Aldoses, chain extension

The reaction is used for the chain extension of aldoses in the synthesis of new or unusual sugars In this case the starting material l arabinose is an abundant natural product and possesses the correct configurations at its three chirality centers for elaboration to the relatively rare l enantiomers of glucose and mannose After cyanohydrin formation the cyano groups are converted to aldehyde functions by hydrogenation m aqueous solution Under these conditions —C=N is reduced to —CH=NH and hydrolyzes rapidly to —CH=0 Use of a poisoned palladium on barium sulfate catalyst prevents further reduction to the alditols... 

Ketose (Section 25 1) A carbohydrate that contains a ketone carbonyl group in its open chain form Kiliam-Fischer synthesis (Section 25 20) A synthetic method for carbohydrate chain extension The new carbon-carbon bond IS formed by converting an aldose to its cyanohydnn Reduction of the cyano group to an aldehyde function com pletes the synthesis... 

Fig. 1. The family of D-aldoses derive from D-glyceraldehyde by chain extension at the carbonyl carbon atom.

Fischer s original method for conversion of the nitrile into an aldehyde involved hydrolysis to a carboxylic acid, ring closure to a cyclic ester (lactone), and subsequent reduction. A modern improvement is to reduce the nitrile over a palladium catalyst, yielding an imine intermediate that is hydrolyzed to an aldehyde. Note that the cyanohydrin is formed as a mixture of stereoisomers at the new chirality center, so two new aldoses, differing only in their stereochemistry at C2, Tesult from Kiliani-Fischer synthesis. Chain extension of D-arabinose, for example, yields a mixture of D-glucose and o-mannose. 

Among the classic methods for the extension of the aldose chain by one carbon atom from the reducing end [9J, the Kiliani-Fischer cyanohydrin synthesis [10] is a milestone in carbohydrate chemistry. However after 110 years from discovery and numerous applications [11], including the preparation of carbon and hydrogen isotopically labeled compounds for mechanistic and structural studies [12], there are still several drawbacks that make the method impractical. These are the low and variable degree of selectivity and the harsh reaction conditions that are required to reveal the aldose from either the aldonic acid or directly from the cyanohydrin. Synthetic applications that have appeared in recent times confirmed these limitations. For instance, a quite low selectivity was registered [13] in the addition of the cyanide ion to the D-ga/acfo-hexodialdo-l,5-pyranose derivative 1... 

Chain extension of aldoses takes place at the aldehyde end of the chain. The aldehyde function of an aldopentose becomes C-2 of an aldohexose, which normally results in two carbohydrates diastereomeric at C-2. Thus, (-l-)-glucose and (-r)-mannose have the same configuration at C-3, C-4, and C-5 they have opposite configurations at C-2. The configuration at C-2, C-3, and C-4 of (-)-arabinose is the same as that at C-3, C-4, and C-5 of (+)-glucose and (-r)-mannose. 

Methods for the chemical synthesis of glycuronic acids include (i) reduction of the monolactones of aldaric acids, (ii) oxidation of the primary alcoholic group of aldose derivatives, (iii) oxidative degradation procedures, (iv) chain-extension reactions on dialdoses, and (v) epimerization reactions. 

Scheme 11. Tandem enzymatic chain extension catalyzed by transketolase, aided by the combination with a suitable ketose-aldose isomerase...

Chain extensions using an insertion reaction of dichloromethyllithium or dibromomethyllithium with (5 )-pinanediol [(benzyloxy)methyl]boronate 26 has been used to generate L-C3-, L-C4-and L-Cs-aldoses [51]. In order to obtain 2,3-di-O-benzyl-L-glyceraldehyde 27, the insertion reaction has to be applied twice (Scheme 13.20). By repeating the process two more times, L-ribose has been prepared with high enantiomeric purity [51]. 

Chain extension by way of cyanohydrin formation (Section 25.20) The Kiliani-Fischer synthesis proceeds by nucleophilic addition of HCN to an aldose, followed by conversion of the cyano group to an aldehyde. A mixture of stereoisomers results the two aldoses are epimeric at C-2. Section 25.20 describes the modern version of the Kiliani-Fischer synthesis. The example at the right illustrates the classical version. 

The pr e-Woodwardhn era largely concerned itself with the collection and classification of synthetic tools chemical reactions suited to broad application to the constitutional construction of molecular skeletons (including Kiliani s chain-extension of aldoses, reactions of the aldol type, and cycloadditions of the Diels-Alder type). The pre- Woodwardian era is dominated by two synthetic chemists Emil Fischer and Robert Robinson. Emil Fischer was emphasizing the importance of synthetic chemistry in biology as early as 1907 [30]. He was probably the first to make productive use of the three-dimensional structures of organic molecules, in the interpretation of isomerism phenomena in carbohydrates with the aid of the Van t Hoff and Le Bel tetrahedron model (cf. family tree of aldoses in Scheme 1-6), and in the explanation of the action of an enzyme on a substrate, which assumes that the complementarily fitting surfaces of the mutually dependent partners are noncovalently bound for a little while to one another (shape complementarity) [31],... 

Chain extension of an aldose by the use of dimethyl (lithiomethyl)phosphonate provides a further route to polyhydroxyphosphonic acid esters. 2,3 4,5-Di-0-isopropylidene-D-arabinose reacts with the lithiated ester to give a mixture of the Abramov 1 1 adducts having the gluco (323 R = H, R = OH) and manno (323 R = OH, R = H) configurations spectroscopic examination of the derived monoacetates indicated the two configurations to be present in the ratio 69 31. ... 

The isopropylidenation of aldose trimethylene dithioacetals is covered in Chapter 6 and the acetolysis of aldose diethyl dithioacetals in Chapter 7. The C-C-l(C-2 bond cleavage of the a-oxoketene dithioacetal 7 on exposure to mineral acid is referred to in Chapters 13 and 14. The phenylthio precursor 8 of 2-keto-3-deoxy-D-flraZ //io-heptonic acid has been prepared by chain-extension of 2,3 4,5-di-O-cyclohexylidene-D-arabinose with PhSCH2C02Me, followed by de-protection. ... 

Chain-extension reactions via aldehyde additions have been used to synthesize higher aldoses, enuloses, branched-chain enuloses and 1-deoxy-alduloses. Addition of 2-lithio-1,3-dithiane to partially blocked carbohydrate derivatives proceeds in certain cases with high stereoselectivity the authors suggest that the reaction is controlled by chelation of the oxygen functions at C-1, C-2, and C-4... 

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