Total synthesis of vancomycin - Part 2: retrosynthetic analysis, synthesisof amino acid building blocks and strategy evaluations

Retrosynthetic analysis of vancomycin (1) defined vancomycin's aglycon (2) and protected triazene 3 (Figure 1) as advanced intermediates for an eventu al total synthesis. Sequential assembly of 3 as shown in Figure:! (strategy I) and Figure 3 (strategy II) led to amino acid building blocks 8-10 and 1 2-15, respectively, representing vancomycin's amino acids AA-1 to AA-7. The se amino acid fragments were constructed by stereoselective routes and the two synthetic strategies were tested for feasibility. Strategy I, postulati ng construction of the vancomycin main framework in the order of D-O-E D-O- E/C-O-D-->D-O-E/C-O-D/A-B, suffered from serious epimerization problems at the AA-4 stereocenter; while strategy II, involving the sequence C-O-D-C-O- D/AB -->C-O-D/AB/D-O-E proved viable. These findings set the stage for the final drive towards vancomycin's aglycon (2) and vancomycin (1).