The GE81112 series, consisting of three naturally occurring
tetrapeptides
and synthetic derivatives, is evaluated as a potential lead structure
for the development of a new antibacterial drug. Although the first
total synthesis of GE81112A reported by our group provided sufficient
amounts of material for an initial in depth biological profiling of
the compound, improvements of the routes toward the key building blocks
were needed for further upscaling and structure–activity relationship
studies. The major challenges identified were poor stereoselectivity
in the synthesis of theC-terminal β-hydroxy
histidine intermediate and a concise access to all four isomers of
the 3-hydroxy pipecolic acid. Herein, we report a second-generation
synthesis of GE81112A, which is also applicable to access further
representatives of this series. Based on Lajoie’sortho-ester-protected serine aldehydes as key building blocks, the described
route provides both a satisfactory improvement in stereoselectivity
of the β-hydroxy histidine intermediate synthesis and a stereoselective
approach toward both orthogonally protectedcisandtrans-3-hydroxy pipecolic acid.