Cleavage protocols

One of the key steps in combinatorial solid-phase synthesis is clearly the cleavage of the desired product from the solid support. A variety of cleavage protocols have been investigated, depending on the nature of the linker employed. A complete micro-wave-assisted protocol, involving attachment of the starting material to the solid support, scaffold preparation, scaffold decoration, and cleavage of the resin-bound product, would seem desirable. 

Two different kinds of cleavage protocols were investigated. The first was a light induced photo-release reaction followed by a chromatographic work-up. Also, reaction monitoring was performed by MALDl/TOF/MS since the LASER cleaves the disaccharide from the support The second is a hydrolytic cleavage reaction under degradation of the polymeric support and subsequent aqueous extraction to yield the pure product The disaccharides (20) were obtained in yields of 27-76%. 

Numerous examples of different variants of this cyclization/cleavage protocol have been reported. Diketopiperazine formation (Section 15.22.1), an unwanted side reaction in solid-phase peptide synthesis, is also an example of this type of compound release. Because intramolecular processes generally take place more readily than the corresponding intermolecular reactions, cyclization/cleavage can occur with alkyl... 

Cleavage Protocols with Simultaneous Ring Closure... 

The formation of 3.83 was highly sensitive to experimental conditions, and the use of previously reported protocols for SP intramolecular cyclizations to hydantoins failed. The most abundant isolated side-product was the acid urea 3.100, derived from basic hydrolysis of the ester function this finding led to the successful validation of an anhydrous cyclative cleavage protocol using five equivalents of potassium r-butox-ide in anhydrous THF at RT under an Ar atmosphere for 1 hr (Fig. 3.38). Compound 3.83 was isolated in a satisfactory overall 20% yield (12 steps). 

Nondestructive Auxiliary Cleavage. One feature which makes the sultam chiral auxiliary, and to an even greater extent the related toluene-2,ot-sultam auxiliaries (see a-Methyltoluene-2,a-sultam), so versatile is the ease with which N-acyl bond fission occurs in derivatives. A great variety of extremely mild, bimolec-ular and intramolecular nondestructive cleavage protocols have been developed which tolerate a wide array of molecular functionality, simple extraction and crystallization usually providing almost quantitative auxiliary recovery without loss of enantiomeric purity. 

Sammelson, R. E., Kurth, M. J. Oxidation-Cope elimination a REM-resin cleavage protocol for the solid-phase synthesis of hydroxylamines. Tetrahedron Lett. 2001,42, 3419-3422. 

Deprotection involving concentrated ammonia is a critical step in the synthetic cycle. In particular, the use of (fluorescent) dyes linked to oligonucleotides or some other specific modifications is limited due to their lack of stability in the presence of concentrated ammonia solution, which is required for cleavage of the amides. Sometimes an improvement in deprotection yields may be achieved by an increase of reaction temperature from 55°C to 80°C, which reduces reaction time to 60 min [48]. A prerequisite for significantly milder cleavage protocols, however, is a change in protective groups at pyrimidine and purine bases. 

Koreeda and Hamann have reported the use of silyl tethers in stereocontrolled syntheses of branched-chain 1,4-diols and 1,5-diols [61]. Exposure of (bromomethyl)silyl ethers prepared from the corresponding homoallylic alcohols with Bu SnH in the presence of AIBN allowed smooth conversion to the corresponding cyclic siloxanes, from which diol products were obtained using standard, oxidative cleavage protocols. While monosubstituted olefin 149 selectively underwent 1-endo cyclization, di- and trisubsti-tuted olefins 150 and 151 preferentially reacted through the 6-exo mode with complete stereocontrol, affording the diol products 152 and 153, respectively (Scheme 10-50). 

A variety of oxidative tether cleavage protocols have also been evaluated which allow regioselective monoprotection of the resulting 1,3-diol products, facilitating differentia-... 

Functionalized organolithiums that are prepared by the cleavage protocol include a-oxidoalkyllithium derived from epoxides, ethoxymethyllithium from chloromethyl ethyl ether, and a masked hydroxymethyllithium from A -(chloromethyloxycarbonyl)-pyrrolidine. Acetals of tricarbonylchromium-complexed benzaldehydes undergo reductive cleavage. ... 

In the traceless, solid-phase synthesis of hetero-annulated l,3-oxazine-6-ones, significant rate enhancement was observed across a range of steps carried out using microwave heating (Scheme 4.15)." ° In a similar traceless, solid-phase approach, a number of 2,4,6-trisubstituted thiazolo[4,5-rf]pyridine-5,7-dione derivatives have been prepared using microwave heating as a key step. An amino ester resin was first swollen in DMSO then an isocyanate was added, and the reaction mixture was heated to 150 °C to yield a thiazolourea, which was converted to the final product in another three steps on the support before a final cleavage protocol (Scheme 4.16). 

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