Anionic epimerization

Under acidic conditions, dehydration to an anhydrotetracycline [20154-34-1] (8), C22H22N20y, occurs under basic ones, ring C opens to an isotetracycline [3811-31-2] (9), C22H24N20g. The anhydrotetracyclines, such as (8), appear to exhibit a mode of antibacterial action, but it is unlike that of tetracycline (24). Epimerization (23,25,26) at C-4 occurs in a variety of solvents within the pH range 2—6, particularly in acetic acid (25). A number of anions (27) facihtate this reaction. The reverse process, from 4-epitetracycline [79-85-6] C22H24N20g, to tetracycline, is promoted by chelation with ions such as calcium and magnesium (28). 

Another route to enantiomcrically pure iron-acyl complexes depends on a resolution of diastereomeric substituted iron-alkyl complexes16,17. Reaction of enantiomerically pure chloromethyl menthyl ether (6) with the anion of 5 provides the menthyloxymethyl complex 7. Photolysis of 7 in the presence of triphenylphosphane induces migratory insertion of carbon monoxide to provide a racemic mixture of the diastereomeric phosphane-substituted menthyloxymethyl complexes (-)-(/ )-8 and ( + )-( )-8 which are resolved by fractional crystallization. Treatment of either diastereomer (—)-(/J)-8 or ( I )-(.V)-8 with gaseous hydrogen chloride (see also Houben-Weyl, Vol 13/9a, p437) affords the enantiomeric chloromethyl complexes (-)-(R)-9 or (+ )-(S)-9 without epimerization of the iron center. 

However, upon dissolution, an epimerization of the anions can occur in the presence of acidic counter-ions. This is particularly true for 16a-16d [39]. The nature of the solvent (MeOH, CHCI3) plays a crucial role on the kinetics of epimerization and the position of the resulting equilibrium. For anions made with a 2R, 3R) tartaric backbone, a A configuration is always preferred in MeOH the selectivity, obtained after a slow equilibration, being independent of the nature of the ester alkyl chain (diastereomeric ratio (d.r.) 3 1). However, in chloroform, the A diastereomer is rapidly obtained and the selectivity is best if the ester side chain is sterically demanding (d.r. 2 1 to 9 1 from 16a to 16d) (Scheme 16). 

For the BINPHAT anion 15, of enantiomeric (A,S) or (A,R) configuration, no such epimerization occurs. However, due to the strain of the 7-membered ring. 

Scheme 16 Solvent-induced (controlled) epimerization of TARPHAT anions 16...

Other anions such as nitronate anion,96 or the conjugate base of (3-ketoesters,97 give similar results. Usually, the 1,2-cw-C-glycosyl compound is formed under kinetic conditions. Thus, in the case of the reaction of the GlcNAc derivative 75 with the Wittig reagent Ph3P=CHCOOEt, the a-C-pyranosyl compound 77a is the major product under conditions of kinetic control. Under basic conditions, 77a is slowly epimerized into the more stable (3-C-pyranosyl derivative 77p (Scheme 25). 

The existence of a protonated oxazolone has been demonstrated indirectly by a simple experiment. When p-nitrophenol was added to an excess of 2-alkoxy-5(4//)-oxazolone in dichloromethane, a yellow color appeared. The color persisted until all the p-nitrophenol had been consumed by the oxazolone. The anion of p-nitro-phenol is yellow. The explanation for the color of the mixture is the presence of the p-nitrophenoxide anion that was generated by abstraction of the proton by the oxazolone. In summary, protonation of the O-acylisourea suppresses the side reaction of oxazolone formation as well as the side reaction of A-acylurea formation and accelerates its consumption by enhancing its reactivity and generating an additional good nucleophile that consumes it. Protonation of the oxazolone suppresses epimerization by preventing its enolization and also increases the rate at which it is consumed.4 68 78 79... 

When HOBt and HOAt are used with phosphonium and uronium salt-based reagents, they are present as anions, and they suppress epimerization by trapping the O-acyloxyphosphonium, O-acy I uronium, and oxazolone intermediates as the activated esters (see Section 2.21). 

Removal of the a-hydrogen in o-glucose leads to enolization (we have omitted the enolate anion in the mechanism). Reversal of this process allows epimerization at C-2, since the enol function is planar, and a proton can be acquired from either face, giving D-mannose as well as o-glucose. Alternatively, we can get isomerization to o-fmctose. This is because the intermediate enol is actually an enediol restoration of the carbonyl function can, therefore, provide either a C-1 carbonyl or a C-2 carbonyl. The equilibrium mixture using dilute aqueous sodium hydroxide at room temperature consists mainly of o-glucose and o-fructose, with smaller amounts of D-mannose. The same mixture would be obtained... 

To neutralize the hydrolysis products the solution is passed through a column (of about 15-cm length and 1-cm width) packed with an anion exchanger (e.g.,anion exchanger from Example 5-10). Neutralization with alkaline earth metal carbonates is to be avoided at all costs, in order to prevent epimerization of glucose to mannose which is favored by complex formation between mannose and alkaline earth metal ions. 

Reduction of a S-aminoketone resulting from the addition of an equivalent of a glycinate anion on ethyl difluoro- or trifluoroacetate is stereoselective and leads to ethyl di- or trifluorothreoninate threo (syn). Release of the acid, performed by saponification, is accompanied by a partial epimerization into an alio compound. However, the amino acids are obtained in enantiopure forms by using a lipase. . It s important to note that (25, 35)-difluorothreonine exhibits activity toward the growth of leukemia cell hnes comparable to 5-fluorouracil. ... 

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