Conjugate addition chiral 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... 

Chiral organomagnesium amides form an efficient method to realize enantioselective conjugate addition. Sibi and Asano have reported the Michael addition of cr-bound magnesium reagents derived from bisoxazolines to enamidomalonates (equation 41). The enantioselectivity of the addition is discussed in Section El. This method allows the preparation of chiral -amino acid derivatives. ... 

An alternative route to nitriles of high enantiomeric excess, based on the conjugate addition of Me,Si-CN to an activated amide 7, has been reported (J. Am. Chem. Soc. 2004,126,9928) by Eric Jacobsen of Harvard University. The key to success in this case was dual catalysis, with a chiral AI complex and a chiral Er complex. 

Mixed aggregates of chiral lithium amide and lithium ester enolate have been employed in the enantioselective conjugate addition on a,/S-unsaturated esters.27 Michael adducts have been obtained in ees up to 76% combining a lithium enolate and a chiral 3-aminopyrrolidine lithium amide. The sense of the induction has been found to be determined by both the relative configuration of the stereogenic centres borne by the amide and the solvent. 

Stereoselective copper-promoted conjugated additions of Grignard reagents in the presence of Zn(II) salts to chiral cinnamoyl- and crotonyl-amides RCH=CHCO(N ) derived from (45,5S)- and (4/J,5f )-trans-hexahydrobenzoxazolidin-2-ones has been employed for the preparation of the corresponding 1,4-addition products.218... 

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. 

SCHEME 39. Diastereoselective conjugate addition of Davies chiral lithium amide followed by diastereocontrolled oxidation of the intermediate enolate169... 

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. 

Diastereoselective Conjugate Addition of Organometallic Reagents to Chiral a,P-Unsaturated Amides and Imidazolidi-nones Derived from Ephedrine. Grignard reagents (2 equiv) add to chiral a,P-unsaturated amides derived from ephedrine in a 1,4-addition manner with high diastereoselectivities. Subsequent acidic hydrolysis affords optically active p-substituted carboxylic acids with 85-99% ee (eq 3). ... 

Various other applications are conjugate addition, 4 the ultrasound-promoted perfluoralkylation of SMP enamines, the enantioselective fluorodehydroxylation of SMP 1-yl-sulfur trifluoride, asymmetric telomerization of butadiene, the chiral modification of ruthenium clusters, and the application of SMP amide bases. ... 

Conjugate addition of a silylcuprate reagent (34) to the a,(3-unsaturated acid amide or ester of a pertinent chiral amine or alcohol, respectively, is an alternative route to (3-silyl amides and esters. Conjugate addition of a cuprate reagent to a P-silyl acrylamide also gives a chiral P-silyl amide. The diastereomeric excess of the newly produced chiral center is fairly high, as summarized in Scheme 14." ... 

The influence of solvent and additives on yield and selectivity has been examined.The conjugate addition of dimethyl cuprate in the presence of a chiral ligand, such as 144, is an example. The use of chiral ligands with Mgl2/l2 and BuaSnl gave conjugate addition products with a,(3-unsaturated amides with... 

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