Expanding the accessible chemical space by solid phase synthesis of bicyclic homodetic peptides

Abstract

Norbornapeptides (bicyclo[2.2.1]heptapeptides) and related bicyclic homodetic peptides were prepared by solid-phase peptide synthesis using an orthogonal protection scheme. These conformationally rigid peptides cover an almost pristine area of peptide topological space and adopt globular shapes similar to those of short α-helical peptides.

Bridged bicyclic peptides as potential drug scaffolds: synthesis, structure, protein binding and stability

“…Expanding from only a handful of examples in the literature prepared by solution phase synthesis, 18 we recently showed that BBPs can be obtained by solid-phase peptide synthesis (SPPS) and on-resin cyclization to a monocyclic peptide, followed by a second cyclization in solution coupling the C-terminal carboxyl group with the ε-amino group of a lysine side-chain to form the final product, a strategy which is also followed for the present paper ( Scheme 1 ). 19 The bridgehead chirality was chosen such as to present the amino- and carboxyl-group on the same stereotopic face of the monocyclic peptide, which favoured the second cyclization. The X-ray crystal structure of a bicyclo[3.3.2]decapeptide established that BBPs cyclize to form a concave bicyclic system 20 with the bridgehead amino acid H–C(α) proton pointing outwards.…”

Exocyclic Control of Turn Induction in Macrocyclic Peptide Scaffolds

“…Bicyclic linkages, in the form of lactam bridges across peptide backbones, have been shown to further rigidify and conformationally lock cyclic peptides. [24] The flexibility of our protocol allowed us to simply change the isocyanide reagent from tert-butyl isocyanide to tert-butyl isocyanoacetate, a protected carboxylic acid, and use Lys in place of Leu 3 . Following the telescopic synthesis route, the macrocycle was deprotected under acidic conditions, and side chains were coupled with PyAOP (Figure 5a).…”

Bicyclic peptides: types, synthesis and applications

“…The resulting monocyclic peptides were then subjected to amide-bond formation conditions under high dilution to perform the second cyclization and to form bicyclic peptides ( Fig. 1e) [26]. This strategy was also used to prepare bridged bicyclic peptides (BBPs) corresponding to the topology of bridged bicyclic alkanes, such as norbornane [27].…”