Chiral auxiliaries conjugate additions

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... 

Diastereoselective conjugate additions to chiral Michael acceptors in which the part initially bearing the chiral information is removable (i.e., a chiral auxiliary) provides a means to synthesize enantiomerically pure conjugate adducts. Chiral auxiliaries should ideally be readily available in both enantiomeric forms. They should... 

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. 

Seebach and coworkers have developed enantioselective conjugate additions of primary dialkylzinc reagents to 2-aryl- and 2-heteroaryl-nitroalkenes mediated by titanium-TADDO-Lates (Eq. 4.90). x a TADDOLs and their derivatives are excellent chiral auxiliaries.9611... 

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... 

As well as organic chiral auxiliaries, organometallic fragments have found some application as chiral auxiliaries in conjugate addition reactions. Particularly noteworthy are chiral molybdenum allyl complexes [69], chiral iron complexes [70], and planar chiral arene chromium species [71]. 

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... 

During our investigations on asymmetric C—C bond formation reactions via conjugate addition of SAMP hydrazones to various a,(3-unsaturated Michael acceptors, it occurred to us to use the chiral hydrazine auxiliary S AM P as a nitrogen nucleophile and a chiral equivalent of ammonia in aza-Michael additions. Thus, we developed diastereo- and enantioselective 1,4-additions for the synthesis of P-amino acids and P-aminosulfonates [14, 15]. 

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). 

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. 

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 ). ... 

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

Asymmetric conjugate addition is a powerful method for the construction of ternary stereogenic centers. Erick Carreria of the ETH-Honggerberg, Zurich reports (Organic Lett. 2004,6,2281) the chiral-auxiliary mediated conjugate addition of alkynes to alkylidene malonate derivatives such as 1, to give, after hydrolysis and decarboxylation, the enantiomerically-enriched acid 3. 

The introduction of a chiral auxiliary on the nitrogen of an azaenolate offers the capability to perform asymmetric conjugate additions of chiral nucleophiles to achiral acceptors. This is in contrast to the typical asymmetric conjugate addition of achiral nucleophiles to chiral acceptors.137 For example, the con-... 

The conversion of an a, -unsaturated aldehyde or ketone into an allylic acetal or ketal, followed by SN2 -type attack of a nucleophile, leads, after hydrolysis of an initially formed enol ether, to a fi-sub-stituted carbonyl compound. The overall sequence (Scheme 23) is equivalent to a direct conjugate addition, but has the advantage that it allows the temporary introduction of a chiral auxiliary group if a chiral (C2-symmetric) diol is used in the acetalization step, die subsequent nucleophilic addition leads to a mix-... 

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. 

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... 

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... 

The cycloaddition of ketene acetals to 3-formylchromone exhibits good diastereoselectivity and meihanolysis of the pyrano[4,3- ] -pyran affords the chromanone ester (21) without racemisation. The chiral auxiliary, the diol (22), can be recyclised and the overall process represents an asymmetric conjugate addition to the chromone (95 JCS(P1 )2293). 

---