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.
Dufour
Jeremy
J
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 1, avenue de la terrasse, 91198 Gif-sur-Yvette, France.
Neuville
Luc
L
Zhu
Jieping
J
D001688:Biological Products / Q000737:chemistry*; D003432:Cross-Linking Reagents / Q000737:chemistry*; D003500:Cyclization; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry
D001688:Biological Products; D003432:Cross-Linking Reagents; D009842:Oligopeptides; D011480:Protease Inhibitors; C488532:arylomycin A2