Design and preparation of serine–threonine protein phosphatase inhibitors based upon the nodularin and microcystin toxin structures: Part 2.1 Synthesis of a functionalised nodularin macrocycle and a stripped-down microcystin macrocycle

Nodularins and microcystins are complex natural isopeptidic hepatotoxins that serve as subnanomolar inhibitors of the eukaryotic serine-threonine protein phosphatases, PP1 and PP2A, In Part 1 (A, P. Mehrotra, K, L, Webster and D, Gani, J. Chem. Sec., Perkin Trans. 1, 1997, preceding paper) each of the key structural or potentially reactive motifs within each macrocycle type was assessed as a contributor towards phosphatase inhibitory efficacy and a stripped-down nodularin-type macrocycle was identified as a suitable precursor to potentially active synthetic inhibitors. Subsequently, synthetic routes to the 19-membered nodularin macrocyclic system were developed, using solution-phase chemistry, which demonstrated that only certain cyclisation protocols were viable, Here we describe an extension of this chemistry to provide a 19-membered nodularin macrocycle, cyclo-[(3R)-3-hydroxymethyl-beta-Ala-(R)-Glu-alpha-OMe-gamma-Sar-(R)-Asp-alpha-OMe-beta-(S)-Phe-], appropriately functionalised with a hydroxymethyl group for the incorporation of lipophilic side-chains, We also demonstrate that the 25-membered microcystin macrocycle, cyclo-[beta-Ala-(R)-Glu-alpha-OMe-gamma-Sar-(R)-Ala-(S)-Leu-(R)-Asp-alpha-OMe-beta-(S)-Phe-], can be prepared in good yield using similar protocols in which macrocyclisation is effected through the reaction of the amino group of the (2S)-phenylalanine residue with the beta-pentafluorophenyl ester of the (2R)-aspartic acid residue.