SuFEx-enabled,chemoselective synthesis of triflates,triflamides and triflimidates

Sulfur(vi) Fluoride Exchange (SuFEx) chemistry has emerged as a next-generation click reaction, designed to assemble functional molecules quickly and modularly. Here, we report the ex situ generation of trifluoromethanesulfonyl fluoride (CF₃SO₂F) gas in a two chamber system, and its use as a new SuFEx handle to efficiently synthesize triflates and triflamides. This broadly tolerated protocol lends itself to peptide modification or to telescoping into coupling reactions. Moreover, redesigning the S^VI–F connector with a S O → S NR replacement furnished the analogous triflimidoyl fluorides as SuFEx electrophiles, which were engaged in the synthesis of rarely reported triflimidate esters. Notably, experiments showed H₂O to be the key towards achieving chemoselective trifluoromethanesulfonation of phenols vs. amine groups, a phenomenon best explained—using ab initio metadynamics simulations—by a hydrogen bonded termolecular transition state for the CF₃SO₂F triflylation of amines.

Triflyl fluoride gas (CF₃SO₂F) and its aza analogues are reported as new SuFEx activators. These S^VI–F reagents react efficiently with a variety of nucleophiles, yet the presence of water grants complete chemoselectivity to phenols.     

Synthesis of mesocyclic and macrocyclic polythioethers using the cesium dithiolate technique

The mesocyclic trithioethers, 1,4,7-trithiacyclodecane, 1,4,7-trithiacycloundecane, 1,4,8-trithiacycloundecane, and 1,5,9-trithiacyclododecane; the mesocyclic trithioether ketones, 1,4,7-trithiacyclodecan-9-one; 1,4,8-trithiacycloundecan-6-one, and 1,5,9-trithiacyclododecan-3-one; and the mesocyclic trithioether alcohols, 1,4,7-trithiacyclodecan-9-ol, 1,4,8-trithiacycloundecan-6-ol, and 1,5,9-trithiacyclododecan-3-ol, have been synthesized using the cesium dithiolate technique. In some cases, the corresponding macrocyclic hexathioether was isolated from the reaction mixture in addition to the mesocyclic trithioether; 1,4,7,11,14,17-hexathiacycloeicosane, 1,4,7,11,14,17-hexathiacycloeicosan-9,19-dione, 1,4,7,12,15,18-hexathiacyclodocosane, and 1,5,9,13,17,21-hexathiacyclotetracosane. Single-crystal X-ray structures have been determined for 1,5,9-trithiacyclododecan-3-ol and 1,4,7,12,15,18-hexathiacyclodocosane. For 1,5,9-trithiacyclododecane-3-ol, the compound crystallizes in the monoclinic space group, C2/c, with a = 10.5926( 9 ) Å, b = 15.582(2) Å, c = 13.6015(8) Å, β = 98.186(6)⁰, Z = 8, and R = 0.038. The macrocycle, 1,4,7,12,15,18-hexathiacyclodocosane, crystallizes in the orthorhombic space group, Pbca, with a = 21.406(5) Å, b = 9.810(2) Å, c = 10.225(2) Å, Z = 4, and R = 0.020.     

Modeling of pair distribution functions for XAFS in disordered systems

A commonly used expression for modeling the XAFS of highly disordered systems is shown to generate substantial systematic errors in the coordination number in many cases of practical interest. This expression is corrected and generalized. Further, a simpler and more flexible model distribution is proposed, and the corresponding XAFS expression is derived. Comparison with experimental and simulated data show that the new expressions are useful in cases of high disorder for which the cumulant expansion loses its utility, and they explicitly account for the k-dependence of the mean free path.     

Lessons for O.R. from A.I.: A Scheduling Case Study

This paper compares operational research (O.R.) with the currently fashionable topic of artificial intelligence (A.I.) at a detailed level. A.I. concepts, techniques and history are summarized, and O.R. and A.I. approaches compared. A case study-the development of a potential aid to scheduling repair jobs on RAF squadrons—is described. The paper shows where A.I. concepts and techniques were used in the prototype program, known as the Fault Identification & Expediting Repair (FIXER) system. Finally, some lessons for O.R. are drawn.     

Crystallization in organo-mineral micro-domains in the crossed-lamellar layer of Nerita undata (Gastropoda, Neritopsina)

Crossed-lamellar shell microstructure consists of a sophisticated arrangement of interspersed lamellae, which is very commonly found in Gastropoda or Bivalvia shell layers. Its smallest constitutive microstructural units are usually described as sub-micrometric fibers, or rods, and form very ordered and regular patterns. Atomic force microscopy (AFM) and transmission electron microscopy (TEM) imaging confirms the presence of even smaller building units in the form of organo-mineral granules, and we further investigate their internal structure within aragonite crossed-lamellar internal layer of Nerita undata (Gastropoda, Neritopsina) shell. Their coalescence may have controlled anisotropically the propagation of the crystallographic coherence through this complex microstructure, as suggested by the propagation of the microtwinning pattern between neighboring granules.     

Poly(cyclodextrin)‐Polydrug Nanocomplexes as Synthetic Oncolytic Virus for Locoregional Melanoma Chemoimmunotherapy

Despite the approval of oncolytic virus (OV) therapy for advanced melanoma, its intrinsic limitations that include the risk of persistent viral infection and cost‐intensive manufacturing motivate the development of analogous approaches that are free from the disadvantages of virus‐based therapies. Herein, reported is a nanoassembly comprised of multivalent host–guest interactions between polymerized paclitaxel (pPTX) and nitric oxide‐incorporated polymerized β‐cyclodextrin (pCD‐pSNO) that through its bioactive components and when used locoregionally recapitulates the therapeutic effects of OV. The resultant pPTX/pCD‐pSNO exhibits significantly enhanced cytotoxicity, immunogenic cell death, dendritic cell (DC) activation, and T cell expansion in vitro compared to free agents alone or in combination. In vivo, intratumoral administration of pPTX/pCD‐pSNO results in activation and expansion of DCs systemically, but with a corresponding expansion of myeloid‐derived suppressor cells and suppression of CD8⁺ T cell expansion. When combined with antibody targeting cytotoxic T lymphocyte antigen‐4 that blunts this molecule's signaling effects on T cells, intratumoral pPTX/pCD‐pSNO treatment elicits potent anticancer effects that significantly prolong animal survival. This formulation thus leverages the chemo‐ and immunotherapeutic synergies of PTX and nitric oxide and suggests the potential for virus‐free nanoformulations to mimic the therapeutic action and benefits of OVs.     

Exhaustive computational search of ionic-charge clusters that mediate interactions between mammalian cytochrome P450 (CYP) and P450-oxidoreductase (POR) proteins

In this work, a model for the interaction between CYP2B4 and the FMN domain of rat P450-oxidoreductase is built using as template the structure of a bacterial redox complex. Amino acid residues identified in the literature as cytochrome P450 (CYP)–redox partner interfacial residues map to the interface in our model. Our model supports the view that the bacterial template represents a specific electron transfer complex and moreover provides a structural framework for explaining previous experimental data.We have used our model in an exhaustive search for complementary pairs of mammalian CYP and P450-oxidoreductase (POR) charge clusters. We quantitatively show that among the previously defined basic clusters, the 433K–434R cluster is the most dominant (32.3% of interactions) and among the acidic clusters, the 207D–208D–209D cluster is the most dominant (29%). Our analysis also reveals the previously not described basic cluster 343R–345K (16.1% of interactions) and 373K (3.2%) and the acidic clusters 113D–115E–116E (25.8%), 92E–93E (12.9%), 101D (3.2%) and 179E (3.2%).Cluster pairings among the previously defined charge clusters include the pairing of cluster 421K–422R to cluster 207D–208D–209D. Moreover, 433K–434R and 207D–208D–209D, respectively the dominant positively and negatively charged clusters, are uncorrelated. Instead our analysis suggests that the newly identified cluster 113D–115E–116E is the main partner of the 433K–434R cluster while the newly described cluster 343R–345K is correlated to the cluster 207D–208D–209D.     

NMR elucidation of a novel (S)-pentacyclo-undecane bis-(4-phenyloxazoline) ligand and related derivatives

The NMR elucidation of a novel ligand (S)-pentacyclo-undecane bis-(4-phenyloxazoline) and related pentacyclo-undecane (PCU) derivatives is reported. Two-dimensional NMR proved to be a powerful technique in overcoming the difficulties associated with the elucidation of these compounds when only one-dimensional NMR data is utilized. A chiral substituent was introduced to both 'arms' of the PCU skeleton to produce derivatives 1-3. These derivatives display C(1) symmetry with all thecage atoms being nonequivalent. Owing to overlapping of peaks in the (1)H spectra, identification of these diastereomeric protons was very difficult. The (13)C spectra gave rise to clear splitting of the nonequivalent carbons. This is unusual compared to similar PCU derivatives with chiral substituents as splitting of all the diastereomeric cage carbons has not yet been reported. Nuclear Overhauser enhancement spectroscopy (NOESY) correlations of derivatives 1-3 confirm the different conformations of the molecule in which the side 'arms' occupy different orientations with respect to cage moiety.     

Cucurbituril binding of trans-[{PtCl(NH3)2}2(micro-NH2(CH2)8NH2)]2+ and the effect on the reaction with cysteine

The effect of encapsulation by cucurbiturils Q[7] and Q[8] on the rate of reaction of the anti-cancer dinuclear platinum complex trans-[{PtCl(NH3)2}2(micro-NH2(CH2)8NH2)]2+ with the model biological nucleophiles glutathione and cysteine has been examined by NMR spectroscopy. It was expected that the octamethylene linking chain would fold inside the cucurbituril host and hence position the reactive platinum centres close to the cucurbituril portals, and thereby, confer resistance to degradation by biological nucleophiles. The upfield shifts of the resonances from the methylene protons in the linking ligand observed in 1H NMR spectra of the platinum complex upon addition of either Q[7] or Q[8] indicate that the cucurbituril is positioned over the linking ligand, with the Pt(II) centres projecting out of the portal. Furthermore, the relative changes in chemical shift of the methylene resonances suggest that the octamethylene linking chain folds within the cucurbituril cavity, particularly in Q[8]. Simple molecular models, based on the observed relative changes in chemical shift, could be constructed that were consistent with the proposed folding of the linking ligand within the cucurbituril cavity. Encapsulation by Q[7] was found to reduce the rate of reaction of the platinum complex with glutathione. Encapsulation by Q[7] and Q[8] was also found to reduce the rate of reaction of the platinum complex with cysteine, with Q[8] slowing the reaction to a greater extent than Q[7], consistent with the inferred encapsulation geometries. Encapsulation of dinuclear platinum complexes within the cucurbituril cavity may provide a novel way of reducing the reactivity and degradation of these promising chemotherapeutic agents with blood plasma proteins.