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Fe^II‐ and α‐ketoglutarate‐dependent halogenases and oxygenases can catalyze site‐selective functionalization of C−H bonds via a variety of C−X bond forming reactions, but achieving high chemoselectivity for functionalization using non‐native functional groups remains rare. The current study shows that directed evolution can be used to engineer variants of the dioxygenase SadX that address this challenge. Site‐selective azidation of succinylated amino acids and a succinylated amine was achieved as a result of mutations throughout the SadX structure. The installed azide group was reduced to a primary amine, and the succinyl group required for azidation was enzymatically cleaved to provide the corresponding amine. These results provide a promising starting point for evolving additional SadX variants with activity on structurally distinct substrates and for enabling enzymatic C−H functionalization with other non‐native functional groups.

Transition metal‐catalyzed C−H bond oxidation of free carboxylic acid stands as an economic, selective, and efficient strategy to generate lactones, hydroxylated products, and acetoxylated products and attracts much of the chemists’ attention. Herein, we performed a density functional theory study on the mechanism and selectivity in Pd‐catalyzed and MPAA ligand‐enabled C−H bond acetoxylation reaction. It was found that the ligand, base, and substrate are important in determining the reaction mechanism and the selectivity. The acetic anhydride additive is critical in leading the reaction to be acetoxylation, instead of the lactonization, through a facile σ‐bond metathesis mechanism that leads to the Pd‐OAc in‐termediate. Our study sheds light on the further development of transition metal‐catalyzed C−H bond oxidation reactions.

In the biosynthesis of the tryptophan‐linked dimeric diketopiperazines (DKPs), cytochromes P450 selectively couple DKP monomers to generate a variety of intricate and isomeric frameworks. To determine the molecular basis for selectivity of these biocatalysts we obtained a high‐resolution crystal structure of selective Csp²−N bond forming dimerase, AspB. Overlay of the AspB structure onto C−C and C−N bond forming homolog NzeB revealed no significant structural variance to explain their divergent chemoselectivities. Molecular dynamics (MD) simulations identified a region of NzeB with increased conformational flexibility relative to AspB, and interchange of this region along with a single active site mutation led to a variant that catalyzes exclusive C−N bond formation. MD simulations also suggest that intermolecular C−C or C−N bond formation results from a change in mechanism, supported experimentally through use of a substrate mimic.

Shortwave infrared (SWIR) dyes are characterized by their ability to absorb light from 900 to 1400 nm, which is ideal for deep tissue imaging owing to minimized light scattering and interference from endogenous pigments. An approach to access such molecules is to tune the photophysical properties of known near‐infrared dyes. Herein, we report the development of a series of easily accessible (three steps) SWIR xanthene dyes based on a dibenzazepine donor conjugated to thiophene (SCR‐1), thienothiophene (SCR‐2), or bithiophene (SCR‐3). We leverage the fact thatSCR‐1undergoes a bathochromic shift when aggregated for in vivo studies by developing a ratiometric nanoparticle for NO (rNP‐NO), which we employed to successfully visualize pathological levels of nitric oxide in a drug‐induced liver injury model via deep tissue SWIR photoacoustic (PA) imaging. Our work demonstrates how easily this dye series can be utilized as a component in nanosensor designs for imaging studies.

The search for more effective and highly selective C–H bond oxidation of accessible hydrocarbons and biomolecules is a greatly attractive research mission. The elucidating of mechanism and controlling factors will, undoubtedly, help to broaden scope of these synthetic protocols, and enable discovery of more efficient, environmentally benign, and highly practical new C–H oxidation reactions. Here, we reveal the stepwise intramolecular S_N2 nucleophilic substitution mechanism with the rate-limiting C–O bond formation step for the Pd(II)-catalyzed C(sp³)–H lactonization in aromatic 2,6-dimethylbenzoic acid. We show that for this reaction, the direct C–O reductive elimination from both Pd(II) and Pd(IV) (oxidized by O₂oxidant) intermediates is unfavorable. Critical factors controlling the outcome of this reaction are the presence of the η³-(π-benzylic)–Pd and K⁺–O(carboxylic) interactions. The controlling factors of the benzylic vs ortho site-selectivity of this reaction are the: (a) difference in the strains of the generated lactone rings; (b) difference in the strengths of the η³-(π-benzylic)–Pd and η²-(π-phenyl)–Pd interactions, and (c) more pronounced electrostatic interaction between the nucleophilic oxygen and K⁺cation in the ortho-C–H activation transition state. The presented data indicate the utmost importance of base, substrate, and ligand in the selective C(sp³)–H bond lactonization in the presence of C(sp²)–H.

Artificial metalloenzymes (ArMs) are commonly used to control the stereoselectivity of catalytic reactions, but controlling chemoselectivity remains challenging. In this study, we engineer a dirhodium ArM to catalyze diazo cross‐coupling to form an alkene that, in a one‐pot cascade reaction, is reduced to an alkane with high enantioselectivity (typically >99 %ee) by an alkene reductase. The numerous protein and small molecule components required for the cascade reaction had minimal effect on ArM catalysis. Directed evolution of the ArM led to improved yields andE/Zselectivities for a variety of substrates, which translated to cascade reaction yields. MD simulations of ArM variants were used to understand the structural role of the cofactor on ArM conformational dynamics. These results highlight the ability of ArMs to control both catalyst stereoselectivity and chemoselectivity to enable reactions in complex media that would otherwise lead to undesired side reactions.

The influence of halogen substitutions (F, Cl, Br, and I) on the energy levels of the self‐assembled hole‐extracting molecule [2‐(9H‐Carbazol‐9‐yl)ethyl]phosphonic acid (2PACz), is investigated. It is found that the formation of self‐assembled monolayers (SAMs) of [2‐(3,6‐Difluoro‐9H‐carbazol‐9‐yl)ethyl]phosphonic acid (F‐2PACz), [2‐(3,6‐Dichloro‐9H‐carbazol‐9‐yl)ethyl]phosphonic acid (Cl‐2PACz), [2‐(3,6‐Dibromo‐9H‐carbazol‐9‐yl)ethyl]phosphonic acid (Br‐2PACz), and [2‐(3,6‐Diiodo‐9H‐carbazol‐9‐yl)ethyl]phosphonic acid (I‐2PACz) directly on indium tin oxide (ITO) increases its work function from 4.73 eV to 5.68, 5.77, 5.82, and 5.73 eV, respectively. Combining these ITO/SAM electrodes with the ternary bulk‐heterojunction (BHJ) system PM6:PM7‐Si:BTP‐eC9 yields organic photovoltaic (OPV) cells with power conversion efficiency (PCE) in the range of 17.7%–18.5%. OPVs featuring Cl‐2PACz SAMs yield the highest PCE of 18.5%, compared to cells with F‐2PACz (17.7%), Br‐2PACz (18.0%), or I‐2PACz (18.2%). Data analysis reveals that the enhanced performance of Cl‐2PACz‐based OPVs relates to the increased hole mobility, decreased interface resistance, reduced carrier recombination, and longer carrier lifetime. Furthermore, OPVs featuring Cl‐2PACz show enhanced stability under continuous illumination compared to ITO/PEDOT:PSS‐based cells. Remarkably, the introduction of the n‐dopant benzyl viologen into the BHJ further boosted the PCE of the ITO/Cl‐2PACz cells to a maximum value of 18.9%, a record‐breaking value for SAM‐based OPVs and on par with the best‐performing OPVs reported to date.

MycG is a multifunctional P450 monooxygenase that catalyzes sequential hydroxylation and epoxidation or a single epoxidation in mycinamicin biosynthesis. In the mycinamicin-producing strain Micromonospora griseorubida A11725, very low-level accumulation of mycinamicin V generated by the initial C-14 allylic hydroxylation of MycG is observed due to its subsequent epoxidation to generate mycinamicin II, the terminal metabolite in this pathway. Herein, we investigated whether MycG can be engineered for production of the mycinamicin II intermediate as the predominant metabolite. Thus, mycG was subject to random mutagenesis and screening was conducted in Escherichia coli whole-cell assays. This enabled efficient identification of amino acid residues involved in reaction profile alterations, which included MycG R111Q/V358L, W44R, and V135G/E355K with enhanced monohydroxylation to accumulate mycinamicin V. The MycG V135G/E355K mutant generated 40-fold higher levels of mycinamicin V compared to wild-type M. griseorubida A11725. In addition, the E355K mutation showed improved ability to catalyze sequential hydroxylation and epoxidation with minimal mono-epoxidation product mycinamicin I compared to the wild-type enzyme. These approaches demonstrate the ability to selectively coordinate the catalytic activity of multifunctional P450s and efficiently produce the desired compounds.

The design of synthetic routes by retrosynthetic logic is decisively influenced by the transformations available. Transition‐metal‐catalyzed C−H activation has emerged as a powerful strategy for C−C bond formation, with myriad methods developed for diverse substrates and coupling partners. However, its uptake in total synthesis has been tepid, partially due to their apparent synthetic intractability, as well as a lack of comprehensive guidelines for implementation. This Review addresses these issues and offers a guide to identify retrosynthetic opportunities to generate C−C bonds by C−H activation processes. By comparing total syntheses accomplished using traditional approaches and recent C−H activation methods, this Review demonstrates how C−H activation enabled C−C bond construction has led to more efficient retrosynthetic strategies, as well as the execution of previously unattainable tactical maneuvers. Finally, shortcomings of existing processes are highlighted; this Review illustrates how some highlighted total syntheses can be further economized by adopting next‐generation ligand‐enabled approaches.

A synthetic approach to the heterodimeric bisindole alkaloid leucophyllidine is disclosed herein. An enantioenriched lactam building block, synthesized through palladium‐catalyzed asymmetric allylic alkylation, served as the precursor to both hemispheres. The eburnamonine‐derived fragment was synthesized through a Bischler–Napieralski/hydrogenation approach, while the eucophylline‐derived fragment was synthesized by Friedländer quinoline synthesis and two sequential C−H functionalization steps. A convergent Stille coupling and phenol‐directed hydrogenation united the two monomeric fragments to afford 16′‐epi‐leucophyllidine in 21 steps from commercial material.