A-Epimerization

A more general route to 4-acetoxy-l,3-dioxanes utilizes the reductive acylation of l,3-dioxane-4-ones [46] (Scheme 21). l,3-Dioxane-4-ones 126 are prepared from the corresponding -hydroxy carboxylic acids. Low temperature reduction with DIBALH generates a diisobutylaluminum hemiacetal (127) which undergoes acylation in situ with AC2O in the presence of pyridine and DMAP. This method allows for the preparation of a wide range of 4-acetoxy-l,3-dioxanes, without the problem of a-epimerization. This method also represents a general approach to acylic a-acetoxy ethers, which are themselves useful synthetic intermediates [47,48]. 

Fig. 5.14. Degradation of the ampicillin prodrug hetacillin (5.42). In an alkaline medium, Pathway a (epimerization at C(6)) is more important than Pathway b (hydrolysis producing... 

Sometimes, Htinig s base91—EtN(z-Pr)2—is used rather than triethy-lamine. This hindered base may help to minimize a-epimerization on some sensitive aldehydes and ketones. 

Quenching is done with saturated aqueous NH4C1 at —78°C, in order to avoid a-epimerization of the aldehyde. 

Side reactions, promoted by the acidity of the protons at the a position of the carbonyl of the product, such as a-epimerizations and migration of alkenes into conjugation with the carbonyl, can be mitigated by the use... 

The action of triethylamine may cause base-induced reactions, such as a-epimerization of carbonyl compounds isomerization of alkenes into conjugation with carbonyl groups and, elimination in carbonyl compounds posssessing a good-leaving group at the (3-position... 

Because of the action of Et3N on the activated alcohol, some side reactions—beginning with a deprotonation—can happen in sensitive substrates. For example, a-epimerization of sensitive aldehydes and ketones,260 and migration of alkenes into conjugation with carbonyl groups261 are occasionally found. 

Although TEMPO-mediated oxidations under Anelli s protocol are routinely performed at a slightly basic pH of 8.6 9.8,10 obtained by buffering the bleach solution with NaHCX>3, sometimes, in order to avoid base-induced side reactions, it is advisable to adjust the pH at 6.5-7.5 by adding an acid.13 A proper adjustment of the pH for example allows to obtain carbonyl compounds without a-epimerization in difficult substrates in which other common oxidants fail.42... 

Because of these side reactions, basic reagents are rarely used with sugars, a. Epimerization of the alpha carbon... 

Allevi, P, Anastasia, M, Ciuffreda, P, Fiecchi, A, Scala, A, Epimerization of a- to (3-C-glucopyranosides under mild basic conditions, J. Chem. Soc., Perkin Trans. 1, 1275-1280, 1989. 

Cleavage of the oxazolidin-2-thione auxiliary was found to be considerably more challenging than expected, mainly due to a-epimerization. After considerable experimentation it was found that solid K2C03 in moist dioxane (rt, 10-12 h), was able to produce directly the key carboxylic acid intermediates 6 and 7 (see Scheme 4.1), from 4 and 5, respectively, in satisfactory yields and with only minor a-epimerization (2% for 6, 9% for 7). 

No enol ether of /3-thebainone-A epimeric with thebainone-A enol methyl ether [vn] has been prepared /3-dihydrothebaine was first thought to be such a compound [16] but subsequently was shown to have the structure [hi] [17]. 

First, derivatives of a-amino acids in which the amino group is part of an amide are considerably more prone to a-epimerization/racemization upon COOH activation than their carbamate congeners. Loss of stereochemical integrity is attributed to cyclization of a generic activated species, 23, to oxazolone 24, which exists in prototropic equilibrium with the aromatic tautomer 25 (Scheme 5). An amide being more nucleophilic than a carbamate, cyclization to an intermediate of type 24 is easier. Second, the tendency to cyclize is even more pronounced if the a-amido... 

Under these conditions, after 16 h the lactone 108 has been obtained in high yields in a regioselective way, without P-elimination and a-epimerization. 

C2-homologizati on of sugars with, 264-265 Acetamide, JV-bromo- (AcNHBr, NBA) bromohydrination with, 275-276, 287 Acetaminophen (= paracetamol), 301 Acetate, piperidinium cat. for aldol add., 82 —, sodium a-epimerization of ketones, 277 opening of oxiranes, 282 Acetic acid, anhydride (AcfO) protection with. See Protection Pummerer rearr. with, 51, 265 —, esters (See also Protection of hydroxy groups) C-H acidity, 10 1-methylethenyi ester pr., 174 transenolization, 58 —, bromo-, esters pr., 179 a2-synthon, 19, 65, 309 d2-synthon, 19, 301 —, chloro-, esters pr., 179 hydantoins from, 308 —, cyano-, esters pr., 177 pyrrolines from, 298 —, (dialkoxyphosphinyl)-, esters pr 188 Wittig-Horner olefinations, 267, 282 —, diazo-, ethyl ester pr, 176, 178 cyclopropanes from, 74—75 —, dichloro- deblocking of pixyl ethers, 342 —, hydroxy-, esters pr., 176 —, hydroxyphenyl-, (S)- (l-mandelic acid) ... 

Alternatively, reductive dehydroxylation of 326 with zinc-copper couple followed by N-acetylation and debenzylation with lithium in liquid ammonia affords 328. Ruthenium dioxide-sodium periodate oxidative cleavage of the furyl ring and conversion to the methyl ester with diazomethane affords the (R)-a-amino acid ester 329, which is a fully protected a-epimeric jS-alkoxy-a-amino acid [114]. 

Preferential esterification. Startg. tricarboxylic acid and Amberlyst 15 in methanol stirred at room temp, for 10 h monomethyl ester. Y 80%. a,p-Unsatd. and ar. carboxyl groups were left unaffected the method failed with higher alcohols (/-PrOH /-BuOH). Under these mild conditions, a-epimerization, c/5-tra 5-rearrangement, and transesterification (of ethyl esters) are avoided, and keto and olefinic groups remain intact. F.e. inch methyl esters of bile acids s. M. Petrini et al., Synth. Commun. 18, 847-53 (1988). 

Interconverions. The mutual transformations of monosaccharides involve the following 3 types of reactions a) epimerization, in which the steric arrangement on a C-atom is reversed by epimerases (e.g. in galactose metabolism) b) isomerization, in which aldoses and ketoses are reversibly interconverted by... 

The authors comment on the easy application of enolizable aldehydes that do not undergo a-epimerization during the exo-selective (19.T) copper(I)-catalyzed reaction. Employment of Oppolzer s sultam chiral auxiliary ultimately determines the... 

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