the macrocycle, which makes the synthesis highly convergent. Overall, arylomycin A 2 was obtained in 13 steps from L ‐Tyr for the longest linear sequence, in 13 % overall yield. Arylomycin B 2 was synthesized in 10 steps from L ‐3‐nitro‐Tyr, in 10 % overall yield.