Enantioselective Conjugate Additions of Heteroatom Nucleophiles

Catalytic asymmetric conjugate additions of heteroatoms such as nitrogen or sulfur nucleophiles provide access to important / -substituted carbonyl deri-vates, and a number of successful strategies have been devised (38, 39, 41). Tomioka developed enantioselective additions of thiophenols to ,/i-unsatu-rated esters (Equation 42) [164]. This reaction proceeds in the presence of the presumed lithium complex 220, which was suggested as the catalytically active species. As a control experiment, the chiral amino diether itself is not a catalyst for the addition of thiophenol 219 to 218. A variety of trans enoates were shown to undergo addition to give the products with high levels of induction, as illustrated by the formation of thioether 221 (99 % yield, 97 % ee). 

For the introduction of /j-amino substituents, enantioselective 1,4-additions using 0-benzylhydroxylamine (Equation 43) have been reported by Sibi [162, 165], The magnesium complex of the bisoxazoline ligand 213 was found to be optimal for activation of pyrazole amide derivatives such as 222 [165], Addition of 0-benzylhydroxylamine to 222 is mediated by 30 mol % each of 213 and MgBr2 to furnish 223 in 80% yield and 95% ee. In the course of investigating this catalyst system, the intervention of a kinetic resolution step involving the product was noted. Thus, the minor enantiomer (ent-223) was observed to undergo more rapid amidolysis than the major enantiomer 223 under the reaction conditions. 

One-pot conjugate addition-amination process followed by cyclization reported by Jorgensen [12] 

Jacobsen has developed a number of methods that employ chiral salen complexes as catalysts for enantioselective conjugate addition processes [166,167]. Notable among these is the addition of azide to substituted N-ben-zoyl imides as acceptors (Equation 44) [166]. The addition of HNj to imide 224 gave azide 226 in high yield (97 %) and optical purity (97 % ee). The subsequent reduction of the azide adducts to the corresponding amines provides convenient access to optically active j8-amino acids. 

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