Lewis catalyzed enolization

In the presence of an electrophile, tautomerization of a substrate with a C=0 double bond to its enol only takes place when catalyzed by either a Bronsted- or a Lewis acid. The proton-catalyzed mechanism is shown for the ketone — enol conversion B — iso-B (Figure 12.4), the carboxylic acid —> enol conversion A — E (Figure 12.6), the carboxylic acid bromide — enol conversion E —> G (Figure 12.7) and the carboxylic acid ester — enol conversion diethyl-malonate —> E (Figure 12.9). Each of these enol formations is a two-step process consisting of the protonation to a carboxonium ion and the latter s deprotonation. The mechanism of a Lewis acid-catalyzed enolization is illustrated in Figure 12.5, exemplified by the ketone —> enol conversion A —> iso-A. Again, a protonation to a carboxonium ion and the latter s deprotonation are involved the Lewis acid-complexed ketone acts as a proton source (see below). 

The catalyzed reaction of enol ethers with carbonyl compounds (Scheme 1) has become an important reaction in synthesis. Compared to the metal enolate reactions (Part 1, Volume 2), the catalyz enol ether reactions offer the following distinct differences. Enol ethers are often isolable, stable covalent compounds, whereas the metal enolates are usually generated and used in situ. Under Lewis acid catalyzed conditions, a number of functional equivalents such as acetals, orthoesters, thioacetals, a-halo ethers and sulfides can participate as the electrophilic components, whereas many of them are normally unreactive towards metal enolates. In synthesis, enol ether reactions now rival and complement the enolate reactions in usefulness. Enol silyl ethers are particularly useful because of their ease of preparation, their reasonable reactivity and the mildness of the desilylation process. 

The most widely used electron-donating a-substituents are alkoxy groups. Indeed, these substrates are so reactive that they enabled the first truly catalytic examples of Lewis acid-catalyzed Nazarov reactions. Whereas stoichiometric quantities of Lewis acid are often required due to slow protonation of the Lewis acid enolate, a-alkoxy appended systems show efficient catalytic turnover. For example, Trauner and co-workers reported the efficient Nazarov cyclization of 37 in the presence of 10 mol % of aluminium trichloride. " Not only do a-alkoxy groups lower the activation barrier to cyclization, but they also localize the resultant positive charge at one a-carbon, ensuring a highly regioselective elimination. 

In an intramolecular aldol condensation of a diketone many products are conceivable, since four different ends can be made. Five- and six-membered rings, however, wUl be formed preferentially. Kinetic or thermodynamic control or different acid-base catalysts may also induce selectivity. In the Lewis acid-catalyzed aldol condensation given below, the more substituted enol is formed preferentially (E.J. Corey, 1963 B, 1965B). 

There has been little study of the stereoselectivity of the reaction under acidic conditions. In the absence of a coordinating Lewis acid, there is no preference for a cyclic transition state. When regioisomeric enols are possible, acid-catalyzed reactions tend to proceed through the more substituted of the enols. This reflects the predominance of this enol. (See Section 7.2.)... 

For example in the so-called Mukaiyama aldol reaction of an aldehyde R -CHO and a trimethylsilyl enol ether 8, which is catalyzed by Lewis acids, the required asymmetric environment in the carbon-carbon bond forming step can be created by employing an asymmetric Lewis acid L in catalytic amounts. 

Aldol reactions occur in many biological pathways, but are particularly important in carbohydrate metabolism, where enzymes called aldolases catalyze the addition of a ketone enolate ion to an aldehvde. Aldolases occur in all organisms and are of two types. Type 1 aldolases occur primarily in animals and higher plants type II aldolases occur primarily in fungi and bacteria. Both types catalyze the same kind of reaction, but type 1 aldolases operate place through an enamine, while type II aldolases require a metal ion (usually 7n2+) as Lewis acid and operate through an enolate ion. 

Once again, excellent selectivity for formation of the j3-methyl isomer is observed in the case of the Lewis acid catalyzed reaction of the boron enolate of (4S )-4-isopropyl-3-(l-oxopropyl)-2-oxazolidinone 4177 (see Appendix). 

As an alternative, tin enolates are very useful in these additions. Usually they are prepared in situ from the amide using tin(II) trifluoromethanesulfonate and a base. They are subsequently reacted with an enone, catalyzed by a Lewis acid47-48 (see Table 3). With triinethylsilyl trifluoromethanesulfonate as a catalyst, in the presence of proline derived diamines anti-adducts are formed exclusively49 (see Section 1.5.2.4.3.1.). 

The Lewis acid catalyzed reactions of silyl enol ethers with nitroalkenes have been reviewed, however the diastereoselectivity of these reactions has not been addressed17. 

Synthesis of highly functionalized 3,4-dihydro-2H-pyrans by high-pressure Lewis-acid-catalyzed cycloaddition of enol ethers and a,/i-unsaturated aldehydes [83]... 

Ferrocen-l,l -diylbismetallacycles are conceptually attractive for the development of bimetal-catalyzed processes for one particular reason the distance between the reactive centers in a coordinated electrophile and a coordinated nucleophile is self-adjustable for specific tasks, because the activation energy for Cp ligand rotation is very low. In 2008, Peters and Jautze reported the application of the bis-palladacycle complex 56a to the enantioselective conjugate addition of a-cyanoacetates to enones (Fig. 31) [74—76] based on the idea that a soft bimetallic complex capable of simultaneously activating both Michael donor and acceptor would not only lead to superior catalytic activity, but also to an enhanced level of stereocontrol due to a highly organized transition state [77]. An a-cyanoacetate should be activated by enolization promoted by coordination of the nitrile moiety to one Pd(II)-center, while the enone should be activated as an electrophile by coordination of the olefinic double bond to the carbophilic Lewis acid [78],... 

The Staudinger reaction [92], a [2 + 2]-cycloaddition of a ketene and a nucleophilic imine, usually proceeds by an initial imine attack on the ketene thus forming a zwitterionic enolate which subsequently cyclizes. This reaction is an expedient route to p-lactams, the core of numerous antibiotics (e.g., penicillins) and other biologically active molecules [93]. In contrast, for Lewis-base catalyzed asymmetric reactions, nonnucleophilic imines are required (to suppress a noncatalyzed background reaction), bearing, for example, an N-Ts [94] or -Boc-substituent [95]. 

The Mukaiyama aldol reaction refers to Lewis acid-catalyzed aldol addition reactions of silyl enol ethers, silyl ketene acetals, and similar enolate equivalents,48 Silyl enol ethers are not sufficiently nucleophilic to react directly with aldehydes or ketones. However, Lewis acids cause reaction to occur by coordination at the carbonyl oxygen, activating the carbonyl group to nucleophilic attack. 

Nitroalkenes are also reactive Michael acceptors under Lewis acid-catalyzed conditions. Titanium tetrachloride or stannic tetrachloride can induce addition of silyl enol ethers. The initial adduct is trapped in a cyclic form by trimethylsilylation.316 Hydrolysis of this intermediate regenerates the carbonyl group and also converts the ad-nitro group to a carbonyl.317... 

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... 

Silyl enol ethers and silyl ketene acetals also offer both enhanced reactivity and a favorable termination step. Electrophilic attack is followed by desilylation to give an a-substituted carbonyl compound. The carbocations can be generated from tertiary chlorides and a Lewis acid, such as TiCl4. This reaction provides a method for introducing tertiary alkyl groups a to a carbonyl, a transformation that cannot be achieved by base-catalyzed alkylation because of the strong tendency for tertiary halides to undergo elimination. 

The use of Lewis acid catalysts greatly expands the synthetic utility of the carbonyl-ene reaction. Aromatic aldehydes and acrolein undergo the ene reaction with activated alkenes such as enol ethers in the presence of Yb(fod)3.35 Sc(03SCF3)3 has also been used to catalyze carbonyl-ene reactions.36... 

Lewis-Acid Catalyzed. Recently, various Lewis acids have been examined as catalyst for the aldol reaction. In the presence of complexes of zinc with aminoesters or aminoalcohols, the dehydration can be avoided and the aldol addition becomes essentially quantitative (Eq. 8.97).245 A microporous coordination polymer obtained by treating anthracene- is (resorcinol) with La(0/Pr)3 possesses catalytic activity for ketone enolization and aldol reactions in pure water at neutral pH.246 The La network is stable against hydrolysis and maintains microporosity and reversible substrate binding that mimicked an enzyme. Zn complexes of proline, lysine, and arginine were found to be efficient catalysts for the aldol addition of p-nitrobenzaldehyde and acetone in an aqueous medium to give quantitative yields and the enantiomeric excesses were up to 56% with 5 mol% of the catalysts at room temperature.247... 

This reaction sequence of conjugate reduction followed by aldol reaction is known as the reductive aldol reaction. In certain instances, reductive elimination from the M-TM-enolate species may occur to furnish M-enolate, which itself may participate in the aldol reaction (Scheme 3). This detour may be described as the background path or stepwise path in one-pot. Indeed, it has been reported that certain cationic Rh complexes such as [Rh(COD)(DPPB)] (COD = 1,5-cyclooctadiene, DPPB = diphenylphosphinobutane) catalyze the aldol reactions of silyl enol ethers and carbonyl compounds by serving as Lewis acids [5-8]. 

This finding is also in agreement with another three-component Michael/aldol addition reaction reported by Shibasaki and coworkers [14]. Here, as a catalyst the chiral AlLibis[(S)-binaphthoxide] complex (ALB) (2-37) was used. Such hetero-bimetallic compounds show both Bronsted basicity and Lewis acidity, and can catalyze aldol [15] and Michael/aldol [14, 16] processes. Reaction of cyclopentenone 2-29b, aldehyde 2-35, and dibenzyl methylmalonate (2-36) at r.t. in the presence of 5 mol% of 2-37 led to 3-hydroxy ketones 2-38 as a mixture of diastereomers in 84% yield. Transformation of 2-38 by a mesylation/elimination sequence afforded 2-39 with 92 % ee recrystallization gave enantiopure 2-39, which was used in the synthesis of ll-deoxy-PGFla (2-40) (Scheme 2.8). The transition states 2-41 and 2-42 illustrate the stereochemical result (Scheme 2.9). The coordination of the enone to the aluminum not only results in its activation, but also fixes its position for the Michael addition, as demonstrated in TS-2-41. It is of importance that the following aldol reaction of 2-42 is faster than a protonation of the enolate moiety. 

Mukaiyama aldol reactions of aldehydes with silyl enol ethers are amongst the most widely used Lewis-acid-mediated or -catalyzed reactions. However, trimethylsilyl triflate is not active enough to promote these reactions,66 and more active silicon-based Lewis acids have been developed. One example is the species generated by mixing trimethylsilyl triflate (or chloride) and B(OTf)3,319,320 for which the formulation R3Si + [B(OTf)4] is suggested by NMR experiments. Only a catalytic amount of this was needed to complete Mukaiyama aldol reactions of... 

Carreira and Kruger reported facile transmetallation of silicon enolates to other soft metal enolates including Gu derivatives.499 They reasoned that the use of soft metal fluoride complexes enabled silyl metal transmetallation with catalytic use of a soft metal source. The concept is illustrated in Scheme 103. Normal Lewis acid-catalyzed reactions of silicon enolates with aldehydes proceed via activation of aldehydes by carbonyl oxygen coordination to Lewis acids, as shown in the upper equation of Scheme 103. A key step for catalytic turnover is the desilyation of 233 by the... 

The aldol reactions introduced thus far have been performed under basic conditions where enolate species are involved as the reactive intermediate. In contrast to the commonly accepted carbon-anion chemistry, Mukaiyama developed another practical method in which enol species can be used as the key intermediates. He is the first chemist to successfully demonstrate that acid-catalyzed aldol reactions using Lewis acid (such as TiCU) and silyl enol ether as a stable enol equivalent can work as well.17 Furthermore, he developed the boron tri-fluoromethane sulfonate (triflate)-mediated aldol reactions via the formation of formyl enol ethers. 

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