Titanium catalysts enantioselective fluorination

A newer approach toward the enantioselective electrophilic fluorination of jS-ketoesters is based on enolization of the substrate under neutral conditions by coordination to a chiral titanium catalyst [211]. The catalyst, a chiral titanium TADDOLato complex (TADDOL = a,a,a, a -tetraaryl-2,2-dimethyl-1,3-dioxolan-4,5-dimethanol) [212, 213], coordinates to the -ketoester, enolizes it, and thus renders it susceptible to electrophilic fluorination (Scheme 2.95). One face of the prochiral enolate substructure is covered by a bulky naphthyl substituent from the TADDOL ligand, impeding electrophilic attack of F-TEDA. 

Another approach to facilitate the recovery of catalytic systems relies on the use of fluorinated analogues of classic chiral ligands. The recycling options offered by the fluorous catalysts have been explored in the field of asymmetric addition of dialkylzinc reagents to aldehydes in presence of titanium tetraisopropoxide. In 2000, the groups of Chan ° and Curran reported independently the synthesis of perfluoroallqrl-substituted BINOL ligands and their evaluation in the titanium-mediated enantioselective addition of diethylzinc to aromatic aldehydes in fluorous biphasic system (Scheme 7.27). 

In these cases, NFSI was preferred to Selectfluor and the reactions were performed either in alcohol or in ionic liquids in which the palladium complexes can be immobilized and reused with excellent reproducibility even after 10 consecutive cycles. For example, the enantioselective electrophilic fluorination of 2-methyl-3-oxo-3-phenylpro-pionic acid tert-butyl ester in [hmim] [BF4] gives the corresponding fluorinated product in 93% yield with 92% ee, and still in 67% yield with 91% ee after 10 cycles. The fluorination of various cyclic and acyclic (3-keto esters was carried out with NFSI in ethanol in the presence of 2.5 mol% of catalyst, leading to excellent ee-values up to 94%. The reaction is not sensitive to water, can be run on a 1-g scale, and proceeds via a palladium enolate complex as for the titanium-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyl-dioxolane (TADDOL) catalyst. The reaction was extended to tert-butoxycarbonyl lactones and lactams. Reactions with lactones proceeded smoothly in an alcoholic solvent with 2.5 mol% of catalyst and NFSI, while the less acidic lactam substrates required concurrent use of the Pd complex and 2,6-lutidine as a co-catalyst. Under the reaction conditions, the fluorinated lactones and lactams were obtained in good yields with excellent enantioselectivities (up to 99%... 

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