Ketosugars

Ketosugars [1-4] e.g. fructose, sucrose, raffinose, lactose Aryl- and heteroarylpropionic acids e.g. flurbiprofen, ketoprofen [5] ... 

The detection limits for aryl- and heteroarylpropionic acids are in the lower nano-gram range (5, 7], In the case of ketosugars 10-40 ng substance can be detected per chromatogram zone [1]. 

Isosteric phosphonate analogues of nucleoside 3 - (9) and 5 -phosphates (10) have been prepared using the reaction between stabilized carbanions and ketosugars. The synthesis of (10) is comparatively simple as nucleoside... 

Given the attractive scenario outlined in Scheme 65, one must ask why 2-ketosugars have not yet emerged as important precursors to C(l) nucleophiles and fulfilled their latent potential. Several factors seem to contribute to this, with the most important being our ability to control the regioselectivity... 

In summary, enolates derived from 2-ketosugars may serve as progenitors to C-glycosides, but this topic is still at an early phase of its development and warrants more extensive investigation and evaluation. 

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). 

Alternatively, vinylation can be achieved in useful yields using readily available vinyl magnesium bromide. The allylic tertiary alcohol resulting from this condensation on a ketosugar can be further elaborated by suitable modification of the vinylic group. 

Ozonolysis and subsequent reduction open the way to formyl and hydroxymethyl branched-chain derivatives [18]. High stereoselectivities are generally observed on Grignard addition on conformationally biased ketosugars such as 3 (Scheme 6), equatorial attack being strongly favored, giving the axial alcohol 4 as the major product. 

Spiro epoxides are also valuable intermediates for the synthesis of type I branched-chain sugars. These spiro epoxides are formed from ketosugars using diazomethane addition or sulfonium chemistry. Further ring opening of the epoxide allows the introduction of various nucleophiles [1], Chloro spiroepoxide 15 (Scheme 9) has been prepared recently from ketosugar 1 dichloromethyllithium [28]. 

Dithiane. Condensation of dithiane or substituted analogues [30J on ketosugars has been described by several groups [1], Further deprotection of dithiane gave formyl derivatives. Acetyl or 2-hydroxyacetyl groups can also be obtained using suitably substituted dithiane derivatives. Extensive work by Paulsen et al. has been reported and typical procedures have been published [31]. 

Etiolates Type Anions. The well-known Reformatsky reaction allows the introduction of a functionalized two-carbon chain. Modified experimental procedures have now been proposed, such as the reaction of ethylbromoacetate with ketosugar 18 (Scheme 10) in the presence of zinc/silver graphite prepared from CgK, giving 19 in excellent yield [32]. 

A three-carbon unit can be introduced on ketosugars under Reformatsky conditions, as recently demonstrated by several groups [33,34], The analogous Dreiding-Schmidt procedure has also been applied in this case with successful double stereodifferentiation [35]. This is exemplified on ketone 18 which yields lactone 20 as a single isomer (see Scheme 10). The condensation on ketosugars of trimethylsilylacetate [36] or acrylate [33], in the presence of fluoride ion, has also been used with success for the synthesis of P-hydroxy acids or ra-methylene-y-lactones, respectively. 

One seminal example has been reported by Butterworth and associates, who described the methylation of a 2-deoxy 3-ketosugar with methyl iodide and barium oxide in dimethylformamide (DMF) [153]. 

Introduction of a two-carbon functionalized chain is easily achieved by the reaction of ketosugars with carboethoxymethylentriphenylphosphorane [172] or related reagents [173], A classic example is given in Section ID [172] (Scheme 44). Here, the problem is... 

Another route to create a carbon-carbon double bond on a ketosugar is the Knoevenagel reaction and its variants. It has been applied by Szarek and Ali to prepare olefin 133 (Scheme 45) suitable for the formation of a doubly branched-chain sugar [177] [see Section 1I.D]. 

Methiniminium salts have been used for the direct introduction of an alkylidene chain at the a-position of a carbonyl group [179]. 3-Chloro-3-phenylprop-2-enylidenedimethyl-iminium perchlorate reacts with 2- or 3-ketosugars 7 and 18 in the presence of DBU to form an E-Z mixture of compounds 141 and 142 (Scheme 48). Amide acetals also react with... 

R. Csuk, A. Fiirstner, and H. Weidmann, Branching of ketosugars by ethyl trimethylsilyl-acetate/tetra-n-butylammonium fluoride, J. Carbohydr. Chem. 5 11 (1986). 

This type of 2 + 2 photocycloaddition [49] is possible with ketosugars on one of the double bond of furan. The less crowded adducts 51 and 52 are formed with equatorial C-C bonds as shown in Scheme 24. 

The a-cleavage of ketosugars has been mainly studied by P. M. Collins and his group and their principal results have been reviewed [1],... 

The differentiation of ketosugars by the position of their carbonyl group on the ring allows a comparative study of their photolytic abilities. 

F. Nicotra, L. Panza, and G. Russo, Epoxidation of exocyclic glycals a new access to glycosides of ketosugars, Tetrahedron Lett., 32 (1991) 4035-4038. 

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