Ortho esters, hydrolysis

As the ortho ester hydrolysis ensues, a lactonization process liberates a singlechain detergent like lipid to destabilize the endosomal membrane. 

Ahmad M et al (1977) Ortho ester hydrolysis. The complete reaction mechanism. J Am Chem Soc 99 4827-4828... 

The rate determining step is the formation of a carbonium ion and as expected, substituents that are able to stabilize the carbonium ion will strongly accelerate the hydrolysis reaction. This effect is shown in Table 1. However, as also shown in Table 1, this is not true for ortho esters where substituent effects are much smaller than would be predicted by analogy with acetal or ketal hydrolysis, and in some cases are in the opposite direction. These data are consistent with the hypothesis that in ortho ester hydrolysis, there is very little carbonium ion character in the transition state and that in the hydrolysis of ortho esters, addition of a proton is concerted with the breaking of a C-O bond. 

Ortho Esters, Hydrolysis of. Mechanism and Catalysis for (Coides). 

Ortho ester hydrolysis direct evidence for a three-stag reaction mechanism. Journal of the American Chemical Society, 101, 2669-77. 

Acylated Corticoids. The corticoid side-chain of (30) was converted iato the cycHc ortho ester (96) by reaction with a lower alkyl ortho ester RC(OR )2 iu benzene solution ia the presence of i ra-toluenesulfonic acid (88). Acid hydrolysis of the product at room temperature led to the formation of the 17-monoesters (97) ia nearly quantitative yield. The 17-monoesters (97) underwent acyl migration to the 21-monoesters (98) on careful heating with. In this way, prednisolone 17a,21-methylorthovalerate was converted quantitatively iato prednisolone 17-valerate, which is a very active antiinflammatory agent (89). The iatermediate ortho esters also are active. Thus, 17a,21-(l -methoxy)-pentyhdenedioxy-l,4-pregnadiene-liP-ol-3,20-dione [(96), R = CH3, R = C Hg] is at least 70 times more potent than prednisolone (89). The above conversions... 

A variety of cyclic ortho esters,including cyclic orthoformates, have been developed to protect czs-1,2-diols. Cyclic ortho esters are more readily cleaved by acidic hydrolysis (e.g., by a phosphate buffer, pH 4.5-7.5, or by 0.005-0.05 M HCl) than are acetonides. Careful hydrolysis or reduction can be used to prepare selectively monoprotected diol derivatives. 

With this ortho ester good selectivity for the axial alcohol is achieved in the acidic hydrolysis of a pyranoside derivative." ... 

This ortho ester does not form a monoester upon deprotection as do acyclic ortho esters, thus avoiding a hydrolysis step. ... 

Enols of simple ketones can be generated in high concentration as metastable species by special techniques. Vinyl alcohol, the enol of acetaldehyde, can be generated by very careful hydrolysis of any of several ortho ester derivatives in which the group RC02 is acetate acid or a chlorinated acetate acid. ... 

The selectivity here relies on the fact that the j3-benzoate is the thermodynamically more stable ester. A mixture of esters is formed upon hydrolysis of the ortho ester and is then equilibrated with DBU. Carbohydrates are selectively protected with this methodology. " ... 

The hydrolysis of acetals and ortho esters is governed hy the stereoelectronic control factor previously discussed (see A and B on p. 427) though the effect can generally be seen only in systems where conformational mobility is limited, especially in cyclic systems. There is evidence for synplanar stereoselection in the... 

Hydrolysis of enol ethers, acetals, or ortho esters... 

Hydrolysis of these polymers regenerates the diol and produces Y-butyrolactone, which rapidly hydrolyzes to w-hydroxybutyric acid. Because poly (ortho esters) are acid-sensitive, a base is used to neutralize the hydroxybutyric acid and to maintain the hydrolysis process under control. 

In these studies cleavage of the endocyclic alkoxy group produces ethylene glycol and since only about 5% was found, it was concluded that hydrolysis proceeds 95% via exocyclic cleavage, in excellent agreement with results found for poly(ortho esters). 

Because ortho ester linkages are acid-sensitive and stable in base, two fundamentally different methods for achieving control over erosion rate can be used, In one method an acidic excipient is used- to accelerate the rate of hydrolysis while in the other method a base is used to stabilize the interior of the device. 

When a hydrophobic polymer with a physically dispersed acidic excipient is placed into an aqueous environment, water will diffuse into the polymer, dissolving the acidic excipient, and consequently the lowered pH will accelerate hydrolysis of the ortho ester bonds. The process is shown schematically in Fig. 6 (18). It is clear that the erosional behavior of the device will be determined by the relative movements of the hydration front Vj and that of the erosion front V2- If Vj > V2, the thickness of the reaction zone will gradually increase and at some point the matrix will be completely permeated with water, thus leading to an eventual bulk erosion process. On the other hand, if V2 = Vj, a surface erosion process wiU take place, and the rate of polymer erosion will be completely determined by the rate at which water intrudes into the matrix. 

Convincing evidence for a surface erosion process is shown in Fig. 8, which shows the concomitant release of the incorporated marker, methylene blue, release of the anhydride excipient hydrolysis product, succinic acid, and total weight loss of the device. According to these data, the release of an incorporated drug from an anhydride-catalyzed erosion of poly (ortho esters) can be unambiguously described by a polymer surface erosion mechanism. 

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