Anhydro formation

Numerous anhydro derivatives have been prepared. These are discussed in Chapter VII. 

In view of the wide distribution of the cyclohexanehexols (called inositols or cyclitols) and the importance of one in particular (myo-inositol) to certain bacteria, plants, and perhaps even to warm-blooded animals, the naturally occurring and synthetic compounds of this carbocyclic class have received considerable study. Naturally occurring members include four inositols, monomethyl ethers, a dimethyl ether, monodeoxy derivatives, one dideoxy derivative, a methyl homolog, and deoxy carboxylic acids. Five inositols and many other synthetic members, including ketones (cycloses or inososes), are known. 

The inositols themselves are typically crystalline, water-soluble, high-melting compounds having a sweet taste. As alcohols, their reactions are similar to those of the acyclic polyols, but because of their ring structure they are inherently more stable. 

Trivial names serve to identify the inositols and the related naturally occurring compounds. It is also possible to identify the inositols by a numerical system, wherein the orientation of hydroxyl groups above and below the ring is represented by a fraction. neo-Inositol (IV), for example, may be designated as 123/456-inositol and allo-inositol (III) as 1234/56-inositol. Formerly the conmion inositol, mi/o-inositol (V), was often called meso-inositol, but use of the latter term is discouraged because all but two 

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Scheme 5. Examples of nucleophiles often present in glycosylation reactions that can compete with the nucleophilic hydroxyl group (A) 1,6-anhydro formation, (B) thio exchange, (C) leaving-group return, (D) promoter-derived components such as triflate anions, (E) additives such as added bases, (F) solvents.

In the beginning of our research program, it was expected that this last reaction especially would result in a smooth esterification without anhydro-formation, due to the better mutual solubility of the reactants. 

Etherification. Carbohydrates are involved in ether formation, both intramoleculady and intermoleculady (1,13). The cycHc ether, 1,4-sorbitan, an 1,4-anhydroalditol, has already been mentioned. 3,6-Anhydro-a-D-galactopyranosyl units are principal monomer units of the carrageenans. Methyl, ethyl, carboxymethyl, hydroxyethyl, and hydroxypropyl ethers of cellulose (qv) are all commercial materials. The principal starch ethers are the hydroxyethyl and hydroxypropylethers (see Cellulose ethers Starch). 

Anhydro bases can attack the a-position, e.g. of thiazolium cations, with the formation of adducts capable of oxidation to cyanine dyes, e.g. Scheme 18 (see Section 4.02.3.3.4). 

Reaction of the A-nitrosoglycine (394) with acetic anhydride gave the anhydro-5-hydroxy-l,2,3-oxadiazolium hydroxide (395). Reaction with DMAD resulted in formation of the intermediate 1 1 cycloadduct (396) which was not isolated and which lost CO2 under the thermal reaction conditions to give dimethyl l-phenylpyrazole-3,4-dicarboxylate (397) (83MI40300). This reaction is capable of considerable variation in terms of the substituents... 

Berberilic acid, CgoHjgOgN, m.p. 177-82°, is dibasic, and furnishes a dimethyl ester, m.p. 173°. When heated to about 180°, the acid passes into ANHYDROBERBERiLic ACID, CjgHjjOgN, colourless needles, m.p. 236°, soluble in alkali carbonate solutions with the formation of berberilates. When ammonium berberilate is dried under reduced pressure, a molecular proportion of ammonia is lost with the formation of the ammonium salt of the anhydro-acid, from which other salts, and the methyl ester, m.p. 178°, have been obtained. Berberilic acid is hydrolysed by hot dilute sulphuric acid to hemipinic acid (I) and oi-aminoethylpiperonylic acid (II), large tabular crystals, m.p. 180-2°. Berberilic acid is therefore represented by (III). 

Support for this suggestion comes from many quarters. Reduction of the jS-carboline anhydro-bases with sodium and alcohol or with tin and hydrochloric acid gives the 1,2,3,4-tetrahydro derivatives, as does catalytic reduction over platinum oxide in an alkaline medium. On the other hand, catalytic reduction with platinum oxide in acetic acid results in the formation of the 5,6,7,8-tetrahydro-j3-carbolinium derivatives (see Section III,A,2,a). It should be noted, however, that reduction of pyrido[l,2-6]indazole, in which the dipolar structure 211 is the main contributor to the resonance hybrid, could not be effected with hydrogen in the presence of Adams catalyst. 

Formation of a quinonoid carboline-type anhydro-base requires loss of resonance stabilization of the indole moiety. In the carboline anhydro-bases this is counterbalanced by the preservation of a 677 system in the hetero ring. No such balancing factor is present in the case of 3,4-dihydro-j3-carboline derivatives. Formation of the exocyclic anhydro-base in the latter case preserves benzenoid resonance. It is noteworthy that in the two cases where formation of a carboUne-type anhydro-base was reported in dihydro derivatives additional aromatic conjugation is present. 

This dimeric formulation also accounts for the thermal disproportionation of the compound into a mixture of 2-methyl-l,2,3,4-tetrahydro-jS-carbohne and 2-methyl-jS-carboline anhydro-base. Normal pseudobase formation (453 R = CHs ) takes place in the case of 9-methyl-3,4-dihydro-j3-carbohne methiodide (452 R = CHg). Neither the dimeric anhydro-base nor the -methyl pseudo-base undergo a base-catalyzed disproportionation reaction to give the 1,2,3,4-tetrahydro-and the l-oxo-l,2,3,4-tetrahydro-jS-carboline in a manner analogous... 

O-isopropylidene derivative (57) must exist in pyridine solution in a conformation which favors anhydro-ring formation rather than elimination. Considerable degradation occurred when the 5-iodo derivative (63) was treated with silver fluoride in pyridine (36). The products, which were isolated in small yield, were identified as thymine and l-[2-(5-methylfuryl)]-thymine (65). This same compound (65) was formed in high yield when the 5 -mesylate 64 was treated with potassium tert-hx Xy -ate in dimethyl sulfoxide (16). The formation of 65 from 63 or 64 clearly involves the rearrangement of an intermediate 2, 4 -diene. In a different approach to the problem of introducing terminal unsaturation into pento-furanoid nucleosides, Robins and co-workers (32,37) have employed mild base catalyzed E2 elimination reactions. Thus, treatment of the 5 -tosylate (59) with potassium tert-butylate in tert-butyl alcohol afforded a high yield of the 4 -ene (60) (37). This reaction may proceed via the 2,5 ... 

The compounds usually known as monosaccharide anhydrides or glycose anhydrides (earlier glycosans ), formation of which involves the anomeric hydroxy group, are named by the same procedure. In these cases the order of preference of ring size designators is pyranose > furanose > septanose. However, three- or four-membered rings should normally be cited as anhydro if there is a choice. 

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