Gian Pietro Miscione

Asymmetric Phase-Transfer-Catalyzed Intramolecular N-Alkylation of Indoles and Pyrroles: A Combined Experimental and Theoretical Investigation

Asymmetric phase-transfer catalysis (PTC) has risen to prominence over the last decade as a straightforward synthetic methodology for the preparation of pharmacologically active compounds in enantiomerically pure form. However, the complex interplay of weak nonbonded interactions (between catalyst and substrate) that could account for the stereoselection in these processes is still unclear, with tentative pictorial mechanistic representations usually proposed. Here we present a full account dealing with the enantioselective phase-transfer-catalyzed intramolecular aza-Michael reaction (IMAMR) of indolyl esters, as a valuable synthetic tool to obtain added-value compounds, such as dihydro-pyrazinoindolinones. A combined computational and experimental investigation has been carried out to elucidate the key mechanistic aspects of this process.

A theoretical DFT investigation of the lysozyme mechanism: Computational evidence for a covalent intermediate pathway

A theoretical DFT(B3LYP) investigation of the catalytic cycle of lysozyme has provided further evidence for a mechanism involving a glycosil‐enzyme covalent intermediate, in agreement with recent experimental data. This type of intermediate has been located along two different pathways. Along the favored path the retention of the anomeric configuration of the peptidoglycan NAM unit involved in the reaction, is the result of two subsequent inversions at the C1 carbon. The other path involves the opening of the pyranose ring and a nucleophilic attack on the prochiral carbonyl group of the open aldehyde, restoring the original anomeric configuration. No evidence has been found for a pathway characterized by the formation of an oxocarbenium ion (stabilized by resonance and electrostatic interactions), as suggested in the most popular mechanistic schemes. Proteins 2005.

Gold(I)‐Catalyzed Dearomative [2+2]‐Cycloaddition of Indoles with Activated Allenes: A Combined Experimental–Computational Study

The gold-catalyzed synthesis of methylidene 2,3-cyclobutane-indoles is documented through a combined experimental/computational investigation. Besides optimizing the racemic synthesis of the tricyclic indole compounds, the enantioselective variant is presented to its full extent. In particular, the scope of the reaction encompasses both aryloxyallenes and allenamides as electrophilic partners providing high yields and excellent stereochemical controls in the desired cycloadducts. The computational (DFT) investigation has fully elucidated the reaction mechanism providing clear evidence for a two-step reaction. Two parallel reaction pathways explain the regioisomeric products obtained under kinetic and thermodynamic conditions. In both cases, the dearomative CC bond-forming event turned out to be the rate-determining step.

Gold(I)‐Assisted α‐Allylation of Enals and Enones with Alcohols

The intermolecular α-allylation of enals and enones occurs by the condensation of variously substituted allenamides with allylic alcohols. Cooperative catalysis by [Au(ItBu)NTf2] and AgNTf2 enables the synthesis of a range of densely functionalized α-allylated enals, enones, and acyl silanes in good yield under mild reaction conditions. DFT calculations support the role of an α-gold(I) enal/enone as the active nucleophilic species.

DFT Mechanistic Investigation of the Gold(I)-Catalyzed Synthesis of Azepino[1,2-a]indoles

We describe a computational DFT investigation on the mechanism of the one‐pot synthesis of azepino‐indoles catalyzed by [Au(IPr)Cl]/AgOTf (IPr=1,3‐bis(2,6‐diisopropylphenyl‐imidazol‐2‐ylidene) by the simultaneous construction of the pyrrolyl and seven‐membered rings. The mechanism of the final ring‐closing event is elucidated, which reveals the counterion‐assisted nucleophilic trapping of the carbonyl moiety by the alkenyl‐gold species formed in situ. The computational evidence supports the labeling control experiments and highlights the presence of a cyclopropyl‐gold‐carbenoid intermediate in the final intramolecular 1,3‐hydrogen‐shift/skeleton‐rearrangement sequence.

Electrosteric Activation by using Ion-Tagged Prolines: A Combined Experimental and Computational Investigation

We have recently proposed the empirical concept of electrosteric activation to explain the improved catalytic performances observed for a series of ion‐tagged catalysts compared to the parent tag‐free structures. Here, the results of a combined experimental and computational investigation on the asymmetric aldol reaction between cyclohexanone and benzaldehyde, catalyzed by a family of tag‐free and ionic‐tagged prolines, are presented. Whereas diastereo‐ and enantioselectivities remain very high in all cases examined, the ion‐tagged catalyst cis‐4‐(2‐(3‐methyl‐imidazol‐3‐ium‐1‐yl)acetoxy)‐proline bistriflimide, cis‐7, displays a remarkably high activity compared to its tagged trans analogue and to the tag‐free catalysts cis and trans‐4‐(2‐phenylacetoxy)‐proline 8. A computational investigation of ion‐tagged and tag‐free model systems shows that the transition state involving cis‐7 is stabilized by a complex interplay of hydrogen bonds (in particular, those involving the counter ion oxygen atoms and the hydrogen atoms of the ionic tag), π‐stacking interactions involving the aldehyde phenyl ring, and similar π interactions between the proline carboxyl group and the imidazole ring. The overall effect of these interactions accounts for the observed enhanced activity.

A theoretical investigation of the oxidation states of palladium complexes and their role in the carbonylation reaction

Two different, yet related, topics are discussed: (i) the reduction of palladium (II) in Pd(OAc)2 complexes reacting with phenyl phosphines and leading to Pd(0) phosphine complexes, and (ii) the carbonylation reaction of allyl chlorides catalyzed by these Pd(0) species. The results show that the overall reduction is an exothermic process that can be accomplished along two different reaction paths, one being clearly favoured over the other. Similarly, three different channels have been determined for the carbonylation reaction that primarily differ in the timing and the way in which the reacting species bind the metal. In the first path (the σ-path), the allyl fragment interacts very weakly with the metal, whereas the CO molecule strongly binds it and reacts with the allyl. The second channel (the π–η3 pathway) is characterized by a π–η3 interaction between the allyl fragment and the palladium, to which the CO molecule binds, before the two units react affording the product. In both cases, two consecutive migrations of the chlorine ‘assist’ the course of the reaction. In the third case (the η2 pathway) the allyl fragment initially enters the palladium coordination sphere, and the CO molecule then simultaneously binds it and the phosphorous atom of one phosphine ligand. The first two paths are favoured.

Chromium(III) complexes bearing bis(benzotriazolyl)pyridine ligands: synthesis, characterization and ethylene polymerization behavior

Abstract Reaction of benzotriazole with 2,6-bis(bromomethyl)pyridine and 2,6-pyridinedicarbonyl dichloride yields the tridentate ligands 2,6-bis(benzotriazol-1-ylmethyl)pyridine (1) and 2,6-bis(benzotriazol-1-ylcarbonyl) pyridine (2). The molecular structures of the ligands were determined by single-crystal X-ray diffraction. These ligands react with CrCl3(THF)3 in THF to form neutral complexes, [CrCl3{2,6-bis(benzotriazolyl)pyridine-N,N,N}] (3, 4), which are isolated in high yields as air stable green solids and characterized by mass spectra (ESI), FTIR spectroscopy, UV–Visible, thermogravimetric analysis (TGA), and magnetic measurements. After reaction with methylaluminoxane (MAO), the chromium(III) complexes are active in the polymerization of ethylene showing a bimodal molecular weight distribution. A DFT computational investigation of the polymerization reaction mechanism shows that the most likely reaction pathway originates from the mer configuration when the spacer is CH2 (complex 3) and from the fac configuration when the spacer is CO (complex 4).

Novel Bacterial Topoisomerase Inhibitors Exploit Asp83 and the Intrinsic Flexibility of the DNA Gyrase Binding Site

DNA gyrases are enzymes that control the topology of DNA in bacteria cells. This is a vital function for bacteria. For this reason, DNA gyrases are targeted by widely used antibiotics such as quinolones. Recently, structural and biochemical investigations identified a new class of DNA gyrase inhibitors called NBTIs (i.e., novel bacterial topoisomerase inhibitors). NBTIs are particularly promising because they are active against multi-drug resistant bacteria, an alarming clinical issue. Structural data recently demonstrated that these NBTIs bind tightly to a newly identified pocket at the dimer interface of the DNA–protein complex. In the present study, we used molecular dynamics (MD) simulations and docking calculations to shed new light on the binding of NBTIs to this site. Interestingly, our MD simulations demonstrate the intrinsic flexibility of this binding site, which allows the pocket to adapt its conformation and form optimal interactions with the ligand. In particular, we examined two ligands, AM8085 and AM8191, which induced a repositioning of a key aspartate (Asp83B), whose side chain can rotate within the binding site. The conformational rearrangement of Asp83B allows the formation of a newly identified H-bond interaction with an NH on the bound NBTI, which seems important for the binding of NBTIs having such functionality. We validated these findings through docking calculations using an extended set of cognate oxabicyclooctane-linked NBTIs derivatives (~150, in total), screened against multiple target conformations. The newly identified H-bond interaction significantly improves the docking enrichment. These insights could be helpful for future virtual screening campaigns against DNA gyrase.

Covalent or Non-Covalent? A Mechanistic Insight into the Enantioselective Brønsted Acid Catalyzed Dearomatization of Indoles with Allenamides

The reaction mechanism of the enantioselective Brønsted acid catalyzed dearomatization of C(2),C(3)‐disubstituted indoles with allenamides is investigated by means of density functional theory (DFT) calculations and ESI‐MS analysis. The first step of the process (rate‐determining step) is the formation of a covalent adduct between allenamide and the chiral organo‐promoter. The resulting chiral α‐amino allylic phosphate undergoes dearomative condensation with indoles. In the first step, the indole moiety remains bonded to the catalyst through strong hydrogen contacts. It can take on two different orientations that make the Re or Si prochiral face available to the subsequent electrophilic attack of allenamide. The attack on the indole faces originates two reaction paths leading to different stereoisomeric products, which differ in the configuration of the new stereocenter at the C3‐indole position.