SELECTIVE DEPROTECTION OF THE N-ALPHA-TERT-BUTYLOXYCARBONYL GROUP IN SOLID-PHASE PEPTIDE-SYNTHESIS WITH CHLOROTRIMETHYLSILANE AND PHENOL

The repetitive deprotection of the N(alpha)-tert-butyloxycarbonyl group during solid phase peptide synthesis was found to be efficient and quantitative by the use of a mild new reagent containing 1 M chlorotrimethylsilane and 1 M phenol in dichloromethane. Kinetic studies showed that the half-life for the reaction at 22-degrees-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 HCI in the reagent. The selectivity between the removal of the N(alpha)-tert-butyloxycarbonyl group and benzylic esters, ethers, and carbonate side chain protecting groups was >10(5) and relative to the anchoring benzyl ester bond to the resin support it was 6 X 10(3). This is a marked improvement over the selectivity of the conventional 50% 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 C6HrOH. The preferred reagent is 1 M Me3SiCl-3 M C6H5OH-CH2Cl2 and the deprotection time is 20 min (t1/2 = 1.8 min for Boc-Val-OCH2-resin). Evidence for the mechanism of the reaction was deduced. Several peptides, including Leu-enkephalin, [valine-5]-angiotensin II, and glucagon were successfully synthesized in high yields and excellent purity by the stepwise solid phase method using this new reagent.