1,1-dimethylallyl esters as useful protecting groups for carboxylic acids

Minoo Sedighi, Purdue University

Abstract

Carboxylic acids were converted in high yield to their 1,1-dimethylallyl (DMA) esters in two steps. Palladium-catalyzed deprotection of DMA esters shown to be compatible with tert-butyl, benzyl and Fmoc protecting groups, and Fmoc deprotection can be carried out selectively in the presence of DMA esters. DMA esters were shown to be resistant to nucleophilic attack, suggesting that they can serve as alternatives to tert-butyl esters when acidic deprotection conditions need to be avoided. An efficient method for one pot regioselective synthesis of 1,1-dimethylallyl esters of different amino acids has been demonstrated. This method is quick, cheap and provides DMA esters for a number of amino acids in a good yield. Dimethylallyl esters of various carboxylic acids have been synthesized using prenyldimethylsulfonium tetrafluroborate, a reagent that can be readily made and stored, in conjunction with CuCl. Protection of the carboxylic acids was complete within several hours and afforded the esters in high yields. Toward the synthesis of callipeltin B, the desired (3S, 4R)-3,4-dimethyl-L-pyroglutamic acid was synthesized on a large scale (> 2g) and the toxic Jones reagent was replaced by a new oxidation procedure using catalytic amount of Ruthenium trichloride to afford a cleaner reaction. Attempted synthesis of pure cis isomer by hydrogenation of an exomethylene compound obtained by the method using Eschenmoser's salt resulted in a mixture of cis and trans isomer. A strategy for the solid phase synthesis of a cyclosporin A analogue has been studied. BAL linker was used for the on resin synthesis of cyclosporin A analogue. Dimethylallyl (DMA) ester was employed as the protecting group for the C-terminal of amino acid. The attachment of the first amino acid as its dimethylallyl (DMA) ester to the aldehyde resin was performed by on-resin reductive amination. The peptide chain assembly was performed by incorporation of the amino acid residues as their N-Fmoc derivatives due to their orthogonality with DMA ester.

Degree

Ph.D.

Advisors

Lipton, Purdue University.

Subject Area

Organic chemistry

COinS