An aromatic ion platform for enantioselective Brønsted acid catalysis

Science  26 Feb 2016:
Vol. 351, Issue 6276, pp. 961-965
DOI: 10.1126/science.aad0591

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Competition for binaphthyl catalysts

The binaphthyl framework has proven extremely effective in biasing a broad range of chemical reactions toward just one of two mirror-image products. The motif was first applied as a ligand in metal catalysis, and more recently as a conjugate base in acid catalysis. Gheewala et al. report a class of chiral carbon acids based around a cyclopentadiene framework that are easily accessible from readily available precursors. The compounds are showcased as highly selective catalysts for asymmetric Mukaiyama Mannich and oxocarbenium aldol reactions.

Science, this issue p. 961


Chiral acid catalysts are useful for the synthesis of enantioenriched small molecules, but the standard catalysts require laborious and expensive preparations. Here, we describe a chiral Brønsted acid prepared in one step from naturally occurring (–)-menthol and readily available 1,2,3,4,5-pentacarbomethoxycyclopentadiene. Aromatic stabilization serves as a key contributing factor to the potent acidity of the resulting compound, which is shown to catalyze both Mukaiyama-Mannich and oxocarbenium aldol reactions with high efficiency and enantioselectivity. Catalyst loadings as low as 0.01 mole percent and preparative scalability (25 grams) are demonstrated. Alternative amide catalysts are also shown to be promising platforms. In addition to proton catalysis, a chiral anion pathway is demonstrated to be viable with this catalyst system.

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