Stereoselective Reductions of 3-Substituted Cyclobutanones: A Comparison between Experiment and Theory.

The stereoselective reduction of carbonyls is of key importance in the total synthesis of natural products and in medicinal chemistry. Nevertheless, models for rationalizing the stereoselectivity of the hydride reductions of cyclobutanones toward cyclobutanols are largely lacking, unlike cyclohexanone reductions. In order to elucidate the factors that control the stereoselectivity of these reductions, we have investigated the effect of the reaction temperature, solvent, substituent, and type of reducing agent using a synergistic experimental-computational approach. On the experimental side, the hydride reduction of 3-substituted cyclobutanones was proven to be highly selective for the formation of cis alcohol (>90%), irrespective of the size of the hydride reagent. The pronounced selectivity can be further enhanced by lowering the reaction temperature or decreasing the solvent polarity. On the computational side, density functional theory and noncovalent interaction analysis reveal that torsional strain plays a major role in the preference for the antifacial hydride approach, consistent with the Felkin-Anh model. In the presence of the benzyloxy substituent, the high selectivity for the cis isomer is also driven by repulsive electrostatic interactions in the case of a syn-facial hydride attack. The computed cis/trans ratios are in good agreement with the experimental ones and thus show the potential of computational chemistry for predicting and rationalizing the stereoselectivity of hydride reductions of cyclobutanones.

Correction: SuFEx-enabled, chemoselective synthesis of triflates, triflamides and triflimidates.

[This corrects the article DOI: 10.1039/D1SC06267K.].

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 SVI-F connector with a S[double bond, length as m-dash]O → S[double bond, length as m-dash]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.

Developments in the Discovery and Design of Protein Kinase D Inhibitors.

Protein kinase D (PKD) is a serine/threonine kinase family belonging to the Ca2+/calmodulin-dependent protein kinase group. Since its discovery two decades ago, many efforts have been put in elucidating PKD's structure, cellular role and functioning. The PKD family consists of three highly homologous isoforms: PKD1, PKD2 and PKD3. Accumulating cell-signaling research has evidenced that dysregulated PKD plays a crucial role in the pathogenesis of cardiac hypertrophy and several cancer types. These findings led to a broad interest in the design of small-molecule protein kinase D inhibitors. In this review, we present an extensive overview on the past and recent advances in the discovery and development of PKD inhibitors. The focus extends from broad-spectrum kinase inhibitors used in PKD signaling experiments to intentionally developed, bioactive PKD inhibitors. Finally, attention is paid to PKD inhibitors that have been identified as an off-target through large kinome screening panels.