Chemoselective Suzuki-Miyaura Cross-Coupling of Di and Tri Boronic Ester Substrates
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In industry and academia, the palladium catalyzed Suzuki-Miyaura cross coupling reaction is one of the most often used methods for the synthesis of new C-C bonds. Recent advancements in this area have expanded the scope of this reaction to include nucleophiles with defined stereochemistry, resulting in enantioenriched, non-racemic products. Prior to this work, the Suzuki-Miyaura cross-coupling reaction was only applicable to processes which formed bonds between sp2 and primary sp3 hybridized carbons. The first successful example of the cross-coupling of enantioenriched secondary boronic esters was published by our group in 2009. The key components in this reaction were the incorporation of silver oxide and excess triphenylphosphine. Not only did these conditions prove effective for the coupling of these substrates, they also showed selectivity for branched benzylic species in the presence of linear alkyl boronic esters. In order to further probe this selectivity, di and tri substrates were prepared that incorporated aryl, secondary benzylic and linear boronic esters. Interestingly, cross-coupling at the secondary benzylic and linear boronic ester requires specialized conditions for the reaction to proceed. This allows introduction of two different substituents in place of the boron groups, based solely off reaction conditions, eliminating the need of protecting groups. In further expansion of the scope, we have prepared the respective enantioenriched substrates and examined their stereoretention. Herein, we discuss the successful iterative Suzuki-Miyaura cross-coupling of both racemic and enantioenriched substrates that contain an aryl sp2 and secondary benzylic sp3 boronic (di boronic ester) or, an aryl sp2, secondary benzylic sp3, and alkyl linear boronic ester (tri boronic ester) with high retention of stereochemistry.