Enolic acid derivatives

Phenylbutazone is an enolic acid derivative in the pyrazolone class of NSAIDs. The pharmacokinetics and pharmacodynamics of phenylbutazone, the most commonly prescribed NSAID for use in horses, have been well studied. In the horse, the plasma half-life of phenylbutazone ranges from 3 to 8 h. The plasma half-life in an individual horse is dependent on the dose administered and the metabolic capacity of that animal. For example, when a single dose of phenylbutazone was administered i.v. at a dose rate of 4.4 mg/kg, the plasma half-life was 5.5 h (Lees et al 1987b). In a... 

Oxicams are a class of recently introduced enolic acid derivatives, including ineloxicain, piroxlcam and tenoxicam. So far only piroxicam has any extensive usage and is mainly used to treat rheumatoid and osteoarthritis, and for musculoskeletal pain. 

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). 

Section 21 7 The malonic ester synthesis is related to the acetoacetic ester synthesis Alkyl halides (RX) are converted to carboxylic acids of the type RCH2COOH by reaction with the enolate ion derived from diethyl mal onate followed by saponification and decarboxylation... 

The reactions of ketenes or ketene equivalents with imines, discussed above, all involve the imine acting as nucleophile. Azetidin-2-ones can also be produced by nucleophilic attack of enolate anions derived from the acetic acid derivative on the electrophilic carbon of the imine followed by cyclization. The reaction of Reformatsky reagents, for example... 

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. 

Propiolactone is subject to attack by enolate ions to give propionic acid derivatives of ketones. It may likewise react with nucleophilic enamines to give carboxyethylation according to the reactions. The morpholide is easily hydrolyzed to the corresponding acid. 

In contrast, highly stereoselective aldol reactions are feasible when the boron etiolates of the mandelic acid derived ketones (/ )- and (5,)-l- t,r -butyldimethylsiloxy-l-cyclohexyl-2-butanone react with aldehydes33. When these ketones are treated with dialkylboryl triflate, there is exclusive formation of the (Z)-enolates. Subsequent addition to aldehydes leads to the formation of the iyn-adducts whose ratio is 100 1 in optimized cases. 

Boron enolates containing the chiral information in C2-symmetric ligands of the metal atom, also provide rmt/-/ -hydroxycarboxylic acid derivatives of high optical purity34 -64-70. When 5-(3-cthylpent-3-yl) thiopropanoate is treated with (5,5)-2,5-dimethyl-l-(trifluoromethylsul-... 

The (acyloxy)borane complex 9, readily available from tartaric acid derivative 8, also catalyzes aldol additions of silyl enol ethers34 and silylketene acetals3 5 in an enantioselective manner. Thus,. u -ketones 10 and /Thydroxy esters 12 are available34, as well as a-unsubstituted ketones 1135. 

Tin(Il) shows considerable affinity towards nitrogen, therefore is expected to activate the imino group. The diastereoselective addition of tin(II) enolates derived from thioesters 1 to x-imino-esters 2 is reported12. This reaction proceeds smoothly to afford. vi w-/j-amino acid derivatives 3 (d.r. 95 5) in good yields. Lithium, magnesium, and zinc enolates do not react while titanium enolates give the adducts in low yield with preferential formation of the anti-isomer. 

I.5.2.4.I.2.3. Glutamic Acid Derivatives via Enolate Additions to a,/l-Unsaturated Esters... 

The addition of a-amino-substituted lithium enolates to a,/ -unsaturated esters is a diastereoselective route to syn- or anti-glutamic acid derivatives and also to fratw-substituted 5-oxo-2-pyrrolidinecarboxylates. 

Alkylation of Li-enolates of N-Boc- or TFA-y -amino acid derivatives (e.g. 126) with various electrophiles has been shown by Hanessian and Schaum [224] to proceed with a high level of 1,3-asymetric induction to yield unlike-y " -amino acid derivatives (e.g. 127) in good yields (Scheme 2.9). This methodology has been used... 

The decarboxylation reaction usually proceeds from the dissociated form of a carboxyl group. As a result, the primary reaction intermediate is more or less a carbanion-like species. In one case, the carbanion is stabilized by the adjacent carbonyl group to form an enolate intermediate as seen in the case of decarboxylation of malonic acid and tropic acid derivatives. In the other case, the anion is stabilized by the aid of the thiazolium ring of TPP. This is the case of transketolases. The formation of carbanion equivalents is essentially important in the synthetic chemistry no matter what methods one takes, i.e., enzymatic or ordinary chemical. They undergo C—C bond-forming reactions with carbonyl compounds as well as a number of reactions with electrophiles, such as protonation, Michael-type addition, substitution with pyrophosphate and halides and so on. In this context,... 

Although the reaction of ketones and other carbonyl compounds with electrophiles such as bromine leads to substitution rather than addition, the mechanism of the reaction is closely related to electrophilic additions to alkenes. An enol, enolate, or enolate equivalent derived from the carbonyl compound is the nucleophile, and the electrophilic attack by the halogen is analogous to that on alkenes. The reaction is completed by restoration of the carbonyl bond, rather than by addition of a nucleophile. The acid- and base-catalyzed halogenation of ketones, which is discussed briefly in Section 6.4 of Part A, provide the most-studied examples of the reaction from a mechanistic perspective. 

A new chiral auxiliary based on a camphor-derived 8-lactol has been developed for the stereoselective alkylation of glycine enolate in order to give enantiomerically pure a-amino acid derivatives. As a key step for the synthesis of this useful auxiliary has served the rc-selective hydroformylation of a homoallylic alcohol employing the rhodium(I)/XANTPHOS catalyst (Scheme 11) [56]. 

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]. 

Clayden and co-workers reported the dearomatiztion of an electron-deficient pyridine ring via intramolecular cyclization of an enolate shown in the scheme above <06OL5325>. Generation of the amino acid derived enolate of 46, with simultaneous activation of the pyridine ring by IV-acylation, leads to a stereoselective transition state 47. The authors postulate that the stereoselectivity arises from the manner in which the bulky PMP (p-... 

The scope of the acid-catalyzed formation of C-glycosyl compounds has been greatly expanded with the finding that enol ethers and ketene acetals can be used as the carbon source in electrophilic substitution reactions at the anomeric center.126 Treatment of 198 with the trimethylsilyl enol ether derived from cyclohexanone, in the presence of stannic chloride, led to 2-(2,3,5-tri-0-benzoyl-/J-D-ribofuranosyl)cyelohexanone (206), presumably by way of the inter-... 

From the reactions shown in Scheme 5, it is obvious that only those uronic acid derivatives whose elimination proceeds with the formation of enolic or aldehydic groups, or both, afford products capable of reducing the Cu(II) ion. Although such structures can be expected from hexo- and hepto-furanuronic, as well as from hep-topyranuronic, acid derivatives, glycosides of pentofuranuronic and of hexopyranuronic acid derivatives do not exhibit reducing properties. However, in view of this generalization, the zero reducing power observed for compound 26 requires a different explanation. 

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