Total Synthesis of A54145 Factor D

An
efficient total synthesis of A54145 factor D (A5D), a member
of the A54145 family of cyclic lipodepsipeptide antibiotics, is reported.
The peptide was constructed by attaching the peptide to the 2′-chlorotrityl
polystyrene resin via Sar5 and developing conditions that avoided
diketopiperazine formation upon subsequent elaboration using 9-fluorenylmethoxycarbonyl
solid-phase peptide synthesis. This route allowed for facile formation
of the crucial depsi bond. A branched acyclic precursor was cyclized
off-resin and then globally deprotected to obtain A5D. Consistent
with recent studies by others, we found that the MeOAsp residue has
the 2S,3R configuration. We also
established that the configuration of the stereocenter in the anteiso-undecanoyl lipid tail does not affect biological
activity.