Saturated N-heterocycles are prevalent in biologically active molecules and are increasingly attractive scaffolds in the development of new pharmaceuticals. Unlike their aromatic counterparts, there are limited strategies for facile construction of substituted saturated N-heterocycles by convergent, predictable methods. In this Synopsis, we discuss recent advances in the synthesis of these compounds, focusing on approaches that offer generality and convenience from widely available building blocks.

Interest in saturated N-heterocycles as scaffolds for the synthesis of bioactive molecules is increasing. Reliable and predictable synthetic methods for the preparation of these compounds, especially medium-sized rings, are limited. We describe the development of SnAP (Sn amino protocol) reagents for the transformation of aldehydes into seven-, eight- and nine-membered saturated N-heterocycles. This process occurs under mild, room-temperature conditions and offers exceptional substrate scope and functional-group tolerance. Air- and moisture-stable SnAP reagents are prepared on a multigram scale from inexpensive starting materials by simple reaction sequences. These new reagents and processes allow widely available aryl, heteroaryl and aliphatic aldehydes to be converted into diverse N-heterocycles, including diazepanes, oxazepanes, diazocanes, oxazocanes and hexahydrobenzoxazonines, by a single synthetic operation.

Substituted piperazines and morpholines are valuable structural motifs in biologically active compounds, but are not easily prepared by contemporary cross-coupling approaches. In this report, we introduce SnAP reagents for the transformation of aldehydes into N-unprotected piperazines and morpholines. This approach offers simple, mild conditions compatible with aromatic, heteroaromatic, aliphatic, and glyoxylic aldehydes and provides mono- and disubstituted N-heterocycles in a single step.

It's a SnAP! The transformation of aldehydes into N‐unsubstituted 3‐thiomorpholines provides a convenient alternative to metal‐catalyzed cross‐coupling reactions, which are generally unsuited to the functionalization of saturated N‐heterocycles. A copper‐mediated radical cyclization is the key to the mild conditions, high functional group tolerance, and broad substrate scope offered by these reagents.

Mixed acetals and organotrifluoroborates undergo BF3•OEt2 promoted cross-couplings to give dialkyl ethers under simple, mild conditions. A survey of reaction partners identified a hydroxamate leaving group that improves the regioselectivity and product yield in the BF3•OEt2-promoted coupling reaction of mixed acetals and potassium alkynyl-, alkenyl-, aryl- and heteroaryltrifluoroborates to access substituted dialkyl ethers. This leaving group enables reaction to proceed rapidly under mild conditions (0 °C, 5–60 min) and permits reactions with electron-deficient potassium aryltrifluoroborates that were less reactive with other acetal substrates. A study of the reaction mechanism and characterization of key intermediates by NMR and X-ray crystallography identified a role for the hydroxamate moiety as a reversible leaving group that serves to stabilize the key oxocarbenium intermediate and the need for a slight excess of organodifluoroborane to serve as a catalyst. A secondary role as an activating ligand for the boron nucleophile is also considered. These studies provide the basis for a general class of reagents that lead to dialkyl ethers by a simple, predictable cross-coupling reaction.

Inhibition of human pancreatic lipase, a crucial enzyme in dietary fat digestion and absorption, is a potent therapeutic approach for obesity treatment. In this study, human pancreatic lipase inhibitory activity of aurone derivatives was explored by molecular modeling approaches. The target protein was human pancreatic lipase (PDB ID: 1LPB). The 3D structures of 82 published bioactive aurone derivatives were docked successfully into the protein catalytic active site, using AutoDock Vina 1.5.7.rc1. Of them, 62 compounds interacted with the key residues of catalytic trial Ser152-Asp176-His263. The top hit compound (A14), with a docking score of −10.6 kcal⋅mol−1, was subsequently submitted to molecular dynamics simulations, using GROMACS 2018.01. Molecular dynamics simulation results showed that A14 formed a stable complex with 1LPB protein via hydrogen bonds with important residues in regulating enzyme activity (Ser152 and Phe77). Compound A14 showed high potency for further studies, such as the synthesis, in vitro and in vivo tests for pancreatic lipase inhibitory activity.

The main protease 3CL pro is one of the potential targets against coronavirus. Inhibiting this enzyme leads to the interruption of viral replication. Chalcone and its derivatives were reported to possess the ability to bind to 3CL pro protease in the binding pocket. This study explored an in-house database of 269 chalcones as 3CL pro inhibitors using in silico screening models, including molecular docking, molecular dynamics simulation, binding free energy calculation, and ADME prediction. C264 and C235 stand out as the two most potential structures. The top hit compound C264 was with the Jamda score of −2.8329 and the MM/GBSA binding energy mean value of −28.23 ± 3.53 kcal/mol, which was lower than the reference ligand. Despite the lower mean binding energy (−22.07 ± 3.39 kcal/mol), in-depth analysis of binding interaction suggested C235 could be another potential candidate. Further, in vitro and in vivo experiments are required to confirm the inhibitory ability. Supplementary Information The online version contains supplementary material available at 10.1007/s11224-022-02000-3.

Die Umwandlung von Aldehyden in N‐unsubstituierte 3‐Thiomorpholine bildet eine einfache Alternative zu metallkatalysierten Kreuzkupplungen, die zur Funktionalisierung gesättigter N‐Heterocyclen im Allgemeinen ungeeignet sind. Eine kupfervermittelte radikalische Cyclisierung ist der Schlüssel für die milden Bedingungen, die hohe Verträglichkeit mit funktionellen Gruppen und den großen Substratbereich, den diese Reagentien bieten.