Using Keto-Sugars

As shown above, many of the methods that are available to form carbon-carbon bonds rely on the reaction of a carbanion with a suitable electrophile. Keto-sugars are readily available by simple oxidation of hydroxyl groups. Thus, the reaction of carbohydrate-derived ketones or aldehydes with carbanions has been extensively explored. However, keto groups are suitable substrates in olefinations, such as Wittig reactions, leading to versatile intermediates for the construction of complex structures. This section will detail some application of keto-sugars in total syntheses along these two main lines. 

The stereochemical outcome of the addition of carbanions to ketones yielding tertiary alcohols (or secondary alcohols in the case of aldehydes) is variable and depends on the substrate, the counterion and the solvent. Numerous applications of this strategy to natural product synthesis from carbohydrates can be found in the literature and this approach was fruitful in pioneering syntheses of polyketide-type products. Here again, the template effect of the sugar plays a tremendous role in the stereochemical outcome of the reaction. Chelation controlled nucleophilic addition can also be used to form chiral centers in a highly predictable way. 

The nucleophilic addition to keto groups of sugars is useful for the production of tertiary alcohols but can also be used to yield tertiary amines. One such example, in relation to the synthesis of the immunosuppressant compound myriocin, is given below. A comparison of several synthetic approaches to this deceptively simple molecule follows because of its interesting biological properties. 

SCHEME 11.20 Reagents i LDA, THF, CH2CI2 ii NaNs, DMPU, 15-crown-5 ether iii (1) H2, Pd/C and (2) BzjO, MeOH. 

SCHEME 11.21 Reagents i LDA, CH2CI2, THF ii NaNj, HMPA, 15-crown-5 ether iii (1) NaBH4, EtOH, (2) MOMCl, iPrEtzN, (3) Hj, Pd/C, (4) BzCl, pyridine, (5) NaBHjCN, TMSCl, (6) (COCl)2, DMSO, EtjN, (7) NaClOz, NH2SO3H and (8) CH2N2. 

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Fortunately, the oxidation of l,2 5,6-di-0-isopropylidene-a-D-glucofura-nose to l,2 5,6-di-0-isopropylidene-a-D-nfoo-hexofuranos-3-ulose (1) can be accomplished using either phosphorus pentoxide (10, 44) or acetic anhydride (10, 52) in methyl sulfoxide although this oxidation is effected with ruthenium tetroxide (6,7, 46), it is exceeding difficult with other oxidizing agents (53). Keto-sugar 1 is reduced stereospecifically... 

C. Miscellaneous.—Among ylides, PhsP CHR, used in conventional olefin synthesis with protected keto-sugars are those with R = H, CN, SMe, and COR. ... 

PCC in the presence of 4 A MS to afford the corresponding keto sugars (175, 176), which after Tebbe methylenation led to the corresponding exoglycals, valuable intermediates for the synthesis of C-disaccharides. Dondoni el al.159 made use of PCC in the presence of powdered 4 A MS to introduce suitable formyl groups in the carbohydrate, and allowing the synthesis of >6)-linked oligosaccharides,... 

A slightly different acyl anion equivalent is transferred in transketolase reactions, and this anion is then used in a subsequent aldol reaction. TVansketolase removes a two-carbon fragment from keto sugars... 

Many DOHs, such as L-daunosamine, L-epivancosamine or L-ristosamine, contain an amino group at C3, which is introduced by an aminotransferase. The substrate for this reaction is the 3-keto sugar intermediate that arises as a consequence of the action of a 2,3-dehydratase. This transaminahon reaction has been biochemically characterized in the biosynthesis of L-epivancosamine [10]. Using a coupled reaction with EvaB (2,3-dehydratase) and EvaC (aminotransferase), with pyridoxal-5-phosphate (PEP) as a coenzyme and L-glutamate as a cosubstrate, they were able to show conversion of TDP-4-keto-2,6-dideoxyglucose into thymidine-5 -diphospho-3-amino-2,3,6-trideoxy-D-threo-hexopyranos-4-ulose. 

Based on the stereospecific transketolase-catalyzed ketol transfer from hydroxy-pyruvate (20) to D-glyceraldehyde 3-phosphate (18), we have thus developed a practical and efficient one-pot procedure for the preparation of the valuable keto-sugar 19 on a gram scale in 82% overall yield [29]. Retro-aldolization of D-fructose 1,6-bisphosphate (2) in the presence of FruA with enzymatic equilibration of the C3 fragments is used as a convenient in-situ source of the triose phosphate 18 (Scheme 2.2.5.8). Spontaneous release of CO2 from the ketol donor 20 renders the overall synthetic reaction irreversible [29]. 

The synthesis of type III branched-chain sugars is based mainly on the use of ketosugars treated under Wittig-type conditions (see path a, Scheme 4) [13]. Several other methods, such as aldolization-crotonization or direct alkylidenation at the a-position of the carbonyl group of a keto sugar have been developed (path b). 

The course of reaction of phosphonium ylides (2a) with sugars is unambiguous only when protected aldehydo or keto sugars are used, although the interaction of (methylthio)methylenetriphenylphospho-nium ylide with free sugars has been reported.8 Such ylides are usually obtained by treatment of the corresponding phosphonium salts with a suitable proton-acceptor, for example, phenyllithium9- or sodium... 

The reaction is useful in the preparation of keto-sugars. Thus the reaction of trityl fluoroborate with the acelonide (4) derived from D-mannitol gives the keto-sugar (5) in 65 % yield. 

Many uses for the addition of lithiated dichloromethane to keto-sugars have been illustrated thus far. With respect to diversity, this noteworthy addition to a 2-keto derivative of D-glucose was used as a key step in the synthesis of sphingofungin E [80]. Additionally, a recent paper by Sato [81] provides a new process for the synthesis of chloroepoxides. 

Continuing, one carbon homologation of 96 was easily achieved by oxidation of the alcohol to the corresponding ketone and a subsequent enolisation-formylation sequence. The last lacking carbon was introduced by nucleophilic addition on the complex keto-sugar 97 using vinyl magnesium bromide in the presence of cerium salts. The diol 98 was further elaborated into a relay compound already prepared from squalestatin [88]. 

A number of more complex structures, useful in total syntheses, are accessible from olefins formed by Wittig olefinations of keto-sugars. A fmitful reaction is the dihydroxylation of double bonds. Obviously, methylene derivatives will give the hydroxymethyl branched-chain derivatives. 

Lactone 30 on oxidation at C2 gives ketolactone (31), which on hydrolysis in acetic acid-water afforded L-ascorbic acid (Scheme 16). This synthesis and the Bakke-Theander synthesis are among the few syntheses that do not have as the last step the lactonization of an appropriate 2- or 3-keto sugar acid or derivative. The approach shown in Scheme 16, the protection of either the C2 or C3 hydroxyl group in an appropriate 1,4-lactone followed by the oxidation of the unprotected hydroxyl to a ketone and then by hydrolysis, can be generally used to convert L-gulono-, L-galactono, and L-talono-l,4-lactone to L-ascorbic acid (50). 

It was found that carbazole and phloroglucinol are unsuitable for determining the heptose content of sugar mixtures because of interference from other sugars similar interference is encountered with resorcinol. With orcinol, cysteine, and diphenylamine, however, specific reactions can be obtained at selected wavelengths. Ketoheptoses (and keto sugars in general) react under milder acid conditions than the aldoses, and this property can be used for identification purposes. In the orcinol test, for... 

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