Solid phase synthesis of partially protected tocinoic acid: Optimization with respect to resin and protecting groups

A few solid phase and solution approaches of good repute were applied in pa rallel with the aim to provide optimized routes to Boc- and Fmoc-tocinoic a cid (3a and 3c) and the corresponding Tyr(Bu-t) derivatives (3b and 3d). Bo c-tocinoic acid is known to couple with tripeptide amides to give substitut ed oxytocin precursors in high yields, requiring only Boc-cleavage to furni sh the corresponding hormone analogs With minimal loss of material. For com parison, two protected linear hexapeptides (2a and 2b) were prepared on thr ee polystyrene supports, two with acid-labile handles and one a conventiona l chloromethylated resin, in yields of 62 - 82 and 58 - 76%, respectively. The intermediate 2a could be converted to 3a with physical data in agreemen t with those earlier reported. Similarly, the intermediate 2b was converted to 3b. The highest yields for both 2a and 2b were obtained with a 2-chloro trityl chloride resin, which in addition provided advantages with respect t o overall speed and convenience. Additional syntheses of 3c and 3d on this and of 3c on SASRIN resin, in conjunction with trityl instead of benzyl for side-chain protection of cysteine, were also elaborated. Copyright (C) 200 1 European Peptide Society and John Wiley & Sons, Ltd.