Solid phase synthesis, ozone

Silyl ethers of aliphatic alcohols are inert towards strong bases, oxidants (ozone [81], Dess-Martin periodinane [605], iodonium salts [610,611], sulfur trioxide-pyridine complex [398]), and weak acids (e.g., 1 mol/L HC02H in DCM [605]), but can be selectively cleaved by treatment with HF in pyridine or with TBAF (Table 3.32). Phenols can also be linked to insoluble supports as silyl ethers, but these are less stable than alkyl silyl ethers and can even be cleaved by treatment with acyl halides under basic reaction conditions [595], Silyl ether attachment has been successfully used for the solid-phase synthesis of oligosaccharides [600,601,612,613] and peptides [614]. 

Solid-phase synthesis. Terminal double bonds in polymer-linked compounds (e.g., (o-alkenoic esters) can be cleaved by ozone. ... 

Use in Solid Phase Synthesis. Solid phase symthesis offers the ability to perform transformations that involve little to no workup and purification. Ozone, possessing the same properties in certain cases, seems well suited to solid phase synthesis. Undec-lO-enoic acid was coupled to merrifield resin under standard conditions using 1,3-dicyclohexylcarbodiimide (DCC). The terminal olefin was then subjected to ozonolysis at low temperature in CH2CI2. The intermediate secondary ozonide could be converted into an alcohol, aldehyde, or carboxylic acid depending on the workup conditions. 

We have focused our attention on the solid phase synthesis of such compounds and described our results here. Alternative routes for the preparation of peptide aldehydes and side-chain protected peptide aldehydes in solid phase synthesis are described. Three new linkers that are stable tmder classical Fmoc or Boc strategies have been developed to obtain the peptide aldehyde from the solid support. One of these linkers was conceptualized on the basis of the Weinreb amide (49) and the other on the basis of phenolic esters (50). Both strategies required the reduction with hydrides of the peptide-linker-resin to release the peptidic aldehydic function. The use of these two different approaches was demonstrated by the synthesis of N-protected a-amino-aldehydes and peptide aldehydes, llie third approach used the ozonolysis reaction for the generation of the desired aldehyde. This concept requires a linker incorporating a double bond in the a-position of the asymmetric carbon of the C-terminal residue that will be cleaved by ozone to produce the carbonyl function. 

Syll997 Sylvain, C., Wagner, A. and Mioskowski, C., Ozone A Versatile Reagent for Solid Phase Synthesis, Tetrahedron Lett., 38 (1997) 1043-1044. 

Amino Acids and Peptides. - Wasserman s method of one-carbon homologation of carboxylic acids to give a-ketocarboxylates involves reaction with cyanomethylenetriphenyl-phosphorane followed by ozone (Scheme 24) and has been used as a key step in a chemo-enzymatic synthesis of isotopically labelled L-valine, L-isoleucine, and o/fo-isoleucine. Alkylation of the carbanion derived from the imino-substituted methylphosphonate diphenyl ester (186) with indol-3-ylmethyl bromide followed by appropriate deprotection has been used to prepare the phosphonate analogue (187) of tryptophan (Scheme 25). The deprotected analogue (188) and derived peptides show activity as inhibitors of chymotrypsin. Two approaches to solid phase Wadsworth-Enunons reactions which have applications in combinatorial chemistry have been reported. In one diethylphosphonoacetamide is bound to PEG-PAL resin via a peptide link, while... 

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