Synthesis of Halo Enol Lactones. Mechanism-Based Inactivators of Serine Proteases

Grant A. Krafft, John A. Katzenellenbogen

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Enol lactones bearing a halogen at the vinylic position are potential mechanism-based inactivators (suicide inactivators) of serine hydrolases, since acyl transfer to the active-site serine releases an α-halo ketone that can react with nucleophilic sites in the active-site region. Efficient syntheses of such halo enol lactones needed for enzymatic studies are described. 5-Hexynoic acids can be cyclized with mercuric ion catalysis to γ-methylene butyrolactones. Cyclization of the 6-bromo and 6-chloro analogs leads stereospecifically to the Z-halo enol lactones (trans addition), but is quite slow. Cyclization of unsubstituted or 6-methyl- or 6-trimethylsilyl-substituted 5-hexynoic acids is more rapid, but olefin isomerization occurs during the reaction. Direct halogenation of γ-methylene butyrolactones leads to preferential elimination in an endocyclic sense, producing the undesired 5-bromomethylidene-2(3H)-furanones; however, the 5-trimethylsilylmethylene and the 5-mercuriomethylene butyrolactones can be converted with moderate efficiency into the desired 5-bromomethylene butyrolactones. The most efficient approach is direct halolactonization of the 5-hexynoic acids with bromine or iodine in a two-phase system with phase-transfer catalysis. This method was used to prepare various 5-halomethylene or 5-haloethylidene 2-phenylbutyrolactones and 6-bromo- and iodomethylene valerolactones. In certain cases where undesired enolization is blocked, γ-halomethylene butyrolactones can be prepared by cyclization of α-halo keto acids (e.g., o-(bromomacetyl)benzoic acid to 5-bromomethylidenebenzo-2(5H)-furanone), and certain endocyclic halo enol lactones can be prepared by Baeyer-Villiger oxidation of cyclic 3-halo 2-enones. Preliminary studies indicate that these halo enol lactones have reasonable hydrolytic stability, and, in studies presented elsewhere, selected compounds have been found to be efficient inactivators of chymotrypsin.

Original languageEnglish (US)
Pages (from-to)5459-5466
Number of pages8
JournalJournal of the American Chemical Society
Issue number18
StatePublished - Sep 1981

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


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