Enantioselective Michael addition chiral metal complexes

The catalytic enantioselective addition of aromatic C - H bonds to alkenes would provide a simple and attractive method for the formation of optically active aryl substituted compounds from easily available starting materials. The first catalytic, highly enantioselective Michael addition of indoles was reported by Jorgensen and coworkers. The reactions used a,fl-unsaturated a-ketoesters and alkylidene malonates as Michael acceptors catalyzed by the chiral bisoxazoline (BOX)-metal(II) complexes as described in Scheme 27 [98,99]. 

The asymmetric 1,4-addition (Michael addition) of a cyanide ion to nitroalkenes is a potentially useful route for preparing p-amino acids via transformation of 3-nitropropanonitriles. ° In 2013, North reported the first vanadium-catalysed, enantioselective Michael addition of trimethylsilyl cyanide to aliphatic p-nitroalkenes, which provided (S)-19, as shown in Scheme 9.9. The reaction was promoted by a 3 mol% catalyst loading of chiral vanadium(v) salen complex 18 ° providing (S)-19 in 74-88% conversions with up to 89% enantiomeric excess. North proposed that the nitro group acts as a bridge for the two vanadium metals in the possible transition... 

With regard to the catalytic asymmetric reaction , only a few successful examples, except those reactions using chiral transition metal complexes, have been reported. For example, the cinchona-alkaloid-catalyzed asymmetric 1,4-addition of thiols or 6-keto esters to Michael acceptors quinidine catalyzed the asymmetric addition of ketene to chloral and the highly enantioselective 1,4-addition of ) -keto esters in the presence of chiral crown ethers to Michael acceptors have been most earnestly studied. 

The products are versatile auxiliaries not only for enantioselective deprotonation and elimination (Section C.), but are also valuable chiral ligands for complex hydrides in the enantioselective reduction of ketones (Section D.1.4.5.)- They are also applied in enolate reactions (Section D.l.5.2.1., D.1.5.2.4.). transition-metal-catalyzed Michael additions (Section D.l.5.8.), 1,3-dipolar cycloadditions (Section D.l.6.1.2.1.), and additions ofGrignard reagents (Section D.l.3.1.4.2.5.). (5 )-2-(Phenylaminomethyl)pyrrolidine has found most application and is also commercially available. Several methods exist for the preparation of such compounds. Two typical procedures for the synthesis of (.S)-2-(l-pyrrolidinylmcthyl)pyrrolidine are presented here. The methodology can be readily extended to other amides and alkylamino derivatives of proline. 

The successful achievement of the (/ )-LSB catalyst in asymmetric Michael addition suggested that the metal centers other than rare earths might lead to a novel heterobime-talhc asymmetric catalyst with unique properties. With this foundation, the same group further developed a new heterobimetallic chiral catalyst (/ )-ALB consisting of aluminum, lithium, and (/ )-BINOL in 1996 (Table 9.3). They reported that this type of catalyst could be more efficiently prepared from LiAlH with two equivalents of (/ )-BINOL. When this AlLibis(binaphthoxide) complex (/ )-ALB was employed as catalyst, up to 99% ee and 88% yield of products could be obtained in the reaction of dibenzyl malonate to 2-cyclohexen-l-one. Notably, both dimethyl and diethyl malonates furnished the 1,4-adducts with more than 90% of enantioselectivities. In particular, the catalytic asymmetric tandem Michael-aldol reactions were also achieved in the presence of (/ )-ALB. This protocol provides a usefid method for the catalytic asymmetric synthesis of complex molecules. 

Low-valent Ru(II) [150] and Rh(I) complexes catalyze aldol and Michael reactions of 2-nitrilo esters. The sequence is thought to be initiated by nitrile complexation to the transition metal. This Lewis acid-activation is followed by an oxidative addition to give a metal hydride and a nitrile complexed enolate as shown in Sch. 36. Examples including diastereoselective Ru(II) catalyzed reactions [151] and enantioselective Rh(I)-catalyzed reactions [152-154] with the large trans-chelating chiral ligand PhTRAP are shown in Tables 8 and 9. 

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