Abstract
Small organic molecules recently emerged as a third class of broadly useful asymmetric catalysts that direct reactions to yield predominantly one chiral product, complementing enzymes and metal complexes1. For instance, the amino acid proline and its derivatives are useful for the catalytic activation of carbonyl compounds via nucleophilic enamine intermediates. Several important carbon–carbon bond-forming reactions, including the Mannich reaction, have been developed using this approach2, all of which are useful for making chiral, biologically relevant compounds. Remarkably, despite attempts3,4, the simplest of all nucleophiles, acetaldehyde, could not be used in this way. Here we show that acetaldehyde is a powerful nucleophile in asymmetric, proline-catalysed Mannich reactions with N-tert-butoxycarbonyl (N-Boc)-imines, yielding β-amino aldehydes with extremely high enantioselectivities—desirable products as drug intermediates and in the synthesis of other biologically active molecules. Although acetaldehyde has been used as a nucleophile in reactions with biological catalysts such as aldolases5 and thiamine-dependent enzymes6, and has also been employed indirectly7,8,9, its use as an inexpensive and versatile two-carbon nucleophile in asymmetric, small-molecule catalysis will find many practical applications.
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Acknowledgements
We acknowledge support by the Max-Planck-Society, the DFG (Priority Program Organocatalysis), Novartis (Young Investigator Award to B.L.), Astra Zeneca (Research Award in Organic Chemistry), and by the Fonds der Chemischen Industrie. We also thank J. Rosentreter and S. Ruthe for gas chromatographic measurements, and A. Deege and H. Hinrichs for HPLC measurements.
Author Contributions J.W.Y. and M.S. planned, conducted and analysed experiments for the aromatic Mannich products. C.C. planned, conducted and analysed experiments for the aliphatic Mannich products. J.W.Y., C.C. and D.K. planned and conducted experiments and analysed the data for the compounds to demonstrate the utility of the Mannich products. B.L. designed and directed the project and wrote the manuscript with contributions by J.W.Y., C.C. and D.K. J.W.Y., C.C. and D.K. compiled most of the Supplementary Information. All authors contributed to discussions.
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The file contains Supplementary Data with spectroscopic data, HRMS data and GC/HPLC chromatograms for the appropriate compounds. (PDF 1818 kb)
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Yang, J., Chandler, C., Stadler, M. et al. Proline-catalysed Mannich reactions of acetaldehyde. Nature 452, 453–455 (2008). https://doi.org/10.1038/nature06740
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DOI: https://doi.org/10.1038/nature06740
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