Search

Intermolecular asymmetric haloamination reactions are challenging due to the inherently high halenium affinity (HalA) of the nitrogen atom, which often leads to N-halogenated products as a kinetic trap. To circumvent this issue, acetonitrile, possessing a low HalA, was used as the nucleophile in the catalytic asymmetric Ritter-type chloroamidation of allyl-amides. This method is compatible with Z and E alkenes with both alkyl and aromatic substitution. Mild acidic workup reveals the 1,2-chloroamide products with enantiomeric excess greater than 95% for many examples. We also report the successful use of the sulfonamide chlorenium reagent dichloramine-T in this chlorenium-initiated catalytic asymmetric Ritter-type reaction. Facile modifications lead to chiral imidazoline, guanidine, and orthogonally protected 1,2,3 chiral tri-amines., Intermolecular haloamination reactions are challenging due to the high halenium affinity of the nitrogen atom. This is circumvented by using acetonitrile as an attenuated nucleophile, resulting in an enantioselective halo-Ritter reaction.

Several fluorene derivatives exhibit excited-state reactivity and relaxation dynamics that remain to be understood fully. We report here the spectral relaxation dynamics of two fluorene derivatives to evaluate the role of structural modification in the intramolecular relaxation dynamics and intermolecular interactions that characterize this family of chromophores. We have examined the time-resolved spectral relaxation dynamics of two compounds, NCy-FR0 and MK-FR0, in protic and aprotic solvents using steady-state and time-resolved emission spectroscopy and quantum chemical computations. Both compounds exhibit spectral relaxation characteristics similar to those seen in FR0, indicating that hydrogen bonding interactions between the chromophore and solvent protons play a significant role in determining the relaxation pathways available to three excited electronic states.

Protein conformational switches or allosteric proteins play a key role in the regulation of many essential biological pathways. Nonetheless, the implementation of protein conformational switches in protein design applications has proven challenging, with only a few known examples that are not derivatives of naturally occurring allosteric systems. We have discovered that the domain-swapped (DS) dimer of hCRBPII undergoes a large and robust conformational change upon retinal binding, making it a potentially powerful template for the design of protein conformational switches. Atomic resolution structures of the apo- and holo-forms illuminate a simple, mechanical movement involving sterically driven torsion angle flipping of two residues that drive the motion. We further demonstrate that the conformational "readout" can be altered by addition of cross-domain disulfide bonds, also visualized at atomic resolution. Finally, as a proof of principle, we have created an allosteric metal binding site in the DS dimer, where ligand binding results in a reversible 5-fold loss of metal binding affinity. The high resolution structure of the metal-bound variant illustrates a well-formed metal binding site at the interface of the two domains of the DS dimer and confirms the design strategy for allosteric regulation.

Visibly transparent luminescent solar concentrators (TLSC) have the potential to turn existing infrastructures into net-zero-energy buildings. However, the reabsorption loss currently limits the device performance and scalability. This loss is typically defined by the Stokes shift between the absorption and emission spectra of luminophores. In this work, the Stokes shifts (SS) of near-infrared selective-harvesting cyanines are altered by substitution of the central methine carbon with dialkylamines. We demonstrate varying SS with values over 80 nm and ideal infrared-visible absorption cutoffs. The corresponding TLSC with such modification shows a power conversion efficiency (PCE) of 0.4% for a >25 cm2 device area with excellent visible transparency >80% and up to 0.6% PCE over smaller areas. However, experiments and simulations show that it is not the Stokes shift that is critical, but the total degree of overlap that depends on the shape of the absorption tails. We show with a series of SS-modulated cyanine dyes that the SS is not necessarily correlated to improvements in performance or scalability. Accordingly, we define a new parameter, the overlap integral, to sensitively correlate reabsorption losses in any LSC. In deriving this parameter, new approaches to improve the scalability and performance are discussed to fully optimize TLSC designs to enhance commercialization efforts.

We introduce a previously unexplored parameter—halenium affinity (HalA)– as a quantitative descriptor of the bond strengths of various functional groups to halenium ions. The HalA scale ranks potential halenium ion acceptors based on their ability to stabilize a “free halenium ion”. Alkenes in particular but other Lewis bases as well, such as amines, amides, carbonyls, and ether oxygen atoms, etc., have been classified on the HalA scale. This indirect approach enables a rapid and straightforward prediction of chemoselectivity for systems involved in halofunctionalization reactions that have multiple nucleophilic sites. The influences of subtle electronic and steric variations, as well as the less predictable anchimeric and stereoelectronic effects, are intrinsically accounted for by HalA computations, providing quantitative assessments beyond simple “chemical intuition”. This combined theoretical–experimental approach offers an expeditious means of predicting and identifying unprecedented reactions.

Utilizing two robust C–C bond-forming reactions, the Baylis–Hillman reaction and the Diels–Alder reaction, we report a highly enantio-, regio-, and diastereoselective synthesis of hexahydro-2H-chromenes via two sequential [4 + 2] cycloadditions. These tandem and formal cycloadditions have also been performed as a “one-pot” sequence to access the corresponding heterocycles constituting up to five contiguous stereocenters in excellent yields and stereoselectivity.

PKCδ has emerged as a novel regulatory molecule of oxidative phosphorylation by targeting the pyruvate dehydrogenase complex (PDHC). We showed that activation of PKCδ leads to the dephosphorylation of pyruvate dehydrogenase kinase 2 (PDK2), thereby decreasing PDK2 activity and increasing PDH activity, accelerating oxygen consumption, and augmenting ATP synthesis. However, the molecular components that mediate PKCδ signaling in mitochondria have remained elusive so far. Here, we identify for the first time a functional complex, which includes cytochrome c as the upstream driver of PKCδ, and uses the adapter protein p66Shc as a platform with vitamin A (retinol) as a fourth partner. All four components are necessary for the activation of the PKCδ signal chain. Genetic ablation of any one of the three proteins, or retinol depletion, silences signaling. Furthermore, mutations that disrupt the interaction of cytochrome c with p66Shc, of p66Shc with PKCδ, or the deletion of the retinol-binding pocket on PKCδ, attenuate signaling. In cytochrome c-deficient cells, reintroduction of cytochrome c Fe3+ protein restores PKCδ signaling. Taken together, these results indicate that oxidation of PKCδ is key to the activation of the pathway. The PKCδ/p66Shc/cytochrome c signalosome might have evolved to effect site-directed oxidation of zinc-finger structures of PKCδ, which harbor the activation centers and the vitamin A binding sites. Our findings define the molecular mechanisms underlying the signaling function of PKCδ in mitochondria.—Acin-Perez, R., Hoyos, B., Gong, J., Vinogradov, V., Fischman, D. A., Leitges, M., Borhan, B., Starkov, A., Manfredi, G., Hammerling, U. Regulation of intermediary metabolism by the PKCδ signalosome in mitochondria.

Reuterin is an antimicrobial compound produced by Lactobacillus reuteri, and has been proposed to mediate, in part, the probiotic health benefits ascribed to this micro-organism. Despite 20 years of investigation, the mechanism of action by which reuterin exerts its antimicrobial effects has remained elusive. Here we provide evidence that reuterin induces oxidative stress in cells, most likely by modifying thiol groups in proteins and small molecules. Escherichia coli cells subjected to sublethal levels of reuterin expressed a set of genes that overlapped with the set of genes composing the OxyR regulon, which senses and responds to various forms of oxidative stress. E. coli cells mutated for oxyR were more sensitive to reuterin compared with wild-type cells, further supporting a role for reuterin in exerting oxidative stress. The addition of cysteine to E. coli or Clostridium difficile growth media prior to exposure to reuterin suppressed the antimicrobial effect of reuterin on these bacteria. Interestingly, interaction with E. coli stimulated reuterin production or secretion by L. reuteri, indicating that contact with other microbes in the gut increases reuterin output. Thus, reuterin inhibits bacterial growth by modifying thiol groups, which indicates that reuterin negatively affects a large number of cellular targets.