ATP-Independent and Cell-Free Biosynthesis of β-Hydroxy Acids Using Vinyl Esters as Smart Substrates

In vitro biosynthetic pathways that condense and reduce molecules through coenzyme A (CoASH) activation demand energy and redox power in the form of ATP and NAD(P)H, respectively. These coenzymes must be orthogonally recycled by ancillary reactions that consume chemicals, electricity, or light, impacting the atom economy and/or the energy consumption of the biosystem. In this work, we have exploited vinyl esters as dual acyl and electron donor substrates to synthesize β-hydroxy acids through a non-decarboxylating Claisen condensation, reduction and hydrolysis stepwise cascade, including a NADH recycling step, catalyzed by a total of 4 enzymes. Herein, the chemical energy to activate the acyl group with CoASH and the redox power for the reduction are embedded into the vinyl esters. Upon optimization, this self-sustaining cascade reached a titer of (S)-3-hydroxy butyrate of 24 mM without requiring ATP and simultaneously recycling CoASH and NADH. This work illustrates the potential of in vitro biocatalysis to transform simple molecules into multi-functional ones.     

Bifunctional Iminophosphorane-Catalyzed Enantioselective Nitroalkane Addition to Unactivated α,β-Unsaturated Esters**

Herein we describe the enantioselective intermolecular conjugate addition of nitroalkanes to unactivated α,β-unsaturated esters, catalyzed by a bifunctional iminophosphorane (BIMP) superbase. The transformation provides the most direct access to pharmaceutically relevant enantioenriched γ-nitroesters, utilizing feedstock chemicals, with unprecedented selectivity. The methodology exhibits a broad substrate scope, including β-(fluoro)alkyl, aryl and heteroaryl substituted electrophiles, and was successfully applied on a gram scale with reduced catalyst loading, and, additionally, catalyst recovery was carried out. The formal synthesis of a range of drug molecules, and an enantioselective synthesis of (S)-rolipram were achieved. Additionally, computational studies revealed key reaction intermediates and transition state structures, and provided rationale for high enantioselectivities, in good agreement with experimental results.     

Methane Oxidation over Cu2+/[CuOH]+ Pairs and Site-Specific Kinetics in Copper Mordenite Revealed by Operando Electron Paramagnetic Resonance and UV/Visible Spectroscopy

Cu-exchanged mordenite (MOR) is a promising material for partial CH₄ oxidation. The structural diversity of Cu species within MOR makes it difficult to identify the active Cu sites and to determine their redox and kinetic properties. In this study, the Cu speciation in Cu-MOR materials with different Cu loadings has been determined using operando electron paramagnetic resonance (EPR) and operando ultraviolet-visible (UV/Vis) spectroscopy as well as in situ photoluminescence (PL) and Fourier-transform infrared (FTIR) spectroscopy. A novel pathway for CH₄ oxidation involving paired [CuOH]⁺ and bare Cu²⁺ species has been identified. The reduction of bare Cu²⁺ ions facilitated by adjacent [CuOH]⁺ demonstrates that the frequently reported assumption of redox-inert Cu²⁺ centers does not generally apply. The measured site-specific reaction kinetics show that dimeric Cu species exhibit a faster reaction rate and a higher apparent activation energy than monomeric Cu²⁺ active sites highlighting their difference in the CH₄ oxidation potential.     

Formal γ−C−H Functionalization of Cyclobutyl Ketones: Synthesis of cis-1,3-Difunctionalized Cyclobutanes

1,3-Difunctionalized cyclobutanes are an emerging scaffold in medicinal chemistry that can confer beneficial pharmacological properties to small-molecule drug candidates. However, the diastereocontrolled synthesis of these compounds typically requires complicated synthetic routes, indicating a need for novel methods. Here, we report a sequential C−H/C−C functionalization strategy for the stereospecific synthesis of cis-γ-functionalized cyclobutyl ketones from readily available cyclobutyl aryl ketones. Specifically, a bicyclo[1.1.1]pentan-2-ol intermediate is generated from the parent cyclobutyl ketone via an optimized Norrish-Yang procedure. This intermediate then undergoes a ligand-enabled, palladium-catalyzed C−C cleavage/functionalization to produce valuable cis-γ-(hetero)arylated, alkenylated, and alkynylated cyclobutyl aryl ketones, the benzoyl moiety of which can subsequently be converted to a wide range of functional groups including amides and esters.     

The Indenyl Effect: Accelerated C−H Amidation of Arenes via Ind*RhIII Nitrene Transfer Catalysis**

Investigations into C−H amidation reactions catalysed by cationic half-sandwich d⁶ metal complexes revealed that the indenyl-derived catalyst [Ind*RhCl₂]₂ significantly accelerated the directed ortho C−H amidation of benzoyl silanes using 1,4,2-dioxazol-5-ones. Ring slippage involving a haptotropic η⁵ to η³ rearrangement of the indenyl complex proposedly enables ligand substitution at the metal centre to proceed via associative, rather than dissociative pathways, leading to significant rate and yield enhancements. Intriguingly, this phenomenon appears specific for C−H amidation reactions involving weakly coordinating carbonyl-based directing groups with no acceleration observed for the corresponding reactions involving strongly coordinating nitrogen-based directing groups.     

Atroposelective PIII/PV=O Redox Catalysis for the Isoquinoline-Forming Staudinger–aza-Wittig Reaction

Herein, we describe the feasibility of atroposelective P^III/P^V=O redox organocatalysis by the Staudinger–aza-Wittig reaction. The formation of isoquinoline heterocycles thereby enables the synthesis of a broad range of valuable atropisomers under mild conditions with enantioselectivities of up to 98 : 2 e.r. Readily prepared azido cinnamate substrates convert in high yield with stereocontrol by a chiral phosphine catalyst, which is regenerated using a silane reductant under Brønsted acid co-catalysis. The reaction provides access to diversified aryl isoquinolines, as well as benzoisoquinoline and naphthyridine atropisomers. The products are expeditiously transformed into N-oxides, naphthol and triaryl phosphine variants of prevalent catalysts and ligands. With dinitrogen release and aromatization as ideal driving forces, it is anticipated that atroposelective redox organocatalysis provides access to a multitude of aromatic heterocycles with precise control over their configuration.     

Phosphine Oxide-Functionalized Terthiophene Redox Systems

Main group systems capable of undergoing controlled redox events at extreme potentials are elusive yet highly desirable for a range of organic electronics applications including use as energy storage media. Herein we describe phosphine oxide-functionalized terthiophenes that exhibit two reversible 1e⁻ reductions at potentials below −2 V vs Fc/Fc⁺ (Fc=ferrocene) while retaining high degrees of stability. A phosphine oxide-functionalized terthiophene radical anion was synthesized in which the redox-responsive nature of the platform was established using combined structural, spectroscopic, and computational characterization. Straightforward structural modification led to the identification of a derivative that exhibits exceptional stability during bulk 2 e⁻ galvanostatic charge–discharge cycling and enabled characterization of a 2 e⁻ redox series. A new multi-electron redox system class is hence disclosed that expands the electrochemical cell potential range achievable with main group electrolytes without compromising stability.     

On-Surface Synthesis and Real-Space Visualization of Aromatic P3N3

On-surface synthesis is at the verge of emerging as the method of choice for the generation and visualization of unstable or unconventional molecules, which could not be obtained via traditional synthetic methods. A case in point is the on-surface synthesis of the structurally elusive cyclotriphosphazene (P₃N₃), an inorganic aromatic analogue of benzene. Here, we report the preparation of this fleetingly existing species on Cu(111) and Au(111) surfaces at 5.2 K through molecular manipulation with unprecedented precision, i.e., voltage pulse-induced sextuple dechlorination of an ultra-small (about 6 Å) hexachlorophosphazene P₃N₃Cl₆ precursor by the tip of a scanning probe microscope. Real-space atomic-level imaging of cyclotriphosphazene reveals its planar D_3h-symmetric ring structure. Furthermore, this demasking strategy has been expanded to generate cyclotriphosphazene from a hexaazide precursor P₃N₂₁ via a different stimulation method (photolysis) for complementary measurements by matrix isolation infrared and ultraviolet spectroscopy.     

Photochemical Bromination of 2,5-Dimethylbenzoic Acid as Key Step of an Improved Alkyne-Functionalized Blue Box Synthesis**

Cyclobis(paraquat-p-phenylene), also known as “blue box”, is a highly electron-deficient macrocycle, widely used as a molecular receptor for small electron-rich molecules. Inserting a reactive functional group onto the molecular structure of this cyclophane is paramount for its inclusion into complex architectures. To this aim, including an alkyne moiety would be ideal, because it can participate in click reactions. However, the synthesis of such alkyne-functionalized cyclophane suffers from several drawbacks: the use of toxic and expensive CCl₄, the need for high-pressure reactors, and overall low yield. We have revised the existing synthesis of this cyclophane derivative bearing an alkyne moiety, to overcome all these limitations. In particular, photochemical radical bromination is adopted to obtain a sensitive intermediate. We demonstrated that the synthesized host molecule can be functionalized via click reactions and take part in radical-radical interactions. Our work makes a key functionalized paraquat macrocycle more accessible, facilitating the development of novel redox-responsive systems.     

Conformational polymorphism of 3-(azidomethyl)benzoic acid

Three conformational polymorphs of 3-(azidomethyl)benzoic acid, C₈H₇N₃O₂, are reported. All three structures maintain similar carboxylic acid dimers and π–π stacking. Crystal structure analysis and computational evaluations highlight the azidomethyl group as a source of conformational polymorphism, thus having potential implications in the design of solid-state reactions.