2-Cyclohexenone enantioselective alkylation

The idea of a reversible alkene-copper complex had been used to explain the enantioselective alkylation of 2-cyclohexenone using a chiral auxiliary ligand.30 Interaction of the cuprate with the re face of C-3 in 2-cyclohexenone was presumed to be favored over complexation with the si face of C-3 for steric reasons (equation 4). 

In view of the selectivity of lithiation of the imine system, to get a -syn deprotonation and subsequently substitution, Fraser investigated the scope of asymmetric induction of a chiral imine, i.e. cyclohexenone imine, that derives from TV-a-phenethylamine 34. On alkylation by Mel or EtI, he obtained a-substituted cyclohexanones in ee of 50%66. Ma-Jacheet and Horeau67 and Yamada and coworkers68, who used this technique, obtained 25-45% ee. Free rotation around the C—N bond, as well as the lack of control of the configuration of the alkylation product, were the reasons ascribed for the low amount of asymmetric induction. A better enantioselectivity was achieved when the imine had an inner ligand (OMe), that makes the lithioenamine 35 more rigid by /w/ramolecular chelation. 

The CpRe-Lewis acid shown in Sch. 25 forms stable complexes with cyclohexenone and cyclopentenone. The enones coordinate to the metal forming an Re-O cr-bond. Addition of organocuprates followed by treatment with HI yield enantiomerically enriched 3-alkylated cycloalkanones and an optically active Re-I complex. MeMgBr-ether and MeLi-ether gave low yields in these reactions. The data shown in Sch. 25 reflect the problem that the yields and enantioselectivity of the organocuprate additions vary widely with the reaction conditions used and the preparation of the organocuprate [122], and must be optimized for every reaction. 

An a,p-unsaturated ketone can contribute as both a Michael donor and a Michael acceptor at the same time. There are cases in which a PTC catalyst has served for the enantioselective dimerisation of a,(3-unsaturated ketones under phase-transfer conditions. In 2004, Corey and coworkers demonstrated a simple and practical pathway to chiral a-alkyl-ated y-keto acids, which are important intermediates for the preparation of peptide isosteres by dimerisation, through a Michael reaction of 1-phenyl-2-buten-l-one (57) with itself. Subsequently, the Bella group reported the asymmetric dimerisation of cyclohexenone (60), catalysed by the newly prepared PTC catalyst 7f with good enantioselectivity (up to 92% enantiomeric excess), and no byproducts or regioisomers were observed (Scheme 16.18). ... 

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