Synthetic approaches to cyclic peptide natural products as chitinase inhibitors

Chitinases catalyse the hydrolysis of chitin, the natural homopolymer
of β(1,4)-linked N-acetyl-D-glucosamine. Chitin is a key structural
component of the cell walls, exoskeletons, and eggshells of pathogenic
fungi, insects, and nematodes, respectively, which all rely on the ability
to hydrolyse chitin at specifi c points in their life cycles. Chitinase
inhibitors are now attracting considerable interest as novel fungicides
and insecticides, as well as chemical tools to study human diseases as
diverse as asthma and malaria. In this context, the cyclic pentapeptide
natural products, argifi n and argadin, are two exciting inhibitors which
pose some interesting synthetic challenges. The argifi n structure
includes two sensitive β-linked Asp residues, as well as an unusual
carbamoylated Arg side chain, while argadin contains a unique Asp β-
semialdehyde residue, that is cyclised to the peptide backbone to generate
a potentially labile hemiaminal. We will describe improved routes to
both compounds that allow us to avoid signifi cant side reactions such
as aspartimide formation and homoserine-mediated backbone cleavage
that are observed in our previously reported syntheses. [1,2] This is
achieved by carrying out the assembly and cyclisation of both peptides,
including key side chain derivatisation steps, entirely on solid phase.
The application of the strategies devised to the automated synthesis
of argifi n and argadin and related natural products will be described.