Highly enantioselective synthesis of γ-, δ-, and ε-chiral 1-alkanols via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)–Cu- or Pd-catalyzed cross-coupling

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-06, Vol.111 (23), p.8368-8373
• Main Authors: Xu, Shiqing, Oda, Akimichi, Kamada, Hirofumi, Negishi, Ei-ichi
• Format: Article
• Language: English
• Subjects: Acetylation; Alcohols; Alcohols - chemical synthesis; Alcohols - chemistry; Alcohols - metabolism; Alkenes; Alkenes - chemistry; Aluminum Compounds - chemistry; Carbon - chemistry; Catalysis; Chirality; Copper - chemistry; Esters; Iodides; Lipase - metabolism; Models, Chemical; Molecular Structure; Nuclear magnetic resonance; Oxidation-Reduction; Palladium - chemistry; Physical Sciences; Reagents; Solvents; Stereoisomerism; Tetrahedrons; Zirconium - chemistry
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1401187111

Despite recent advances of asymmetric synthesis, the preparation of enantiomerically pure (≥99% ee) compounds remains a challenge in modern organic chemistry. We report here a strategy for a highly enantioselective (≥99% ee) and catalytic synthesis of various γ- and more-remotely chiral alcohols from terminal alkenes via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA reaction)–Cu- or Pd-catalyzed cross-coupling. ZACA–in situ oxidation of tert -butyldimethylsilyl (TBS)-protected ω-alkene-1-ols produced both (R)- and (S)-α,ω-dioxyfunctional intermediates (3) in 80–88% ee , which were readily purified to the ≥99% ee level by lipase-catalyzed acetylation through exploitation of their high selectivity factors. These α,ω-dioxyfunctional intermediates serve as versatile synthons for the construction of various chiral compounds. Their subsequent Cu-catalyzed cross-coupling with various alkyl (primary, secondary, tertiary, cyclic) Grignard reagents and Pd-catalyzed cross-coupling with aryl and alkenyl halides proceeded smoothly with essentially complete retention of stereochemical configuration to produce a wide variety of γ-, δ-, and ε-chiral 1-alkanols of ≥99% ee . The MαNP ester analysis has been applied to the determination of the enantiomeric purities of δ- and ε-chiral primary alkanols, which sheds light on the relatively undeveloped area of determination of enantiomeric purity and/or absolute configuration of remotely chiral primary alcohols.