Hydrolysis of cyclic orthoesters

The formation of esters from the mild acid hydrolysis of orthoesters proceeds through the formation of a hemi-orthoester tetrahedral intermediate as described by the following equation (47-53). 

In a cyclic orthoester such as (Fig. 5) when the two alkoxy groups are different, there is the possibility of forming three different henli-orthoesters (56, 57, and which can lead to three different esters, the two hydroxy-esters M and and the lactone 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. 

A cyclic orthoester such as in v/hich the two alkoxy groups are identical will first be examined. There are nine gauche conformers which are theoretically possible for this type of cyclic orthoester and they are described in Fig, 6. The next task is to analyze each of these conformers on the basis of the principle of stereoelectronic control. 

On that basis, conformers A and E can break down by the loss of the axial alkoxy group. Conformer can undergo a cleavage via the fission of the carbon-oxygen bond of the ring but conformer cannot break down (no primary electronic effect). Conformer must therefore be unreactive and this prediction was verified experimentally (38, 50) by studying the reactivity of the tricyclic orthoester 62 (54-66) which is a perfect rigid model for conformer , as shown by X-ray analysis (57). Indeed, compound 62 was found completely stable under the mild acid conditions that are normally used for the hydrolysis of other cyclic orthoesters. Thus, conformer is a remarkably unreactive conformer which must be eliminated. 

The next operation consists in the analysis of the hydration of lactonium ion and the subsequent breakdown of the resulting hemi-orthoester. A stereoelectronically controlled attack of water on the lactonium ion must take place on the B face yielding the tetrahedral conformer (Fig. 7). As previously discussed for the case of lactones (cf. p. 70), a reaction with water on the a face of M would result in a tetrahedral intermediate having a boat conformation, and this process is therefore eliminated. 

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Selective removal of the hydroxyl protecting groups included in this review is generally difficult to achieve and of little practical importance. Selective hydrolysis of cyclic orthoesters to give monoesters merits attention for its practical interest. 

Li S, Dory P. Hydrolysis of cyclic orthoesters experimental observations and theoretical rationalization. Tetrahedron 1996 52 14841. 

Hydrolysis of cyclic orthoesters Ozonolysis of tetrahydropyranyl ethers Cleavage of vinyl orthoesters... 

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... 

Experimental evidence to prove this postulate come from four sources. A study of the oxidation of acetals by ozone, acid hydrolysis of cyclic orthoesters, concurrent carbonyl-oxygen exchange and hydrolysis of esters by using oxygen-18 labeling, and basic hydrolysis of N,N-dialkylated imidate salts. We will briefly examine results from the last three approaches. Then we will try to apply this concept to the hydrolysis of ester and amide substrates by serine proteases. 

Reaction with sodium methoxide in methanol afforded the dimethoxyester. In the presence of deuterated sodium methoxide the mixed cyclic orthoester was obtained in over 90% yield with the deuterated methoxy group exclusively in the axial orientation. The hydrolysis of the orthoester in water containing p-toluenesulfonic acid resulted in the formation of only the non-deuterated hydroxyester. These results confirm that the hydrolysis of cyclic orthoesters proceed by loss of the axial alkoxy group. It is a further proof that conformer F can be eliminated as a reactive conformer and consequently the hydrolysis of the cyclic dialkoxyorthoester takes place through the reaction of conformer A. 

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,... 

This model was used to explain a number of intriguing experimental observations such as the preference for the acyclic products to the formation of lactones in hydrolysis of cyclic hemi-orthoesters (involved, for example in ozonolysis of acetals ). In this reaction, the equatorial C-O bond needs to be broken for the... 

Figure 5.45 Stereoelectronic control in hydrolysis of cyclic hemi-orthoesters. Only p-type lone pairs antiperipla-...

The first results reported (41) showed that the mild acid hydrolysis of the five cyclic orthoesters 72-76 (Ri H ) gave the corresponding hydroxy-ester as the sole product of the reaction. It was found later by Capon and Grieve (58) that the hydrolysis of orthoester Ti (R=CH3 or C2H5) gave a mixture of hydroxy-ester (=70%) and lactone (30%). The hydrolysis of orthoesters 72-76 was subsequently repeated (59). It was confirmed that orthoester 73 indeed gave a =7 3 mixture of hydroxy-ester and lactone. A similar result was observed with orthoester 72 but the other three orthoesters 74-76 gave exclusively hydroxy-ester as previously reported. 

Orthoesters are usually cleaved by acid hydrolysis using conditions similar to those normally employed for acetals however, OBO groups can be hydrolysed in the presence of acetals.225 As with acetals, cyclic orthoesters are more stable than their acyclic counterparts. The product of mild acid hydrolysis is itself an ester which must then be further treated with base (pH 10-11) to... 

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]. 

Treating diethyl (-h )-(i ,i )-tartrate (lb) with triethyl orthoacetate under acidic conditions provides the cyclic orthoester 530, which is then ring opened with acid to afford the monoacetate 531 in 94% overall yield. Protection of the free hydroxyl group followed by basic hydrolysis of the acetate furnishes 532. The regioselective reduction of 532 with borane-dimethylsulfide complex and a catalytic amount of sodium borohydride followed by acetonide... 

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). 

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... 

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). 

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