5,10,15,20-Tetrakis(pentafluorophenyl)porphyrin as a Functional Platform for Peptide Stapling and Multicyclisation.

Polyfluorinated aromatic reagents readily react with thiolates via nucleophilic aromatic substitution (SN Ar) and provide excellent scaffolds for peptide cyclisation. Here we report a robust and versatile platform for peptide stapling and multicyclisation templated by 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin, opening the door to the next generation of functional scaffolds for 3D peptide architectures. We demonstrate that stapling and multicyclisation occurs with a range of non-protected peptides under peptide-compatible conditions, exhibiting chemoselectivity and wide-applicability. Peptides containing two cysteine residues are readily stapled, and the remaining perfluoroaryl groups permit the introduction of a second peptide in a modular fashion to access bicyclic peptides. Similarly, peptides with more than two cysteine residues can afford multicyclic products containing up to three peptide 'loops'. Finally, we demonstrate that a porphyrin-templated stapled peptide containing the Skin Penetrating and Cell Entering (SPACE) peptide affords a skin cell penetrating conjugate with intrinsic fluorescence.

Protodeboronation of (Hetero)Arylboronic Esters: Direct versus Prehydrolytic Pathways and Self-/Auto-Catalysis.

The kinetics and mechanism of the base-catalyzed hydrolysis (ArB(OR)2 → ArB(OH)2) and protodeboronation (ArB(OR)2 → ArH) of a series of boronic esters, encompassing eight different polyols and 10 polyfluoroaryl and heteroaryl moieties, have been investigated by in situ and stopped-flow NMR spectroscopy (19F, 1H, and 11B), pH-rate dependence, isotope entrainment, 2H KIEs, and KS-DFT computations. The study reveals the phenomenological stability of boronic esters under basic aqueous-organic conditions to be highly nuanced. In contrast to common assumption, esterification does not necessarily impart greater stability compared to the corresponding boronic acid. Moreover, hydrolysis of the ester to the boronic acid can be a dominant component of the overall protodeboronation process, augmented by self-, auto-, and oxidative (phenolic) catalysis when the pH is close to the pKa of the boronic acid/ester.

Trialkylammonium salt degradation: implications for methylation and cross-coupling.

Trialkylammonium (most notably N,N,N-trimethylanilinium) salts are known to display dual reactivity through both the aryl group and the N-methyl groups. These salts have thus been widely applied in cross-coupling, aryl etherification, fluorine radiolabelling, phase-transfer catalysis, supramolecular recognition, polymer design, and (more recently) methylation. However, their application as electrophilic methylating reagents remains somewhat underexplored, and an understanding of their arylation versus methylation reactivities is lacking. This study presents a mechanistic degradation analysis of N,N,N-trimethylanilinium salts and highlights the implications for synthetic applications of this important class of salts. Kinetic degradation studies, in both solid and solution phases, have delivered insights into the physical and chemical parameters affecting anilinium salt stability. 1H NMR kinetic analysis of salt degradation has evidenced thermal degradation to methyl iodide and the parent aniline, consistent with a closed-shell SN2-centred degradative pathway, and methyl iodide being the key reactive species in applied methylation procedures. Furthermore, the effect of halide and non-nucleophilic counterions on salt degradation has been investigated, along with deuterium isotope and solvent effects. New mechanistic insights have enabled the investigation of the use of trimethylanilinium salts in O-methylation and in improved cross-coupling strategies. Finally, detailed computational studies have helped highlight limitations in the current state-of-the-art of solvation modelling of reaction in which the bulk medium undergoes experimentally observable changes over the reaction timecourse.

Biosynthesis of the Bis-Prenylated Alkaloids Muscoride A and B.

Prenylation is a common step in the biosynthesis of many natural products and plays an important role in increasing their structural diversity and enhancing biological activity. Muscoride A is a linear peptide alkaloid that contain two contiguous oxazoles and unusual prenyl groups that protect the amino- and carboxy-termini. Here we identified the 12.7 kb muscoride (mus) biosynthetic gene clusters from Nostoc spp. PCC 7906 and UHCC 0398. The mus biosynthetic gene clusters encode enzymes for the heterocyclization, oxidation, and prenylation of the MusE precursor protein. The mus biosynthetic gene clusters encode two copies of the cyanobactin prenyltransferase, MusF1 and MusF2. The predicted tetrapeptide substrate of MusF1 and MusF2 was synthesized through a novel tandem cyclization route in only eight steps. Biochemical assays demonstrated that MusF1 acts on the carboxy-terminus while MusF2 acts on the amino-terminus of the tetrapeptide substrate. We show that the MusF2 enzyme catalyzes the reverse or forward prenylation of amino-termini from Nostoc spp. PCC 7906 and UHCC 0398, respectively. This finding expands the regiospecific chemical functionality of cyanobactin prenyltransferases and the chemical diversity of the cyanobactin family of natural products to include bis-prenylated polyoxazole linear peptides.