Chiral substrates, asymmetric conjugate

SCHEME 1. Asymmetric conjugate addition of Grignard reagents to substrates containing chiral auxiliaries... 

Although desirable, the recovery of a chiral auxiliary is not always crucial. Some techniques employ a, -unsaturated carbonyl compounds containing a disposable stereogenic center, which is removed after the (asymmetric) conjugate addition step has been performed. This concept appears to be useful only if the chiral substrate is easily accessible in high enantiomeric purity. 

As described in Section 6.2.1.1, earlier application of conjugate addition involved transferable aluminum hydrides and alkyls. This section is devoted to asymmetric conjugate addition using a chiral aluminum catalyst and newer aspects that enable substrate generality wifh respect to both Michael acceptor and donor components, by use of well-designed aluminum reagents. 

The chromium complex 46 of benzaldehyde imine is also a good substrate for asymmetric conjugate addition of organolithium reagents, where the reaction was mediated by a stoichiometric amount of chiral diether 18 in toluene to give, following propargylic electrophile incorporation, the cyclohexadienal 48 in up to 93% ee (Scheme 13) [38]. SAMP [(S)-l-amino-2-(methoxymethyl)pyrrolid-ine] hydrazones were used effectively in diastereoselective nucleophilic additions to (arene)Cr(CO)3 complexes [39]. 

In an effort to develop a more efficient method to S5mthesize enantioenriched allylic amine substrates for [2,3]-rearrangements, Davies and Smyth reported an asymmetric conjugate addition with chiral lithium amide 74 tScheme 1S.16T ° The resulting aminoester 75 was reduced to alcohol 76, which was treated with m-CPBA to furnish chiral amine iV-oxide 77. 

The development of highly effective organocatalytic asymmetric conjugate addition of simple ketones to chalcones is very challenging due to the low reactivity and high steric hindrance of both substrates. For such a reaction, Zhang and Corey [52] presented their pioneering achievement with A(-aIkylated cinchona alkaloid derivative 55 as catalyst (Scheme 5.26). The optical active products could be further used in the asymmetric syntheses of (5)-ornithine and chiral 2-cyclohexenones. 

A dihydroquinidine-derived chiral thiourea (DHQD-30), which demonstrated significantly better stereocontrol than other cinchona alkaloids, was utilized in the aza-Henry reaction with nitroalkanes and aldimines by Schaus and coworkers (Scheme 13.8) [26]. The utility of the nitroethane pronucleophile conveniently offers a tertiary stereogenic center in the P-nitroamine product 32. The methodology is also conveniently applicable to novel a,P-unsaturated aliphatic imines 29, which are difficult substrates in asymmetric conjugate addition reactions. Similar reaction conditions can be appHed towards to the use of dimethyl malonates as pronucleophiles that generate adducts in high enantioselectivity, which then convert smoothly into P-amino esters under the Nef conditions. 

An auxiliary approach was developed by Meyers, who found that unsaturated oxazolines such as 58 participate in asymmetric conjugate addition reactions with organolithium reagents (Equation 11) [74, 75]. With these substrates, a wide variety of chiral /1-substituted acids, including 59, were obtained with excellent enantioselectivity [75]. The yields were highest for substrates lacking allylic protons, as y-deprotonation was observed as a competing unwanted side reaction. 

Chiral amidocuprates have also been demonstrated to function as catalysts in asymmetric conjugate additions for selected substrates [43], A seminal result was disclosed by Lippard, who used amidocuprate 170 (Equation 30) [135]. This complex is generated from the deprotonated aminotropone... 

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