Synthesis of Fluorinated Carbohydrates

This Section deals with the methods of preparation of glycosyl fluorides generally (for the synthesis of glycosyl fluorides by addition reactions to glycals, see Section 11,6), and gives a number of examples from the types of glycosyl fluorides that have been prepared. 

Treatment of the acylated glycosyl halide (bromide or chloride) of the opposite anomeric configuration with silver fluoride in acetonitrile was the method initially developed40 for the synthesis of the less stable anomers, as exemplified by the synthesis of peracylated /S-D-glucopyranosyl fluoride40 from the corresponding a-bromide. It has 

Silver tetrafluoroborate in ether or toluene has also been used for the synthesis of glycosyl fluorides. Peracetylated 2-chloro-2-deoxy-D-gluco- and -mannopyranosyl fluorides have been prepared by treatment of the corresponding chlorides with the aforementioned reagent.50,51 Products of kinetic control were obtained when diethyl ether was used as the solvent, whereas products of thermodynamic control were obtained when toluene was used instead. Peracetylated 

A number of fluorinated glycosyl fluorides has also been obtained  

The cis-glycosyl fluorides of the peracetylated 2-deoxy-2-fluoro saccharides have been obtained by addition of trifluoro(fluoroxy)meth-ane to the corresponding peracetylated glycals, whereas the preparation of the other derivatives was achieved by treatment of a suitable precursor with hydrogen fluoride or silver fluoride in acetonitrile peracetylated 2-deoxy-2-fluoro-a-Drmannopyranosyl fluoride70,71 was prepared by equilibration of the /3 anomer in hydrogen fluoride. 

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The Arbuzov reaction has been applied for the synthesis of fluorinated carbohydrates. 1,2 3,4-Di-O-isopropylidene-a-D-galactopyran-ose 6-(N,N-diethyl-P-methylphosphonamidite) was treated with ethyl fluoroacetate, to afford 6-deoxy-6-fluoro-l,2 3,4-di-O-isopropylidene-a-D-galactopyranose in 19% yield.241 The corresponding 6-deoxy-6-fluoride was obtained in 60% yield by treatment of l,2 3,4-di-0-isopropylidene-a-D-galactopyranose 6-(dipropylphosphinite) with hexafluoropropene.242 The mechanism of this reaction has been discussed.243,244 In contrast, treatment of 1,2 -.3,4-di-O-isopropylidene-a-D-galactopyranose 6-(tetraethylphosphorodiamidite) with benzoyl fluoride yielded the corresponding 6-benzoate, not the 6-deoxy-6-flu-oride expected.245... 

The biochemical rationale for incorporating fluorine in the carbohydrate residue is that replacement of a hydroxyl by fluorine would cause only a very minor steric perturbation of the structure or conformation while at the same time would have a profound electronic effect on neighboring groups. The substitution is possible while retaining the capacity of the position as an acceptor in hydrogen bonding. Yet these same attributes make the synthesis of fluorinated carbohydrates difficult. The synthesis of fluorinated carbohydrates offers a particularly fruitful field for the combination of modem chemical and enzymatic synthetic techniques. Total synthesis would be difficult because of the stereochemical control required at the multiple adjacent asymmetric centers of a fluorinated carbohydrate (105). 

The active collaborations of Dr. Peter Card in the synthesis of fluorinated carbohydrates, Mr. Kevin Ripp in protein purification and preparation of antibodies. Dr. Vincent Francheschi in immunohistochemistry and Dr. Judy Schmalstig in the metabolism of 1 -deoxy-1 -flurosucrose are greatfully acknowledged. 

A review has appeared on the synthesis of fluorinated carbohydrates including glycosyl fluorides and their use in the pre-... 

The synthesis of fluorinated carbohydrates by selective fluorination has been reviewed (in Chinese), and a review on the reactions of carbohydrates in anhydrous liquid HF is noted in Chapter 1. The selective synthesis of /3-glycosyl fluorides has been achieved by heating acylated glycosyl bromides with Et3N.3HF in CQ4. ... 

A number of reviews on the chemical synthesis of fluorinated carbohydrates have been published, as well as others covering the chemoenzymic synthesis of fluorosugars, the preparation and reactions of glycosyl fluorides, and the preparation of F-deo3 uorohexoses7... 

Davis FA, Qi HY, Sundarababu G. Application of oxazoUdi-none a-fluoro amide chiral building blocks in the asymmetric synthesis of fluorinated carbohydrates 2-deoxy-2-fluoropentoses. Tetrahedron 2000 56 5303-5310. 

The same sequence of diastereoselective reduction of a /i-oxo-y-fluoro sulfoxide followed by Pummerer rearrangement and hydrolysis to the aldehyde has been used successfully in the synthesis of fluorine-containing carbohydrates.10... 

A. B. Foster Synthesis and biological activity of fluorinated carbohydrates... 

Fluorinated carbohydrates have recently received much attention because of their importance in the study of the enzyme-carbohydrate interactions and their interesting biological activity [56], Hara et al. [57] achieved the deoxyfluorination of primary and anomeric hydroxyl groups of a series of protected carbohydrates, for example 65 into 66 (70%) (Scheme 12.31, a representative example) and 67 into 68 (90%) (Scheme 12.32, a representative example), with good yields, by use of N,N-diethyl-a,a-difluoro-(m.-methylbenzyl)amme (DFMBA), which has previously proved to be a selective reagent for the synthesis of fluorinated alcohols and carboxylic acids [58], Chemoselective deoxyfluorination at the anomeric position... 

Chanteau F, Plantier-Royon R, PorteUa C (2004) Synthesis of fluorinated homo-C-nucleoside analogues from new carbohydrate-derived acylsUanes. Synlett 512-516... 

Synthesis and Biological Activities of Compounds Containing Fluorinated Carbohydrates. 186... 

The number of naturally occurring, organic fluorine compounds is very small indeed. Compound 1 is1 a nucleoside antibiotic that contains fluorine attached to the carbohydrate ring, replacing H-4 in the D-ribosyl moiety. The presence of fluorine was shown by -n.m.r.-, 19F-n.m.r.-, and mass-spectral data, and the structure of this compound has been confirmed by independent synthesis.9,10... 

The availability, in gram quantities, of the fluorinated carbohydrates thus far synthesized has also made possible their use as starting materials for the synthesis of other analogs and intermediates for example, the preparation of 3,5-dideoxy-3,5-difluoro-D-xylose from 3-deoxy-3-fluoro-D-xylose,88 which is itself preparable from 3-deoxy-3-fluoro-l,2-0-isopropylidene-a-D-glucofuranose. Electrolytic oxidation of 3-deoxy-3-fluoro-D-glucose afforded, after treatment with an acidic... 

K. Dax, V. Grassberger, and A. E. Stiitz, Simple synthesis of l,5,6-trideoxy-l,5-imino-D-glucitol, the first fluorine-containing derivative of glucosidase inhibitor 1-deoxynojirimycin, J. Carbohydr. Chem., 9 (1990) 903-908. 

In a series of papers, Kent and coworkers reported on the synthesis of the racemic 2-fluorotetritols and 2-fluoropentitols, and related carbohydrates from simple, non-carbohydrate precursors containing a fluorine atom in the carbon chain. Thus, synthesis of 2-deoxy-2-fluoro-DL-erythritol (537) and its threo isomer (538) was accomplished303 by vigorous reduction of ethyl ethoxalylfluoroacetate (536) with lithium... 

M. Sharma, R. J. Bernacki, M. J. Hillman, and W. Korytnyk, Fluorinated carbohydrates as potential plasma membrane modifiers. Synthesis of 3-deoxy-3-fluoro derivatives of 2-acetamido-2-deoxy-D-hexopyranoses, Carbohydr. Res., 240 (1993) 85-93. 

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