Dithioacetals Fischer

Acyclic derivative of sugars have played a significant rede in the area of synthetic carbohydrate chemistry, permitting numerous useful transformations that are not possible with the parent sugars, which exist almost exclusively in the hemiacetal form. Trapping of aldoees in die acyclic form as their dialkyl dithioacetals, by treatment with thiols in fire presence of acid, has been a synthetically important method ever since Emil Fischer s first report some 100 years ago [1], and remains an important tool in modem synthetic carbohydrate chemistry. 

Emil Fischer s initial studies [1] focused on dithioacetal formation from a variety of simple aldopentoses, aldohexoses, and aldoheptoses. The products were obtained by simply treating the sugar with an excess of ethanethiol in concentrated hydrochloric acid at low temperature ( 0°C). Many of these dithioacetals have low water solubility, crystallize spontaneously from the reaction mixtures, and can be isolated by simple filtration and washing with odd water. Fischer s key paper [1] also outlined most of the major reaction modes of the diethyl dithioacetal derivatives, later developed in detail, and thus paved the way for subsequent studies into this important class of sugar derivative. 

This is a slight modification of the method of Fischer [1], D-Arabinose (250 g, 1.66 mol) is dissolved at room temperature in 37% hydrochloric add (230 mL) in a 1-L Erienmeyer flask, and cooled at once to 0°C. Technical ethanethiol (230 mL) is added, die flask is stoppered, and the two layers ate shaken vigorously. Copious crystallization occurs after 13 min and, after 30 min, the crude product is collected by filtration and washed with ice cold water Recrystallization from water affords the pure dithioacetal (380 g, 91%) mp 124-125°C, [a], 0° (c 3.0, pyridine). 

As the glycofuranosides are the final thermodynamic products, there is no need to control the reaction conditions closely, unlike the isolation of kinetic products in the Fischer method. Constant agitation is needed, to ensure reaction of the insoluble mercuric oxide, and a desiccant (Drierite) is used for removing the water as it is formed. In most of the examples cited in this review, the diethyl dithioacetal is used as the starting material. 

Schmidt and Wernicke found that concentrated hydrochloric acid and a-toluenethiol, allowed to react with 2-0-benzyl-o-fucose overnight at room temperature, caused elimination of the benzyl group. It was retained however, when ethanethiol and hydrochloric acid (saturated at —15°) were employed for 0.5 hour at 0°. Kenner, Taylor and Todd converted 5-0-benzyl-D-ribose into 5-0-benzyl-D-ribose diethyl dithioacetal by the action of ethanethiol and concentrated hydrochloric acid on the sugar in dioxane at 0° during 25 minutes. Ballou and Fischer obtained an excellent yield of 2-0-benzyl-o-glycerose diethyl dithioacetal from 2-0-benzyl-o-glyc-erose, ethanethiol, and concentrated hydrochloric acid at 0° during 30 minutes. 

Water-soluble and low-melting dithioacetals (for example, derivatives of D-xylose) were virtually inaccessible to Fischer, as his technique of isolation relied on spontaneous separation of a crystalline product after dilution of the reaction mixture with water. Alternative isolative methods that were subsequently developed to deal with such problems of solubility include the use of lead carbonate,16 barium carbonate,17 or an anion-exchange resin18 to remove the acid catalyst, with subsequent removal of all or part of the diluent by evaporation, and the use of chloroform19 or ether20 to remove the excess of thiol from the water layer and induce crystallization of the product. 

Figure 1.23 Formation of straight-chain dithioacetals with thiols. Reactions are probably preassociated 5 n2 reactions similar to the reactions in the Fischer glycoside synthesis, but the thiacarbenium ion is drawn to emphasise that the stability of the dithioacetal reflects, not only the weaker basicity of sulfur as compared to oxygen, but also its lesser ability to stabilise a carbenium ion centre by conjugation (see Section 1.3).

Finally MacDonald and Fischer have prepared the free ajyZo-pento-dialdose (8) by the sulfone-degradation method. The diethyl dithioacetal of scyllo-inosose (12) was oxidized to the corresponding disulfone which, on treatment with ammonia, gave the dialdose (8). The structure was proved by converting the compound into the bis(ethylene dithioacetal) derivative, which was identical with that obtained from a /io-pentodialdose prepared by a previous method. ... 

MacDonald and Fischer prepared D- fluco-hexodialdose (27) by two different methods. By use of the Nef reaction, 6-deoxy-l,2-0-isopropyli-dene-6-nitro-n-glucose (26) was converted into the dialdose (27), which was isolated from the aqueous solution as its insoluble, crystalline bis-(diethyl dithioacetal) (in 48% yield, after recrystallization). It is of interest to note that the starting material (26) is one of the two isomeric 6-deoxy-6-nitro sugars which Grosheintz and Fischer prepared from 1,2-0-iso-propylidene-a-D-x2/lo-pentodialdo-l, 4-furanose (7). Thus, the synthesis discussed here is an ascent from a pentodialdose to a hexodialdose. 

When the paromobiosamine fraction is W-benzoylated and then hydrolyzed with dilute acid, D-ribose is one of the products. More-vigorous hydrolysis destroys the D-ribose but yields a diaminodideoxyhexose which was called paromose. A study of the products of periodate oxidation of paromose, of its di-W-acetyl derivative, and of the borohydride reduction product of the latter, revealed that paromose is a 2,6-diamino-2,6-di-deoxyhexose. In a preliminary report, Haskell and Hanessian have presented degradative evidence which establishes the stereochemical structure of paromose as that of 2,6-diamino-2,6-dideoxy-L-idose (7). Their ingenious application of the degradation described by MacDonald and Fischer and by Hough and coworkers of the 1, l-bis(ethanesulfonyl) derivatives of aldoses enabled Haskell and Hanessian to obtain, from iV,fV -diacetylparomose diethyl dithioacetal, a product which they identi-... 

D-Xylose has been converted to (25)-3-(indol-3-yl)propane-l,2-diol 237 by two different routes, one involving direct Fischer indolization of 238. The dibenzyl-dithioacetal 239 was elaborated to the fused triazoline 240 following reaction with MCPBA. Initial oxidation was followed by elimination of acetic acid allowing intramolecular 1,3-dipolar cycloaddition reaction to construct the triazole ring. The bicyclic iV,S -acetals 242 and 241 were prepared by reaction of the 2,3-0-isopropylidene-D-ribofuranose with 2-aminoethane thiol followed by Mitsunobu reaction. These products are considered analogues of castanosper-mine and australine. ... 

This reaction was first reported by MacDonald and Fischer in 1952. It is the degradation of hexoses into pentoses involving the steps of formation of dithioacetal, oxidation to unsaturated disulfone by means of perphthalic acid, hydrazine treatment, and benzalde-hyde splitting of the corresponding hydrazone. Therefore, the whole process is known as the MacDonald-Fischer degradation. In addition, when the unsaturated disulfone is dissolved in aqueous ammonia or methanol saturated with ammonia, 2-deoxy-2-amino sugar is resolved. This reaction in combination with mass spectroscopy was used to study the structure and stereochemistry of carbohydrates. ... 

Our retrosynthetic plans have been detailed elsewhere (ref. 15), but the salient features arise from recognition that there is a repeating pattern of vicinal CH3 and OH groups in the ansa chain, 4, as a consequence of its biosynthesis from propionate residues. These features can be summarized by the fragment 8, which could be derived from a pyranoside, 10, via the dithioacetal 9, as pioneered by Emil Fischer (ref 16), and Raney nickel reduction, as pioneered by Wolfrom (ref 17). 

In their reaction with alcohols under acid catalysis, the aldoses differ from the simple, or unhydroxylated, aldehydes in forming mixed monocylic acetals (glycosides) rather than acyclic dialkyl acetals. However, Fischer 138) found that, on shaking a cold solution of an aldose in concentrated hydrochloric acid with a thiol, a crystalline product separated which was the dithioacetal (mercaptal) of the acyclic structure. These substances have... 

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