Bilik reactions

The Bilik reaction applied to 2-ketoses yield 2-hydroxymethyl aldoses in which the tertiary carbon originates from C2 of the ketose and the C2 hydroxyl is on the opposite side to the C3 hydroxyl of the ketose (in the Fischer projection). Thus, o-fructose yield o-hamamelose. The position of equilibrium, however, lies towards the straight-chain sugar, although it can be pulled over somewhat towards the branched-chain aldose by the addition of borate. The mechanism in Figure 6.9 again explains the main reaction, but not the formation of sorbose as a by-product, which probably arises from a metal ion-promoted hydride shift, as there is no isotope exchange with solvent. The Bilik reaction can be applied to the production of l-deoxy-o-xylulose from 2-C-methyl-D-erythrose the reaction is particularly clean and only the two... 

Figure 6.9 (a) Possible reverse aldol-aldol pathways for the Bilik reaction of xylose. 

The structures of the complexes formed from sugars and Mo " under the conditions of the Bilik reaction have been studied by NMR spectroscopy and X-ray crystallography They are based on two oxygen-coordinated Mo ... 

The enzyme 2-C-methyl-D-erythritol-4-phosphate synthetase appears to catalyse a Bilik reaction (Figure 6.10) the substrate l-deoxyxylulose-5-phosphate is converted to the title compound via an intermediate aldehyde, whose carbonyl derives from C3 of the substrate. The first step is thus a Bilik reaction and the aldehyde is subsequently reduced by the enzyme using NADPH as reductant, The X-ray crystal structure of the Escherichia coli enzyme in complex with the promising antimalarial Fosmidomycin (a hydroxamic acid) reveals a bound Mn " coordinated to oxygens equivalent to the substrate carbonyl and 03. The stereochemistry and regiochemistry follow the normal Bilik course, although the crystallographers favour an alkyl shift rather than a reverse aldol-aldol mechanism. The intermediate aldehyde has been shown to be a catalytically competent intermediate. 

A short summary of the Bilik reaction (molybdic add-catalysed epimeric interconversion of aldoses with skeletal rearrangement) has been published. The... 

As a result of extensive studies performed with as many epimeric pairs of aldoses as possible, the scope and Umitations of the Bilik reaction (Scheme 1) can be summed up as follows. The treatment of an aldose, not shorter than a tetrose, in a mild acidic solution in the presence of molybdate ions (usually by heating an aqueous solution containing 10-20% of starting aldose and 0.1-0.2% molybdic acid for 2 - 6 h at 70- 90 °C) gives rise to an equilibrium mixture of epimeric aldoses, without formation of the complementary 2-ketose, and independent of which aldose is used as starting material. In every case, a conformation-ally more stable aldose prevails in the thermodynamic mixture of the epimeric aldoses. 

Since one aldose of any epimeric pair is usually more easily available than the other, either directly isolable from its natural source or in combination with a chain-length modification, the apphcation of the Bilik reaction enables the other, less-available aldose to be obtained. Thus, the following equilibria can be obtained ... 

The importance of the presence of the OH group at C-4 for an unambiguous course of the molybdate-catalyzed epimerization was further shown in studies with trioses [19, 20], 4-deoxy-D-/yxo-hexose and several other 4-0-substituted derivatives of aldoses [20]. Much more important is the OH group at C-3 which is essential for the Bilik reaction. Its absence causes a quite different structural change in both 3-deoxy-D-arafcmo-hexose (1) and 3-deoxy-D-nfco-hexose (2) under otherwise the same reaction conditions both sugars on treatment with molybdic acid are irreversibly transformed to 3-deoxy-D-ei7f/zro-hex-2-ulose (3, Scheme 2) [21]. 

All the experimental data strongly suggest that the mechanism of the secondary process that operates in parallel under the conditions of the Bilik reaction may proceed via a transition state consisting of two tricentric C-3-H-C-2 bonds of an aldopyranose bidentately hnked via C-3-OH and C-2-OH in a molybdate... 

Other indirect support for the pyranose half-chair structure of the transition state of the secondary process is provided by the behavior of alditols [21] and furanoid tetroses or 5-deoxypentoses [5, 6] under the conditions of the Bilik reaction. The former, which although able to form planar bidentate complexes are without the deformation necessary for the hydrogen exchange, do not undergo any structural change while the latter, sterically much more demanding furanoses (aparently unable to form bidentate molybdate complexes via their trans-oriented 2,3-hydroxyls), do not undergo racemization. 

Application of the Bilik Reaction for the Mutual Interconversion of 2-Ketoses and 2-C-(Hydroxymethyl)aldoses... 

An immediately applicable example was the interconversion of 2-ketoses and 2-C-(hydroxymethyl)aldoses predictable from the analysis of the mechanism of the primary process of the Bilik reaction (Scheme 4). However, the primary studies performed with hex-2-uloses [47] and pent-2-uloses [48] did not provide results consistent with those expected according to the mechanism revealed later, as no 2-C-(hydroxymethyl)aldose was detected in the reaction mixtures. Based on the results of the primary studies, as well as on the assumption that the thermodynamic equilibrium of a pertinent 2-ketose and 2-C-(hydroxyme-thyl)aldose might be shifted totally in favor of the former, the investigation of the interconversion was approached from the side of the latter sugar. Some inspiration might be provided also by the analytical studies of the transformation of 2-ketoses to the corresponding 2-C-(hydroxymethyl)aldoses catalyzed by nickel(II)-ethylenediamine complexes [49] (see Osanai,this voL). 

In cases where a 2-C-(hydroxymethyl)aldose is easily available via base-catalyzed aldolization of a 2,3-0-alkylidene-aldofuranose with formaldehyde, the carbon-skeleton rearrangement operating in the Bilik reaction can also be conveniently exploited for preparation of 2-ketoses. The method is especially advantageous for synthesis of heptuloses and octuloses as (1) in special cases the 2-C-hydroxymethyl side chain construction is simpler than the classical aldose chain elongations, and (2) the equilibrium of a 2-C-(hydroxymethyl)aldose and its corresponding 2-ketose in the Bilik interconversion is much more favorably shifted to the side of the latter sugar (always > 85%) than the LdB-AvE transformation of the pertinent unbranched aldose. 

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