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.

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O-Benzoyl derivatives of meta-, orthoand para-pyridine aldoximes and amidoximes are novel efficient DNA photo-cleavage agents. In particular O-p-nitro-benzoyl derivatives 4, 8 and 15 were effective at concentrations as low as 1 μM. Both aldoximes and amidoximes were active under aerobic and anaerobic conditions, with a double-stranded to single-stranded DNA cleavage ratio of up to 1. These results give prospects for multiple applications, including phototherapeutic treatment of solid tumors.Med. Chem. Commun. This journal isThessaloniki, 54124, Thessaloniki, Greece † Electronic supplementary information (ESI) available: 1 H and 13 C-NMR spectra of all compounds, photochemistry and pH experiments, and UV spectra are available. See

Several stable O-alkyl and aryl sulfonyl conjugated p-nitro-Ph and o-, m-, p-pyridine N'-hydroxy imidamides, were subjected to UV irradiation at 312 nm with supercoiled circular plasmid DNA pBluescript KS II. The generated amidinyl and sulfonyloxyl radicals led to effective DNA photo-cleavage. Both alkyl and aryl sulfonyl derivatives were active and the order p-pyridine > p-nitro-Ph > o-pyridine > m-pyridine was schematized for the N'-hydroxy imidamides moiety. Calf thymus-DNA affinity studies which comprised UV interactions, viscosity experiments and competitive studies with ethidium bromide showed good to excellent affinity of the compounds. These properties revealed sulfonyl amidoximes as novel effective DNA-photo-cleavers and may serve in the discovery of new leads for "on demand" biotechnological and medical applications.

A triazene-based synthetic strategy for the construction of the complex biaryl ethers and a Suzuki coupling reaction were the key steps in the synthesis of precursor 1 of the aglycon of vancomycin, which already contains the complete skeleton of the target compound. The cleavage of the triazene unit from the D ring and the removal of the other protecting groups led to the aglycon of vancomycin. These strategies should be particularly valuable for the synthesis of other naturally occurring glycopeptide antibiotics and offer opportunities for the synthesis of combinatorial libraries of compounds of the vancomycin family for chemical biology studies.