Asymmetric conjugate additions amides

Asymmetric conjugate addition of lithium amides to alkenoates has been one of the most powerful methods for the synthesis of chiral 3-aminoalkanoates. High stereochemical controls have been achieved by using either chiral acceptors as A-enoyl derivatives of oxazolidinones (Scheme 4) 7 7a-8 chiral lithium amides (Schemes 5 and 6),9-12 or chiral catalysts.13,14... 

Tab. 3.3 Asymmetric conjugate addition of organoboronic acids to a,/ -unsaturated amides [22].

Scheme 3.9 Asymmetric conjugate addition to cyclic a,jS-unsaturated amides [23],...

If no component has stereochemistry, asymmetric conjugate addition can be ensured by a C2 symmetric chiral auxiliary attached to the enolate partner. Addition of the lithium enolate of the amide 31 to the unsaturated ester 32 gives the lithium enolate 33 with good stereochemical control at both the new centres.8... 

The asymmetric conjugate addition reaction has been applied to a,P-unsaturated amides,alkenylphosphonates, and ethenesulfonamides. Hayashi and co-workers have also applied the standard reaction conditions to nitroalkenes. The reaction was found to be applicable to a variety of arylboronic acids. The reaction was also extended to acyclic nitroalkenes without loss of selectivity, but not to nitrocycloheptene or nitrocyclopentene. Interestingly, the thermodynamically less stable cis isomers, e.g., 266, were formed in the reaction of nitrocyclohexene (265) with a wide range of arylboronic acids, e.g., 254. The initial products could be readily converted to the more stable trans isomers by treatment with base. 

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. 

K. Soal, H. Machida, and A. Ookawa, J. Chem. Soc. Chem. Commun., 1985, 469. Asymmetric conjugate addition of RMgX to a,8-unsaturated amides derived from (S)-2-(l-H0-l-Prl)pyrrolldine or ( )-prollnol. 

Although quaternary onium bromides and chlorides as phase-transfer catalysts are generally beUeved to require base additives for phase-transfer reactions of active methylene and methine compounds, which were discussed above, we have recently discovered an hitherto unknown base-free neutral phase-transfer reaction system in asymmetric conjugate additions (Scheme 14.5) [23]. The reactions were efficiently promoted by chiral bifunctional ammonium bromide (S)-7 under neutral conditions with water-rich biphasic solvent. The role of hydroxy groups in the bifunctional catalyst was clearly shown in the transition-state model of the reaction based on the single-crystal X-ray structure of ammonium amide [23b] and nitro-nate [23c]. 

Neurokinin-1 receptor antagonists such as 120 (Scheme 2.19) have been identified as potential antiinflammatory agents by researchers at Merck Research Laboratories. To access the tra 5-3,4-disubstituted 8-lactone 119, a key intermediate in the synthesis of 120, an asymmetric conjugate addition strategy was developed. As depicted in Scheme 2.19, reaction of the lithium enolate derived from the amide 115 with enoate 116 afforded... 

Substantially high diastereoselectivity was accomplished by the conjugate addition of Grignard reagents to the amide 1 derived from 1-ephedrine32. The reagent attacked from the Re-face of the double bond, as shown in 2, via a chelated intermediate. Low asymmetric induction was observed when butyllithium was used instead of butylmagnesium bromide. 

Sodium borohydride (160) was found to serve as a hydrogen donor in the asymmetric reduction of the presence of an a,pi-unsaturated ester or amide 162 catalyzed by a cobalt-Semicorrin 161 complex, which gave the corresponding saturated carbonyl compound 163 with 94-97% ee [93]. The [i-hydrogen in the products was confirmed to come from sodium borohydride, indicating the formation of a metal enolate intermediate via conjugate addition of cobalt-hydride species (Scheme 2.17). 

Boron—nitrogen coordination polymers, with ferrocene, 6, 208 Boron nucleophiles, in conjugate additions asymmetric 1,4-additions, 10, 388 mechanisms, 10, 384 to nitroolehns, 10, 388 to a,/3-unsaturated amides, 10, 386 to a,/3-unsaturated esters, 10, 386 to a,/3-unsaturated ketones, 10, 384 Boron-silicon bonds, addition to alkenes, 10, 760 to alkynes, 10, 758 to allenes, 10, 760 to carbenoids, 10, 766 to 1,3-dienes, 10, 762 to isocyanides, 10, 765... 

The conjugate addition of (K)-N-methyl-N-a-methylbenzyl amide 33 to tert-butyl cinnamate 34, followed by an asymmetric aldol reaction and subsequent N-oxidation/Cope elimination afforded the -substituted homochiral Baylis-Hillman product 39 in good yield (Scheme 7) [37]. This chemistry requires the use of stoichiometric rather than catalytic amounts of the chiral base. 

Asymmetric -methylation of a, -enones. Chiral bidendate ligands derived from L-prolinol can be used for asymmetric Michael additions to a, 3-enones with cuprates of the type CH,L CuMgBr (10, 266). The highest optical yield in conjugate addition to chalcone is observed when L is (S)-N-methylprolinol (88% ee). The tridentate chiral ligand 1 is equally effective for asymmetric 3-methylation of chalcone with CH,L CuLi and CuBr the chemical yield is 95%. Reduction of the amide carbonyl group of 1 results in practically total loss of chiral induction. 

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