Asymmetric conjugate addition unsaturated ester

Other interesting electron-deficient olefin substrates for the asymmetric conjugate addition include cr-acet-amidoacrylic ester SI,101 dimethyl itaconate S2,114 ct,/3-unsaturated sulfones S3,115 and alkenylphosphonate S4116 (Figure 8). 

TABLE 9. Asymmetric conjugate addition of organolithium reagents to a,/ -unsaturated esters and imines in the presence of chiral diether hgand 28 or (—)-sparteine (29) ... 

The rhodium-catalyzed asymmetric conjugate addition is applicable to a,yS-unsaturated esters (Scheme 3.8). Hayashi reported [20] that the reachon of 5,6-dihydro-2H-pyran-2-one 19a with phenylboronic acid gave a 94% yield of phenylated lactone (S)-20am with 98% enanhomeric excess. For the linear enoates, organoboronic acids did not give... 

Scheme 3.8 Asymmetric conjugate addition of organoboron reagents to a,jS-unsaturated esters [20].

For a Rh-catalyzed asymmetric conjugate addition of arylboronic reagents to a,/)-unsaturated esters, see S. Sakuma, M. Sakai, R. Itooka and N. Miyaura, J. Org. Chem., 65, 5951 (2000) and references cited therein. 

Related a,p-Unsaturated Esters. Similar a,p-unsaturated esters bearing a heterocyclic chiral auxiliary of a-amino acid origin at the p-position are known and have been utilized in asymmetric synthesis. Effective asymmetric conjugate additions of cuprates to (2), (3), and (5)J epoxidations of (3), and dipolar cycloadditions of (2) have been reported. Although oxazoli-dine (4) is only obtained as an 86 14 equilibrating mixture of stereoisomers, reactions with the lithium (Z)-enolate of methyl N-benzylideneglycinate (see Ethyl N-Benzylideneglycinate) are exclusively diastereoselective. 

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... 

Lassaletta and coworkers reported in 2007 the asymmetric conjugate addition of formaldehyde iV,Ar-dialkylhydrazones to p,y-unsaturated a-keto esters.Utilising 10 mol% of 68 [(15, 2J )-enantiomer of Ricci s catalyst], the corresponding products were afforded in high yields and good enantio-selectivities (Scheme 19.80). 

Scheme 15.24 Copper-catalysed asymmetric conjugated addition of Grignard reagents to a,p-unsaturated methyl esters.

P-Borylation of a,P-Unsaturated imines. Fernandez and coworkers have also developed a route to y-ainino alcohols via a tandem sequence of enantioselective -borylation of a,p-unsaturated imines, followed by iterative imine reduction and boronic ester oxidation. In the presence of B2pin2, CuOTf and a binapthol-derived phosphoramidite ligand, asymmetric conjugate addition of (V-protected Q ,/3-unsaturated imines occurred in high yield and with excellent enantioselectivity. Diasteroselective reduction of the imine to the corresponding jyn-y-amino alcohol was achieved with BH3 THF (eq 56). The authors postulated that... 

A dihydroquinidine-derived chiral thiourea (DHQD-30), which demonstrated significantly better stereocontrol than other cinchona alkaloids, was utilized in the aza-Henry reaction with nitroalkanes and aldimines by Schaus and coworkers (Scheme 13.8) [26]. The utility of the nitroethane pronucleophile conveniently offers a tertiary stereogenic center in the P-nitroamine product 32. The methodology is also conveniently applicable to novel a,P-unsaturated aliphatic imines 29, which are difficult substrates in asymmetric conjugate addition reactions. Similar reaction conditions can be appHed towards to the use of dimethyl malonates as pronucleophiles that generate adducts in high enantioselectivity, which then convert smoothly into P-amino esters under the Nef conditions. 

Another approach to conduct asymmetric conjugate addition reactions has been the use of ester auxiliaries derived from chiral alcohols [81]. Oppolzer [82, 83] reported a notable example using unsaturated esters such as 68 derived from (-)-8-phenylmenthol [84] (Equation 14) [82]. The addition of phenylcopper to 68 was catalyzed by BF3-OEt2 [70] and afforded the acid 70 in > 99 % ee after saponification. Analysis of the stereochemical outcome led to the suggestion that the observed induction results from addition to the exposed olefin face in conformer 69 [82], which is favored because of stabilizing orbital overlap between the enone and aromatic groups [85]. 

M. Hirama u. S. Ito, Heterocycles 28, 1229-1247 (1989) . .Asymmetric Induction in the Intramolecular Conjugate Addition of y- or d-Carbamoyloxy-a,/ -unsaturated Esters. A New Method for Diastcreo-selective Amination and Divergent Syntheses of 3-Amino-2,3,6-trideoxyhcxoscs". 

In the first attempts to use a chiral a-sulfinyi ester enolate as donor in Michael additions to a -un-saturated esters, only low selectivities were observed.185 186 Better results are obtained when the a-lithio sulfoxide (174), a chiral acyl anion equivalent, is employed. Conjugate addition of (174) to cyclopent-enone derivatives occurs with reasonably high degrees of asymmetric induction, as exemplified by the preparation of the 11-deoxy prostanoid (175 Scheme 63).187 188 Chiral oxosulfonium ylides and chiral li-thiosulfoximines can be used for the preparation of optically active cyclopropane derivatives (up to 49% ee) from a, -unsaturated carbonyl compounds.189... 

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