Enantioselectivity Grignard reagents

The first reports on enantioselective addition reactions of achiral organometallic reagents, modified by aprotic chiral additives, described the addition of Grignard reagents to prostereogenic carbonyl compounds in the presence of ( + )-(/ ,/J)-2,3-dimethoxybutane (l)4 5, (-)-tetrahydro-2-methylfuran (2)6, (-)-l-[(tetrahydro-2-furanyl)methyl]pyrrolidine (3)7 or (-)-sparteine (4)8. The enantioselectivity, however, was poor (0-22% ee). 

The enantioselective addition of organometallic reagents to, V-(trimethylsilyl)benzaldehyde imine (1) in the presence of enantiomerically pure modifiers has been investigated. The best result is obtained with butyllithium (the corresponding Grignard reagent affords both lower yield and selectivity, 1 fails to react with diethylzinc) and two equivalents of the enantiomerically pure diol 2 in diethyl ether. It should be noted that the choice of the solvent is crucial for the stereoselectivity of the reaction1 2 3 5 7 8 9. 

Grignard reagents with allylic substrates, providing the corresponding y-pro-ducts in enantioselectivities of up to 50% ee (Scheme 1.47). ... 

Aromatic and vinylic sulfides take part in cross-coupling reactions with Grignard reagents in the presence of Ni catalysts.336,337 This reaction has been applied to the enantioselective synthesis of binaphthyls using a standard chiral oxazoline ligand (Equation (25)) 338... 

In the presence of 5 mol% CuBr SMe2 and 6mol% 17b, acyclic aliphatic enones can also react with Grignard reagents to provide / -substituted linear ketones in high yields (62-91%), good regioselectivities (>94 6), and excellent enantioselectivities (90-98%) (Scheme 10).24... 

The catalytic RCM with 31 as substrate (Scheme 7) is significantly more facile when the reaction is carried out under an atmosphere of ethylene, presumably due to the formation of the more active Mo=CH2 system (see below for further details). Thus, after catalytic removal of the directing unit, the chiral unsaturated alcohol (S)-32,the formal product of an enantioselective addition of the Grignard reagent to unfunctionalized heterocycle 33, is obtained. An additional in-... 

The availability of oxepins that bear a side chain containing a Lewis basic oxygen atom (entry 2, Table 6.4) has further important implications in enantioselective synthesis. The derived alcohol, benzyl ether, or methoxyethoxymethyl (MEM) ethers, in which resident Lewis basic heteroatoms are less sterically hindered, readily undergo diastereoselective uncatalyzed alkylation reactions when treated with a variety of Grignard reagents [17]. The examples shown below (Scheme 6.7) demonstrate the excellent synthetic potential of these stereoselective alkylations. 

Q.-L. Zhou, A. Pfaltz, Chiral Mercaptoaryl-oxazolines as Ligands in Enantioselective Copper-Catalyzed 1,4-Additions of Grignard Reagents to Enones, Tetrahedron, 1994, 50, 4467-4478. 

---