Macrocyclisation of small peptides enabled by oxetane incorporation.

Cyclic peptides are an important source of new drugs but are challenging to produce synthetically. We show that head-to-tail peptide macrocyclisations are greatly improved, as measured by isolated yields, reaction rates and product distribution, by substitution of one of the backbone amide C[double bond, length as m-dash]O bonds with an oxetane ring. The cyclisation precursors are easily made by standard solution- or solid-phase peptide synthesis techniques. Macrocyclisations across a range of challenging ring sizes (tetra-, penta- and hexapeptides) are enabled by incorporation of this turn-inducing element. Oxetane incorporation is shown to be superior to other established amino acid modifications such as N-methylation. The positional dependence of the modification on cyclisation efficiency is mapped using a cyclic peptide of sequence LAGAY. We provide the first direct experimental evidence that oxetane modification induces a turn in linear peptide backbones, through the observation of d NN (i, i + 2) and d αN (i, i + 2) NOEs, which offers an explanation for these improvements. For cyclic peptide, cLAGAY, a combination of NMR derived distance restraints and molecular dynamics simulations are used to show that this modification alters the backbone conformation in proximity to the oxetane, with the flexibility of the ring reduced and a new intramolecular H-bond established. Finally, we incorporated an oxetane into a cyclic pentapeptide inhibitor of Aminopeptidase N, a transmembrane metalloprotease overexpressed on the surface of cancer cells. The inhibitor, cCNGRC, displayed similar IC50 values in the presence or absence of an oxetane at the glycine residue, indicating that bioactivity is fully retained upon amide C[double bond, length as m-dash]O bond replacement.

Asymmetric Synthesis of 2-Substituted Azetidin-3-ones via Metalated SAMP/RAMP Hydrazones.

2-Substituted azetidin-3-ones can be prepared in good yields and enantioselectivities (up to 85% ee) by a one-pot procedure involving the metalation of the SAMP/RAMP hydrazones of N-Boc-azetidin-3-one, reaction with a wide range of electrophiles, including alkyl, allyl, and benzyl halides and carbonyl compounds, followed by hydrolysis using oxalic acid.

Ring closing metathesis reactions of α-methylene-ß-lactams: application to the synthesis of a simplified phyllostictine analogue with herbicidal activity.

Ring closing metathesis (RCM) reactions of α-methylene-ß-lactams are used to construct strained 11- and 12-membered macrocycles that mimic key structural elements of phyllostictine A. The highest yield and stereoselectivity was achieved making 12-membered macrocycle Z-19 with use of a p-methoxyphenyl group on the lactam nitrogen. Interestingly, substrate concentration had an important influence on the stereochemical course of the reaction. A simplified analogue produced using this approach displays phytotoxic activity against Chlamydomonas reinhardtii suggesting that the α-methylene-ß-lactam subunit is responsible, at least in part, for the herbicidal activity of phyllostictine A.

Asymmetric synthesis of 2-substituted oxetan-3-ones via metalated SAMP/RAMP hydrazones.

2-Substituted oxetan-3-ones can be prepared in good yields and enantioselectivities (up to 84% ee) by the metalation of the SAMP/RAMP hydrazones of oxetan-3-one, followed by reaction with a range of electrophiles that include alkyl, allyl, and benzyl halides. Additionally, both chiral 2,2- and 2,4-disubstituted oxetan-3-ones can be made in high ee (86-90%) by repetition of this lithiation/alkylation sequence under appropriately controlled conditions. Hydrolysis of the resultant hydrazones with aqueous oxalic acid provides the 2-substituted oxetan-3-ones without detectable racemization.

Palladium-catalyzed multicomponent synthesis of 2-aryl-2-imidazolines from aryl halides and diamines.

An efficient palladium-catalyzed three-component reaction that combines aryl halides, isocyanides, and diamines provides access to 2-aryl-2-imidazolines in yields up to 96%. Through variation of the diamine component, the reaction can be extended to the synthesis of 2-aryl-1H-benzimidazoles and 2-aryl-1,4,5,6-tetrahydropyrimidines.

Bond rotation dynamics of enamides: the effect of the acyl group and potential for chirality transfer during 5-endo trig radical cyclizations.

Barriers to rotation of the N-alkenyl bond in a series of N-cycloalkenyl-N-benzyl acetamide derivatives have been measured in different solvents by variable-temperature NMR experiments. The barriers range from 9.7 to 14.2 kcal/mol, depending on substituents on the acetamide acyl group. Polar solvents such as chloroform and methanol increase the barrier to rotation compared to nonpolar solvents such as toluene. The barrier to rotation of "mimics" for acetamide-based radicals are estimated. The relative order of the values of k(rot) for different acyl groups parallels their reported Taft E(s) paramaters. For successful chirality transfer in 5-endo trig radical cyclization, it is evident that rotations would need to be significantly slower than those reported here.

Regiochemistry of copper(I)-mediated cyclization reactions of halo-dienamides.

Reaction of 2-substituted dienamides with catalytic amounts of copper halide/tripyridylamine (TPA) furnishes either 5-exo or 6-endo products with the outcome dependent upon the radical initiating unit. Reaction of 3-substituted dienamides produces beta-lactams via a 4-exo cyclization with termination of the reaction occurring via either halogen atom transfer, trapping with oxygen, elimination, or radical-radical coupling depending upon the diene.

Solid-supported copper catalysts for atom-transfer radical cyclizations: assessment of support type and ligand structure on catalyst performance in the synthesis of nitrogen heterocycles.

A range of solid supported pyridinemethanimine 9-11 and polyamine 12-15 ligands have been prepared on silica, polystyrene, and JandaJel supports. The CuCl and CuBr complexes of these supported ligands have been used to assess both the effect of the ligand type and the nature of the support upon a representative range of copper-mediated atom transfer 5-exo-trig 6, 24-25, 5-exo-dig 26, 4-exo-trig 28, and 5-endo-trig 27, 38 radical cyclizations to give nitrogen heterocycles. In addition, the effect of the nature of the support on the stereochemical outcome of the 5-exo cyclization of 25 has been probed. Generally, it was found that the type of support (e.g., polystyrene, silica, or JandaJel) had very little effect upon the efficiency and selectivity of the processes but that the nature of the ligand type immobilized was the important factor. Thus, the 5-exo cyclization of 6 and 24-26 proceeded more rapidly with the PMI ligands 9-11, whereas 4-exo cyclizations 28 and 5-endo radical polar crossover reactions 27 and 38 proceeded more efficiently with the JJ-TEDETA ligand 15. The efficiency of the supported ligands was also compared to their solution counterparts 4 and 5. The reusability of P-PMDETA ligand system 13 was assessed in the cyclization of 6.

Oxidative 5-endo cyclization of enamides mediated by ceric ammonium nitrate.

[reaction: see text] Ceric ammonium nitrate mediates the oxidative 5-endo radical-polar crossover reactions of beta-enamide esters to give 5,5-C,O-disubstituted-gamma-lactams. Trapping of the intermediate cations leads to 5-hydroxy- or 5-alkoxy-gamma-lactams depending upon the reaction conditions. The methodology was used to synthesize the basic heterocyclic ring fragments of the natural products L-755,807, Quinolacticin C, and PI-091.