Enolates carboxylic acid-derived

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

The formulated mechanism is supported by the finding that no halogen from the phosphorus trihalide is transferred to the a-carbon of the carboxylic acid. For instance, the reaction of a carboxylic acid with phosphorus tribromide and chlorine yields exclusively an a-chlorinated carboxylic acid. In addition, carboxylic acid derivatives that enolize easily—e.g. acyl halides and anhydrides—do react without a catalyst present. 

A common procedure in C-C-bond formation is the aldol addition of enolates derived from carboxylic acid derivatives with aldehydes to provide the anion of the [5-hydroxy carboxylic acid derivative. If one starts with an activated acid derivative, the formation of a [Mac lone can follow. This procedure has been used by the group of Taylor [137] for the first synthesis of the l-oxo-2-oxa-5-azaspiro[3.4]octane framework. Schick and coworkers have utilized the method for their assembly of key intermediates for the preparation of enzyme inhibitors of the tetrahydrolipstatin and tetrahydroesterastin type [138]. Romo and coworkers used a Mukaiyama aldol/lac-tonization sequence as a concise and direct route to 3-lactones of type 2-253, starting from different aldehydes 2-251 and readily available thiopyridylsilylketenes 2-252 (Scheme 2.60) [139]. 

Carbonyl compounds including ketones, aldehydes and carboxylic acid derivatives constitute a class of carbon acids, the acidity of which falls in the pifa range of 25 to 35 in dimethylsulfoxide (DMSO). Representative values for selected carbonyl substrates are summarized in Table 2-1.1 Different methods may be invoked for generating the enolates according to the pifa value of their parent compounds. 

Treatment of aldehydes or ketones with acceptor-substituted carbene complexes leads to formation of enol ethers [1271-1274], oxiranes [1048], or 1,3-dioxolanes [989,1275] by O-alkylation of the carbonyl compound. Carboxylic acid derivatives... 

Enolate anions from carboxylic acid derivatives... 

The a-hydrogens of carboxylic acid derivatives show enhanced acidity, as do those of aldehydes and ketones, and for the same reasons, that the carbonyl group stabilizes the conjugate base. Thus, we can generate enolate anions from carboxylic acid derivatives and use these as nucleophiles in much the same way as we have already seen with enolate anions from aldehydes and ketones. 

An enolate anion generated from a carboxylic acid derivative may be used in the same sorts of nucleophilic reactions that we have seen with aldehyde and ketone systems. It should be noted, however, that the base used to generate the enolate anion must be chosen carefully. If sodium hydroxide were used, then hydrolysis of the carboxylic derivative to the acid (see Section 7.9.2) would compete with enolate anion formation. However, the problem is avoided by using the same base, e.g. ethoxide, as is present in the ester... 

Alkylation of the a-position of suitable carboxylic acid derivatives may be achieved using the enolate anion as nucleophile in a typical Sn2 reaction (compare Section 10.2). In the example shown, the... 

Nucleophilic addition of an enolate anion from a carboxylic acid derivative onto an aldehyde or ketone is simply an aldol-type reaction (see Section 10.3). 

Now this is exactly the same situation we encountered when we compared the reactivity of aldehydes and ketones with that of carboxylic acid derivatives (see Section 7.8). The net result here is acylation of the nucleophile, and in the case of acylation of enolate anions, the reaction is termed a Claisen reaction. It is important not to consider aldol and Claisen reactions separately, but to appreciate that the initial addition is the same, and differences in products merely result from the absence or presence... 

To participate in this sort of reaction, the carboxylic acid derivative acting as nucleophile must have a-hydrogens in order to generate an enolate anion. In practice, esters are most commonly employed in Claisen-type reactions. 

A method for enantioselective synthesis of carboxylic acid derivatives is based on alkylation of the enolates of /V-acyl oxazolidinones.59 The lithium enolates have the structures shown because of the tendency for the metal cation to form a chelate. 

Therefore, using either direct Birch reduction alkylation or Birch reduction-protonation-enolate formation alkylation, both followed by auxiliary removal, it is possible to prepare either enantiomer of a desired 2,5-cyclohexadiene-l -carboxylic acid derivative in excellent enantiomeric purity from the same starting materials. 

Enolate hydroxylation is a problem of long standing. Direct oxygenation succeeds with the fully substituted enolates of certain a,a-disubstituted ketones and a variety of carboxylic acid derivatives (ester anions, acid dianions, amide anions), but the reaction of enolates, RCH = C(0 )R or CH2 = C(0 )R, with oxygen results in complex products of overoxidation. The stable... 

Dibromocyclopropanes with vicinal chloromethoxy or mesyloxymethyl substituents undergo [Ni(CO)4]-induced ring opening-carbonylation in the presence of alcohol or amine, leading to y.S-un-saturated carboxylic acid derivatives selectively via intermediate nickel enolates (equation 115).262 Di-... 

The most common procedure is ozonolysis at -78 °C (P.S. Bailey, 1978) in methanol or methylene chloride in the presence of dimethyl sulfide or pyridine, which reduce the intermediate ozonides to aldehydes. Unsubstituted cydohexene derivatives give 1,6-dialdehydes, enol ethers or esters yield carboxylic acid derivatives. Oxygen-substituted C—C bonds in cyclohexene derivatives, which may also be obtained by Birch reduction of alkoxyarenes (see p. 103f.), are often more rapidly oxidized than non-substituted bonds (E.J. Corey, 1968 D G. Stork, 1968 A,B). Catechol derivatives may also be directly cleaved to afford conjugated hexa-dienedioic acid derivatives (R.B. Woodward, 1963). Highly regioselective cleavage of the more electron-rich double bond is achieved in the ozonization of dienes (W. KnOll, 1975). 

Simultaneous treatment of a carbonyl compound with a Lewis acid and a tertiary amine or another weak base ( soft enolization ) can sometimes be used to generate enolates of sensitive substrates which would have decomposed under strongly basic reaction conditions [434]. Boron enolates, which readily react with aldehydes at low temperatures, can also be prepared in situ from sensitive, base-labile ketones or carboxylic acid derivatives [293, 295, 299]. Unwanted decomposition of a carbanion may also be prevented by generating it in the presence of an electrophile which will not react with the base (e.g. silyl halides or silyl cyanides [435]). 

Enolates prepared by deprotonation of carboxylic acid derivatives can also undergo elimination to yield ketenes. This is rarely seen with amides, but esters, thiolesters, imides, or N-acylsulfonamides can readily decompose to ketenes if left to warm to room temperature (Scheme 5.58). At -78 °C, however, even aryl esters can be converted into enolates stoichiometrically without ketene formation [462, 463],... 

Alkylation of Quantitatively Prepared Enolates and Aza-enolates Chain-Elongating Syntheses of Carbonyl Compounds and Carboxylic Acid Derivatives... 

Side Note 13.4 presents the diastereoselective alkylation of a very special ester enolate in which one can easily understand what the stereocontrol observed is based upon. However, only very specific carboxylic acid derivatives are made accessible by those alkylations. Much more broadly applicable diastereoselective alkylations of chiral ester or amide enolates will be introduced in Figures 13.42 and 13.43. Figure 13.42 shows alkylations of a propionic acid ester—derived from an enantiomerically pure chiral alcohol—via the and Z -enolate. 

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