Antony B. Maude, Amit P. Mehrotra and David Gani
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. Soc.,
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-β-Ala-(
R)-Glu-α-OMe-γ-Sar-(R)-Asp-
α-OMe-β-(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-[β-Ala-(R)-Glu-α-
OMe-γ-Sar-(R)-Ala-(S
)-Leu-(
R)-Asp-α-OMe-β-(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
β-pentafluorophenyl ester of the (2R)-aspartic
acid residue.