Unsaturated, enantioselective conjugate

The reaction of butyllithium with 1-naphthaldehyde cyclohexylimine in the presence of (/C )-l,2-diphenylethane-1,2-diol dimethyl ether in toluene at —78 °C, followed by treatment with acetate buffer, gave 2-butyl-1,2-dihydronaphthalene-l-carbaldehyde, which was then reduced with sodium borohydride in methanol to afford (1 R,2.S)-2-butyl-1 -hydroxymcthyl-1,2-dihydronaphthalene in 80% overall yield with 91 % ee83. Similarly, the enantioselective conjugate addition of organolithium reagents to several a,/J-unsaturated aldimines took place in the presence of C2-symmetric chiral diethers, such as (/, / )-1,2-butanediol dimethyl ether and (/, / )- ,2-diphenylethane-1,2-diol dimethyl ether. 

Shibasaki s lanthanide-alkaline metal-BINOL system, discussed in Chapters 2 and 3, can also effect the asymmetric conjugate addition reaction. As shown in Scheme 8-35, enantioselective conjugate addition of thiols to a,/ -unsaturated carbonyl compounds proceeds smoothly, leading to the corresponding products with high yield and high ee.76... 

Scheme 7.23. Enantioselective conjugate addition to , -unsaturated nitroacetates 87.

C synthons, synthetic equivalents of which being the amino-acetaldehyde-derived metallated aminonitrile D bearing the chiral auxiliary (S,S)-53 and an a,P-unsaturated ester E, respectively. This should make it possible to open up a pathway to an enantioselective conjugate addition of an a-aminoacyl carbanion equivalent D to enoates in order to access the target 3-substituted 5-ainino-4-oxo esters. 

TABLE 8. Enantioselective conjugate addition of MeMgBr to a, 6-unsaturated thioesters ... 

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. 

A chiral cationic rhodium complex has been shown to catalyse the enantioselective conjugate addition of silyl anion equivalents to cyclic a,fl-unsaturated ketones and esters, thus providing a facile access to chiral organosilicon compounds.247... 

Inexpensive and readily available Grignard reagents and stable dinuclear Cu complexes have been used for the first time in catalytic enantioselective conjugate addition reactions to simple acyclic a -unsaturated methyl esters.95 These reactions have provided access to highly valuable -substituted chiral esters in good yields and with excellent enantioselectivities (up to 99% ee). 

Enantioselective Conjugate Addition. A Cu-(S,S)-NOR-PHOS catalyst has been used to promote conjugate addition of diethylzinc to a, 3-unsaturated ketones (eq 6), e.g., cyclohexen-2-one, chalcone, and benzalacetone. The use of (S,S)-CfflRAPHOS (7) and (R)-PROPHOS (8) afforded (S)-3-ethylcyclohexanone in somewhat improved chemical and optical yields relative to those obtained with Cu-(S,S)-NORPHOS catalyst. ... 

Enantioselective Copjugate Additions. The use of chiral imines for the enantioselective conjugate addition of carbonyl compounds to a,p-unsaturated systems is well established, mostly with imines derived from a-methylbenzylamine. Recently, (1) has been used to effect the Michael addition of a 4-piperidone to acrylonitrile and methyl acrylate (eq 2) ... 

A sugar-based ligand such as 172 served as a promising chiral ligand for the catalytic enantioselective conjugate addition of cyanide to a, 8-unsaturated A-acylpyrroles as shown in... 

Recently reported uses of optically pure stilbene diol in asymmetric synthesis include. (1) the dimethyl ether as a ligand for effecting enantioselective conjugate addition (2) the preparation of a,p-unsaturated ketals for achieving diastereoselective Simmons-Smith cyclopropanation <3 (3) the preparation of enantlomercially pure p-halohydrins i and (4) the preparation of chirai crown... 

Malonate and related activated methylene compounds have also been used as the nucleophile in conjugate addition/Michael reactions. Taylor and co-workers have developed a new methodology that utilizes (salen)aluminum complexes such as 43 as a catalyst to effect the enantioselective conjugate addition to a,p-unsaturated ketones by a variety of nucleophiles.25 For example, nitriles, nitroalkanes, hydrazoic acids, and azides have found utility in this reaction. Additionally, cyanoacetate (42) has been demonstrated to undergo a highly enantioselective conjugate addition to 41. The Krapcho decarboxylation is then necessary to produce cyanoketone 44, an intermediate in the synthesis of enantioenriched 2,4-cw-di substituted piperidine 45. 

Enantioselective conjugate addition to a,8-unsaturated carbonyl compounds has been performed using two alternative strategies. The possibility of achieving useful... 

Here is an example, which picks up where we left off a catalytic enantioselective conjugate addition. As you know from Chapter 11, aldehydes and ketones react with secondary amines to form enamines, via iminium ions. But this unsaturated aldehyde can t form an enamine because the iminium ion that is generated by condensation with the cyclic secondary amine... 

Alternatively, the iminium-activation strategy has also been apphed to the Mukaiyama-Michael reaction, which involves the use of silyl enol ethers as nucleophiles. In this context, imidazolidinone 50a was identified as an excellent chiral catalyst for the enantioselective conjugate addition of silyloxyfuran to a,p-unsaturated aldehydes, providing a direct and efficient route to the y-butenolide architecture (Scheme 3.15). This is a clear example of the chemical complementarity between organocatalysis and transition-metal catalysis, with the latter usually furnishing the 1,2-addition product (Mukaiyama aldol) while the former proceeds via 1,4-addition when ambident electrophiles such as a,p-unsaturated aldehydes are employed. This reaction needed the incorporation of 2,4-dinitrobenzoic acid (DNBA) as a Bronsted acid co-catalyst assisting the formation of the intermediate iminium ion, and also two equivalents of water had to be included as additive for the reaction to proceed to completion, which... 

---