Synthesis of Viridicatumtoxin B

Key words

viridicatumtoxin B - structural revision - tetracycline - spirocyclization - annulation

Significance

Structurally related to the tetra­cycline family of broad-spectrum antibiotics, the viridicatumtoxins feature a densely oxidized tetracyclic carbon skeleton with an appended highly congested spirocycle. The viridicatumtoxins have been shown to exhibit strong antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), comparable to vancomycin. Nicolaou and co-workers tackled viridicatumtoxin B and accomplished the total synthesis of this impressive target which had previously been incom­pletely characterized. The synthesis allowed for the revision of the originally proposed structure and the full stereochemical assignment of viridicatumtoxin B.

Comment

Using a highly convergent strategy, the authors constructed the challenging spirocyle E by virtue of a Lewis acid catalyzed Friedel–Crafts alkylation. The Michael–Dieckmann annulation of F with isoxazole G completed the full-carbon skeleton. However, the remaining two hydroxylations proved difficult and were finally achieved by nickel-catalyzed DMDO- and Davis α-hydroxylation, respectively. Critical to the success of these reactions was the choice of oxidation state and protecting-group pattern of the underlying core. Deprotection, oxidation, and hydrogenation of K afforded synthetic viridicatumtoxin B, which exists as the hydroxy ketone rather than the originally proposed epoxy hemiacetal.