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Advantages of the highly base-sensitive benzo(B)thiophenesulfone-2-methoxycarbonyl amino -protecting group for the assembly of peptides subject to base -catalyzed side reactions

George Anthony Truran, University of Massachusetts Amherst


Two new, highly base-labile urethane-based $\alpha$-amino protecting groups were examined for their utility in peptide synthesis. The first such system examined, 3H-benz(e)indene)-1-methoxycarbonyl (eBimoc) 59, was synthesized from 1H-benz(e)indene 60 for which a practical large-scale synthesis was developed. Treatment of an eBimoc protected model amine shows that both deblocking and by-product scavenging are much faster than for the corresponding 9-fluorenemethoxycarbonyl derivative (Fmoc) 3. Unfortunately eBimoc protection proved to be too sensitive for general use in peptide synthesis as significant decomposition was noted even in the absence of base in the commonly used solvent DMF. The system was stable in the non-polar solvent CH$\sb2$Cl$\sb2$ but this limitation suggested a search for a more appropriate group of this type. The desired properties were found in the case of the benzo(b)thiophenesulfone-2-methoxycarbonyl (Bsmoc) group 47 which has previously been used for peptide synthesis but only under standard Fmoc conditions in spite of the fact that the Bsmoc residue is far more sensitive to base than the Fmoc group. It has now been found that with Bsmoc protection very short deblocking times and very dilute solutions of organic amines are of practical utility for solid phase syntheses. Methods were developed for the loading of a range of Bsmoc amino acids onto normal resins for the assembly of peptide acids or peptide amides. Monitoring techniques were developed in anticipation of executing automated syntheses. Several model peptides including leucine enkephalin, acyl carrier protein (65-74), and the 1-6 fragment of toxin #2 of the scorpion Androctonus Australis Hector (Val-Lys-Asp-Gly-Tyr-Ile) were assembled. The last-named sequence is known to suffer formation of aminosuccinimide side products upon application of Fmoc chemistry. Such side reactions could be reduced by application of the Bsmoc group. A general protocol for the use of Bsmoc protection involved deblocking via 2% piperidine for 5 minutes, a method which gave good results for all three model sequences. In addition to switching to lower concentrations of piperidine for deblocking, one could shift to weaker bases such as morpholine to avoid problems arising from the presence Asp-Gly and related sequences. ^

Subject Area

Organic chemistry

Recommended Citation

Truran, George Anthony, "Advantages of the highly base-sensitive benzo(B)thiophenesulfone-2-methoxycarbonyl amino -protecting group for the assembly of peptides subject to base -catalyzed side reactions" (1998). Doctoral Dissertations Available from Proquest. AAI9841928.