Carboxylic hydroxycarboxylic acid

Acetylsultam 15 is also used for stereoselective syntheses of a-unsubstituted /1-hydroxy-carboxylic acids. Thus, conversion of 15 into the silyl-A/O-ketene acetal 16 and subsequent titanium(IV) chloride mediated addition to aldehydes lead to the predominant formation of the diastereomers 17. After separation of the minor diastereomer by flash chromatography, alkaline hydrolysis delivers /f-hydroxycarboxylic acids 18, with liberation of the chiral auxiliary reagent 1919. 

No or little side reactions either with the unprotected hydroxy group present in the phenylamines, or with the unprotected hydroxyl group present in the carboxylic acids are observed. The catalytic amidation of unprotected a-hydroxycarboxylic acids also proceeds well under similar conditions. 

The A -acyl derivatives of 4-substituted-3,4,5,6-tetrahydro-27/-l,3-oxazin-2-ones proved to behave as effective chiral auxiliaries in asymmetric enolate alkylations and aldol reactions, the stereoselectivities of which were found to be higher for 4-isopropyl than for 4-phenyl derivatives <2006OBC2753>. The transformations of 4-isopropyl-6,6-dimethyl-3-propa-noyl-3,4,5,6-tetrahydro-2/7-l,3-oxazin-2-one 251 to 252 or 253 proceeded with excellent diastereoselectivities (Scheme 47). 6,6-Dimethyl substitution within the oxazine ring facilitated exclusive exocyclic cleavage upon hydrolysis of the C-alkylated and the aldol products 252 and 253, to furnish a-substituted carboxylic acids 254 or a-methyl-/ -hydroxycarboxylic acids 256. 

Alkyl oxazoline-5-carboxylates 71, precursors of P-amino-a-hydroxycarboxylic acids, have been produced by iodocyclisation of alkyl 3-benzamidocatboxylates 70. The oxazolines can be resolved enzymatically <99SL1727>. The amides 72 are cyclised to N-aryloxazolium salts 73 by fluoroboric acid <99EJ0297>. 

Some aromatic hydroxycarboxylic acids, on treatment with sodium nitrite, lose carbon dioxide with the introduction of a nitroso group to replace the carboxylate group. 

Complexes with 2-hydroxycarboxylic acids, pyridine-2-carboxylate, and dicarboxylates are described in Sections II,C,6,c, II,C,4,f, and II,C,6,p, respectively. 

Similar polyacetals were prepared by BASF scientists from CO-aldehydic aliphatic carboxylic acids (189,190) and by the addition of poly(hydroxycarboxylic acid)s such as tartaric acid to divinyl ethers (191) as biodegradable detergent polymers. 

Masked chiral a-hetero substituted carboxylic acid enolates have also shown utility in dia-stereoselective additions to nitroalkenes. For example, derivatives of a-hydroxycarboxylic acids, e.g. l,3-dioxolan-4-ones (187) a-amino acids, e.g. 1,3-imidazolidin-4-ones (188) and a-amino-fi-hydroxy-carboxylic acids, e.g. methyl 1,3-oxazolidin-4-carboxylates (189) and methyl l,3-oxazolin-4-carboxy-lates (190), have been employed.1S0a Further, diastereoselective additions of chiral (3-hydroxyesters (191), via the enediolates, to nitroalkenes (40) afford predominant anr/ -P-hydroxyesters (192 Scheme... 

When the formation of the lactone is purposefully looked at, DMF that promotes the oxidation of primary alcohols in carboxylic acids can be used as solvent in PDC oxidations. The resulting hydroxycarboxylic acid would cyclize to a lactone if favoured.173... 

Normally, it is possible to perform selective oxidation of allylic and benzylic alcohols with M11O2 in the presence of free carboxylic acids.54 a-Hydroxycarboxylic acids suffer an oxidative breakage on contact with active Mn02.55... 

The electrocarboxylation of aldehydes and ketones leads to the corresponding a-hydroxycarboxylic acids that can easily be converted into carboxylic acids via a hydrogenation reaction [7]. It has been reported that the electrocarboxylation of aromatic ketones occurs through the reaction of C02 onto the activated carbon atom of the carbonyl group of the ketyl radical anion generated upon electron transfer to the ketone [7]. Otherwise, the aforementioned intermediate is likely to be a resonance hybrid (see Equation 12.23), and its electrophilic reaction with C02 may take place both at the carbon or the oxygen atom [42, 43]. 

Lajunen, L.H.J. Portanova, R. Piispanen, J. Tolazzi, M. Critical evaluation of stability constants for alpha-hydroxycarboxylic acid complexes with protons and metal ions and the accompanying enthalpy changes. Part I. Aromatic ortho-hydroxy carboxylic acid. PureAppl. Chem. 1997, 69 (2), 329-381. 

The carbonylation of alkene in AcOH-acetic anhydride in the presence of NaCl affords the /i-acetoxy carboxylic anhydride 123 in good yields and the method offers a good synthetic route to the /i-hydroxycarboxylic acid 124 [92],... 

The carboxyl group seems to activate epoxides slightly toward nucleophilic attack by amines, and in the absence of catalysts most 2,3-epoxycarboxylic acids react with amines to yield 2-amino-3-hydroxycarboxylic acids [346-348], This regioselectivity can, however, be overridden by complex formation with Ti(OiPr)4 (Scheme4.77). 

P-Hydroxy carboxylic acids (12,3).2 This acetate on double deprotonation with LDA undergoes diastereoselective aldol reactions with aldehydes. The adducts are easily hydrolyzed to optically active P-hydroxycarboxylic acids with release of (R)-(+)-1,1,2-triphenyl-1,2-ethanediol, the precursor to 1. Optically pure acids can be obtained by crystallization of the salt with an optically active amine such as (S)-(—)-1 -pheny lethylamine. 

Figure 3.53 shows an addition of a carboxybc acid to isobutene, which takes place via the tert-butyl cation. This reaction is a method for forming ferf-butyl esters. Because the acid shown in Figure 3.53 is a /i-hydroxycarboxylic acid whose alcohol group adds to an additional isobutene molecule, this also shows an addition of a primary alcohol to isobutene, which takes place via the ferf-butyl cation. Because neither an ordinary carboxylic acid nor, of course, an alcohol is sufficiently acidic to protonate the alkene to give a carbenium ion, catalytic amounts of a mineral or sulfonic acid are also required here. 

For work on a 1 -mole scale one would thus have to use a 1.000-liter flask to activate and then lactonize the entire ft)-hydroxycarboxylic acid. Of course, it is much more practical to work in a smaller reaction vessel. However, one must also not exceed the mentioned concentration limit of < 1 pmol/L. Therefore, one can introduce only as much of the carboxylic acid in this smaller reaction vessel at a time so that its concentration does not exceed 1 pmoEL. Subsequently, one would have to activate this amount of acid and would then have to wait until it is lactonized. After that additional acid would have to be added and then activated, and so on. A more practical alternative is shown in Side Note 6.3. 

Fig. 13.40. Alkylation of an ester enolate for the preparation of an a-hydroxycarboxylic acid (for the preparation of enantiomerically pure a-hydroxy carboxylic acid through alkylation of an enantiomerically pure ester enolate cf. Figure 13.41). The initially formed benzyl ester B contains two benzylic C—0 bonds, which can be cleaved by means of hydrogenolysis.

The lactic acid, which initiates the reaction sequence. S -lactic acid —> acetal A — enolate B —> acetal C —> R hydroxy carboxylic acid D, has a stereocenter with a well-defined absolute configuration that is destroyed in the enolate intermediate B, but finally restored in the hydroxycarboxylic acid C. This is why the principle concerning the stereochemistry of the key step ( acetal A —> enolate B —> acetal C) is referred to as the self-reproduction of chirality. ... 

An aldol addition involves the addition of the a-C atom of a carbonyl compound, a carboxylic acid, a carboxylic ester, or a carboxylic amide to the C=0 double bond of an aldehyde or a ketone. The products of aldol additions are /3-hydroxylcarbonyl compounds (aldols), /i-hydroxycarboxylic acids, /Thydroxycarboxylic esters, or j3-hydroxycarboxylic amides. 

The simple diastereoselectivity of aldol reactions was first studied in detail for the Ivanov reaction (Figure 13.45). The Ivanov reaction consists of the addition of a carboxylate enolate to an aldehyde. In the example of Figure 13.45, the diastereomer of the /1-hydroxycarboxylic acid product that is referred to as the and-diastereomer is formed in a threefold excess in comparison to the. vy/j-diastereoisomer. Zimmerman and Traxler suggested a transition state model to explain this selectivity, and their transition state model now is referred to as the Zimmer-man-Traxler model (Figure 13.46). This model has been applied ever since with good success to explain the simple diastereoselectivities of a great variety of aldol reactions. 

Titanium chelates are formed from tetraalkyl titanates or halides and bi- or polydentate ligands. One of the functional groups is usually alcoholic or enolic hydroxyl, which interchanges with an alkoxy group, RO, on titanium to liberate ROH. If the second function is hydroxyl or carboxyl, it may react similarly. Diols and polyols, CC-hydroxycarboxylic acids and oxalic acid are all examples of this type. P-Keto esters, P-diketones, and alkanolamines are also excellent chelating ligands for titanium. 

This procedure offers a convenient method for the esterification of carboxylic acids with alcohols2 and thiols2 under mild conditions. Its success depends on the high efficiency of 4-dialkylaminopyridines as nucleophilic catalysts 1n group transfer reactions. The esterification proceeds without the need of a preformed, activated carboxylic acid derivative, at room temperature, under nonacidic, mildly basic conditions. In addition to dichloromethane other aprotic solvents of comparable polarity such as diethyl ether, tetrahydrofuran, and acetonitrile can be used. The reaction can be applied to a wide variety of acids and alcohols, including polyols,2 6 a-hydroxycarboxylic acid esters,7 and even very acid labile... 

Reufer Ch., Hateley, M., Lehmann, Th., Weckbecker, Ch., Sanzenbacher R. and Bilz, J. (2006) Process for the preparation of a-substituted carboxylic acids from the series comprising a-hydroxycarboxylic acids and N-substituted a-aminocarboxylic acids. European patent EP... 

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