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Proline-catalysed Mannich reactions of acetaldehyde

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Yang,  Jung Woon
Research Department List, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Chandler,  Carley
Research Department List, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Stadler,  Michael
Research Department List, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Kampen,  Daniela
Research Department List, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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List,  Benjamin
Research Department List, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Citation

Yang, J. W., Chandler, C., Stadler, M., Kampen, D., & List, B. (2008). Proline-catalysed Mannich reactions of acetaldehyde. Nature, 452, 453-455. doi:10.1038/nature06740.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000F-90C9-3
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.