Applications of BOP reagent in solid phase synthesis. II: Solid phase side-chain to side-chain cyclizations using BOP reagent

Using a variety of activating agents, a kinetic study was carried out to evaluate the rate of solid phase side-chain to side-chain cyclization of Asp3 to Lys12 in the model peptide-resin, [Ala15]-GRF(1–29)-BHA-resin. Asp3 and Lys12 were introduced in the peptide chain by using Nα-Boc amino acids in conjunction with the OFm/Fmoc side-chain protection scheme. The OFm and Fmoc side-chain protecting groups were shown to be stable to diisopropylethylamine and selectively deprotected on treatment with 20% piperidine in DMF. Solid phase side-chain to side-chain cyclization (lactamization) was shown to proceed to completion within 2 h using benzotriazol-1-yl-oxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent) while the reaction was only 55% completed in 24h using DCC/HOBt. Solid phase side-chain to side-chain cyclization by the BOP procedure not only proceeded more rapidly but also gave a purer cyclic product.