Radical Coupling Initiated by Organophosphine Addition to Ynoates.

Dual nucleophilic phosphine photoredox catalysis is yet to be developed due to facile oxidation of the phosphine organocatalyst to the phosphoranyl radical cation. Herein, we report a reaction design that avoids this event and exploits traditional nucleophilic phosphine organocatalysis with photoredox catalysis to allow the Giese coupling with ynoates. The approach has good generality, while its mechanism is supported by cyclic voltametric, Stern-Volmer quenching, and interception studies.

Intramolecular photochemical [2 + 1]-cycloadditions of nucleophilic siloxy carbenes.

Visible light induced singlet nucleophilic carbenes undergo rapid [2 + 1]-cycloaddition with tethered olefins to afford unique bicyclo[3.1.0]hexane and bicyclo[4.1.0]heptane scaffolds. This cyclopropanation process requires only visible light irradiation to proceed, circumventing the use of exogenous (photo)catalysts, sensitisers or additives and showcases a vastly underexplored mode of reactivity for nucleophilic carbenes in chemical synthesis. The discovery of additional transformations including a cyclopropanation/retro-Michael/Michael cascade process to afford chromanones and a photochemical C-H insertion reaction are also described.

Flow-Assisted Synthesis of Alkyl Citrate Natural Products.

The development of a flow-assisted synthesis of alkyl citrate natural products is described. The flow route harnesses a number of steps including the generation of ketene silyl acetal, a formal [2 + 2] cycloaddition, and a methanolysis cascade to efficiently generate a highly substituted, and stereodefined tetrahydrofuran intermediate. A heterogeneous pseudo-Finkelstein reaction and zinc-mediated elimination furnish a key alkene alkyl citrate fragment in high yield over a multistep sequence that provides direct entry to compounds such as (-)-CJ-13982 (1), (-)-CJ-13,981 (2), L-731,120 (3), and related natural products. The flow methodology developed in this study enables a new machine-assisted approach toward the efficient and scalable synthesis of the alkyl citrate family of natural products.

Fluorinated Ketones as Trapping Reagents for Visible-Light-Induced Singlet Nucleophilic Carbenes.

Singlet nucleophilic carbenes (SNCs) containing only one heteroatom donor remain underutilized in chemical synthesis. We recently discovered that visible-light-induced SNC intermediates can be trapped by fluorinated ketones via 1,2-carbonyl addition to afford benzoin-type products. This discovery represents a rare example of nucleophilic carbenes reacting with ketones and delivers an efficient, user-friendly, and scalable process for accessing fluorinated tertiary alcohol derivatives driven only by light circumventing the use of exogenous catalysts or additives.

Tandem Photoredox Catalysis: Enabling Carbonylative Amidation of Aryl and Alkylhalides.

We report a new visible-light-mediated carbonylative amidation of aryl, heteroaryl, and alkyl halides. A tandem catalytic cycle of [Ir(ppy)2 (dtb-bpy)]+ generates a potent iridium photoreductant through a second catalytic cycle in the presence of DIPEA, which productively engages aryl bromides, iodides, and even chlorides as well as primary, secondary, and tertiary alkyl iodides. The versatile in situ generated catalyst is compatible with aliphatic and aromatic amines, shows high functional-group tolerance, and enables the late-stage amidation of complex natural products.

Photoexcited Pd(ii) auxiliaries enable light-induced control in C(sp3)-H bond functionalisation.

Herein we report the photophysical and photochemical properties of palladacycle complexes derived from 8-aminoquinoline ligands, commonly used auxiliaries in C-H activation. Spectroscopic, electrochemical and computational studies reveal that visible light irradiation induces a mixed LLCT/MLCT charge transfer providing access to synthetically relevant Pd(iii)/Pd(iv) redox couples. The Pd(ii) complex undergoes photoinduced electron transfer with alkyl halides generating C(sp3)-H halogenation products rather than C-C bond adducts. Online photochemical ESI-MS analysis implicates participation of a mononuclear Pd(iii) species which promotes C-X bond formation via a distinct Pd(iii)/Pd(iv) pathway. To demonstrate the synthetic utility, we developed a general method for inert C(sp3)-H bond bromination, chlorination and iodination with alkyl halides. This new strategy in auxiliary-directed C-H activation provides predictable and controllable access to distinct reactivity pathways proceeding via Pd(iii)/Pd(iv) redox couples induced by visible light irradiation.

A Chemoselective and Scalable Transfer Hydrogenation of Aryl Imines by Rapid Continuous Flow Photoredox Catalysis.

The chemoselective reduction of diaryl imines in the presence of competitively reducible groups is uniquely accessed through precise control of reaction and irradiation time by continuous flow visible light photoredox catalysis. The method enables the mild and efficient transfer hydrogenation of diaryl imines in the presence of sensitive functionality including halides, ester, ketone, and cyano groups. The flow protocol is efficient, rapid (>98% conversion within 9 min) and readily scaled to deliver multigram quantities of amine products in high purity.

The Tandem Photoredox Catalysis Mechanism of [Ir(ppy)2(dtb-bpy)]+ Enabling Access to Energy Demanding Organic Substrates.

We report the discovery of a tandem catalytic process to reduce energy demanding substrates, using the [Ir(ppy)2(dtb-bpy)]+ (1+) photocatalyst. The immediate products of photoinitiated electron transfer (PET) between 1+ and triethylamine (TEA) undergo subsequent reactions to generate a previously unknown, highly reducing species (2). Formation of 2 occurs via reduction and semisaturation of the ancillary dtb-bpy ligand, where the TEA radical cation serves as an effective hydrogen atom donor, confirmed by nuclear magnetic resonance, mass spectrometry, and deuterium labeling experiments. Steady-state and time-resolved luminescence and absorption studies reveal that upon irradiation, 2 undergoes electron transfer or proton-coupled electron transfer (PCET) with a representative acceptor (N-(diphenylmethylene)-1-phenylmethanamine; S). Turnover of this new photocatalytic cycle occurs along with the reformation of 1+. We rationalize our observations by proposing the first example of a mechanistic pathway where two distinct yet interconnected photoredox cycles provide access to an extended reduction potential window capable of engaging a wide range of energy demanding and synthetically relevant organic substrates including aryl halides.

Metallo-Cubosomes: Zinc-Functionalized Cubic Nanoparticles for Therapeutic Nucleotide Delivery.

Development of an effective and potent RNA delivery system remains a challenge for the clinical application of RNA therapeutics. Herein, we describe the development of an RNA delivery platform derived from self-assembled bicontinuous cubic lyotropic liquid crystalline phases, functionalized with zinc coordinated lipids. These metallo-cubosomes were prepared from a series of novel lipidic zinc(II)-bis(dipicolylamine) (Zn2BDPA)) complexes admixed with glycerol monooleate (GMO). The zinc metallo-cubosomes showed the high affinity to siRNA through interaction between Zn2BDPA and the phosphate groups of RNA molecules. Using a combination of dynamic light scattering (DLS), small-angle X-ray scattering (SAXS), and cryogenic transmission electron microscopy (cryo-TEM), we demonstrated that a variety of Zn2BDPA lipid derivatives can be loaded into GMO cubosomes and the introduction of Zn2BDPA lipids effected an internal cubic phase transition of the resulting metallo-cubosomes. The findings of this study lay the foundations for the development of a new class of noncationic lipid-based encapsulation systems, metallo-cubosomes for RNA therapeutic delivery.

Regioselectivity of aryl radical attack onto isocyanates and isothiocyanates.

The combination of multistage mass spectrometry experiments employing the distonic radical approach together with DFT calculations are used to examine addition of the N-methyl-pyridinium-4-yl radical cation (γ-NMP) to iso(thio)cyanates in the gas-phase. The type of products formed depend on the nature of the iso(thio)cyanate: (1) hydrogen atom abstraction occurs for alkyl isocyanates; (2) aryl isocyanates undergo radical-ipso substitution; (3) radical attack occurs at the C[double bond, length as m-dash]C bond of allyl isocyanate; (4) radical attack occurs at the C[double bond, length as m-dash]S bond of isothiocyanates to generate S adducts of γ-NMP and isonitriles. DFT calculations provide insight into the reactivity differences of these heterocumulenes towards the electrophilic C-centered γ-distonic radical cations. Translation of these gas phase results to the solution phase were hampered by dominating radical recombination reactions which appear to be favoured over the radical-iso(thio)cyanate reactions.

Radical Carbonylation Mediated by Continuous-Flow Visible-Light Photocatalysis: Access to 2,3-Dihydrobenzofurans.

The annulative carbonylation of alkenyl-tethered arenediazonium salts using visible-light photocatalysis in continuous flow is described. The method furnishes a diverse series of novel acetate-functionalized 2,3-dihydrobenzofurans at room temperature and moderate CO pressure (25 atm), delivering these products in a short time with straightforward scale-up. This continuous flow and free-radical approach overcomes the limitation of traditional Pd-catalyzed annulative carbonylation, giving valuable 2,3-dihydrobenzofurans in a predictable and regioselective manner.

Bidirectional Synthesis of Di- tert-butyl (2 S,6 S,8 S)- and (2 R,6 R,8 R)-1,7-Diazaspiro[5.5]undecane-2,8-dicarboxylate and Related Spirodiamines.

Efficient syntheses of both enantiomers of a spirodiamine diester from (l)- and (d)-aspartic acid are described. The key transformation was the conversion of Boc-protected tert-butyl aspartate into the derived aldehyde, two-directional Horner-Wadsworth-Emmons olefination, hydrogenation, and selective acid-catalyzed Boc-deprotection and spirocyclization. An alternative, two-directional approach to derivatives of 1,7-diazaspiro[5.5]undecane is described.

Photocatalytic and Chemoselective Transfer Hydrogenation of Diarylimines in Batch and Continuous Flow.

A visible-light photocalytic method for the chemoselective transfer hydrogenation of imines in batch and continuous flow is described. The reaction utilizes Et3N as both hydrogen source and single-electron donor, enabling the selective reduction of imines derived from diarylketimines containing other reducible functional groups including nitriles, halides, esters, and ketones. The dual role of Et3N was confirmed by fluorescence quenching measurements, transient absorption spectroscopy, and deuterium-labeling studies. Continuous-flow processing facilitates straightforward scale-up of the reaction.

Auxiliary-Directed C(sp3 )-H Arylation by Synergistic Photoredox and Palladium Catalysis.

Herein we describe the auxiliary-directed arylation of unactivated C(sp3 )-H bonds with aryldiazonium salts, which proceeds under synergistic photoredox and palladium catalysis. The site-selective arylation of aliphatic amides with α-quaternary centres is achieved with high selectivity for ß-methyl C(sp3 )-H bonds. This operationally simple method is compatible with carbocyclic amides, a range of aryldiazonium salts and proceeds at ambient conditions.

Amphiphilic lipopeptide significantly enhances uptake of charge-neutral splice switching morpholino oligonucleotide in spinal muscular atrophy patient-derived fibroblasts.

Splice-switching antisense oligonucleotides (SSOs) are emerging therapeutics with two SSOs recently approved by the FDA for Duchenne muscular dystrophy and spinal muscular atrophy. SSOs are administered without any delivery vector and require large doses to achieve the therapeutic benefit, primarily due to their poor cellular uptake. Although cell-penetrating peptides (CPP) have shown great potential in delivering SSOs into cells, their capacity as delivery vector is limited. Here we have studied the effect of lipid conjugation on the cell permeability of a known CPP (ApoE). Myristic acid was coupled at the N-terminus of ApoE to a C-terminal cysteine residue. The myristoylated ApoE (Myr-ApoE) was conjugated to a maleimide functionalised phosphorodiamidate morpholino oligonucleotide (PMO). The Myr-ApoE-PMO conjugate showed no cytoxicity and had significantly higher efficiency in cell permeability with 30% higher splice-switching activity compared to ApoE-PMO. The self-assembly properties of this amphiphilic lipopeptide-PMO conjugate was assessed. Transmission electron microscopy showed formation of nanoparticles with amphiphile behaviour and spherical structure. The self-assembly of Myr-ApoE-PMO into nanoparticles enabled it to better bind to cell membranes and to be more efficiently taken up by fibroblast cells. These results showed that modification of physico-chemical properties of peptides to produce peptide amphiphiles enhances cellular uptake and can be used as an efficient delivery vector for therapeutic SSOs.

Luminescence of a Transition Metal Complex Inside a Metamaterial Nanocavity.

Modification of the local density of optical states using metallic nanostructures leads to enhancement in the number of emitted quanta and photocatalytic turnover of luminescent materials. In this work, the fabrication of a metamaterial is presented that consists of a nanowire separated from a metallic mirror by a polymer thin film doped with a luminescent organometallic iridium(III) complex. The large spin-orbit coupling of the heavy metal atom results in an excited state with significant magnetic-dipole character. The nanostructured architecture supports two distinct optical modes and their assignment achieved with the assistance of numerical simulations. The simulations show that one mode is characterized by strong confinement of the electric field and the other by strong confinement of the magnetic field. These modes elicit drastic changes in the emitter's photophysical properties, including dominant nanocavity-derived modes observable in the emission spectra along with significant increases in emission intensity and the total decay rate. A combination of simulations and momentum-resolved spectroscopy helps explain the mechanism of the different interactions of each optical mode supported by the metamaterial with the excited state of the emitter.

A QCM-D and SAXS Study of the Interaction of Functionalised Lyotropic Liquid Crystalline Lipid Nanoparticles with siRNA.

Biophysical studies were undertaken to investigate the binding and release of short interfering ribonucleic acid (siRNA) from lyotropic liquid crystalline lipid nanoparticles (LNPs) by using a quartz crystal microbalance (QCM). These carriers are based on phytantriol (Phy) and the cationic lipid DOTAP (1,2-dioleoyloxy-3-(trimethylammonium)propane). The nonlamellar phase LNPs were tethered to the surface of the QCM chip for analysis based on biotin-neutravidin binding, which enabled the controlled deposition of siRNA-LNP complexes with different lipid/siRNA charge ratios on a QCM-D crystal sensor. The binding and release of biomolecules such as siRNA from LNPs was demonstrated to be reliably characterised by this technique. Essential physicochemical parameters of the cationic LNP/siRNA lipoplexes-such as particle size, lyotropic phase behaviour, cytotoxicity, gene silencing and uptake efficiency-were also assessed. The SAXS data show that when the pH was lowered to 5.5 the structure of the lipoplexes did not change, thus indicating that the acidic conditions of the endosome were not a significant factor in the release of siRNA from the cationic lipidic carriers.

Synthesis and Reactions of Benzannulated Spiroaminals: Tetrahydrospirobiquinolines.

An efficient two-step synthesis of symmetrical and unsymmetrical tetrahydrospirobiquinolines from o-azidobenzaldehydes is reported. A novel series of tetrahydrospirobiquinolines was prepared by sequential double-aldol condensation with acetone, cyclopentanone, and cyclohexanone to form the corresponding o,o'-diazido-dibenzylidene-acetone, -cyclopentanone, and -cyclohexanone derivatives, respectively, and hydrogenation-spirocyclization. The spirodiamines were further derivatized by electrophilic aromatic bromination, Suzuki coupling, and N-alkylation, all of which proceeded with preservation of the spirocyclic core.

Continuous flow synthesis of a carbon-based molecular cage macrocycle via a three-fold homocoupling reaction.

The facile synthesis of the cage molecule (C110H56Br2) via a remarkable three-fold homo-coupling macrocyclization reaction using continuous flow methodology is reported. Synthesis via continuous flow chemistry improves the residence time, safety, and environmental profile of this synthetically challenging reaction. Further, the new cage possesses halogen atoms at its apex that serve to expand the potential reaction space of these intrinsically porous, all carbon-carbon bonded molecular cage molecules.