An Improved Synthetic Approach to Head-to-Tail Cyclic Tetrapeptides

摘要

A number of cyclic tetrapeptides are bioactive natural products (fungal metabolites). For example, trapoxin B [1], chlamydocin [2], HC-toxin [3], WF-3161 [4], Cyl-2 [5] and more recently CJ-15,208 [6]. Their broad range of biological activity has spurred scientists to investigate both their in vitro and in vivo biological effects and use these compounds as templates in the design of newer drug candidates to explore more potent drugs. However, formation of 12 member constrained cyclic structure from a linear tetrapeptide can be difficult since more favored dimers and trimers could occur due to intermolecular condensation. Herein we report a simple, straightforward and general procedure for the svnthesis of proline containing cyclic tetrapeptides. Peptides synthesized by this procedure were found to be stable both in solution and as solids over extended period of time. The individual linear tetrapeptide precursors were synthesized using either [l+(2+l)] or (2+2) solution phase fragment condensations. Thus, the following are cyclic tetrapeptides synthesized using this protocol: