Preparation of Tetrasubstituted 3‑Phosphonopyrroles through Hydroamination: Scope and Limitations

Phosphonylated pyrroles were obtained by a ZnCl₂-catalyzed 5-<i>exo</i>-<i>dig</i> hydroamination of propargylic enamines. These starting compounds were obtained in two steps from commercially available β-ketophosphonates. The method tolerates a wide variety of substituents at the 1,2- and 5-position of the pyrrole, while further derivatization allows for the introduction of substituents at the 4-position via lithiation or halogenation

Governing Parameters of Long-Range Intramolecular <i>S</i>‑to‑<i>N</i> Acyl Transfers within (<i>S</i>)‑Acyl Isopeptides

The governing parameters for the long-range intramolecular <i>S</i>-to-<i>N</i> acyl transfer in (<i>S</i>)-acyl isopeptides are shown by computational and statistical methods (principal component analysis and cluster analysis) to be driven by enthalpic and geometric effects over the range <i>n</i> = 5–20. The results emphasize the dependency of Δ<i>G</i>^‡ on the geometrical parameters governing the approach of the reactive termini and the importance of stabilizing intramolecular hydrogen bonds in the transition states (TSs), rather than the effects of TS ring-size. The competition between the intra- (uni-) and inter- (bi)­molecular acyl transfers were studied for representative examples

Synthetic Entry into 1‑Phosphono-3-azabicyclo[3.1.0]hexanes

3-Azabicyclo­[3.1.0]­hex-2-en-1-yl phosphonates were prepared in a five-step reaction route from β-ketophosphonates. The key steps in this sequence are an atom-transfer radical cyclization and an unforeseen lithium–halogen exchange with <i>n</i>-BuLi. The cyclization reaction proceeds with excellent diastereoselectivity. The resulting cyclic imines were reduced, and 3-azabicyclo[3.1.0]­hexan-1-yl phosphonates were obtained

Data_Sheet_1_Recovering Actives in Multi-Antitarget and Target Design of Analogs of the Myosin II Inhibitor Blebbistatin.PDF

<p>In multitarget drug design, it is critical to identify active and inactive compounds against a variety of targets and antitargets. Multitarget strategies thus test the limits of available technology, be that in screening large databases of compounds vs. a large number of targets, or in using in silico methods for understanding and reliably predicting these pharmacological outcomes. In this paper, we have evaluated the potential of several in silico approaches to predict the target, antitarget and physicochemical profile of (S)-blebbistatin, the best-known myosin II ATPase inhibitor, and a series of analogs thereof. Standard and augmented structure-based design techniques could not recover the observed activity profiles. A ligand-based method using molecular fingerprints was, however, able to select actives for myosin II inhibition. Using further ligand- and structure-based methods, we also evaluated toxicity through androgen receptor binding, affinity for an array of antitargets and the ADME profile (including assay-interfering compounds) of the series. In conclusion, in the search for (S)-blebbistatin analogs, the dissimilarity distance of molecular fingerprints to known actives and the computed antitarget and physicochemical profile of the molecules can be used for compound design for molecules with potential as tools for modulating myosin II and motility-related diseases.</p

3‑Imidoallenylphosphonates: <i>In Situ</i> Formation and β‑Alkoxylation

3-Imidoallenylphosphonates, allenes bearing both an electron-withdrawing and -donating group, were isolated for the first time. An alkoxy substituent was introduced into these unprecedented intermediates in a one-pot approach, yielding β-functionalized aminophosphonates in excellent yields and short reaction times. The mechanistic insights gained are important additions to the domain of allene chemistry. Addition of biologically important molecules, including monoglycerides, amino acids, and nucleosides, proves the general applicability of the developed method

Tandem Addition of Phosphite Nucleophiles Across Unsaturated Nitrogen-Containing Systems: Mechanistic Insights on Regioselectivity

The addition of phosphite nucleophiles across linear unsaturated imines is a powerful and atom-economical methodology for the synthesis of aminophosphonates. These products are of interest from both a biological and a synthetic point of view: they act as amino acid transition state analogs and Horner–Wadsworth–Emmons reagents, respectively. In this work the reaction between dialkyl trimethylsilyl phosphites and <i>α,β,γ,δ</i>-diunsaturated imines was evaluated as a continuation of our previous efforts in the field. As such, the first conjugate 1,6-addition of a phosphite nucleophile across a linear unsaturated <i>N</i>-containing system is reported herein. Theoretical calculations were performed to rationalize the observed regioselectivites and to shed light on the proposed mechanism

Compositional Characterization of Pyrolysis Fuel Oil from Naphtha and Vacuum Gas Oil

Steam cracking of crude oil fractions gives rise to substantial amounts of a heavy liquid product referred to as pyrolysis fuel oil (PFO). To evaluate the potential use of PFO for production of value-added chemicals, a better understanding of the composition is needed. Therefore, two PFO’s derived from naphtha (N-PFO) and vacuum gas oil (V-PFO) were characterized using elemental analysis, SARA fractionation, nuclear magnetic resonance (NMR) spectroscopy, and comprehensive two-dimensional gas chromatography (GC × GC) coupled to a flame ionization detector (FID) and time-of-flight mass spectrometer (TOF-MS). Both samples are highly aromatic, with molar hydrogen-to-carbon (H/C) ratios lower than 1 and with significant content of compounds with solubility characteristics typical for asphaltenes and coke (i.e. <i>n</i>-hexane insolubles). The molar H/C ratio of V-PFO is lower than the one measured for N-PFO, as expected from the lower molar H/C ratio of the VGO. On the other hand, the content of <i>n</i>-hexane insolubles is lower in V-PFO compared to the one in N-PFO (i.e., 10.3 ± 0.2 wt % and 19.5 ± 0.5 wt %, respectively). This difference is attributed to the higher reaction temperature applied during naphtha steam cracking, which promotes the formation of poly aromatic cores and at the same time scission of aliphatic chains. The higher concentrations of purely aromatic molecules present in N-PFO is confirmed via NMR and GC × GC–FID/TOF-MS. The dominant chemical family in both samples are diaromatics, with a concentration of 28.6 ± 0.1 wt % and 27.8 ± 0.1 wt % for N-PFO and V-PFO, respectively. Therefore, extraction of valuable chemical industry precursors such as diaromatics and specifically naphthalene is considered as a potential valorization route. On the other hand, hydro-conversion is required to improve the quality of the PFO’s before exploiting them as a commercial fuel