Carbon nucleophiles, aldol reactions reaction

Enolates can also serve as carbon nucleophiles in carbonyl addition reactions. The addition reaction of enolates with carbonyl compounds is of very broad scope and is of great synthetic importance. Essentially all of the enolates considered in Chapter 7 are capable of adding to carbonyl groups. The reaction is known as the generalized aldol addition. 

Chapters 1 and 2 focus on enolates and other carbon nucleophiles in synthesis. Chapter 1 discusses enolate formation and alkylation. Chapter 2 broadens the discussion to other carbon nucleophiles in the context of the generalized aldol reaction, which includes the Wittig, Peterson, and Julia olefination reactions. The chapter and considers the stereochemistry of the aldol reaction in some detail, including the use of chiral auxiliaries and enantioselective catalysts. 

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. 

More traditional carbon nucleophiles can also be used for an alkylative ring-opening strategy, as exemplified by the titanium tetrachloride promoted reaction of trimethylsilyl enol ethers (82) with ethylene oxide, a protocol which provides aldol products (84) in moderate to good yields <00TL763>. While typical lithium enolates of esters and ketones do not react directly with epoxides, aluminum ester enolates (e.g., 86) can be used quite effectively. This methodology is the subject of a recent review <00T1149>. 

Nucleophilic attack of hydroxide ion on the a-carbon atom, with subsequent cleavage of the Ca—Cp bond, has been proposed to account for the kinetics of retro-aldol reaction of substituted benzylidene malononitriles with hydroxide ion in 90%... 

For the mixed aldol reaction to be of value in synthetic work, it is necessary to restrict the number of combinations. This can be accomplished as follows. First, if one of the materials has no a-hydrogens, then it cannot produce an enoiate anion, and so cannot function as the nucleophile. Second, in aldehyde plus ketone combinations, the aldehyde is going to be a better electrophile, so reacts preferentially in this role. A simple example of this approach is the reaction of benzaldehyde with acetone under basic conditions. Such reactions are synthetically important as a means of increasing chemical complexity by forming new carbon-carbon bonds. 

We can insert the heteroatom into the rest of the carbon skeleton, or attempt to join two units, one of which contains the heteroatom, by means of C-C and C-heteroatom linkages. To make the new bonds, two reaction types are most frequently encountered. Heteroatom-C bond formation is achieved using the heteroatom as a nucleophile to attack an electrophile such as a carbonyl group (see Section 7.7.1). Aldol-type reactions may be exploited for C-C bond formation (see Section 10.3), employing enamines and enols/enolate anions (see Section 10.5). 

The reactions described in this chapter include some of the most useful synthetic methods for carbon-carbon bond formation the aldol and Claisen condensations, the Robinson annulation, and the Wittig reaction and related olefination methods. All of these reactions begin by the addition of a carbon nucleophile to a carbonyl group. The product which is isolated depends on the nature of the substituent (X) on the carbon nucleophile, the substituents (A and B) on the carbonyl group, and the ways in which A, B, and X interact to control the reaction pathways available to the addition intermediate. 

Until then, only heterogeneous catalyst had been successful. However, in the mid-1980s, the work of Ito et al. led to an outstanding discovery in a catalytic asymmetric aldol reaction. In this case, enantioselectivity was given by a chiral ferrocene diphosphine ligand, with a carbon nucleophile addition to a carbonyl... 

Magnesium, 235 Samarium(II) iodide, 270 Titanium(IV) chloride, 304 Addition reactions to carbonyl groups—Addition of functionalized CARBON NUCLEOPHILES (see also Aldol reaction and other specific condensation reactions, Meth-ylenation, Peterson Olefination, Refor-matsky reaction, Wittig reaction, Wittig-Horner reaction)... 

The two possible valence-bond structures of the enolate anion, 7a and 7b, show that the anion should act as an ambident nucleophile—a nucleophile with nucleophilic properties associated with both carbon and oxygen. The addition step in the aldol reaction therefore may be expected to take place in either of two ways The anion could attack as a carbon nucleophile to form a carbon-carbon bond, 8, leading ultimately to the aldol 9, or it might attack as an oxygen nucleophile to form a carbon-oxygen bond, thereby leading to the hemiacetal 10. By this reasoning, we should obtain a mixture of products 9 and 10. However, the aldol 9 is the only one of these two possible products that can be isolated ... 

By using the neutral enamine as the carbon nucleophile rather than an eno-late anion, the biological system avoids the need for strongly basic reaction conditions in aldol addition. 

Nature builds carbon-carbon bonds essentially by aldol or Claisen-type reactions, both involving a carbonyl group as an electrophile, and an enol or enolate as a nucleophile. A less-frequent reaction bears a formal analogy to the Claisen acyloin condensation. The aldol reaction of carbohydrates always involves an aldehyde as the electrophile, and an aldehyde or ketone as the nucleophile (see Eq. 1). 

Even greater diastereoselectivity in die aldol reaction can be achieved using boron etiolates as the carbon nucleophile. Boron etiolates are easily prepared from aldehydes and ketones, and the syn and die anti isomers can be separated as pure compounds. They react with aldehydes and ketones to give aldol products by a similar transition state. The difference is fliat boron oxygen bonds are shorter than lidiium oxygen bonds, and thus steric interactions in the transition state are magnified and result in greater diastereoselectivity. 

The Mukaiyama reaction is a versatile crossed-aldol reaction that uses a silyl enol ether of an aldehyde, ketone, or ester as the carbon nucleophile and an aldehyde or ketone activated by a Lewis acid as the carbon electrophile. The product is a /1-hydroxy carbonyl compound typical of an aldol condensation. The advantages to this approach are that it is carried out under acidic conditions and elimination does not usually occur. 

Aldol reactions of aldehydes with cycloakanones were performed in ionic liquids and catalyzed by FeCl3-6H20 [32]. Mukaiyama aldol reactions of silylenol ethers with aldehydes can be carried out in aqueous media however, among several Lewis acidic catalysts investigated, iron compounds were not the optimal ones [33], If silyl ketene acetals are applied as carbon nucleophiles in Mukaiyama aldol reactions, cationic Fe(II) complexes give good results. As catalysts, CpFe(CO)2Cl [34] and [CpFe(dppe) (acetone)] BF4 [35] [dppe = l,2-bis(diphenylphosphano)ethane] were applied (Scheme 8.8). No diastereomeric ratio was reported for product 26a. 

Transketolase removes a two-carbon fragment from ketols such as fructose 6-phosphate (alternatively xylulose 5-phosphate or sedoheptu-lose 7-phosphate) through the participation of thiamine diphosphate. Nucleophilic attack of the thiamine diphosphate anion on to the carbonyl results in an addition product which then fragments by a reverse aldol reaction, generating the chain-shortened aldose erythrose 4-phosphate, and the two-carbon carbanion unit attached to TPP (Figure 8.5) (compare the role of TPP in the decarboxylation of a-keto... 

The carbon alpha to the carbonyl of aldehydes and ketones can act as a nucleophile in reactions with other electrophilic compounds or intermolecu-larly with itself. The nucleophilic character is imparted via the keto-enol tau-tomerism. A classic example of this reactivity is seen in the aldol condensation (41), as shown in Figure 23. Note that the aldol condensation is potentially reversible (retro-aldol), and compounds containing a carbonyl with a hydroxyl at the (3-position will often undergo the retro-aldol reaction. The aldol condensation reaction is catalyzed by both acids and bases. Aldol products undergo a reversible dehydration reaction (Fig. 23) that is acid or base catalyzed. The dehydration proceeds through an enol intermediate to form the a,(3-unsaturated carbonyl containing compound. 

Another interesting extension of the proline-catalyzed aldol reaction was recently reported by the Jorgensen group (Scheme 6.22), who used keto malonates as acceptors and a-substituted acetone derivatives as donors [78]. In contrast with the classic proline-catalyzed reaction discussed above, in this reaction the stereogenic center is formed at the nucleophilic carbon atom of the donor. The resulting products of type 46 are formed in good yields, from 88% to 94%, and with enantioselectivity between 84 and 90% ee (Scheme 6.22). The reactions were performed with a catalytic amount of 50 mol% [78],... 

In addition to the classic aldol reaction described, e.g., in Sections 6.2.1 and 6.2.2, several modified versions have been reported. These methods are based on the use of nucleophiles related to the standard ketones. In particular, y-dienolates, nitromethane, and nitrones are interesting carbon nucleophiles in aldol reactions and the use of these types of substrate has been investigated in aldol reactions catalyzed by organocatalysts. 

In the aldol condensation, an enolate anion acts as a carbon nucleophile and adds to a carbonyl group to form a new carbon-carbon bond. Thus, the a-carbon of one aldehyde molecule becomes bonded to the carbonyl carbon of another aldehyde molecule to form an aldol (a 3-hydroxyaldehyde). In the mixed aldol condensation, the reactant with an a-hydrogen supplies the enolate anion, and the other reactant, usually without an a-hydrogen, supplies the carbonyl group to which the enolate ion adds. The aldol reaction is used commercially and also occurs in nature. 

Base-catalyzed hydration of conjugated carbonyls, followed by retro-aldol fragmentation has been a common strategy for studying the reaction cascade (1-4). The kinetically important step in the base-catalyzed hydration of an alpha/beta unsaturated carbonyl is similar to a nucleophilic substitution reaction at carbon 3. The reaction cascade proceeds rapidly from the conjugated carbonyl through its hydration and subsequent fragmentation. 

The carbon that lost a proton is now a nucleophilic center and can therefore react with formaldehyde. As mentioned above, formaldehyde has an electrophilic center on carbon. Therefore, the carbon of formaldehyde can react with the nucleophilic carbon on the enolate of glycolaldehyde to form a new compound containing three carbon atoms, a three-carbon carbohydrate called glyceraldehyde. The overall reaction sequence is often called an aldol addition reaction, here of formaldehyde and glycolaldehyde. 

Reactions in which hydride leaves are less common but can occur if other reactions are precluded and the hydride is transferred directly to an electrophile. One example occurs when an aldehyde without any hydrogens on its a-carbon is treated with NaOH or KOH. (If the aldehyde has hydrogens on its a-carbon, the aldol condensation is faster and occurs instead.) In this reaction, called the Cannizzaro reaction, two molecules of aldehyde react. One is oxidized to a carboxylate anion and the other is reduced to a primary alcohol. The mechanism for this reaction is shown in Figure 20.5. The reaction begins in the same manner as the reactions described in Chapter 18 a hydroxide ion nucleophile attacks the carbonyl carbon of the aldehyde to form an anion. The reaction now begins to resemble the reactions in Chapter 19. 

There is also a frontier orbital effect that assists conjugate addition over the aldol reaction, You will reeall that the carbonyl carbon is a relatively hard centre, whereas the 3 carbon of an enone is soft, As the nucleophilic enolate becomes more stabilized with extra electron-withdrawing groups, it beeomes increasingly soft and hence more likely to attack the [J carbon,... 

The six-member ed transition state for the reaction of an allylic borane or boron ate is very reminiscent of the cyclic transition state for the aldol reaction you met in Chapter 34. In this case the only change is to replace the oxygen of the enolate with a carbon to make the allyl nucleophile. The transition state for the aldol reaction was a chair and the reaction was stereospecific so that the geometry of the enolate determined the stereochemistry of the product aldol. The same is true in these reactions. -Crotyl boranes (or boronates) give anti homoallylic alcohols and Z-crotyl boranes (or boronates)... 

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