We report the design, synthesis, and characterization of a novel class of all-peptide macrocycles, Cyclo-Polyprolines (CP). Exploiting the precision of Fmoc-based solid-phase peptide synthesis (SPPS) and head-to-tail macrocyclization, this platform grants unparalleled control over the macrocycle's primary sequence and secondary structure, offering a viable route toward exo-/endo-functionalization and addressing a bottleneck of traditional synthetic host macrocycles. The resulting CP scaffold is highly amphiphilic, exhibiting excellent solubility in both organic and aqueous media. Structural analysis via NMR spectroscopy and single-crystal x-ray diffraction reveals a distinct chameleonic character: the macrocycle shifts from an all-junctions-cis conformation in organic solvents to a predominantly all-junctions-trans isomer in water. We demonstrate that this transition is driven by a cooperative hydration effect, wherein water molecules stabilize the expanded framework through precise two-point hydrogen bonding. Demonstrating responsive host-guest capabilities, CP undergoes induced-fit isomerization to bind ligands, successfully forming, among other species, an all-peptide pseudo-rotaxane. This methodology establishes a robust platform for creating functionalized, proline-based hosts with significant potential in medicinal chemistry, drug delivery, and organocatalysis, thereby bridging the gap between supramolecular systems and enzyme mimetics.

Multistep cascade reactions offer a powerful synthetic strategy to build significant molecular complexity without the reliance on protecting group chemistry and the isolation and purification of intermediates following each transformation. Herein, we describe novel multistep one-pot bio-organocatalytic methodology to access quinolizidine and indolizidine containing compounds with multiple chiral centers. The cascade incorporates a transaminase to generate a reactive intermediate in situ and a subsequent proline-mediated Mannich-aza-Michael reaction for the construction of privileged aza-bicyclic scaffolds. The addition of further biocatalysts enables the late-stage functionalization of these molecules, affording a panel of natural products and novel N-heterocycle derivatives. Notably, we report a three-step cascade, involving a transaminase, L-proline, and an alcohol dehydrogenase, to transform the linear diamine, cadaverine, and a beta-aryl enone, to the sp3-rich natural product, (-)-lasubine II, isolated as a single diastereoisomer. The methodology showcases the synthetic capabilities of enzymes for the generation of reactive intermediates in situ, the resolution of stereoisomers and the selective installation of multiple chiral centers, all while operating under ambient aqueous reaction conditions.

A route to triarylsulfonium salts containing polyfluorinated aryl rings is reported. Ten novel polyfluorinated arylsulfonium salts have been synthesized in up to 99% yield. A range of substitution patterns are well tolerated by this methodology. Preliminary results using these salts as alternatives to unstable polyfluorinated arylboronic acids, in the construction of new C-C bonds via ligand-coupling reactions and photochemical Giese additions are reported.

In organophosphorus chemistry, several established reactions, such as the conversion of phosphorus trichloride into tertiary phosphines, followed by oxidation and quaternization to form phosphine oxides and phosphonium salts, are widely recognized and routinely applied. In contrast, other potentially valuable transformations, including reverse or complementary versions of these standard synthetic routes, remain largely unexplored or technically challenging. This work introduces two new reaction pathways that broaden the scope of organophosphorus synthesis. The first involves a P-C bond-forming process that enables interconversion of symmetrical phosphine oxides, such as triphenylphosphine oxide (Ph3PO), into P-stereogenic phosphine oxides and quaternary phosphonium salts. The second transformation is based on the distinctive reactivity of methoxymethyl (MOM)-substituted quaternary phosphonium salts. These compounds undergo a P-C bond cleavage reaction that results in de-quaternization, allowing the synthesis of mixed-substituent tertiary phosphines from triphenylphosphine as a common precursor. Together, these two processes provide multiple efficient synthetic routes to phosphines, phosphine oxides, and quaternary phosphonium salts. The overall synthetic approach is flexible, so that the target compounds can be obtained through several pathways using different substituent combinations as starting materials.

The rational and controlled synthesis of metallo-organic cages using polyaromatic ligands is well established in the literature. There is a strong interest to advance this field towards the use of chiral ligands capable of yielding cages in a stereoselective manner. Herein, we demonstrate that the classical approach for designing metallo-organic cages can be translated to polyproline peptides, a biocompatible class of chiral ligands. We have successfully designed a series of polyprolines, which mimic the topology of ditopic polyaromatic ligands, to yield the stereoselective synthesis of a novel Pd lantern cage. This work will pave the way towards the stereospecific synthesis of more complex, functionalized peptide cages.

Herein, we describe an efficient catalytic enantioselective synthesis of a variety of alpha-allyl-alpha-aryl 1-indanones. All carbon quaternary stereocentres bearing a variety of substituted aryl groups were accessed in moderate to excellent yields up to 94 %. The enantioselectivities of the products were heavily dependent on the stereo-electronic properties of the aryl group and substitution of the indanone moiety. Excellent ees of up to 97 % were obtained with the sterically hindered di-ortho substituted arenes. In an attempt to explain the selectivities obtained, the role of the aryl moiety in the transition state was investigated using variable temperature NMR spectroscopy. The results led to further development of our current stereochemical rationale for the allylation of alpha-aryl containing substrates.

The novel synthesis of racemic cis- and trans-3-fluorofebrifugine and halofuginone is described. This straight-forward seven-step process relies on an electrophilic fluorination-allylation sequence that generates a mixture of N-Cbz protected, diastereomeric 2-allyl-3-fluoropiperidines. On separation, a Wacker oxidation-methyl functionalisation sequence enabled introduction of the required quinazolinone portion. Finally, removal of the N-Cbz protecting group lead to isolation of the 3-fluorofebrifugine dihydrobromide analogues that are of potentially pharmacological use. Analysis of the NMR spectra for each stereoisomer provides information concerning the preferred conformers of the different diastereomers. Evidence indicates that the cis-diastereomer favours a conformation where the F-atom occupies an axial orientation. In contrast, for its trans-stereoisomeric counterpart, the 2-substituent overrides any F-atom effect and it preferentially occupies a conformer where both substituents occupy equatorial positions. Finally, interconversion between the cis- and trans-diastereomers was studied. In DMSO-d6 and as their free-bases, isomerisation of each diastereomer gave a common 65 : 35 ratio of trans- to cis-3-fluorofebrifugine. Determination of the reaction rate constants for the isomerisation process at different temperatures enabled calculation of the activation energy barriers, for each process, using an Arrhenius plot. The activation energy barrier for the isomerisation of the trans-isomer was 94.3 +/- 4.9 kJ mol-1, whereas for the cis-isomer it was 84.5 +/- 3.9 kJ mol-1.

Activation of a silent gene cluster in Streptomyces nodosus leads to synthesis of a cinnamoyl-containing non-ribosomal peptide (CCNP) that is related to skyllamycins. This novel CCNP was isolated and its structure was interrogated using mass spectrometry and nuclear magnetic resonance spectroscopy. The isolated compound is an oxidised skyllamycin A in which an additional oxygen atom is incorporated in the cinnamoyl side-chain in the form of an epoxide. The gene for the epoxide-forming cytochrome P450 was identified by targeted disruption. The enzyme was overproduced in Escherichia coli and a 1.43 Å high-resolution crystal structure was determined. This is the first crystal structure for a P450 that forms an epoxide in a substituted cinnamoyl chain of a lipopeptide. These results confirm the proposed functions of P450s encoded by biosynthetic gene clusters for other epoxidized CCNPs and will assist investigation of how epoxide stereochemistry is determined in these natural products.

We report a new and straightforward route toward substituted benzo[b]fluorenes via the direct photochemical conversion of alkynylated chalcones. This transformation exploits a high-power light-emitting diode emitting ultraviolet A light to enable the rapid formation of the target products (tres = 5 min). A continuous flow approach thereby facilitates reproducibility and scalability, granting streamlined access to these important scaffolds and their derivatives. A mechanistic proposal based on a biradical species is presented and supported by deuteration studies.

Reversible proton-induced spin state switching of an FeIII complex in solution is observed at room temperature. A reversible magnetic response was detected in the complex, [FeIII (sal2 323)]ClO4 (1), using Evans' method 1 H NMR spectroscopy which indicated cumulative switching from low-spin to high-spin upon addition of one and two equivalents of acid. Infrared spectroscopy suggests a coordination-induced spin state switching (CISSS) effect, whereby protonation displaces the metal-phenoxo donors. The analogous complex, [FeIII (4-NEt2 -sal2 323)]ClO4 (2), with a diethylamino group on the ligand, was used to combine the magnetic change with a colorimetric response. Comparison of the protonation responses of 1 and 2 reveals that the magnetic switching is caused by perturbation of the immediate coordination sphere of the complex. These complexes constitute a new class of analyte sensor which operate by magneto-modulation, and in the case of 2, also yield a colorimetric response.

Herein, we report the design and synthesis of a series of chiral pyrrolidine-substituted ferrocene-derived ligands. The proficiency of this novel structural motif was demonstrated in the Rh-catalyzed asymmetric hydrogenation of dehydroamino acid esters and α-aryl enamides. The products were obtained with full conversions and excellent levels of enantioselectivities of up to >99.9% ee and 97.7% ee, respectively, using a BINOL-substituted phosphine-phosphoaramidite ligand which possesses planar, central, and axial chirality elements.

4-Substituted prolines, especially 4-fluoroprolines, have been widely used in protein engineering and design. Here, we report a robust and stereoselective approach for the synthesis of (2S,4S)-methylproline starting from (2S)-pyroglutamic acid. Incorporation studies with both (2S,4R)- and (2S,4S)-methylproline into the Trx1P variant of the model protein thioredoxin of E. coli show that the stereochemistry of the 4-methyl group might be a key determinator for successful incorporation during ribosomal synthesis of this protein.

Polyethylene glycol grafting has played a central role in preparing the surfaces of nano-probes for biological interaction, to extend blood circulation times and to modulate protein recognition and cellular uptake. However, the role of PEG graft dynamics and conformation in determining surface recognition processes is poorly understood primarily due to the absence of a microscopic picture of the surface presentation of the polymer. Here a detailed NMR analysis reveals three types of dynamic ethylene glycol units on PEG-grafted SiO2 nanoparticles (NPs) of the type commonly evaluated as long-circulating theranostic nano-probes; a narrow fraction with fast dynamics associated with the chain ends; a broadened fraction spectrally overlapped with the former arising from those parts of the chain experiencing some dynamic restriction; and a fraction too broad to be observed in the spectrum arising from units closer to the surface/graft which undergo slow motion on the NMR timescale. We demonstrate that ethylene glycol units transition between fractions as a function of temperature, core size, PEG chain length and surface coverage and demonstrate how this distribution affects colloidal stability and protein uptake. The implications of the findings for biological application of grafted nanoparticles are discussed in the context of accepted models for surface ligand conformation.

Directional internal rotation in molecular systems, generally controlled by chirality, is known to occur in natural and artificial systems driven by light or fueled chemically, but spontaneous directional molecular rotation is believed to be forbidden. We have designed a molecular rotor, whereby ferrocene and triptycene linked by a methylene bridge provide two rotational degrees of freedom. On the basis of experimental observations, in conjunction with computational data, we show that the two different modes of rotation are strongly coupled and the spatial orientation of the bistable ferrocene moiety controls the barrier to its own rotation about the triptycene axis. It is proposed that the barrier to clockwise 120° rotation across each individual triptycene blade is lower in the M-enantiomer and for counterclockwise 120° rotation, it is lower in its P-counterpart. These findings demonstrate the possibility of locally preferred thermal directional intramolecular rotation for each dynamically interconverting enantiomer.

Rights © 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. This is the pre peer reviewed version of the following article: Byrne, P. A., Muldoon, J. , Ortin, Y. , Müller‐Bunz, H. and Gilheany, D. G. (2014), Investigations on the Operation of Stereochemical Drift in the Wittig Reaction by NMR and Variable‐Temperature NMR Spectroscopy of Oxaphosphetane Intermediates and Their Quench Products. Eur. J. Org. Chem., 2014: 86-98, which has been published in final form at https://doi.org/10.1002/ejoc.201301103. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."

An amphiphilic iron(iii) complex with a tridentate Schiff-base ligand was prepared by condensation of a hexadecyloxy functionalised salycylaldehyde with a diamine followed by complexation with FeCl2 and anion methathesis with NaClO4. The complex shows spin crossover both in the solid state and solution. However in solution self-assembly and consequently aggregation of individual molecules form concentration dependent particles with sizes of 300 nm for higher concentrations, or 5 nm for lower concentrations. Aggregate formation was confirmed by NANO-flex 180° DLS Size, scan-rate dependent cyclic voltammetry and scanning electron microscopy. Molecular simulations were used to investigate the self-assembly of the complex in solution, including the role of residual water molecules. The simulations showed the self-assembly of reverse micelle-like structures when a small water cluster is inserted in solution, whereas no large aggregates formed in dehydrated environments. The perchlorate anions were found near the metal centres, stabilizing the aggregates around the water pool. Simulations of pre-assembled structures further showed the lack of stability of large aggregates in the absence of water. The larger aggregates promoted efficient communication between the iron(iii) centres and the compound displayed spin crossover in solution at around 220 K with a 10 K hysteresis window, as measured by NMR and SQUID magnetometry.

Continuous extraction of bitter kola nuts, followed by liquid-liquid extraction and flash column chromatography leads to the isolation of garcinoic acid (-tocotrienoloic acid), as the main lipophilic component in a 0.8% yield of the initial dry weight. This compound, an oxidised member of the vitamin E family, was structurally characterised using nuclear magnetic resonance spectroscopy. Key words: Vitamin E, tocopherol, antioxidant, two-dimensional nuclear magnetic resonance spectroscopy.

The synthesis of six novel N-heterocyclic carbene silver(I) acetate complexes, three symmetrical and three non-symmetrical, were achieved using 4,5-diphenylimidazole to produce intermediate imidazolium salts and then obtain the corresponding silver(l) complexes through complexation with silver acetate via the Youngs' method. In vitro biological testing, using the Kirby-Bauer disk diffusion method, was conducted against Methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli, with a NHC-silver(I) acetate compound, SBC3, and Tetracycline as standards. Silver(I) acetate complex 7 resulted in a 4 mm clearance against MRSA, showing the highest antibiotic activity of the novel derivatives. Crystallographic data revealed similar bond lengths and angles to previously reported NHC-silver(1) acetate complexes, with complex 8 showing interesting eta(2)-coordination between the silver atom and acetate oxygens. Ag-109 NMR studies were conducted, highlighting the effects of the substituents of the imidazole ring on the silver atom shown by the corresponding shifts in the Ag-109 NMR spectra. The incorporation of isopropyl groups to several of the novel complexes resulted in larger upfield Ag-109 NMR shift values compared to all other substituents. (C) 2018 Elsevier Ltd. All rights reserved.