Retrosynthetic analysis of vancomycin (1) defined vancomycins aglycon (2) and protected triazene 3 (Figure 1) as advanced intermediates for an eventual total synthesis. Sequential assembly of 3 as shown in Figure 2 (strategy I) and Figure 3 (strategy II) led to amino acid building blocks 8 ± 10 and 12 ± 15, respectively, representing vancomycins amino acids AA-1 to AA-7. These amino acid fragments were constructed by stereoselective routes and the two synthetic strategies were tested for feasibility. Strategy I, postulating construction of the vancomycin main framework in the order of

The total synthesis of vancomycin (1, Figure 1) is described. The successful plan for this synthesis involves sequential and stereoselective coupling of vancomycin aglycon acceptor 6 and glycosyl donors, trichloroacetimidate 50 and glycosyl fluoride 27 (Scheme 8). Acceptor 6 was synthesized from vancomycin aglycon (2) (Scheme 1), which was derived both by total synthesis and by semisynthesis from vancomycin itself (1) (Scheme 2). The vancosamine derivative 27 was obtained by total synthesis (Scheme 3) while the glycosyl derivative 50 was prepared from glucal (46) (Scheme 6).A number of glycosidation model studies, carried out in order to establish the final route to vancomycin (1), are also described and so are a number of failed attempts to secure the target molecule (1).

The total synthesis of the vancomycin aglycon (2, Figure 1) is described. Construction of the key intermediate, tricyclic triazene 3 a (Figure 2), was accomplished in the orderThe C-O-D ring system 18 a (Scheme 2) was formed by using the triazene ring-closure methodology from a precursor (17) already possessing the AB biaryl fragment 6, synthesized by a Suzuki coupling reaction. At this point, a macrolactamization reaction furnished the AB ring system. Tripeptide 5 was incorporated in the main framework and the triazene ring-closure methodology was applied again to achieve the formation of D-O-E ring system, providing tricyclic triazene 3 a (Scheme 6). The latter was converted to the fully protected vancomycin aglycon 45 a by first introducing the phenolic moiety (derivative 43 a) and then oxidizing the AA-7 side chain (Scheme 12). Finally, global deprotection afforded vancomycins aglycon (2). Atropisomerization was successfully performed for D-O-E ring systems.