The hallmark of enzymes from secondary metabolic pathways is the pairing of powerful reactivity with exquisite site selectivity. The application of these biocatalytic tools in organic synthesis, however, remains under-utilized due to limitations in substrate scope and scalability. Here we report the reactivity of a monooxygenase (PikC) from the pikromycin pathway is modified through computationally-guided protein and substrate engineering, and applied to the oxidation of unactivated methylene C-H bonds. Molecular dynamics and quantum mechanical calculations were employed to develop a predictive model for substrate scope, site selectivity, and stereoselectivity of PikC mediated C-H oxidation. A suite of menthol derivatives was screened computationally and evaluated through in vitro reactions where each substrate adhered to the predicted models for selectivity and conversion to product. This platform was also expanded beyond menthol-based substrates to the selective hydroxylation of a variety of substrate cores ranging from cyclic to fused bicyclic and bridged bicyclic compounds.

Alkyl chlorides and aryl chlorides are among the most abundant and stable carbon electrophiles. Although their coupling with carbon nucleophiles is well developed, the cross-electrophile coupling of aryl chlorides with alkyl chlorides has remained a challenge. We report here the first general approach to this transformation. The key to productive, selective crosscoupling is the use of a small amount of iodide or bromide along with a recently reported ligand, pyridine-2,6-bis(Ncyanocarboxamidine) (PyBCam CN ). The scope of the reaction is demonstrated with 35 examples (63 ± 16% average yield), and we show that the Br − and I − additives act as cocatalysts, generating a low, steady-state concentration of more-reactive alkyl bromide/ iodide.

Transition-metal-catalyzed addition of aryl halides across carbonyls remains poorly developed, especially for aliphatic aldehydes and hindered substrate combinations. We report here that simple nickel complexes of bipyridine and PyBox can catalyze the addition of aryl halides to both aromatic and aliphatic aldehydes using zinc metal as the reducing agent. This convenient approach tolerates acidic functional groups that are not compatible with Grignard reactions, yet sterically hindered substrates still couple in high yield (33 examples, 70% average yield). Mechanistic studies show that an arylnickel, and not an arylzinc, adds efficiently to cyclohexanecarboxaldehyde, but only in the presence of a Lewis acid co-catalyst (ZnBr 2 ).

Patterns created by the inkjet printing of functionalized gold nanoparticles (NPs) can be selectively detected by laser desorption/ionization imaging mass spectrometry (LDI-IMS). These patterns can only be visualized by mass, providing a robust yet tunable system for potential anti-counterfeiting applications.

Although alcohols are one of the largest pools of alkyl substrates, approaches to utilize them in cross-coupling and crosselectrophile coupling are limited. We report the use of 1°and 2°alcohols in cross-electrophile coupling with aryl and vinyl halides to form C(sp 3 )− C(sp 2 ) bonds in a one-pot strategy utilizing a very fast (<1 min) bromination. The reaction's simple benchtop setup and broad scope (42 examples, 56% ± 15% average yield) facilitates use at all scales. The potential in parallel synthesis applications was demonstrated by successfully coupling all combinations of 8 alcohols with 12 aryl cores in a 96-well plate.

The diversification of late stage synthetic intermediates provides significant advantages in efficiency in comparison to conventional linear approaches. Despite these advantages, accessing varying ring scaffolds and functional group patterns from a common intermediate poses considerable challenges using existing methods. The combination of regiodivergent nickel-catalyzed C–C couplings and site-selective biocatalytic C–H oxidations using the cytochrome P450 enzyme PikC addresses this problem by enabling a single late-stage linear intermediate to be converted to macrolactones of differing ring size and with diverse patterns of oxidation. The approach is made possible by a novel strategy for site-selective biocatalytic oxidation using a single biocatalyst, with site selectivity being governed by a temporarily installed directing group. Site selectivities of C–H oxidation by this directed approach can overcome positional bias due to C–H bond strength, acidity, inductive influences, steric accessibility, or immediate proximity to the directing group, thus providing complementarity to existing approaches.

Ultraviolet B radiation (UVB) has profound effects on human skin that results in a broad spectrum of immunological local and systemic responses and is the major cause of skin carcinogenesis. One important area of study in photobiology is how UVB is translated into effector signals. As the skin is exposed to UVB light, subcellular microvesicle particles (MVP), a subtype of bioactive extracellular vesicles, are released causing a variety of local and systemic immunological effects. In this review, we highlight keratinocyte MVP release in keratinocytes in response to UVB. Specifically, Platelet-activating factor receptor agonists generated by UVB result in MVP released from keratinocytes. The downstream effects of MVP release include the ability of these subcellular particles to transport agents including the glycerophosphocholine-derived lipid mediator Platelet-activating factor (PAF). Moreover, even though UVB is only absorbed in the epidermis, it appears that PAF release from MVPs also mediates systemic immunosuppression and enhances tumor growth and metastasis. Tumor cells expressing PAF receptors can use this mechanism to evade chemotherapy responses, leading to treatment resistance for advanced cancers such as melanoma. Furthermore, novel pharmacological agents provide greater insight into the UVB-induced immune response pathway and a potential target for pharmacological intervention. This review outlines the need to more clearly elucidate the mechanism linking UVB-irradiation with the cutaneous immune response and its pathological manifestations. An improved understanding of this process can result in new insights and treatment strategies for UVB-related disorders from carcinogenesis to photosensitivity.

Articles you may be interested inReinvestigation of the molecular structure of gaseous beryllium borohydride BeB2H8 by electron diffraction (1969). The formulas given here apply, specifically, to fourelectron atoms, but the reduction to three electrons should be obvious. We shall continue to follow this practice throughout the entire paper.18 However, if {31~O, then it becomes possible to find a terminating power series for n=O. The latter choice will have advantages for other applications (cf. Ref. 28). Although we have not repeated the calculations presented here, it is expected that conversion to n=O will have little effect on the final numerical results.19 R. M. Sternheimer, Phys. Rev. 96, 951 (1954).Analysis of electron-diffraction patterns from gaseous N2h at 25°C has verified conclusions from earlier work that the material contains both trans and galtClte conformers. Assuming that these conformers have the same parameter values except for the torsion angle, the following principal results were obtained: 71.2% (8.1) trans, rNN=1.492 A (0.007), rNF=1.372 A (0.002), LFNF=103.1° (0.6), LNNF=101.4° (0.4),8 (the dihedral angle N2N IF4, NIN2FI) =64.2° (3.7), lNN=O.04~ A (0.005), and lNF=0.044 A (0.002). These distances and root-mean-square amplitudes are r4 and la values; the errors are 20' and include estimates of systematic error. The diffraction results indicate that the energy difference Rg -R. is roughly less than 1.0 kcal but that the rotational barrier may be several kilocalories.