Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 61, Issue 48, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202206111
Keywords
Biomimetic Catalysis; Carbonyl Catalysis; C-H Functionalization; Chiral Pyridoxal; Organocatalysis
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Funding
- National Natural Science Foundation of China [21871181]
- Shanghai Municipal Education Commission [2019-01-07-00-02-E00029]
- Shanghai Municipal Committee of Science and Technology [18ZR1447600, 20JC1416800]
- Shanghai Engineering Research Center of Green Energy Chemical Engineering [18DZ2254200]
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This study successfully achieved the direct asymmetric functionalization of the inert alpha C-H bonds of N-unprotected propargylic amines using a chiral pyridoxal as a carbonyl catalyst. The method showed high yields and excellent stereoselectivities, providing a solution to a major challenge in organic chemistry.
Direct asymmetric functionalization of the inert alpha C-H bonds of N-unprotected propargylic amines is a big challenge in organic chemistry, due to the low acidity (pK(a)approximate to 42.6) of the alpha C-H bonds and interruption of the nucleophilic NH2 group. By using a chiral pyridoxal as carbonyl catalyst, we have successfully realized direct asymmetric alpha-C-H addition of N-unprotected propargylic amines to trifluoromethyl ketones, producing a broad range of chiral alkynyl beta-aminoalcohols in 54-84 % yields with excellent stereoselectivities (up to 20 : 1 dr and 99 % ee). The alpha C-H bonds of propargylic amines are greatly activated by the pyridoxal catalyst via the formation of an imine intermediate, resulting in the increase of acidity by up to 10(22) times (from pK(a) 42.6 to pK(a) 20.1), which become acidic enough to be deprotonated under mild conditions for the asymmetric addition. This work presented an impressive example for asymmetric functionalization of inert C-H bonds enabled by an organocatalyst.
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