Stereoselective halogenation is a highly useful organic transformation for multistep syntheses because the resulting chiral organohalides can serve as precursors for various medicinally relevant derivatives. Even though decarboxylative halogenation of aliphatic carboxylic acids is a useful and fundamental synthetic method for the preparation of a variety of organohalides, an enantioselective version of this reaction has not been reported. Here we report a highly enantioselective decarboxylative chlorination of β-ketocarboxylic acids to obtain α-chloroketones under mild organocatalytic conditions. The present method is also applicable for the enantioselective synthesis of tertiary α-chloroketones. The conversions of the resulting α-chloroketones into α-aminoketones and α-thio-substituted ketones via SN2 reactions at the tertiary carbon centres are also demonstrated. These results constitute an efficient approach for the synthesis of chiral organohalides and are expected to enhance the availability of enantiomerically enriched chiral compounds with heteroatom-substituted chiral stereogenic centres.
The enantioselective formation of α-aryloxy-β-keto esters is described for the first time. Lewis acid catalyzed enantioselective chlorination of β-keto esters and subsequent SN 2 reactions with phenols yielded α-aryloxy-β-keto esters with up to 96% ee. Favorskii rearrangement of α-chloro-β-keto esters was also found to give 1,2-diesters with slightly reduced enantiopurity.
For the first time, the enantioselective synthesis of α‐aryloxy‐β‐keto esters through the sequential enantioselective chlorination of cyclic and non‐cyclic β‐keto esters followed by nucleophilic substitution of chlorine atoms with phenols is described.
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