Acid labile

The cyclic carbonate of benzoin (4,5-diphenyl-l,3-dioxol-2-one, prepared from benzoin and phosgene) blocks both hydrogen atoms of primary amines after dehydration acid stable, easily crystallizable Sheehan oxazolinones are formed, which are also called Ox derivatives. The amine is quantitatively deblocked by catalytic hydrogenation in the presence of 1 equiv. of aqueous acid (J.C Sheehan, 1972, 1973 M.J. Miller, 1983). An intelligent application to syntheses of acid labile -lactams is given in the previous section (p. 161). 

One potential approach extends the idea of chemical amplification introduced in our preceding description of dry-film resists. In 1982, Ito and co-workers (37,38) recognized that if a photosensitizer producing an acidic product is photolyzed in a polymer matrix containing acid-labile groups, the acid will serve as a spatially localized catalyst for the formation or cleavage of chemical bonds. 

Pos twe-Tone Photoresists. The ester, carbonate, and ketal acidolysis reactions which form the basis of most positive tone CA resists are thought to proceed under specific acid catalysis (62). In this mechanism, illustrated in Figure 22 for the hydrolysis of tert-huty acetate (type A l) (63), the first step involves a rapid equihbrium where the proton is transferred between the photogenerated acid and the acid-labile protecting group ... 

The rate of the reaction in such case is R = k [PH ], where P is the reactant (ie, a repeat unit bearing the acid-labile protecting group). 

Fig. 23. Representative protecting groups for phenolic and carboxylic acid-based systems, (a) The polymer-based protecting groups are fisted in order of increasing activation energy for acid-catalyzed deprotection, (b) Acid-labile monomeric dissolution inhibitors, a bifunctional system based on protected bisphenol A. (c) Another system that combines the function of dissolution inhibitor and PAG in a single unit.

Fig. 28. Traditional duv-resist design using derivatives of polyhydroxystyrene. Monomer (a) contributes hydrophilic character to the polymer, and its acidic phenol group enhances aqueous base solubiUty monomer (b) provides acid-labile pendent groups.

In some instances, the resist polymer can be prepared in a single step by direct polymerization of the protected monomer(s) (37,88), entirely avoiding the intermediate PHOST. HOST-containing resist polymers have also been prepared by free-radical copolymerization of a latent HOST and a stable, acid-labile monomer, eg, the copolymerization of acetoxystyrene with tert-huty acrylate, followed by selective removal of the acetoxy group (89) (Fig. 30). 

Fig. 30. Synthesis of an acid-labile copolymer by radical copolymerization using a latent HOST, followed by selective deprotection (89).

Sugar is destroyed by pH extremes, and inadequate pH control can cause significant sucrose losses in sugar mills. Sucrose is one of the most acid-labile disaccharides known (27), and its hydrolysis to invert is readily catalyzed by heat and low pH prolonged exposure converts the monosaccharides to hydroxymethyl furfural, which has appHcations for synthesis of glycols, ethers, polymers, and pharmaceuticals (16,30). The molecular mechanism that occurs during acid hydrolysis operates, albeit slowly, as high as pH 8.5 (18). 

These were originally prepared by Khorana as selective protective groups for the 5 -OH of nucleosides and nucleotides. They were designed to be more acid-labile than the trityl group because depurination is often a problem in the acid-catalyzed removal of the trityl group. Introduction of p-methoxy groups increases the rate of hydrolysis by about one order of magnitude for each p-methoxy substituent. For 5 -protected uridine derivatives in 80% AcOH, 20°, the time for hydrolysis was... 

This substantial group was developed as a fluorescent, acid-labile protective group for oligonucleotide synthesis. It has properties very similar to those of the DMTr group except that it can be detected down to 10 M on TLC plates with 360-nm ultraviolet light. 

Diphenylmethyl esters are similar in acid lability to r-butyl esters and can be cleaved by acidic hydrolysis from 5-containing peptides that poison hydrogenolysis catalysts. 

Enteroviruses separated from rhinoviruses by acid lability of the latter... 

Despite the statement above concerning the acid lability of cyclic formals, Gold and Sghibartz have shown that the acid catalyzed hydrolysis of these compounds is markedly depressed by some metal ions . Although the smaller cyclic formals did not exhibit a substantial rate reduction even in the presence of small cations like lithium, in certain larger systems the rate reduction was more than an order of magnitude. 

Reactions with selenium dioxide appear to be sensitive to the medium employed. Refluxing t-butanol is the usual solvent, often with small amounts of acid present, although pyridine has been introduced with acid labile substrates. 

Attempts to develop a more acid labile protecting group than the Pmc group ... 

Even though the Pictet-Gams reaction requires strong acid and high temperatures to form the desired isoquinoline framework, it remains the method of choice when acid labile substituents are not present in the molecule. This is particularly true now that the mechanism has also been elucidated and the reaction more predictable. 

The Wolff-Kishner reduction is an important alternative method to the Clem-mensen reduction, and is especially useful for the reduction of acid-labile or high-molecular substrates. Yields are often below 70%, due to various side-reactions such as elimination or isomerization reactions. ... 

The proper design of the side chains thus accessible has served not only to overcome many of the shortcomings of the early penicillins, such as acid lability, lack of oral activity, and ready destruction by bacterial penicillinase enzymes, but has provided antibiotics with broadened antibacterial spectra. 

Intermediate D-a-6 must now be converted into a form amenable to the crucial lactamization reaction. To this end, treatment of D-a-6 with hydrazine accomplishes the removal of the phthalimide protecting group and provides D-a-18 (Scheme 5) after acidification with dilute aqueous HC1. It is noteworthy that the acid-labile tert-butyl ester function withstands the latter step. Introduction of the... 

Contained within intermediate 25 is an acid-labile mixed acetal group and it was found that treatment of 25 with camphorsulfonic acid (CSA) results in the formation of dioxabicyclo[3.3.0]octane 26 in 77 % yield. Acid-induced cleavage of the mixed cyclic acetal function in 25, with loss of acetone, followed by intramolecular interception of the resultant oxonium ion by the secondary hydroxyl group appended to C leads to the observed product. Intermediate 26 clearly has much in common with the ultimate target molecule. Indeed, the constitution and relative stereochemistry of the dioxabicyclo[3.3.0]octane framework in 26 are identical to the corresponding portion of asteltoxin. 

Azocine is extremely acid labile and must be stored below — 50 rC, but can be characterized by mass and NMR spectroscopy. 

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