Aldol reaction enolate equivalents

On the other hand, carbonyl condensation reactions require only a catalytic amount of a relatively weak base rather than a full equivalent so that a small amount of enolate ion is generated in the presence of unreacted carbonyl compound. Once a condensation has occurred, the basic catalyst is regenerated. To carry out an aldol reaction on propanal, for instance, we might dissolve the aldehyde in methanol, add 0.05 equivalent of sodium methoxide, and then warm the mixture to give the aldol product. 

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

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. 

The Mukaiyama aldol reaction can provide access to a variety of (3-hydroxy carbonyl compounds and use of acetals as reactants can provide (3-alkoxy derivatives. The issues of stereoselectivity are the same as those in the aldol addition reaction, but the tendency toward acyclic rather than cyclic TSs reduces the influence of the E- or Z-configuration of the enolate equivalent on the stereoselectivity. 

Stereochemical Control by the Enolate or Enolate Equivalent. The facial selectivity of aldol addition reactions can also be controlled by stereogenic centers in the nucleophile. A stereocenter can be located at any of the adjacent positions on an enolate or enolate equivalent. The configuration of the substituent can influence the direction of approach of the aldehyde. 

Enantioselective Catalysis of the Aldol Addition Reaction. There are also several catalysts that can effect enantioselective aldol addition. The reactions generally involve enolate equivalents, such as silyl enol ethers, that are unreactive toward the carbonyl component alone, but can react when activated by a Lewis acid. The tryptophan-based oxazaborolidinone 15 has proven to be a useful catalyst.148... 

As in the case of aldol addition, the scope of conjugate addition reactions can be extended by the use of techniques for regio- and stereospecific preparation of enolates and enolate equivalents. If the reaction is carried out with a stoichiometrically formed enolate in the absence of a proton source, the initial product is the enolate of the adduct. The replacement of a tt bond by a ct bond ensures a favorable AH. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

In Section 3.5 on alkene isomerization, it was mentioned that Li and co-workers reported a RuCl2(PPh3)3-catalyzed shuffling of functional groups of allylic alcohols in water (Eq. 3.35).140 Since the reaction proceeds through an enol intermediate, allyl alcohols can thus be considered as enol equivalents.203 This has been developed into an aldol-type reaction by reacting allyl alcohols with aldehyde (Scheme 3.11).204 The presence of In(OAc)3 promoted the aldol reaction with a-vinylbenzyl alcohol and aldehyde.205... 

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. 

Silyloxy)alkenes were first reported by Mukaiyama as the requisite latent enolate equivalent to react with aldehydes in the presence of Lewis acid activators. This process is now referred to as the Mukaiyama aldol reaction (Scheme 3-12). In the presence of Lewis acid, anti-aldol condensation products can be obtained in most cases via the reaction of aldehydes and silyl ketene acetals generated from propionates under kinetic control. 

Besides the silyl enolate-mediated aldol reactions, organotin(IY) enolates are also versatile nucleophiles toward various aldehydes in the absence or presence of Lewis acid.60 However, this reaction requires a stoichiometric amount of the toxic trialkyl tin compound, which may limit its application. Yanagisawa et al.61 found that in the presence of one equivalent of methanol, the aldol reaction of an aldehyde with a cyclohexenol trichloroacetate proceeds readily at 20°C, providing the aldol product with more than 70% yield. They thus carried out the asymmetric version of this reaction using a BINAP silver(I) complex as chiral catalyst (Scheme 3-34). As shown in Table 3-8, the Sn(IY)-mediated aldol reaction results in a good diastereoselectivity (,anti/syn ratio) and also high enantioselectivity for the major component. 

A review of enantioselective aldol additions of latent enolate equivalents covers a variety of Sn", boron, Ti, Cu, lanthanide, and Lewis base catalysts. Asymmetric aldol reactions using boron enolates have been reviewed (401 references). ... 

Catalysed enantioselective aldol additions of latent enolate equivalents have been reviewed and electronic effects of the aldehyde component on such reactions of trichlorosilylenolates of cyclopentanone and cycloheptanone, catalysed by chiral phos-phoramides, have been interpreted in terms of initial aldehyde coordination to the trichlorosilyl enolate and aldolization via a six-membered boat-like transition state. 

We have an aldehyde, an amine, and a ketone. As in part (b), the amine reacts first to give an imine, and this behaves as a carbonyl analogue, which in the Mannich reaction is then the electrophile for an enolate anion equivalent. How can we remember the sequence of events The most common mistake is to react the aldehyde and ketone via an aldol reaction, but this then leads to an alcohol and one is faced with a substitution reaction to incorporate the amine. It is the mild acidic conditions that help us to avoid wrong... 

Thioamides of secondary amines are deprotonated with isopropyhnagnesium to give (Z)-enolates. Thioamides of primary amines react with two equivalents of /-PrMgBr to afford dianions that have been shown to have the (Z)-configuration. These magnesium species are versatile intermediates in stereoselective aldol reaction (equation 50, Table 5 ... 

An important reaction of silylenol ethers is their use as enolate equivalent in Mukaiyama aldol additions. An example of the synthetic utility of this reaction with a magnesium enolate as starting reagent is shown below. 

Zinc bisenolate 136 (Figure 11) is prepared by the transmetallation of propiophenone lithium enolate with 0.5 equivalents of ZnBr2 136 reacts with aldehydes, both aliphatic and aromatic, in a domino aldol reaction which mimics the action of aldolases167. The first aldol reaction between 136 and the aldehyde produces zinc aldolate 137, which then undergoes a second intramolecular aldol addition to adduct 138. Spontaneous hemiacetalization affords 139, where all large substituents occupy equatorial positions168. 

A directed aldol reaction requires that one partner provides a preformed enolate (or chemically equivalent reactive species) and is then added to the second carbonyl-containing molecule. 

The aldol reaction of an enolate or enolate equivalent with an imine is referred to as the Mannich-type reaction. Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched p-amino acid derivatives, which are versatile chiral building blocks for the synthesis of nitrogen-containing biologically important compounds [23]. Despite the enormous progress made in asymmetric aldol reactions [24], the corresponding asymmet-... 

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

This reaction can initiate intramolecular cyclization of unsaturated thioketals and of enol silyl ethers containing a thioketal group to provide an equivalent of a directed intramolecular aldol reaction.3 Examples ... 

Claisen condensation equivalent, 10, 174 Claisen rearrangement equivalent, 10, 176 enolate alkylation equivalent, 10, 171 Mannich reaction equivalent, 10, 174 as strategic reaction, 10, 171 intermolecular carbene insertion, C-H activation-Cope rearrangement characteristics, 10, 177 as strategic reaction, 10, 178 tandem aldol reaction-siloxy-Cope rearrangement equivalent, 10, 181... 

We need a formaldehyde equivalent that is less electrophilic than formaldehyde itself and will therefore add only once to enol(ate)s. The solution is the Mannich reaction.7 Formaldehyde is combined with a secondary amine to give an iminium salt that adds 47 to the enol of the aldehyde or ketone in slightly acidic conditions to give the amino ketone (or Mannich base ) 48. If the product of the aldol reaction 50 is wanted, alkylation on nitrogen provides a good leaving group and ElcB elimination does the trick. 

The Claisen reaction involves the condensation or linking of two ester molecules to form a 3-ketoester (Fig.T). This reaction can be considered as the ester equivalent of the Aldol reaction The reaction involves the formation of an enolate ion from one ester molecule which then undergoes nucleophilic substitution with a second ester molecule (Fig.U, Step 1). 

Aldol reaction. Silyl enol ethers react with aldehydes at 25° to give aldols - the presence of BiCl, (5 mole %). The classical version (Mukaiyama, 6, 590- 11 of this reaction usually requires a full equivalent of TiCl4 as the promotor. 7>,e BiCl, version permits use of ketones as well as aldehydes in reactions carried ut at 25°, but a longer time is required and yields are only moderate (20-65%). Both versions show only slight diastereoselectivity. 

The reverse aldol reaction is catalyzed by an enzyme called aldolase. One of the roles of the enzyme is to stabilize the enolate anion intermediate because such ions are too basic to be produced under physiological conditions. In animals, aldolase accomplishes this task by forming an inline bond between the carbonyl group of fructose-1,6-bisphosphate and the amino group of a lysine amino acid of the enzyme. As a result, the product of the reverse aldol step is an enamine derived from DHAP rather than its enolate anion. (Section 20.8 shows that enamines are the synthetic equivalents of enolate anions.) The formation of the strongly basic enolate anion is avoided. This process is outlined here ... 

Transmetallation between stannyl esters and SnCl2 affords tin(ll) enolate equivalents. The reaction of cr-stannyl esters with a-alkoxy or hydroxyl ketones in the presence of SnCl2 gives aldol-type products with high selectivities in a chlelation-controlled manner (Equation (88)).245... 

Controlling aldol reactions with specific enol equivalents... 

In Chapter 26 we saw that the alkylation of enolates was most simply controlled by preparing a specific enol equivalent from the carbonyl compound. The same approach is the most powerful of all the ways to control the aldol reaction. The table is a reminder of some of the most useful of these specific enol equivalents. 

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