Base-free enantioselective SN2 alkylation of 2-oxindoles via bifunctional phase-transfer catalysis.

N-Protected oxindole derivatives of unprecedented malleability bearing ester moieties at C-3 have been shown to participate in enantioselective phase-transfer-catalysed alkylations promoted by ad-hoc designed quaternary ammonium salts derived from quinine bearing hydrogen-bond donating substituents. For the first time in such phase-transfer-catalysed enolate alkylations, the reactions were carried out under base-free conditions. It was found that urea-based catalysts outperformed squaramide derivatives, and that the installation of a chlorine atom adjacent to the catalyst's quinoline moiety aided in avoiding selectivity-reducing complications related to the production of HBr in these processes. The influence of steric and electronic factors from both the perspective of the nucleophile and electrophile were investigated and levels of enantiocontrol up to 90% ee obtained. The synthetic utility of the methodology was demonstrated via the concise enantioselective synthesis of a potent CRTH2 receptor antagonist.

The human tRNA-guanine transglycosylase displays promiscuous nucleobase preference but strict tRNA specificity.

Base-modification can occur throughout a transfer RNA molecule; however, elaboration is particularly prevalent at position 34 of the anticodon loop (the wobble position), where it functions to influence protein translation. Previously, we demonstrated that the queuosine modification at position 34 can be substituted with an artificial analogue via the queuine tRNA ribosyltransferase enzyme to induce disease recovery in an animal model of multiple sclerosis. Here, we demonstrate that the human enzyme can recognize a very broad range of artificial 7-deazaguanine derivatives for transfer RNA incorporation. By contrast, the enzyme displays strict specificity for transfer RNA species decoding the dual synonymous NAU/C codons, determined using a novel enzyme-RNA capture-release method. Our data highlight the broad scope and therapeutic potential of exploiting the queuosine incorporation pathway to intentionally engineer chemical diversity into the transfer RNA anticodon.

Enantioselective Alkylation of 2-Oxindoles Catalyzed by a Bifunctional Phase-Transfer Catalyst: Synthesis of (-)-Debromoflustramine†B.

A new bifunctional phase-transfer catalyst that employs hydrogen bonding as a control element was developed to promote efficient enantioselective SN 2 reactions for the construction all-carbon quaternary stereocenters in high yield and excellent enantioselectivity (up to 97 % ee) utilizing the alkylation of a malleable oxindole substrate. The utility of the methodology was demonstrated through a concise and highly enantioselective synthesis of (-)-debromoflustramine B.

Enantioselective Alkylative Kinetic Resolution of 2-Oxindole-Derived Enolates Promoted by Bifunctional Phase Transfer Catalysts.

The first strategy for bringing about highly enantioselective alkylative enolate kinetic resolutions using a simple phase-transfer protocol via SN2 chemistry has been developed. In the presence of a new squaramide-based quaternized cinchona alkaloid-derived catalyst and aqueous base, benzyl, allyl, and propargyl halides react with racemic substituted oxindoles to generate densely functionalized products with the two contiguous stereocenters, one of which is an all-carbon quaternary.