Sulfamates, Sweet

Cyclamate is about 30 times (8% sucrose solution sweetness equivalence) more potent than sugar. Its bitter aftertaste is minor compared to saccharin and acesulfame-K. The mixture of cyclamate and saccharin, especially in a 10 1 ratio, imparts both a more rounded taste and a 10—20% synergy. Cyclamate (6) is manufactured by sulfonation of cyclohexylamine (7). Many reagents can be used, including sulfamic acid, salts of sulfamic acid, and sulfur trioxide (74—77). 

Hi) Sulfamates.—The two most well known sweet compounds in this class are cyclamate (9) and saccharin (10). Considerable structural modifications have been recorded, and their tastes ascertained. 

It was further found that substitution of a methyl group at C-1 of either cyclohexyl- or cycloheptyl-sulfamate destroys the sweetness of these compounds.. -(l-Adamantyl)sulfamate (107), which possesses an imino hydro-... 

This approach did not seem to be as satisfactory for those sulfamates having heteroatom substituents (hetero-sulfamates). Spillane suggested that the various electronic effects of the hetero-atoms probably introduce an additional variable that is apparently absent, or constant, for the carbosulfamates. Because molecular connectivity correlates structure with molecular volume and electronic effects, Spillane included molecular connectivity, (computed for the entire molecule, RNHSOO to the four variables, x, y, z, and V, and applied the statistical technique of linear-discrimination analysis to 33 heterosulfamates (10 sweet, 23 not sweet). A correlation of >80% was obtained for the x, z, x subset 5 of the 33... 

The chemical structure of the most important nonnutritive sweeteners is shown in Figure 11-4. Saccharin is available as the sodium or calcium salt of orthobenzosulfimide. The cyclamates are the sodium or calcium salts of cyclohexane sulfamic acid or the acid itself. Cyclamate is 30 to 40 times sweeter than sucrose, and about 300 times sweeter than saccharin. Organoleptic comparison of sweetness indicates that the medium in which the sweetener is tasted may affect the results. There is also a concentration effect. At higher concentrations, the sweetness intensity of the synthetic sweeteners increases at a lower rate than that which occurs with sugars. This has been ascribed to the bitter-... 

Cyclamate, sodium (= Hexylsulfamate, sodium)] (alicyclic sulfamate) Synthetic Sweet (30X >sucrose)... 

Many sulfamic acid derivatives are sweet and much work has been carried out on structure-taste relationships. For example, research showed that sodium exo-2-norbornylsulfamate (89) was some five times sweeter than sodium cyclamate (88), although the corresponding endo-isomer (90) was tasteless (Figure 3). 

Many heterocyclic sulfamates have been synthesised, e.g. the compounds (93)-(95) (Figure 5). Compound (93) is sweet but not the corresponding sulfone nor the oxacompound (94) or the morpholino derivative (95) in contrast, all the carbon analogues of these heterocycles are sweet. 

The sulfur derivative (87) is 1000 times as sweet as sugar and without the bitter after-taste of saccharin however, it was discovered that N-alkylation of (87) removed the sweetness. On the other hand, in the saccharins (88a)-(88e) containing substituents in the 4-position and 6-position, sweetness was retained after N-alkylation. Many sulfamic acid derivatives are sweet, and there have been numerous studies of structure-taste relationships which have highlighted the importance of molecular shape and stereochemistry (see Chapter 9, p. 162). Two sulfamates which are commercial, non-nutritive sweeteners are cyclamate (85) and acesulfame potassium (86) (Figure 11). Cyclamate (85) is manufactured by refluixing cyclohexylamine either with triethylamine-sulfur trioxide in dichloromethane or with sulfamic acid (see Chapter 9, p. 162). 

Another artificial sweetener, which gained wide use in the 1960s and 1970s, is sodium cyclamate. Sodium cyclamate, which is 33 times as sweet as sucrose, belongs to the class of compounds known as the sulfamates. The sweet taste of many of the sulfamates has been known since 1937, when Sveda accidentally discovered that sodium cyclamate had a powerfully sweet taste. The availability of sodium cyclamate spurred the popularity of diet soft drinks. Unfortunately, in the 1970s, research showed that a metabolite of sodium cyclamate, cyclohexylamine, posed some potentially serious health risks, including a risk of cancer. This sweetener has thus been withdrawn from the market. 

Cyclic Amines, Ketones and Alcohols, Possible Metabolites Sweet Sulfamates J. Chromatogr. 136(2) 318-322 (1977) ... 

Many organic sulfamic acids are sweet, consequently a wide range of alkyl, alicyclic and aromatic derivatives has been synthesized in the search for new nonnutritive sweeteners. One of the best synthetic routes to sulfamic acids involved treatment of the appropriate primary amine 140 (three equivalents) with chlorosulfonic acid (one equivalent) in an inert organic solvent such as chloroform, followed by neutralization with sodium hydroxide to yield the corresponding sodium sulfamate 141 and the amine for recovery and recycling (Equation 57). ""... 

In A-substituted sulfamic acids, exceptional sweetness was discovered to be generally limited to those members containing a cyclohexyl ring which may be substituted, a free hydrogen atom attached to the nitrogen atom and almost any salt-forming group (X) as shown 142. ... 

Eighteen sodium alicyclic and heterocyclic sulfamates (141, R = alicyclic or heterocyclic radical) were examined for sweetness. The sweetest was sodium exo-bicyclo[2.2.1]heptan-2-ylsulfamate 143 which was five times sweeter than cyclamate although the endo isomer 144 was tasteless. 

Many other sulfamates are sweet and considerable studies have been made on structure-taste relationships in this group of chemicals (Chapter 6, ref 33). 

The most famous application of sulfamic acid is in the synthesis of sweet-tasting compounds. Reaction with cyclohexylamine followed by addition of NaOH gives CeHiiNHSOsNa, sodium cyclamate. 

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