Nuria A. Solé

A novel, convenient, three-dimensional orthogonal strategy for solid-phase synthesis of cyclic peptides☆☆☆★

Abstract Head-to-tail cyclic peptides are made by an efficient three-dimensional orthogonal solid-phase strategy (Fmoc/tBu/allyl), featuring side-chain anchoring to PAC or PAL supports, selective palladium (O)-catalyzed allyl removal, and resin-bound cyclization mediated by BOP/HOBt/DIEA.

“High‐load” polyethylene glycol–polystyrene (PEG–PS) graft supports for solid‐phase synthesis

The choice of a polymeric support is a key factor for the success of solid‐phase methods for syntheses of organic compounds and biomolecules such as peptides and oligonucleotides. Classical Merrifield solid‐phase peptide synthesis (SPPS), performed on low cross‐linked hydrophobic polystyrene (PS) beads, sometimes suffers from sequence‐dependent coupling difficulties. The concept of incorporating polyethylene glycol (PEG) into supports for solid‐phase synthesis represents a successful approach to alleviating such problems. Previous reports from our laboratories have shown the advantages of “low‐load” PEG–PS (0.15–0.25 mmol/g) for SPPS. Herein, we demonstrate that the beneficial aspects of the PEG–PS concept can be extended with resins that have higher loadings (0.3–0.5 mmol/g).

Solid-Phase Synthesis of Cyclic Peptides

Interest in cyclic peptides dates back almost half a century to the discovery that the antibiotic gramicidin S is a cyclic decapeptide (Consden et al., 1947). Since then, numerous naturally occurring cyclic antibiotics and toxins have been found. Many of these are homodetic, that is, with only peptide (lactam) linkages connecting the constituent amino acid residues, whereas others are heterodetic, and include other functions such as disulfide, ester (lactone), ether, or thioether bridges that contribute to the ring(s). Duplication of the natural cycles, and the introduction of unnatural rings, have attracted the attention of chemists because of the extra level of synthetic complexity of such endeavors. Concurrently, a variety of biological studies have suggested that cyclic structures may exhibit improved metabolic stabilities, increased potencies, better receptor selectivities, and more controlled bioavailabilities. Further, the constrained geometries of cyclic peptides are conducive to conformational investigations, and for modeling and/or “locking” key secondary structural elements in protein folding. Early synthetic work focused on peptides with a small ring size, particularly cyclic hexapeptides. With the development of improved methods for peptide synthesis, larger ring sizes and more complex targets have become accessible.

Detection and minimization of H-phosphonate side reaction during phosphopeptide synthesis by a post-assembly global phosphorylation strategy

In the course of solid-phase synthesis of phosphopeptides by a post-assembly global phosphorylation strategy, the corresponding H-phosphonate peptides form as byproducts. We describe model studies to investigate this side reaction as a function of reaction conditions, and use this information to develop conditions that minimize the problem, i.e., use of dibenzyl N,N-di-isopropyl phosphoramidite for phosphitylation, followed immediately by oxidation with anhydrous tert-butyl hydroperoxide in dry tetrahydrofuran under argon, and final acidolytic cleavage.