Enantioselective decarboxylative chlorination of β-ketocarboxylic acids

Abstract

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.

C5‐Disubstituted Meldrum's Acid Derivatives as Platform for the Organocatalytic Synthesis of C3‐Alkylated Dihydrocoumarins

“…[8,9] Scheme 1. [13] This investigation began with the phenol 1 a as a model substrate (Scheme 2, see SI for full-details). We recently introduced disubstituted Meldrum's acid (MA) derivatives as stable alternatives to hemimalonic esters for the enantioselective decarboxylative protonation reaction upon phase-transfer catalytic conditions, [10] while this architecture also affords new synthetic opportunities in heterocycle formation.…”

“…At the onset, we considered the beautiful and unprecedented enantioselective decarboxylative chlorination reaction recently reported by Shibatomi et al [13], [20] This strategy applied to our domino cyclization-decarboxylative process would provide an unprecedented entry to dihydrocouramins 6 having a C3chlorinated tetrasubstituted stereocenter (Scheme 7). At the onset, we considered the beautiful and unprecedented enantioselective decarboxylative chlorination reaction recently reported by Shibatomi et al [13], [20] This strategy applied to our domino cyclization-decarboxylative process would provide an unprecedented entry to dihydrocouramins 6 having a C3chlorinated tetrasubstituted stereocenter (Scheme 7).…”

“…Furthermore, by means of these MA-based platforms, a proof of concept of a sparingly reported asymmetric decarboxylative chlorination reaction was demonstrated allowing the construction of chiral C3-chlorinated dihydrocoumarins. [13] This investigation began with the phenol 1 a as a model substrate (Scheme 2, see SI for full-details). A screening of an array of chiral Brønsted bases revealed that quinine 3 a achieved the domino transformation into the desired 2 a in smooth conditions (rt, 2 hours), in a complete conversion and promising 37.5:62.5 er.…”

“…Next, we wondered whether it could be possible to take advantage of the reactivity of the readily available Meldrum's acid platforms 4, for the construction of more substituted dihydrocoumarin derivatives. At the onset, we considered the beautiful and unprecedented enantioselective decarboxylative chlorination reaction recently reported by Shibatomi et al [13], [20] This strategy applied to our domino cyclization-decarboxylative process would provide an unprecedented entry to dihydrocouramins 6 having a C3chlorinated tetrasubstituted stereocenter (Scheme 7).…”

Stereoselective Construction of Halogenated Quaternary Carbon Centers by Brønsted Base Catalyzed [4+2] Cycloaddition of α‐Haloaldehydes

“…[10] From as ynthetic perspective,t he inherently unique reactivity of halogens can enable efficient transformations such as stereospecific S N 2s ubstitution, cross-coupling,a nd other related derivatizations. [14] However,b oth approaches generated the desired cyclic products based on a"substituent-modification" strategy starting from cycloketone substrates.A lternatively, an asymmetric cycloaddition strategy,w hich enables direct construction of halogenated cyclic structures with multiple stereocenters,has been scarcely explored, despite its inherent advantages of atom economy and potentially higher synthetic efficiency (Scheme 1B,c). Construction of ahalogenated quaternary center by enolate catalysis with cycloadditions trategy.Boc = tert-butoxycarbonyl.…”