Total synthesis of vancomycin - Part 1: Design and development of methodology

o-Halosubstituted aromatic triazenes (e.g. I, Scheme 1) react with aryloxid es (e.g. II, Scheme 1) in the presence of CuBr . Me2S, K2CO3 and pyridine i n acetonitrile at reflux to afford biaryl ethers (e.g. V, Scheme i). This g eneral methodology (Tables 1 and 2) was applied to the construction of the C-O-D and D-O-E vancomycin model systems 37 (Scheme 2) and 50 (Scheme 3), d emonstrating its potential in a projected total synthesis of vancomycin (1, Figure 1). For the construction of the vancomycin model AB biaryl ring sys tem, a sequential strategy involving a Suzuki coupling of the C-O-D aryl io dide 74 (Scheme 7) and boronic acid 53 (Scheme 4), followed by macrolactami zation was demonstrated, in which the preformed C-O-D ring framework served to preorganize the precursor for cyclization. The latter investigation led to Suzuki-coupling-based asymmetric synthesis of biaryl systems in which 2 ,2-bis(diphenylphosphino)-1,1 1-binaphthyl (BINAP) was found to be the opti mum ligand (Tables 3 and 1).