Preparation and Reactions of Enantiomerically Pure α‑Functionalized Grignard Reagents

• Published in: Journal of the American Chemical Society 2013-05, Vol.135 (21), p.8071-8077
• Main Authors: Rayner, Peter J, O’Brien, Peter, Horan, Richard A. J
• Format: Article
• Language: English
• Subjects: Indicators and Reagents - chemistry; Stereoisomerism
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja4033956

A strategy for the generation of enantiomerically pure α-functionalized chiral Grignard reagents is presented. The approach involves the synthesis of α-alkoxy and α-amino sulfoxides in ≥99:1 dr and ≥99:1 er via asymmetric deprotonation (s-BuLi/chiral diamine) and trapping with Andersen’s sulfinate (menthol derived). Subsequent sulfoxide → Mg exchange (room temperature, 1 min) and electrophilic trapping delivers a range of enantiomerically pure α-alkoxy and α-amino substituted products. Using this approach, either enantiomer of products can be accessed in 99:1 er from asymmetric deprotonation protocols without the use of (−)-sparteine as the chiral ligand. Two additional discoveries are noteworthy: (i) for the deprotonation and trapping with Andersen’s sulfinate, there is a lack of stereospecificity at sulfur due to attack of a lithiated intermediate onto the α-alkoxy and α-amino sulfoxides as they form, and (ii) the α-alkoxy-substituted Grignard reagent is configurationally stable at room temperature for 30 min.