Synthesis of Oxetane- and Azetidine-Containing Spirocycles Related to the 2,5-Diketopiperazine Framework

A simple two-step sequence is used to efficiently make novel spirocyclic analogues of the diketopiperazine nucleus. Conjugate addition of chiral α-amino esters to nitroalkenes, generated from oxetan-3-one or N-Boc-azetidin-3-one, followed by nitro group reduction provides, after spontaneous cyclization, the spirocycles in good overall yields. These rigid scaffolds can be functionalized by selective N-alkylations as well as by carbonyl reduction to the corresponding piperazines

Synthesis of oxetane- and azetidine-containing spirocycles related to the 2,5-diketopiperazine framework

A simple two-step sequence is used to efficiently make novel spirocyclic analogues of the diketopiperazine nucleus. Conjugate addition of chiral α-amino esters to nitroalkenes, generated from oxetan-3-one or N-Boc-azetidin-3-one, followed by nitro group reduction provides, after spontaneous cyclization, the spirocycles in good overall yields. These rigid scaffolds can be functionalized by selective N-alkylations as well as by carbonyl reduction to the corresponding piperazines

Solid-phase synthesis of oxetane modified peptides

Solid-phase peptide synthesis (SPPS) is used to create peptidomimetics in which one of the backbone amide C=O bonds is replaced by a four-membered oxetane ring. The oxetane containing dipeptide building blocks are made in three steps in solution, then integrated into peptide chains by conventional Fmoc SPPS. This methodology is used to make a range of peptides in high purity including backbone modified derivatives of the nonapeptide bradykinin and Met- and Leu-enkephalin

Impact of oxetane incorporation on the structure and stability of alpha-helical peptides

Peptide-based drugs combine advantages of larger biological therapeutics with those of small molecule drugs, but they generally display poor permeability and metabolic stability. Recently, we introduced a new type of peptide bond isostere, in which the backbone carbonyl is replaced with a 3-amino oxetane heterocycle, into short linear peptides with the aim of improving their therapeutic potential. In this study, we have explored the impact of oxetane modification on α-helical peptides to establish whether or not this modification is tolerated in this biologically important structural motif. The oxetane modification was introduced at two positions in a well-characterised helical peptide sequence, and circular dichroism and NMR spectroscopy were used to measure the resulting secondary structure content under different experimental conditions. Our data demonstrated that introduction of an oxetane into the peptide backbone results in a significant loss of helicity, regardless of where in the sequence the modification is placed. The molecular determinants of this destabilisation were then explored using steered molecular dynamics simulations, a computational method analogous to single molecule spectroscopy. Our simulations indicated that oxetane modification introduces a kink in the helical axis, alters the dihedral angles of residues up to three positions away from the modification, and disrupts the (i, i + 4) hydrogen bonding pattern characteristic of α-helices in favour of new, short-range hydrogen bonds. The detailed structural understanding provided in this work can direct future design of chemically modified peptides

Development of oxetane modified building blocks for peptide synthesis

The synthesis and use of oxetane modified dipeptide building blocks in solution and solid-phase peptide synthesis (SPPS) is reported. The preparation of building blocks containing non-glycine residues at the N-terminus in a stereochemically controlled manner is challenging. Here, a practical 4-step route to such building blocks is demonstrated, through the synthesis of dipeptides containing contiguous alanine residues. The incorporation of these new derivatives at specific sites along the backbone of an alanine-rich peptide sequence containing eighteen amino acids is demonstrated via solid-phase peptide synthesis. Additionally, new methods to enable the incorporation of all 20 of the proteinogenic amino acids into such dipeptide building blocks are reported through modifications of the synthetic route (for Cys and Met) and by changes to the protecting group strategy (for His, Ser and Thr)

Development of a Flexible Approach to Nuphar Alkaloids via Two Enantiospecific Piperidine-Forming Reactions

In this paper we describe the stereoselective synthesis of functionalized lactam 7 via two enantiospecific piperidine-forming techniques and its employment in a general synthetic approach to Nuphar alkaloids. Specifically, the formation of piperidine 18 by formal [3 + 3] cycloaddition and stepwise annelation processes is described; the latter technique was found to be significantly more efficient than the Pd-catalyzed TMM addition process. Finally, exploitation of the exocyclic alkene installed in the piperidine-forming reaction in the transformation of 18 to (−)-deoxynupharidine ((−)-2), (−)-castoramine ((−)-3), and (−)-nupharolutine ((−)-4) via intermediate lactam 7 is delineated

Synthesis and structure of oxetane containing tripeptide motifs

A new class of peptidomimetic is reported in which one of the amide C[double bond, length as m-dash]O bonds of the peptide backbone is replaced by an oxetane ring. They are synthesised by conjugate addition of various α-amino esters to a 3-(nitromethylene)oxetane, reduction of the nitro group and further coupling with N–Z protected amino acids to grow the peptide chain. Structural insights are provided by X-ray diffraction and molecular dynamics simulations

Enzymatically-stable oxetane-based dipeptide hydrogels

Low molecular weight gelators that are not easily degraded by enzymes have a range of potential applications. Here, we report new Fmoc-protected dipeptides in which the amide carbonyl group has been replaced by an oxetane ring. Remarkably one of these peptidomimetics, but not the corresponding dipeptide, is an effective gelator, forming hydrogels at a concentration of 3 mg/mL. On assembly, there is a lack of beta-sheet structure, implying that there is no requirement for this motif in such a gel. Furthermore, the modified dipeptide is also stable to proteolysis compared to the parent dipeptide

An iron-catalysed C–C bond-forming spirocyclization cascade providing sustainable access to new 3D heterocyclic frameworks

Heterocyclic architectures offer powerful creative possibilities to a range of chemistry end-users. This is particularly true of heterocycles containing a high proportion of sp3-carbon atoms, which confer precise spatial definition upon chemical probes, drug substances, chiral monomers and the like. Nonetheless, simple catalytic routes to new heterocyclic cores are infrequently reported, and methods making use of biomass-accessible starting materials are also rare. Here, we demonstrate a new method allowing rapid entry to spirocyclic bis-heterocycles, in which inexpensive iron(III) catalysts mediate a highly stereoselective C–C bond-forming cyclization cascade reaction using (2-halo)aryl ethers and amines constructed using feedstock chemicals readily available from plant sources. Fe(acac)3 mediates the deiodinative cyclization of (2-halo)aryloxy furfuranyl ethers, followed by capture of the intermediate metal species by Grignard reagents, to deliver spirocycles containing two asymmetric centres. The reactions offer potential entry to key structural motifs present in bioactive natural products