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.