Synthesis of Fluorinated Macrocyclic Bis(indolyl)maleimides as Potential19F NMR Probes for Protein Kinase C

Abstract

Six macrocyclic bis(indolyl)maleimides 1−6 bearing a fluorine label on the aliphatic portion of the macrocycle have been prepared as potential fluorine NMR probes for the catalytic domain of protein kinase C. The macrocyclic bis(indolyl)maleimides such as LY333531 are reversible, ATP competitive, and isoform-selective inhibitors of protein kinase C and may thus serve to probe for subtle differences between protein kinase catalytic domains. The key stereochemical elements were put in place by a Welch aldol condensation between ethyl fluoroacetate and (R)-cyclohexylidene glyceraldehyde, which was followed by allylation of the secondary alcohol, elaboration of the alkene and ester to alcohols, and mesylation. The macrocycle was formed by slow addition of a mixture of the fluorine-labeled aliphatic dimesylate and N-methyl 2,3-bis[1H-indol-3-yl]maleimide to a suspension of cesium carbonate. Adjusting the functionality led to the six fluorine-labeled macrocyclic bis(indolyl)maleimides. These compounds retain th...