Halomethyl ketones carbonylation

Peptidyl fluoromethyl ketones are widely used as fairly potent inhibitors for a variety of proteases, including serine, cysteine, and aspartyl proteases. Unlike other halomethyl ketones (Section 15.1.3), fluoromethyl ketones are reversible transition-state mimics. The electron-withdrawing fluorine(s) next to the carbonyl group enhances the electrophilicity of the a-fluoroalkyl ketone functionality, thereby making the carbonyl more susceptible to nucleophilic attack. a-Fluoroalkyl ketones are good mimics of peptide bonds due to the small size of the fluorine and the stability of C F bonds. There are three general classes of peptidyl fluoromethyl ketones fluoromethyl ketones (irreversible inhibitors of cysteine proteases), difluoromethyl ketones (reversible inhibitors of both serine and aspartyl proteases), and trifluoromethyl/perfluoroalkyl ketones, which typically exist in hydrated forms and are excellent inhibitors of both serine and cysteine proteasesJ1 ... 

Some halides of sp carbons can be carbonylated. Carbonylation of a-halo ketones and esters is a known reaction [68,69]. jS-Keto esters are prepared by the carbonylation of halomethyl ketones [70,71]. Methyl benzoylacetate (160) was obtained in 86 % yield by the carbonylation of 2-chloroacetophenone (159) in MeOH using PdCl2(PPh3)2 as a catalyst at 110°C and 10 atm in the presence of n-BusN [71]. 

The a-halomethyl silyl ether intermediate has also been effectively applied in the context of anion chemistry. Treatment of iodide (or bromide) 25 with 2 equiv of t-BuLi rapidly affords an a-silyllithium species that smoothly undergoes intramolecular addition to the carbonyl group affording bridged bicyclic [3.3.1] alcohol 26 in excellent yield (eq 7). Equally notable is the observation that formation of the ketone enolate of 25 provides the bridged bicyclic [3.2.2] system 27 via intramolecular alkylation. 

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