Highly Enantioselective Aldol Reactions between Acetaldehyde and Activated Acyclic Ketones Catalyzed by Chiral Primary Amines

• Published in: Chemistry : a European journal Vol. 19; no. 22; pp. 7143 - 7150
• Main Authors: Deng, Yu-Hua, Chen, Jin-Quan, He, Long, Kang, Tai-Ran, Liu, Quan-Zhong, Luo, Shi-Wei, Yuan, Wei-Chen
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 27.05.2013; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Subjects: Acetaldehyde; Activated; Aldehydes; aldol reactions; Amines; Carbonyl compounds; Chemical reactions; Chemistry; Chemistry, Multidisciplinary; enantioselectivity; Enrichment; Esters; Ketones; lactones; Physical Sciences; Science & Technology; enantioselectivity; ORGANIC-SYNTHESIS; aldol reactions; ONE-POT; amines; ALIPHATIC-KETONES; ALPHA; ketones; QUATERNARY CARBON CENTERS; UNACTIVATED KETONES; 2-STEP SYNTHESIS; lactones; 2-DEOXYRIBOSE-5-PHOSPHATE ALDOLASE; MANNICH REACTIONS; ASYMMETRIC ALDOL
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.201300478

Highly enantioselective cross‐aldol reactions between acetaldehyde and activated acyclic ketones are reported for the first time. Various acyclic ketones, such as saturated and unsaturated keto esters, reacted with acetaldehyde in the presence of a chiral primary amine and a Brønsted acid to afford optically enriched tertiary alcohols in good yields and with excellent enantioselectivities. Trifluoromethyl ketones were tolerable under the reaction conditions, thereby affording the trifluoromethyl carbinol in good‐to‐excellent yields and enantioselectivities. Structural modification of the chiral amines from the same chiral source switched the stereoselectivity of the products. The utility of aldol chemistry was demonstrated in the brief synthesis of functionally enriched δ‐lactones. Theoretical calculations on the transition‐state structure indicated that the protonated tertiary amine could effectively activate the carbonyl group of a keto ester to promote the addition process through hydrogen‐bonding interaction and, simultaneously, provide an appropriate attacking pattern for the approach of the keto ester to the enamine, which is formed from acetaldehyde and the chiral catalyst, on a particular face, resulting in high enantioselectivity. Primary education: Chiral primary amines catalyze enantioselective aldol reactions between acetaldehyde and activated acyclic ketones (see scheme). Optically enriched tertiary alcohols were obtained in good yields with excellent enantioselectivities.