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DOI: 10.1055/sos-SD-201-00304

Nguyen, B. N.; Hii, K. K.; Szymański, W.; Janssen, D. B.Science of Synthesis: Stereoselective Synthesis, (20111642.

The oxyanion hole of hydrolases, previously shown to facilitate the Michael addition of stabilized C-nucleophiles (see Section, is also able to catalyze the Michael addition of N-nucleophiles to α,β-unsaturated carbonyl compounds.[‌161‌] A wide range of N-nucleophiles are reported to undergo this reaction, both in aqueous and organic environments, including primary[‌162‌,‌163‌] and secondary[‌162‌,‌164‌] aliphatic amines as well as N-heterocycles[‌165‌] such as purines,[‌166‌] pyrimidines,[‌167‌] and imidazoles.[‌168‌‌170‌] In most cases, no enantioselectivity is found or reported; the only exception is the Candida antarctica lipase B (CalB)-catalyzed addition of benzylamine to methyl but-2-enoate, where a competitive formation of the Michael and ester aminolysis products is observed (Scheme 30).[‌161‌] Solvent polarity has an important effect on the chemoselectivity and stereoselectivity of the reaction. Thus, using hydrophobic hexane as a reaction medium, the Michael adduct 89 is obtained as the predominant product (95:5), but only exhibits low optical activity ([α]D+0.45). On the other hand, the use of the protic solvent 2-methylbutan-2-ol results in opposite chemoselectivity in favor of the amide product 90 (20:80). The minor Michael adduct displays a notable optical rotation of +11, from which the authors inferred an enantiomeric excess of <60%.

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