Selective Deprotection of the Nα-tert-Butyloxycarbonyl Group in Solid Phase Peptide Synthesis with Chlorotrimethylsilane and Phenol

Article abstract of DOI:10.1021/jo00071a028

The repetitive deprotection of the N^α-tert-butyloxycarbonyl group during solid phase peptide synthesis was found to be efficient and quantitative by use of a mild new reagent containing 1 M chlorotrimethylsiane and 1 M phenol in dichloromethane.Kinetic studies showed that the half-life for the reaction at 22 deg C with Boc-Val-resin was 17.5 min, a 40-fold increase over the rate in the absence of phenol.The reaction is not due to the presence of HCl in the reagent.The selectivity between the removal at the N^α-tert-butyloxycarbonyl group and benzylic esters, ethers, and carbonate side chain protecting groups was >1E5 and relative to the anchoring benzyl ester bond to the resin support it was 6E3.This is a marked improvement over the selectivity of the conventional 50percent trifluoroacetic acid in CH2Cl2 deprotecting agent and significantly reduces the accumulated byproducts resulting from losses of benzylic groups.The cleavage of the tert-butyl urethane was first order in Me3SiCl and second order in C6H5OH.The preferred reagent is 1 M Me3SiCl-3 M C6H5OH-CH2Cl2 and the deprotection time is 20 min (t_1/2 = 1.8 min for Boc-Val-OCH2-resin).Evidence for the mechanism of the reaction was deduced.Several peptides, including Leu-enkephalin, -angiotensin II, and glucagon were successfully synthesized in high yields and excellent purity by the stepwise solid phase method using this new reagent.