Acidic Cleavage Conditions

The cyclative-cleavage strategy is different to the cases in which the cycUzation occurs in solution after the cleavage (Scheme 3.6). This is true for most acidic cleavage conditions in these cases the uncyclized reactant is also found in the hquid-phase. Examples of this strategy are the synthesis of benzofurans [184], imidazo-quinoxalinones [185, 186] and diketopiperazines [187]. 

Cys(Acm) and Cys(rcrr-Bu) are stable in 95% TFA. These protecting groups must be removed after cleavage. In the case of these amino acids cleavage condition 3 should be used. 

The methods of choice for the synthesis of polybasic lipi-dated peptides such as those corresponding to the C-termini of RhoA, K-Ras4B, and D-Ral are solid-phase approaches using the trityl hnker or the chlorotrityl hnker (37, 38). The mildly acidic cleavage conditions of these resins are still orthogonal to the farnesyl moiety and often also to the geranylgeranyl moiety. Attachment of the peptide via the C -terminus would limit the... 

Physical and Chemical Properties. The (F)- and (Z)-isomers of cinnamaldehyde are both known. (F)-Cinnamaldehyde [14371-10-9] is generally produced commercially and its properties are given in Table 2. Cinnamaldehyde undergoes reactions that are typical of an a,P-unsaturated aromatic aldehyde. Slow oxidation to cinnamic acid is observed upon exposure to air. This process can be accelerated in the presence of transition-metal catalysts such as cobalt acetate (28). Under more vigorous conditions with either nitric or chromic acid, cleavage at the double bond occurs to afford benzoic acid. Epoxidation of cinnamaldehyde via a conjugate addition mechanism is observed upon treatment with a salt of /-butyl hydroperoxide (29). 

R SiBr, trace MeOH. Methoxymethyl ethers are stable to these cleavage conditions. Methoxymethyl esters are unstable to silica gel chromatography, but are stable to mild acid (0.01 N HCl, EtOAc, MeOH, 25°, 16 h)." ... 

The acid cleavage of the aryl— silicon bond (desilylation), which provides a measure of the reactivity of the aromatic carbon of the bond, has been applied to 2- and 3-thienyl trimethylsilane, It was found that the 2-isomer reacted only 43.5 times faster than the 3-isomer and 5000 times faster than the phenyl compound at 50,2°C in acetic acid containing aqueous sulfuric acid. The results so far are consistent with the relative reactivities of thiophene upon detritia-tion if a linear free-energy relationship between the substituent effect in detritiation and desilylation is assumed, as the p-methyl group activates about 240 (200-300) times in detritiation with aqueous sulfuric acid and about 18 times in desilylation. A direct experimental comparison of the difference between benzene and thiophene in detritiation has not been carried out, but it may be mentioned that even in 80.7% sulfuric acid, benzene is detritiated about 600 times slower than 2-tritiothiophene. The aforementioned consideration makes it probable that under similar conditions the ratio of the rates of detritiation of thiophene and benzene is larger than in the desilylation. A still larger difference in reactivity between the 2-position of thiophene and benzene has been found for acetoxymercuration which... 

Somewhat milder oxidative conditions lead to loss of but one carbon. Periodic acid cleavage of the side chain in 65, leads to the so-called etio acid (66). Reaction with propionic anhydride leads to acylation of the 17-hydroxyl group (67). Possibilities for neighboring group participation severely limit the methods available for activating the acid for esterification. Best results seemed to have been obtained by use of a mixed anhydride from treatment with diphenyl chloro-... 

The reaction is in methanol, like iododestannylation, first-order in each reagent. The second-order rate coefficient at 23 °C was reported as 20,900 and thus the reaction occurs very much more readily than cleavage of the corresponding tin compound, which repeats the pattern observed in acid-cleavage reactions (see p. 342). The magnitude of the rate coefficient may be subject to the same error that appears to be present in the measurement of the corresponding tin compound (see footnote to Table 264) since the rates were determined under the same conditions. 

A variety of cleavage conditions have been reported for the release of amines from a solid support. Triazene linker 52 prepared from Merrifield resin in three steps was used for the solid-phase synthesis of aliphatic amines (Scheme 22) [61]. The triazenes were stable to basic conditions and the amino products were released in high yields upon treatment with mild acids. Alternatively, base labile linker 53 synthesized from a-bromo-p-toluic acid in two steps was used to anchor amino functions (Scheme 23) [62]. Cleavage was accomplished by oxidation of the thioether to the sulfone with m-chloroperbenzoic acid followed by 13-elimination with a 10% solution of NH4OH in 2,2,2-trifluoroethanol. A linker based on l-(4,4 -dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) primary amine protecting group was developed for attaching amino functions (Scheme 24) [65]. Linker 54 was stable to both acidic and basic conditions and the final products were cleaved from the resin by treatment with hydrazine or transamination with ra-propylamine. 

Utilizing the novel syringaldehyde resin, smooth release from the support could be achieved upon microwave heating of a suspension of the resin-bound pyridinones in trifluoroacetic acid/dichloromethane (5 95) at 120 °C for just 10 min. The very mild cleavage conditions for this new linker, as well as its stability towards various reaction conditions and its easy accessibility, make it highly suitable for ongoing pyrazinone chemistry. 

The photolytic activation of 5m was also shown to lead to DNA cleavage [33,35-38]. This reaction appeared to be faster and more efficient than the Cu+-catalyzed cleavage conditions. The mechanism(s) of DNA cleavage should be different because aryl cations (not aryl radicals) are believed to be produced under photolytic conditions (Fig. 12) [7]. Such electrophiles should target the nucleic acid bases and/or the positively charged phosphodiester backbone, and both of these could lead to DNA cleavage. 

Each microreactor consists of a polymer-bound substrate and a radiofrequency encoded microchip enclosed within a small porous vessel. The radiofrequency tag allows the identity of the substrate contained within each microreactor to be established readily. Using this technology, the polymer-bound substrates 86 were individually elaborated, within separate microreactors, by sequential reactions with acids 87 and alcohols 88 in a similar way to the solution-phase processes [25c]. Each of the microreactors was then subjected to the tandem RCM resin-cleavage conditions employing initiator 3. The products from each microreactor were obtained as a mixture of four compounds (89-92). The library of analogs prepared by this technique was then screened for biological activity [25c]. 

Many acid-labile linkers are used to assemble combinatorial libraries. Compounds are cleaved in the final step by TFA/DCM solution with various concentrations for a certain period of time. Mild cleavage conditions may lead to incomplete cleavage of the desired compound from a solid support. On the other hand harsh conditions may cause compound degradation and side reactions. Harsh conditions will also cause the partial breakdown of resin and the leaching of unidentified impurities into the final products. Harsh cleavage conditions demand the stabihty of all compounds under such conditions. This may limit the scope of combinatorial synthesis... 

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