Michael additions simple, enolates

Whilst simple alkylations of enolates and Michael additions have been successfully catalyzed by phase-transfer catalysts, aldol-type processes have proved more problematic. This difficulty is due largely o the reversible nature of the aldol reaction, resulting in the formation of a thermodynamically more stable aldol product rather than the kinetically favored product. However, by trapping the initial aldol product as soon as it is formed, asymmetric aldol-type reactions can be carried out under phase-transfer catalysis. This is the basis of the Darzens condensation (Scheme 8.2), in which the phase-transfer catalyst first induces the deprotonation of an a-halo... 

The synthetic problem is now reduced to cyclopentanone 16. This substance possesses two stereocenters, one of which is quaternary, and its constitution permits a productive retrosynthetic maneuver. Retrosynthetic disassembly of 16 by cleavage of the indicated bond furnishes compounds 17 and 18 as potential precursors. In the synthetic direction, a diastereoselective alkylation of the thermodynamic (more substituted) enolate derived from 18 with alkyl iodide 17 could afford intermediate 16. While trimethylsilyl enol ether 18 could arise through silylation of the enolate oxygen produced by a Michael addition of a divinyl cuprate reagent to 2-methylcyclopentenone (19), iodide 17 can be traced to the simple and readily available building blocks 7 and 20. The application of this basic plan to a synthesis of racemic estrone [( >1] is described below. 

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. 

When chiral enolates or chiral Michael acceptors are used, for instance, when stereogenic centers are present in the substrate or when X or Y are chiral auxiliaries, both simple and induced diastereoselectivity is observed. This results, in principle, in the formation of four diastereomers 1 -4. The diastereoselectivity in the Michael addition of lithium enolates to enones can be rationalized by consideration of chelated transition states A-D372. 

The intramolecular Michael addition of an achiral metal enolate is similarly subject to simple diastereoselection. 

Version (b) has a four-channel flow guidance that encompasses two mixing tees in two simple mixing tees (Figure 4.5) [8]. An example of this function is the flow guidance for the Michael addition. In a first step, the base and 1,3-dicarbonyl compound streams merge. The enolate stream thus formed is then mixed with the Michael acceptor. Microporous silica frits are set into the channels to minimize... 

The use of oxygen-containing dienophiles such as enol ethers, silyl enol ethers, or ketene acetals has received considerable attention. Yoshikoshi and coworkers have developed the simple addition of silyl enol ethers to nitroalkenes. Many Lewis acids are effective in promoting the reaction, and the products are converted into 1,4-dicarbonyl compounds after hydrolysis of the adducts (see Section 4.1.3 Michael addition).156 The trimethylsilyl enol ether of cyclohexanone reacts with nitrostyrenes in the presence of titanium dichloride diisopropoxide [Ti(Oi-Pr)2Cl2], as shown in Eq. 8.99.157 Endo approach (with respect to the carbocyclic ring) is favored in the presence of Ti(Oi-Pr)2Cl2. Titanium tetrachloride affords the nitronates nonselectively. 

In contrast to these transformations, Michael additions of simple enolates to acceptor-substituted dienes often yield mixtures of 1,4- and 1,6-addition products27-30. For example, a 70 30 mixture of 1,4- and 1,6-adducts was isolated from the reaction of the lithium enolate of methyl propionate with methyl sorbate30. This problem can be solved by using the corresponding silyl ketene acetal in the presence of clay montmorillonite as acidic promoter under these conditions, almost exclusive formation of the 1,4-addition product (syn/anti mixture) was observed (equation ll)30. Highly regioselective 1,4-additions... 

Much milder conditions are used in the double Michael addition approach, in which a divinyl ketone is condensed with hydrogen sulfide in mildly basic medium (equation 77) (77JOC2777). Enol acetates (R1 = MeCC>2) may be used, and the product obtained then contains a 2-mercapto function (R1 = SH see also equation 82) (59% yield). Although this is a very versatile synthesis, its biggest drawback is the lability of simple divinyl ketones, and phenyl substitution at position 2 is frequently used to overcome this. 

Similar changes take place in the acidification of the enol salt of a carbonyl compound, the principal difference being the much longer life of the acf-nitro compound compared to that of an enol of a simple ketone (see Section 17-IB), Primary and secondary nitro compounds undergo aldol additions and Michael additions with suitable carbonyl compounds and basic catalysts ... 

The neutral 1,4- and 1,2-quinone methides react as Michael acceptors. However, the reactivity of these quinone methides is substantially different from that of simple Michael acceptors. The 1,6-addition of protonated nucleophiles NuH to simple Michael acceptors results in a small decrease in the stabilization of product by the two conjugated 7T-orbitals, compared to the more extended three conjugated 7T-orbitals of reactant. However, the favorable ketonization of the initial enol product (Scheme 1) confers a substantial thermodynamic driving force to nucleophile addition. By comparison, the 1,6-addition of NuH to a 1,4-quinone methide results in a large increase in the -stabilization energy due to the formation of a fully aromatic ring (Scheme 2A). This aromatic stabilization is present to a smaller extent at the reactant quinone methide, where it is represented as the contributing zwitterionic valence bond structure for the 4-0 -substituted benzyl carbocation (Scheme 1). The ketonization of the product phenol (Scheme 2B) is unfavorable by ca. 19 kcal/mol.1,2... 

The use of simple silyl enol ethers for the asymmetric organocatalyzed Mukaiyama-Michael addition was recently reported. For reference, see W. Wang, H. Li, J. Wang, Org. Lett. 

The (3-keto stannyl enolates will give aldol reactions with aldehydes (Scheme 14-5),121 and are more reactive than the simple enolates in that they also show Michael additions with unsaturated carbonyl compounds (equation 14-67).122... 

Do not suppose that the regioselectivity problem is now trivial. In a study mainly aimed at achieving asymmetric reactions, Braun34 showed just how narrow is the gap between 1,2 and 1,4 addition. The silyl enol ether 101, easily made from the enantiomerically pure ester 100, gave mainly (>95 5) direct (1,2) addition to a simple enone under the usual conditions (TiCl4 catalysis) for Michael addition. 

The. V-alkylation of ephedrine is a convenient method for obtaining tertiary amines which are useful as catalysts, e.g., for enantioselective addition of zinc alkyls to carbonyl compounds (Section D. 1.3.1.4.), and as molybdenum complexes for enantioselective epoxidation of allylic alcohols (Section D.4.5.2.2.). As the lithium salts, they are used as chiral bases, and in the free form for the enantioselective protonation of enolates (Section D.2.I.). As auxiliaries, such tertiary amines were used for electrophilic amination (Section D.7.I.), and carbanionic reactions, e.g., Michael additions (Sections D. 1.5.2.1. and D.1.5.2.4.). For the introduction of simple jV-substituents (CH3, F.t, I-Pr, Pretc.), reductive amination of the corresponding carbonyl compounds with Raney nickel is the method of choice13. For /V-substituents containing further functional groups, e.g., 6 and 7, direct alkylations of ephedrine and pseudoephedrine have both been applied14,15. 

This reaction was first reported by Schollkopf in 1979. It is a synthesis of an unnatural nonproteinogenic amino acid from the lithiated enolate equivalent of a simple amino acid (e.g., glycine, alanine and valine), which involves the diastereoselective alkylation of the lithiated bis-lactim ether of an amino acid with an electrophile or an Aldol Reaction or Michael Addition to an o ,jS-unsaturated molecule and subsequent acidic hydrolysis. Therefore, the intermediate of the bis-lactim ether prepared from corresponding amino acids is generally referred to as the Schollkopf bis-lactim ether, " Schollkopf chiral auxiliary, Schollkopf reagent, or Schollkopf bis-lactim ether chiral auxiliary. Likewise, the Schollkopf bis-lactim ether mediated synthesis of chiral nonproteinogenic amino acid is known as the Schollkopf bis-lactim ether method, Schollkopf bis-lactim method, or Schollkopf methodology. In addition, the reaction between a lithiated Schollkopf bis-lactim ether and an electrophile is termed as the Schollkopf alkylation, while the addition of such lithiated intermediate to an Q ,j8-unsaturated compound is referred to as the Schollkopf-type addition. ... 

Diesters.—Michael addition of malonic ester enolates to chiral a/3-unsaturated aldimines (obtained from optically pure a-amino-acids) gives, after hydrolysis, aldehyde-diesters (125) in variable chemical (26—54%) and optical (36—86%) yields. The amino-acid components are recovered optically pure. Attack of simple nucleophiles on the bromoalkylidene malonate (126) gives cyclopropane diesters (127) in good yields. A ready, five-step route to the bicyclo[l,l,0]butane triester (128) has been described. ... 

Michael additions of active methylene compounds (e.g. 1,3-dicarbonyls, /3-keto-esters, and malonates) to a,/3-unsaturated esters, leading to 5-keto-ester derivatives, can be effected very efficiently and under near neutral conditions by using Ni(acac)2 as catalyst. The Michael addition of O-silyl ester enolates to cycloalkenones to give 5-keto-esters can be carried out in the absence of a catalyst if the two reactants are simply heated together in acetonitrile (Scheme 20) Yields with simple models are 90% not only is this method a... 

Stannyl enol ethers react with electron-deficient alkenes like or, -unsaturated esters and alkynes in the presence of AIBN to give radicalic carbostannylation adducts, y-stannyl ketones, " " in sharp contrast to the Bu4NBr-mediated reaction, which gives simple Michael adducts. In addition, 1,6-enynes, when applied to this carbostannylation, produce five-membered cyclic adducts. For this particular transformation, electron-deficient groups are not needed (Scheme 3-222). 

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