Piperazic acid-containing natural products: isolation, biological relevance and total synthesis.

Since their first discovery in 1959, natural products containing the piperazic acid motif have been isolated from a variety of sources and exhibit diverse biological activity profiles. This review provides information about their isolation and biological activities, and presents an overview of recent total syntheses of these molecules.

Total synthesis of chloptosin: a dimeric cyclohexapeptide.

Here we describe in full our investigations into the synthesis of the dimeric cyclohexapeptide chloptosin in 17 linear steps. Particularly, this work features an organocatalytic tandem process for the synthesis of the embedded piperazic acids, in which a differentially protected azodicarboxylate is used together with pyrrolidinyl tetrazole as the catalyst. The central biaryl bond is being formed by Stille coupling of two sterically demanding ortho-chloropyrroloindole fragments. The inherent flexibility of the synthetic strategy proved beneficial as the route could be adjusted smoothly during the progression of the synthesis programme.

Kinase inhibition by deoxy analogues of the resorcylic lactone L-783277.

The natural product L-783277 is a resorcylic lactone type covalent kinase inhibitor. We have prepared the 5'-deoxy analogue of L-783277 (1) in a stereoselective fashion. Remarkably, this analogue retains almost the full kinase inhibitory potential of natural L-783277, with low nanomolar IC50 values against the most sensitive kinases, and it exhibits essentially the same selectivity profile (within the panel of 39 kinases investigated). In contrast, removal of both the 4'- and the 5'-hydroxyl groups leads to a more significant reduction in kinase inhibitory activity and so does a change in the geometry of the C7'-C8' double bond in 1 from Z to E. These findings offer new perspectives for the design of second generation resorcylic lactone-based kinase inhibitors.