Michael addition of ester enolates

TABLE 15. Enantioselective Michael additions of ester enolates using chiral amides (equation 53)... 

A study of the Michael addition of ester enolates R CH=C(OLi)OR to a-benzylidene and a-alkylidene -dicarbonyl compounds, for example, R CH=C(C02Me)2, has demonstrated that the diastereoselectivity depends on the substitution pattern of the Michael acceptor and the geometry of the enolate, which in turn can be controlled by the method of their generation (i.e. EDA in THF vs EDA and HMPA in THF). Thus, (E)-enolates exhibit iyn-diastereoselectivity, whereas (Z)-enolates afford the anti-diastereoisomers. Eow stereocontrol was observed with unsaturated nitriles and Meldrum s acid derivatives. A stereochemical model has been proposed to accounts for all experimental results. ... 

In the Michael addition of achiral enolates and achiral Michael acceptors the basic general problem of simple diastereoselection (see Section D.1.5.1.3.2.), as described in Section 1.5.2.3.2. is applicable. Thus, the intermolecular 1,4-addition of achiral metal enolates to enones, a.jS-unsat-urated esters, and thioamides, results in the formation of racemic syn-1,2 and/or anti-3,4 adducts. 

The Michael addition of lithium enolates of amides, which have preferentially the Z geometry, under kinetically controlled conditions to a,/i-unsaturated esters provides a highly... 

Stereoselective Michael additions. In the absence of strong steric effects, the stereochemistry of Michael addition of amide enolates depends on the enolate geometry, with (Z)-enolates giving mainly antf-adducts and (E)-enolates giving mainly syn-adducts.1 Ester enolates show higher stereoselectivity than amide enolates, as shown by the (E)- and (Z)-enolates of r-butyl propionate (1). The (E)-... 

Akiyama s group employed naturally occurring L-quebrachitol 6 to prepare the C2-symmetrical 18-membered chiral crown ether 7 [14]. Compound 7 was found to be an active catalyst for the enantioselective Michael additions of glycine enolates. Thus, deprotonation of ester 8 using potassium tert-butoxide in dichloromethane (DCM) in the presence of crown ether 7 (20 mol %), followed by addition of a Michael acceptor, gave amino-acid derivatives 9 with up to 96% ee, as shown in Scheme 8.4. 

Michael addition of tin enolates to a,/3-unsaturated esters is accomplished in the presence of catalytic amount of Bu4NBr. Other typical system using lithium enolates or silyl enolates with catalysts (Lewis acid or Bu4NF) fails to give the Michael products. An ab initio calculation reveals that higher reactivity is caused by high coordination of the tin enolate and the keto enol tautomerization for Michael adducts contributes to thermodynamical stabilization (Equation (77)).231 232... 

Enolates derived from 2-phenylselanyl esters can react with various electrophiles. The Michael addition of the enolate formed from /-butyl 2-phenylselanyl propanoate 129 to furanone 130 followed by iodination afforded the key intermediate 131 for the total synthesis of (—)-avenaciolide 132 (Scheme 33).213... 

TABLE 8. Conditions for the Michael addition of ketone enolates to a, 6-unsaturated esters, according to equation 37... 

Michael addition of metal enolates to a,/3-unsaturated carbonyls has been intensively studied in recent years and provides an established method in organic synthesis for the preparation of a wide range of 1,5-dicarbonyl compounds (128) under neutral and mild conditions . Metal enolates derived from ketones or esters typically act as Michael donors, and a,-unsaturated carbonyls including enoates, enones and unsaturated amides are used as Michael acceptors. However, reaction between a ketone enolate (125) and an a,/3-unsaturated ester (126) to form an ester enolate (127, equation 37) is not the thermodynamically preferred one, because ester enolates are generally more labile than ketone enolates. Thus, this transformation does not proceed well under thermal or catalytic conditions more than equimolar amounts of additives (mainly Lewis acids, such as TiCU) are generally required to enable satisfactory conversion, as shown in Table 8. Various groups have developed synthons as unsaturated ester equivalents (ortho esters , thioesters ) and /3-lithiated enamines as ketone enolate equivalents to afford a conjugate addition with acceptable yields. 

Ethyl phenylpropiolate and 1 in the presence of tributyl phosphine gave cinnamate 136a in only 10% yield in addition to 136 and 136b in 13% and 7% yield, respectively. The latter was obtained due to the cyclization of 136a via an intramoleculer Michael addition of the enolate to the vinyl ester followed by migration of the double bond (05T2287) (Scheme 23). 

Scheme 5.29. Proposed chelated transition structures (and topicities) for Michael additions of lithium enolates of ketones, esters, and amides to enones [157,158]. Only one enantiomeric transition structure and product is shown for each topicity (Si face of the acceptor).

Highly substituted 6-keto-esters [e.g. (215)] having vicinal quaternary centres can be prepared by Michael additions of ketone enolates to highly active acceptors containing two electron withdrawing groups.200 Substituted 6-keto-esters (218) have been obtained with good to excellent enantiomeric enrichments by Michael... 

Asymmetric Michael Addition of SUyl Enol Ethers of Thiol Esters to Enones. 99... 

The highly electrophilic cationic bis(8-quinolinolato)aluminum complex 407 enabled Yamamoto and coworkers to perform Mukaiyama-Michael additions of silyl enol ethers to crotonylphosphonates 406. The procedure was not only applicable to enol silanes derived from aryl methyl and alkyl methyl ketones (a-unsubstituted silicon enolates) but also to several cycfic a-disubstituted silyl enol ethers, as illustrated for the derivatives of a-methyl tetralone and indanone 405 in Scheme 5.105. Despite the steric demand of that substitution pattern, the reaction occurred in relatively high chemical yield with varying diastereoselectivity and excellent enantiomeric excess of the major diastereomer. The phosphonate residue was replaced in the course of the workup procedure to give the methyl esters 408. The protocol was extended inter alia to the silyl enol ether of 2,6,6-tetramethylcyclohexanone. The relative and absolute configuration of the products 408 was not elucidated [200]. 

Four different orientations are possible when the enantiofaces of (E)- and (Z)-enolates and an ( )-enone combine via a closed transition state, in which the olefinic moieties of the donor and the acceptor are in a syn arrangement. It should be emphasized that, a further four enan-tiomorphous orientations of A-D are possible leading to the enantiomers 2 and 3. On the basis of extensive studies of Michael additions of the lithium enolates of esters (X = OR) and ketones (X = R) to enones (Y = R) it has been concluded ... 

The utilization of copper complexes (47) based on bisisoxazolines allows various silyl enol ethers to be added to aldehydes and ketones which possess an adjacent heteroatom e.g. pyruvate esters. An example is shown is Scheme 43[126]. C2-Symmetric Cu(II) complexes have also been used as chiral Lewis acids for the catalysis of enantioselective Michael additions of silylketene acetals to alkylidene malonates[127]. 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

Enantiocontrolled anti-selective Michael additions of the metalated ylides derived from a-(alkylideneamino)alkanoates are attractive as a new synthetic route to enantiomers of a-amino esters. Although there are a variety of chiral glycine equivalents available, only the enolates derived from 1,4-dihydropyrazine have been successfully applied to asymmetric Michael additions (Scheme 11.22) (103-105). In these reactions, the diastereoselectivities are high. 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

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