Aldonic lactones epimerization

In the presence of a tertiary amine, in particular pyridine (Sec. 31.6), an equilibrium is established between an aldonic acid and its epimer. This reaction is the basis of the best method for converting an aldose into its epimer, since the only configuration affected is that at C-2. The aldose is oxidized by bromine water to the aldonic acid, which is then treated with pyridine. From the equilibrium mixture thus formed, the epimeric aldonic acid is separated, and reduced (in the form of its lactone) to the epimeric aldose. See, for example, Fig. 34.4. 

Aldol condensation of 2,2-diethyl-l,3-dioxolan-4-one lithium or zirconium enolates with aldehydo sugars has afforded higher carbon aldonic acid derivatives, e.g. 1. The synthesis of L-ribono-1,4-lactone has been achieved from d-isoascorbic acid by way of the tetrose and pentitol derivatives 2 and 3 and the d-ribonolactone derivative 4 has been efficiently epimerized to the L-lyxonolactone 5 (Scheme 1). A selective i yn-epoxidation of racemic 2-0-benzyl-4-alkenamides followed by hydrolysis has afforded 3-deoxy-pentono-1,4-lactones. 

Closely related to this reaction is the base-catalyzed epimerization of aldonic acids and their lactones (see Lundt and Madsen, this voL). This reaction is, of course, even older than the LdB-AvE process, and was first used by Emil Fischer [29]. Potassium hydroxide and tertiary amines (pyridine, quinoline) have been used as bases. The reaction is much slower than the epimerization of sugars and requires prolonged heating, but the aldonic acids are much more stable to the action of bases than the sugars, and no side reactions occur. The reaction proceeds even if the hydroxyl group at C-2 is methylated [30]. The kinetics and the mechanism of the interconversion of the aldopentonic acids in potassium hydroxyde solution have been studied this reaction also occurs via the enediol and the removal of H-2 is the rate-determining step [31]. It is of industrial importance, as indicated by numerous patents [32]. 

Due to the electronegativity of the carboxylic function, it is possible to isomerise aldonolactones at C-2 in the presence of a base. The reaction, which has been known for more than a century, can be carried out in water at 100-140°C with calcium or barium hydroxide or with pyridine as the base [8]. With hydroxide it is possible to isomerise the aldonate while the weaker base pyridine can isomerise the lactone form. The reaction is slow to reach equiUbrium and then typically gives an epimeric ratio of 3 1 in favour of the 2,3-t/ireo-epimer [8]. After separation of the two epimers by crystallisation, the starting material can be recycled. However, due to the harsh conditions, the isolated yields of the two epimers are often moderate to low. As a result, the base-catalysed C-2 isomerisation is most useM in cases where the starting aldonolactone is very cheap and the C-2 epimer very expensive, as is the case for the isomerisation of galactonolactone... 

It already has been mentioned (Chapter 2) that the cyanohydrin reaction of adding hydrogen cyanide to carbohydrates played an important role in the elucidation of the configurational structures of the carbohydrates. The reaction increases the length of the carbohydrate chain by one carbon but, unfortunately, forms two epimeric products that must be separated. Sometimes one of the two products is produced in much larger amounts than the other, facilitating the separation, but sometimes also providing the unwanted product. The nitrile products can be converted into the aldonic acids by hydrolysis with sodium hydroxide. The aldonic acid can be converted into the lactone by treatment with sulfuric acid. The lactone can then be reduced by sodium borohydride to the hemiacetal (reaction 4.41). 

On the other hand if an aldonic acid is treated with alkali, partial conversion to the C-2 epimer occurs. After separation, the pure epimeric acid can be converted to the y-lactone by heating, and this on controlled reduction yields the corresponding aldose uncontaminated with ketose produced in the Lobry de Bru3m reaction (see p. 40). In this way a rare sugar such as talose may be S3mthesised from the aldonic acid of the comparatively abundant sugeur, galactose. ... 

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