Abstract
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 language | English (US) |
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Pages (from-to) | 5459-5466 |
Number of pages | 8 |
Journal | Journal of the American Chemical Society |
Volume | 103 |
Issue number | 18 |
DOIs | |
State | Published - Sep 1981 |
ASJC Scopus subject areas
- Catalysis
- General Chemistry
- Biochemistry
- Colloid and Surface Chemistry