Chiral auxiliaries Conjugate addition with

Scheme 8.24 Asymmetric conjugate addition with ephedrine as chiral auxiliary.

The first asymmetric iron-catalyzed conjugate addition was reported in 1977. Benzylidene malonate 56 with an ephedrine moiety as chiral auxiliary was converted with Grignard reagents such as nBuMgBr in the presence of catalytic amounts of various metal salts. The optically active phenylpropionic acid 57 was obtained with... 

Asymmetric conjugate addition with organocopper reagents has been investigated using chiral auxiliaries or chiral ligands. For example, the 2-oxazolidinone-... 

The formation of asymmetric carbon-carbon and carbon-heteroatom bonds by lithiation-substitution at a carbon adjacent to nitrogen can be accomplished by deprotonations or des-tannylations, followed by reaction with electrophiles. Apphcations of these sequences for amine elaboration are summarized for reactions controlled by chiral hgands and chiral auxiliaries. Notable features include syntheses of alkaloids, the ability to make both enantiomers with a single chiral ligand and diastereoselective and enantioselective conjugate additions with benzylic and allylic lithiation intermediates. The sequences are classified, where information is available, in terms of stereocontrol in the lithiation or substitution step. 

Several conjugate addition reactions have been used for the synthesis of amino acids, as seen in chapter three. It is easy to prepare conjugated esters and using chiral auxiliary or a chiral template, conjugate addition can lead to amino acids with high diastereoselectivity and enantioselectivity. 

Alexakis A, Sedrani R, Mangeney P, Normant JF. Diastereo-selective conjugate addition with acetals, oxazolidines and imidazolidines as chiral auxiliaries. Tetrahedron Lett. 1988 29 4411 14. 

Diastereosdective Conjugate Additions with Use of Chiral Auxiliaries... 

As is the case for aldol addition, chiral auxiliaries and catalysts can be used to control stereoselectivity in conjugate addition reactions. Oxazolidinone chiral auxiliaries have been used in both the nucleophilic and electrophilic components under Lewis acid-catalyzed conditions. (V-Acyloxazolidinones can be converted to nucleophilic titanium enolates with TiCl3(0-/-Pr).320... 

Enantioselective Reactions of Organocopper Reagents. Several methods have been developed for achieving enantioselectivity with organocopper reagents. Chiral auxiliaries can be used for example, oxazolidinone auxiliaries have been utilized in conjugate additions. The outcome of these reactions can be predicted on the basis of steric control of reactant approach, as for other applications of the oxazolidinone auxiliaries. 

Conjugate addition. In general, the use of chiral auxiliaries able to promote chirality transfer with a predictable stereochemistry on newly generated stereocenters is recognized as indispensable in asymmetric synthesis.79... 

Chiral /3,/3-diaryIpropionic acid moieties are often found in compounds showing biological activities, such as antiarrhythmics vasodilators antidepressives " , antihistamines and controllers of cerebral insufficiency ". In the course of synthetic studies of chiral -diaryIpropionic acid derivatives, Merck researchers developed stereoselective conjugate addition of aryllithium reagents to the a,/ -unsaturated fert-butyl esters 18 bearing a chiral imidazolidine or oxazolidine auxiliary at the ortho position of an aryl group. The addition furnished chiral -diaryIpropionic acid derivatives 19 with... 

Using these optimized conditions, the conjugate addition of 45 to the malonates 49 in the presence of the solid base provided access to the Michael adducts in good yields and high diastereoselectivities. The removal of the chiral TADDOL auxiliary could be accomplished without epimerization or racemization in this case, too. After esterification of the very polar acid intermediates with diazomethane the corresponding dimethyl esters 52 were obtained with yields of 72-94% and enantiomeric excesses ee of 84-94% (Scheme 1.1.13). 

The first successful approaches were based on the, often Cu-mediated, conjugate addition of organolithium and organomagnesium (Grignard) reagents to o ,/ -unsaturated systems covalently modified with chiral auxiliaries (Scheme 1 ). ... 

Lewis acid-catalyzed stereoselective addition of crotylsilanes to chiral 74 has been studied in detail111,112. The presence of the chiral auxiliary at C2 (e.g. p-tolylsulfinyl or menthoxy carbonyl group) induces the diastereofacially selective addition of cyclopentenones with crotylsilanes. Thus, ( )-crotylsilane favors the erythro product, whilst (Z)-isomer favors the threo product. High enantioselectivity is observed in both reactions (equation 48). In a similar manner, conjugated addition of allylsilane to 75 proceeds with high efficiency (equation 49)113. Interestingly, the yield and enantiomeric excess of the product is dependent on the amount of TiCL used and the best selectivity... 

Acyclic stereocontrol remains a challenging problem in synthesis. While enan-tiomerically pure sulfoxides are valuable synthetic intermediates for enantiocon-trolled carbon-carbon bond formation by conjugate addition in cyclic cases, their usefulness for such alkylations in acyclic cases has not been firmly established. Moreover, most sulfoxide directed alkylation protocols utilize the valuable sulfur auxiliary just once, which limits the synthetic versatility of the process. Marino et al. have recently reported SN2 displacements of acyclic allylic mesyloxy vinyl sulfoxides with organocopper reagents (Scheme 10).33 In addition to the excellent observed stereoselectivities, the newly created chiral center is adjacent to a vinyl sulfoxide which should allow for subsequent chirality transfer operations. On treatment with organocopper nucleophiles, both sulfoxide diastereoisomers 40b and 43b underwent SN2 displacements with high Z selectivity to yield products 42b and 45b, respectively (Table 2). The oxidation state on the sulfur was varied... 

Asymmetric Michael additions The anions of hydrazones (2), obtained from 1 and methyl ketones, undergo conjugate addition to a,p-unsaturated esters with virtually complete 1,6-asymmetric induction to give the adducts (S,R)-3. Ozonolysis converts these products into P-substituted 8-keto esters, (R)-4, obtained in optical yields of 96-l(X)%, with recovery of the chiral auxiliary as the nitrosamine (S)-5. The overall chemical yields of 4 are 45-62%. 

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