Sequence Dependent Cyclization-Cleavage of Dipeptides from the Oxime Resin and Its Prevention

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Abstract
The rates of cyclization-cleavage of dipeptides with various sequences assembled on the Kaiser’s oxime resin were determined. cyclo(–Ala–Ala–) was liberated from the H–Ala–Ala–oxime resin with the apparent first-order rate constant, kapp, 1.8 × 10−1 min−1 under basic conditions. While cyclo(–Ala–Pro–) was much more rapidly formed (kapp = 1.5 min−1) from the H–Ala–Pro–resin, cyclo(–Ala–Val–) was produced with kapp, 2.2 × 10−2 and 5.5 × 10−2 min−1 from H–Ala–Val–resin and H–Val–Ala–resin, respectively. During the coupling reaction for tripeptides by the dicyclohexylcarbodiimide/1-hydroxybenzotriazole or the symmetrical anhydride method was observed significant loss of dipeptides by cyclization, which was successfully prevented by the [(benzotriazol-1-yl)oxy]tris(dimethylamino)phosphonium hexafluorophosphate (BOP) method except in the case of H–Ala–Pro–resin. In consequence of elucidating the defect and describing the method for the prevention, the reliability of the oxime resin was increased to be widely used in the practical synthesis of protected peptides.

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