Stereoelectronic Features of a Complex Ketene Dimerization Reaction

The amidation reaction of a tetrahydroisoquinolin-1-one-4-carboxylic acid is a key step in the multi-kilogram-scale preparation of the antimalarial drug SJ733, now in phase 2 clinical trials. In the course of investigating THIQ carboxamidations, we found that propanephosphonic acid anhydride (T3P) is an effective reagent, although the yield and byproducts vary with the nature and quantity of the base. As a control, the T3P reaction of a 3-(2-thienyl) THIQ was performed in the absence of the amine, and the products were characterized: among them are three dimeric allenes and two dimeric lactones. A nucleophile-promoted ketene dimerization process subject to subtle steric and stereoelectronic effects accounts for their formation. Two novel monomeric products, a decarboxylated isoquinolone and a purple, fused aryl ketone, were also isolated, and mechanisms for their formation from the ketene intermediate are proposed.

Evaluating the Efficiency of the Martini Force Field to Study Protein Dimerization in Aqueous and Membrane Environments

<p>Protein-protein complex assembly is one of the major drivers of biological response. Understanding the mechanisms of protein oligomerization/dimerization would allow one to elucidate how these complexes participate in biological activities and could ultimately lead to new approaches in designing novel therapeutic agents. However, determining the exact association pathways and structures of such complexes remains a challenge. Here, we use parallel tempering metadynamics simulations in the well-tempered ensemble to evaluate the performance of Martini 2.2P and Martini open-beta 3 (Martini 3) force fields in reproducing the structure and energetics of the dimerization process of membrane proteins and proteins in an aqueous solution in reasonable accuracy and throughput. We find that Martini 2.2P systematically overestimates the free energy of association by estimating large barriers in distinct areas, which likely leads to overaggregation when multiple monomers are present. In comparison, the less viscous Martini 3 results in a systematic underestimation of the free energy of association for proteins in solution, while it performs well in describing the association of membrane proteins. In all cases the near-native dimer complexes are identified as minima in the free energy surface albeit not always as the lowest minima. In the case of Martini 3 we find that the spurious supramolecular protein aggregation present in Martini 2.2P multimer simulations is alleviated and thus this force field may be more suitable for the study of protein oligomerization. We propose that the use of enhanced sampling simulations with a refined coarse-grained force field and appropriately defined collective variables is a robust approach for studying the protein dimerization process, although one should be cautious of the ranking of energy minima.</p>

Evaluating the Efficiency of the Martini Force Field to Study Protein Dimerization in Aqueous and Membrane Environments

<p>Protein-protein complex assembly is one of the major drivers of biological response. Understanding the mechanisms of protein oligomerization/dimerization would allow one to elucidate how these complexes participate in biological activities and could ultimately lead to new approaches in designing novel therapeutic agents. However, determining the exact association pathways and structures of such complexes remains a challenge. Here, we use parallel tempering metadynamics simulations in the well-tempered ensemble to evaluate the performance of Martini 2.2P and Martini open-beta 3 (Martini 3) force fields in reproducing the structure and energetics of the dimerization process of membrane proteins and proteins in an aqueous solution in reasonable accuracy and throughput. We find that Martini 2.2P systematically overestimates the free energy of association by estimating large barriers in distinct areas, which likely leads to overaggregation when multiple monomers are present. In comparison, the less viscous Martini 3 results in a systematic underestimation of the free energy of association for proteins in solution, while it performs well in describing the association of membrane proteins. In all cases the near-native dimer complexes are identified as minima in the free energy surface albeit not always as the lowest minima. In the case of Martini 3 we find that the spurious supramolecular protein aggregation present in Martini 2.2P multimer simulations is alleviated and thus this force field may be more suitable for the study of protein oligomerization. We propose that the use of enhanced sampling simulations with a refined coarse-grained force field and appropriately defined collective variables is a robust approach for studying the protein dimerization process, although one should be cautious of the ranking of energy minima.</p>

BODIPY dimers: structure, interaction, and absorption spectrum

The object of the present study are BODIPY molecules obtained previously by Piskorz et al. (Dyes Pigm. 178:108322, 2020) for their antimicrobial activity. Structural analysis of the BODIPY dimers is presented in context of the aggregation influence on the photophysical properties. The thorough investigation of the nature of intermolecular interaction in the representative BODIPY dimers is provided together with the decomposition of the interaction energy into the components of well-defined origin according to SAPT procedure. For the model BODIPY systems the careful examination of the interaction nature for the dimer structure based on experimental crystal study as well as fully optimized is given. The tendencies observed in the model dimers are further on investigated for two pairs of BODIPY systems designed for biomedical application. The analyzed molecules are shown to maximize the mutual interaction by the optimization of the stacking dispersion contacts between the aromatic rings of the molecules, therefore producing stable dimers. The estimation of SAPT0 interaction energy components confirms the dominating dispersion character arising from mutual BODIPY core contacts. The influence of the dimerization process on the photophysical properties of the systems studied theoretically depends to the high extend on the dimerization mode and is significant for parallel and antiparallel dispersion-governed dimers.

Generation and trapping of electron-deficient 1,2-cyclohexadienes. Unexpected hetero-Diels–Alder reactivity

Keto-substituted 1,2-cyclohexadienes undergo a novel dimerization process and can be trapped with various furan-based 1,3-dienes or enamine dienophiles.

A 1,5-Oligosilanylene Dianion as Building Block for Oligosiloxane Containing Cages, Ferrocenophanes, and Cyclic Germylenes and Stannylenes

Starting out from dipotassium 1,5-oligosiloxanylene diide 2, a 3,7,10-trioxa-octasilabicyclo[3.3.3]undecane was prepared, which represents the third known example of this cage structure type. Reaction of 1,3-dichlorotetramethyldisiloxane with 1,1’-bis[bis(trimethylsilyl)potassiosilyl]ferrocene gave a ferrocenophane with a disiloxane containg bridge. The compound can be further derivatized by conversion into a 1,5-oligosilanyl diide. Reacting 1,5-oligosiloxanylene diide 2 with SnCl2 or GeCl2·dioxane in the presence of PMe3 gave cyclic disilylated tetrylene PMe3 adducts. Release of the base-free stannylene led to a dimerization process which gave a bicyclic distannene as the final product. Abstraction of the PMe3 from the cyclic disilylated germylene PMe3 adduct with B(C6F5)3 caused oxidative addition of the germylene into a para-C-F bond of Me3P·B(C6F5)3.