Orthoesters, cyclic intermediate

Orthoesters. The value of cyclic orthoesters as intermediates for selective acylation of carbohydrates has been demonstrated (73). Treatment of sucrose with trimethylorthoacetate and DMF in the presence of toluene-p-sulfonic acid followed by acid hydrolysis gave the 6-0-acetylsucrose as the major and the 4-0-acetylsucrose [63648-80-6] as the minor component. The latter compound underwent acetyl migration from C-4 to C-6 when treated with an organic base, such as / -butylamine, in DMF to give sucrose 6-acetate in >90% yield (74). When the kinetic reagent 2,2-dimethoxyethene was used,... 

In a cyclic orthoester such as 55 (Fig. 5) when the two alkoxy groups are different, there is the possibility of forming three different hemi-orthoesters (56, 57, and 58) which can lead to three different esters, the two hydroxy-esters 59 and 60 and the lactone 6K Thus, there is a possibility that some specific hemi-orthoesters will be generated which will lead to the preferential formation of one of the ester products. The mild acid hydrolysis of orthoesters is therefore a potential method to test the principle of stereoelectronic control in the formation and cleavage of hemi-orthoester tetrahedral intermediates. 

Similar experiments were also carried out with dichloroketene diethyl and dimethyl acetals but no intermediate could be detected. This is readily explained since the cyclic ketene acetals undergo acid-catalysed hydration about 30 times more rapidly than the corresponding acyclic ones (Straub, 1970 Chiang et al., 1974 Kresge and Straub, 1983) whereas cyclic hemi-orthoesters undergo acid-catalysed breakdown 50-60 times more slowly than the corresponding acyclic ones do (see p. 70). Therefore the ratio of rate constants favourable for the detection of the cyclic hemiorthoesters becomes unfavourable with the acyclic hemiorthoesters. 

As a class of compounds, nitriles have broad commercial utility that includes their use as solvents, feedstocks, pharmaceuticals, catalysts, and pesticides. The versatile reactivity of organonitriles arises both from the reactivity of the C=N bond, and from the ability of the cyano substituent to activate adjacent bonds, especially C—H bonds. Nitriles can be used to prepare amines, amides, amidines, carboxylic acids and esters, aldehydes, ketones, large-ring cyclic ketones, imines, heterocycles, orthoesters, and other compounds. Some of the more common transformations involve hydrolysis or alcoholysis to produce amides, acids and esters, and hydrogenation to produce amines, which are intermediates for the production of polyurethanes and polyamides. An extensive review on hydrogenation of nitriles has been recendy published (10). 

The cyclic enol ethers 76 either form 1-alkoxy furans 77 by elimination44,1 or, more interestingly, they are oxidized by bromosuccinimide to brominated intermediates 78 which give a,J3-unsaturated y-oxoesters 79 after base treatment45). Reaction of the cyclic orthoesters 76 with LiAlH4 leads to y-oxoaldehydes 80 or their acetals 81 depending on the work-up procedure 46). 

Pinacol rearrangement. A combination of SnCl and trimethyl orthoformate is an effective inducer for the rearrangement, which presumably involves intermediate cyclic orthoesters. 

When enantiomerically pure frani-2-acetoxycyclohexyl tosylate is solvolyzed, the product is racemic fran.y-diacetate. This result is consistent with the proposed mechanism, because the acetoxonium intermediate is achiral and can only give rise to racemic material. Additional evidence for this interpretation comes from the isolation of a cyclic orthoester when the solvolysis is carried out in ethanol, where the acetoxonium ion is captured by the solvent. 

The alcohol 470 was prepared from the mesylate 469 by reaction with diethyl malonate followed by reduction to give 470, whose selective acetylation was carried out by reaction with trimethyl orthoacetate followed by acid hydrolysis of the cyclic orthoester intermediate. Bromination and then coupling gave 471 [88JCS(P1)2757]. 

One attractive feature of the 2,3-dihydroxy groups present in tartaric acid derivatives is the fact that they can be incorporated into cyclic derivatives in which the protecting group also maintains a reactive center, as already discussed in the case of the orthoester protected tartrates. Cylic carbonates and cyclic sulfur compounds of tartaric acids offer additional opportunities for exploitation of the chirality of the tartaric acids in the preparation of very useful chiral intermediates. 

The 5-phosphates of several antiviral acyclonucleosides (50) have been prepared in yields between 60 and 65% by reaction of the corresponding iodo derivatives with trisodium thiophosphate in water. The iodo derivatives were synthesised from the parent acyclonucleosides by initial formation of the N, 0-bis acetyl derivatives (51) by reaction with triethylorthoformate followed by acid hydrolysis of the cyclic orthoester intermediate and then iodination with iodine/ trphenylphosphine/ imidazole. None of the derivatives were active against HSV-1, HSV-2 or CMV. 

An Italian group [51,52] showed that an alternative method, the Sharpless enantioselective dihydroxylation [53], was an efficient procedure for the preparation of AB block (J )-10. Thus enone 37, obtained by acylation (Acf l-AlCb) of dihydronaphthalene 36 [54], on treatment with the enriched (1% K2OSO4 2H2O) AD-mix-a [55] gave diol 38 in 71% yield and 98% ee (Scheme 7). Reaction of 38 with trimethylorthoacetate and subsequent treatment of the intermediate cyclic orthoester with trimethylsilyl chloride afforded chloroacetate 39. Reduction of 39 with tributyltin hydride, followed by hydrolysis, furnished enantiopure (R)-IO in 52% overall yield (from 37). 

Deslongchamps P, Chenevert R, Taillefer RJ, Moreau C, Saunders JK (1975) Hydrolysis of cyclic orthoesters. Stereoelectronic control in the cleavage of hemiorthoester tetrahedral intermediates. Can J Chem 53 1601-1615... 

Synthesis of the useful 2 -protected nucleoside has been undertaken by way of a 2, 3 -cyclic orthoester intermediate. The orthoester protects the 2, and 3 -hydroxyls so that the primary hydroxyl can then selectively be protected, if desired. Hydrolysis of the fully protected nucleoside with acid... 

The hemiorthoester intermediate decomposes in a completely specific manner yielding exclusively an hydroxyester and no trace of a lactone is detected. To explain this result we have to examine all the possible conformers of the intermediate. Theoretically, there are nine different gauche conformers for an hemiorthoester tetrahedral intermediate. Figure 4.6 represents the nine possibilities for the case of the cyclic orthoester. 

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