Macrocyclisation of small peptides enabled by oxetane incorporation

Abstract

Head-to-tail peptide macrocyclisations are significantly improved, as measured by isolated yields, reaction rates and product distribution, by substitution of one of the backbone amide CO bonds with an oxetane ring.

Development of oxetane modified building blocks for peptide synthesis

“…After hydrolysis of the C-terminus cumyl ester, the utility of these building blocks was demonstrated through the preparation of OMP analogues of several naturally occurring linear and cyclic peptides via SPPS (Figure 1c). 11,12 Clearly, there is considerable scope to use this chemistry to make much larger and more complex OMP libraries for medicinal chemistry. 13 However, the feasibility of this is hampered by the rather incomplete coverage of R 1 and R 2 within the dipeptide building blocks.…”

“…Furthermore, with respect to R 2 , only nine of the twenty proteinogenic amino acids (A, D, F, G, K, P, R, S, and V) have been incorporated. 11,12 Of the remaining R 2 side chains, incompatibility with one or more steps in the synthesis were foreseen (Figure 1b). 11 Here, we report improved synthetic routes to the building blocks that allow all twenty proteinogenic amino acids to be installed at R 2 .…”

“…9 Additionally, Carreira has shown that an oxetane modified Leuenkephalin analogue is less vulnerable towards proteolytic degradation increasing its serum half-life while retaining in vivo analgesic properties. 10 12 (c) Examples of natural product OMP analogues made:…”

Peptide Cyclization at High Concentration

“…Other turn inducers that are known to promote cyclization include oxetane 17 and dihydrophenylalanine. 18 However, side products from dimerization were observed through the use of these methods.…”

Consecutive Ring-Expansion Reactions for the Iterative Assembly of Medium-Sized Rings and Macrocycles

“…Most of these synthetic methods are based on the end-toend cyclization of a linear precursor, which is often a challenging process; 3 achieving efficient cyclization whilst avoiding unwanted intermolecular reactions such as dimerization or polymerization is usually the main problem to overcome. Various innovative strategies to help favor cyclization have emerged over the years, including the use of high-dilution conditions, 4 pseudo-high-dilution conditions, 5 templated systems, 6 and the incorporation of internal structural features to help bias conformation towards cyclization, 7 amongst others. 8 All these methods are based on improving the efficiency of an often-difficult long-chain end-to-end cyclization step.…”