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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Tert-Butylation of Hydroxyl Group Using MTBESorour Ramezanpour and Saeed Balalaie *Peptide Chemistry Research Center, K. N. Toosi University of Technology, Tehran,P.O.Box 15875-4416, Iran; balalaie@kntu.ac.irIntroductionAmino acids with hydroxyl group in side chain exert special functions in biologicallyactive peptides and proteins. Serine, threonine and tyrosine are amino acids which containhydroxyl group in side chain. In serine and threonine proteases, these two amino acids areinvolved in the catalytic mechanism. Meanwhile, there are different unusual amino acidssuch as hydroxy proline with hydroxyl group. Protection of hydroxyl group in the sidechain is an essential role for selection of synthesis strategy.The protecting groups of hydroxyl moieties can be classified into three different types,namely alkyl ethers, carbonic acid esters, and silyl ethers[1].The protection of hydroxyl group as benzyl ether or tert-butyl ether are the mostfrequently applied protection methods. Tert-Butyl ethers could be formed using isobutylenewith p-toluenesulfonic acid or a concentrated inorganic acid and with different startingmaterials [1]. This gaseous reagent is volatile and its use can generate high pressures,therefore using isobutylene as a reagent in the laboratory has some disadvantages.Results and DiscussionThe synthesis of t-butyl ether usually require isobutylene cylinder and suffer fromdrawbacks such as laborious synthesis procedure. Thus, the development of a method forsynthesis of t-butyl ethers using cheap reagents would be desirable. Following our researchwork about the novel methodologies in synthesis of amino acid derivatives, weconcentrated on the new approach for the synthesis of O-tert butylated serine derivatives.Herein, we wish to report methyl tert-butyl ether (MTBE) as a starting material for thein situ generation of isobutylene in the presence of acid. First of all, the starting material [2]was prepared according to the following reaction; a) formation of Z-Ser-OH using Z-ONSub) protection of C-terminal using p-nitro benzyl bromide (Scheme 1).The role of methyl t-butyl ether as a tert-butylating agent using different acids andalso using different starting materials was investigated. In this approach, reaction of methylt-butyl ether with Z-Ser-ONbz and also Cl - H 3 N + -Ser-OMe was carried out under differentreaction conditions.Firstly, reaction of Z-Ser-ONbz with MTBE or isobutylene in the presence of 60%HClO 4 were carried out and the desired O-tert butyl ether was formed in 20% and 80%yields, respectively (Scheme 2).OONO OOH 2 NOHCOOHONa 2 CO 3 O NHOHCOOHOO NHOHCOOHNO 2BrN(C 2 H 5 ) 3OO NHOHOONO 2Scheme 1. Synthesis of Z-Ser-ONbz.68