Halo enol lactones

Halo-lactonization of ketophosphoranes has been achieved via reaction with cyclic anhydrides and subsequent halogenation. " The products, halo enol lactones (75), are synthetically useful compounds, and an alternative synthesis via incorporation of the halogen at the ylid stage is also described. Mechanistic investigation of the Wittig reactions involved reveals subtle variations in pathway, allowing optimum experimental conditions to be selected to allow for the variation in reactivity of different anhydrides and halides. 

Halo enol lactones are an example of suicide Inhibitors for serine proteases. These analogues were developed by Katzenellenbogen and coworkers at the University of Illinois (34). On normal catalytic processing by the serine hydroxyl functionality, they give rise to a reactive halo-methyl ketone, which subsequently alkylates a nearby nucleophilic residue on the enzyme (Fig. 5.16). Other suicide Inactivators for the serine proteases have been designed by various researchers (32). 

Kraft GA, Katzenellenbogen JA. Synthesis of halo enol lactones. Mechanism-based inactivators of serine proteases. J Am Chem Soc 1981 103 5459-5466. 

Alkylation of oxazolones with a-halo ketones under phase-transfer catalysis generated an enolate 155 from initial alkylation at C-4 that immediately translac-tonized to produce an enol lactone 156 (Scheme 7.46)." Selected examples of 5(47/)-oxazolones prepared via alkylation are shown in Table 7.17 (Fig. 7.19). 

An alternate approach, which also uses enzyme-catalyzed ring-opening of a lactone to generate a mechanism-activated inhibitor, was developed by Katzenellenbogen and his co-workers [183], who found enol lactones, exemplified by (13-8) and (13-9), to be potent, selective inhibitors of HLE. The haloenol lactone (13-9) was an irreversible inactivator of HLE and chymotrypsin, and after exposure to (13-9), active enzyme could not be regenerated even upon treatment with hydrazine. Enol lactone (13-8), on the other hand, was an alternate-substrate inhibitor, which produced only transient inhibition of HLE and chymotrypsin. These results have been interpreted to mean that, with the halo-substituted compounds, ring opening results in formation of an acyl-enzyme that contains a reactive halomethyl ketone, which then alkylates His-57. That these compounds... 

The halogens in o-bromo- or o-iodo-veratric acids are replaced by ketone enolates to give primary products which on lactonization or lactamization lead to benzazepines or benzoxepines respectively.126 There would appear to be no reason why this reaction could not be extended to reactions of o-halo-phenylacetic acids in general. 

New fatty compounds have been synthesized in high yields using radical addition reactions. Alkyl 2-haloalkanoates have been added to the double bond of unsaturated fatty compounds to give y-lactones. 2-Haloalkanenitriles have been added as well to give 4- haloalkanenitriles. 2-Halo fatty compounds, e.g., methyl 2-bromopalmitate, have been added to alkenes, allyl alcohol, vinyl esters, and trimethylsilyl enol ethers to give interesting branched and functionalized compounds. Key features of the re-... 

---