A-Keto acetals

Significant progress in the substrate scope of the Pt-cinchona systems has been made in the last 5 years. Besides a-keto acids and esters, a-keto acetals, a-keto ethers, and some trifluoromethyl ketones have been shown to give high ee s. It is now possible to classify ketones concerning their suitability as substrates for the Pt-cinchona catalyst system, as depicted in Figure 18.6. Nevertheless, for the synthetic chemist, the substrate scope is still relatively narrow, and it is not expected that new important substrate classes will be found in the near future. However, the chemoselectivity of this system has not yet been exploited to its full value, and this might be a potential for future synthetically useful applications. 

STfP 2 Decarboxylation and phosphorylation. Decarboxylation of oxaio acetate, a -keto acid, occurs by a mechanism similar to that of step 4 in the citric aci d cycle (Figure 29.6X but phosphon Iation of the resultant pyruvate enolatc ion occurs concufTeutly to gkve phot[Pg.1219]

Methyl isothiazole-4-acetate is nitrosated by pentyl nitrite, and the oximino ester formed can be hydrolyzed to the a-keto ester (78GEP2745246). Secondary alcohols (94) can be oxidized to the ketones (72GEP2223648). 

A solution of bismuth trioxide in hot glacial acetic acid provides a specific method for the oxidation of acyloins. " The reaction rate is dependent on the steric accessibility of the ketol system. A 2,3-ketol requires less than one hour for completion but an 11,12-ketol is not yet fully oxidized in thirty hours." The reaction is highly selective as a-keto acids, hydrazines and phenols are not oxidized. In a direct comparison with cupric acetate, this procedure is somewhat superior for the preparation of a 2,3-diketone from a 2-keto-3-hydroxy steroid. ... 

H2O2, NaHC03, THF. The 10-acetate, which is an a-keto acetate, is cleaved in the presence of the taxol side chain that is prone to hydrolysis with other reagents. ... 

The diastereoselectivity of the reaction may be rationalized by assuming a chelation model, which has been developed in the addition of Grignard reagents to enantiomerically pure a-keto acetals7,8. Cerium metal is fixed by chelation between the N-atom, the methoxy O-atom and one of the acetal O-atoms leading to a rigid structure in the transition state of the reaction (see below). Hence, nucleophilic attack from the Si-face of the C-N double bond is favored4. 

This product is also obtained on alkaline hydrolysis of compounds of the formula RCOCHX2. Similar reactions have been performed on a-keto acetals and y-keto... 

Conversion of A -3-ketosteroids or their trimethylsilyl or acetyl derivatives in fluorescent components, whereby the detection limits were improved by 65% for the acetates. A -3-keto- and A -3-OH-steroids also react with the same sensitivity. 

Chlorination of of a-Keto Compounds Investigated in Micro Reactors Cas/liquid reaction 14 [CL 14] Chlorination of acetic acid... 

Another observation on oxalate formation is that other a-keto acids, such as oxalosuccinic acid (74) and a-ketoglutaric acid (106) do not seem to yield oxalate directly but indirectly (123). This appears to be due to the fact that only oxaloacetic acid can function as an acetate donor. In this connection the intervention of Coenzyme A may be considered, since it is reported to function in the acetylation of sulfanilamide and choline (73) and recently was shown to take part in the enzymatic synthesis of citric acid. This concept may be illustrated as follows ... 

In the early 1990s, Burk introduced a new series of efficient chiral bisphospholane ligands BPE and DuPhos.55,55a-55c The invention of these ligands has expanded the scope of substrates in Rh-catalyzed enantioselective hydrogenation. For example, with Rh-DuPhos or Rh-BPE as catalysts, extremely high efficiencies have been observed in the asymmetric hydrogenation of a-(acylamino)acrylic acids, enamides, enol acetates, /3-keto esters, unsaturated carboxylic acids, and itaconic acids. 

Catalyst 86a also catalyzed the enantioselective aldol reaction between a-keto esters and silylketene acetals or enolsilanes with high ee (ranging from 93% to 99%).58... 

Thiazoles play a prominent role in nature. For example, the thiazolium ring present in vitamin Bi serves as an electron sink and its coenzyme form is important for the decarboxylation of a-keto-acids. Furthermore, thiazoles are useful building blocks in pharmaceutical agents as exemplified by 2-(4-chlorophenyl)thiazole-4-acetic acid, a synthetic anti-inflammatory agent. 

Much work [42] has been devoted to cinchona alkaloid modified Pd and Pt catalysts in the enantioselective hydrogenation of a-keto esters such as ethyl pyruvate (Scheme 5.11). Optimal formulation and conditions include supported Pt, the inexpensive (—)-cinchonidine, acetic acid as solvent, 25 °C and 10-70 bar H2. Presently, the highest e.e. is 97.6% [to (R)-ethyl lactate]. 

The iminophosphoranes of methyl arylhydrazono acetates (338) possessing a keto function in an o-position afford l//-l,2,4-benzotriazepines (339) upon heating (Scheme 123). The yield depends on the substituents and solvents employed. Methoxycarbonyl-, 4-pyridyl-, and 3-pyridyl groups activate the carbonyl function and improve the yield. Reactions of alkyl ketones and aldehydes proved to be unsuccessful [91JCR(S)2],... 

Ethyl-a-Keto-y-dimethylaminobutyrate p-Acetylphenylhydrazone. (JMC, 7, 144 (1966)). 40 g of p-aminoacetophenone in 250 ml of water and 143 ml of coned hydrochloric acid is diazotized at 0-5° with 21 g of sodium nitrite in 200 ml of water. To the resulting solution is added 60.3 g of ethyl a-(2-dimethylaminoethyl)aceto-acetate followed by 63 g of sodium acetate. Raise the pH to 6.5 and maintain with the addition of 3 N NaOH (also use the 3 N for the initial raise to 6.5). Stir, with external cooling for 2 hours, make basic, and extract with three 400 ml portions of ehloroform. Combine the extracts and dry over sodium sulphate, eoneentrate in vacuo. Crystallize the residue with a mixture of benzene-petroleum ether, after purification with charcoal, to get 65 g. Crystallize two more times to get a melting point of 84-85°. 

Another way of avoiding reduction of the keto group in a keto ester is protection by acetalization. Ketals are evidently not reduced by lithium... 

Recently, Kim and colleagues have described a new efficient method for the preparation of a-keto esters 48 via a free-radical acylation approach using (phenylsulfonyl) methoxycarbonyl oxime ether 46 as carbonyl equivalent radical acceptor (Scheme 28). The oxime 46 was conveniently prepared from readily available methylphenylsulfonyl acetate 44 by a two-step sequence (via oxime 45) as shown in Scheme 28. Nitrosation of 44 with isoamyl nitrite in the presence of sodium methoxide gave oxime 47 in 78% yield. 

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