Accurate and Efficient Conformer Sampling of Cyclic Drug-Like Molecules with Inverse Kinematics.

Identification of all of the influential conformers of biomolecules is a crucial step in many tasks of computational biochemistry. Specifically, molecular docking, a key component of in silico drug development, requires a comprehensive set of conformations for potential candidates in order to generate the optimal ligand-receptor poses and, ultimately, find the best drug candidates. However, the presence of flexible cycles in a molecule complicates the initial search for conformers since exhaustive sampling algorithms via torsional random and systematic searches become very inefficient. The devised inverse-kinematics-based Monte Carlo with refinement (MCR) algorithm identifies independently rotatable dihedral angles in (poly)cyclic molecules and uses them to perform global conformational sampling, outperforming popular alternatives (MacroModel, CREST, and RDKit) in terms of speed and diversity of the resulting conformer ensembles. Moreover, MCR quickly and accurately recovers naturally occurring macrocycle conformations for most of the considered molecules.

Interrupted Dance of Five Heteroatoms: Reinventing Ozonolysis to Make Geminal Alkoxyhydroperoxides from C═N Bonds.

Four heteroatoms dance in the cascade of four pericyclic reactions initiated by ozonolysis of C═N bonds. Switching from imines to semicarbazones introduces the fifth heteroatom that slows this dance, delays reaching the thermodynamically favorable escape path, and allows efficient interception of carbonyl oxides (Criegee intermediates, CIs) by an external nucleophile. The new three-component reaction of alcohols, ozone, and oximes/semicarbazones greatly facilitates synthetic access to monoperoxyacetals (alkoxyhydroperoxides).

Two-Component versus Three-Component Condensations in the Race between Hydrazide, Triketone, and Hydrogen Peroxide-How do All Six Reactive Centers Cooperate to Incorporate the Most Diverse Set of Heteroatomic Bridges in a Tricyclic Frame?

Relief of stereoelectronic frustration drives the acid-catalyzed three-component condensation of ß,δ'-triketones with hydrazides and H2O2 to the direction where both nucleophiles and all three electrophilic carbons are involved in the formation of a tricyclic sp3-rich ring system that includes four heteroatoms. The otherwise inaccessible tricyclic N-substituted aminoperoxides are prepared rapidly and selectively from relatively simple substrates in good to high yields.

Activation of O-Electrophiles via Structural and Solvent Effects: SN2@O Reaction of Cyclic Diacyl Peroxides with Enol Acetates.

The reactions of O-electrophiles, such as organic peroxides, with carbon nucleophiles are an umpolung alternative to the common approaches to C-O bond formation. Nucleophilic substitution at the oxygen atom of cyclic diacyl peroxides by enol acetates with the following deacylation leads to α-acyloxyketones with an appended carboxylic acid in 28-87% yields. The effect of fluorinated alcohols on the oxidative functionalization of enol acetates by cyclic diacyl peroxides was studied experimentally and computationally. Computational analysis reveals that the key step proceeds as a direct substitution nucleophilic bimolecular (SN2) reaction at oxygen (SN2@O). CF3CH2OH has a dual role in assisting in both steps of the reaction cascade: it lowers the energy of the SN2@O activation step by hydrogen bonding to a remote carbonyl and promotes the deacylation of the cationic intermediate.

Cascade Assembly of Bridged N-Substituted Azaozonides: The Counterintuitive Role of Nitrogen Source Nucleophilicity.

Counterintuitively, the low basicity of the NH2 group in hydrazides makes them preferred nucleophiles for the synthesis of the N-substituted azaozonides in acid-catalyzed three-component condensation with 1,5-diketones and H2O2. In the case of more basic N sources, e.g., hydrazine and primary amines, such condensation does not occur under these reaction conditions. The method can be applied to a wide range of hydrazides and affords the target bicyclic azaozonides in 27-86% yields.

Inverse α-Effect as the Ariadne's Thread on the Way to Tricyclic Aminoperoxides: Avoiding Thermodynamic Traps in the Labyrinth of Possibilities.

Stable tricyclic aminoperoxides can be selectively assembled via a catalyst-free three-component condensation of ß,δ'-triketones, H2O2, and an NH-group source such as aqueous ammonia or ammonium salts. This procedure is scalable and can produce gram quantities of tricyclic heterocycles, containing peroxide, nitrogen, and oxygen cycles in one molecule. Amazingly, such complex tricyclic molecules are selectively formed despite the multitude of alternative reaction routes, via equilibration of peroxide, hemiaminal, monoperoxyacetal, and peroxyhemiaminal functionalities! The reaction is initiated by the "stereoelectronic frustration" of H2O2 and combines elements of thermodynamic and kinetic control with a variety of mono-, bi-, and tricyclic structures evolving under the conditions of thermodynamic control until they reach a kinetic wall created by the inverse α-effect, that is, the stereoelectronic penalty for the formation of peroxycarbenium ions and related transition states. Under these conditions, the reaction stops before reaching the most thermodynamically stable products at a stage where three different heterocycles are assembled and fused at the acyclic precursor frame.

Correction: Stereoelectronic power of oxygen in control of chemical reactivity: the anomeric effect is not alone.

Correction for 'Stereoelectronic power of oxygen in control of chemical reactivity: the anomeric effect is not alone' by Igor V. Alabugin et al., Chem. Soc. Rev., 2021, DOI: 10.1039/d1cs00386k.

Anomeric effect, hyperconjugation and electrostatics: lessons from complexity in a classic stereoelectronic phenomenon.

Understanding the interplay of multiple components (steric, electrostatic, stereoelectronic, dispersive, etc.) that define the overall energy, structure, and reactivity of organic molecules can be a daunting task. The task becomes even more difficult when multiple approaches based on different physical premises disagree in their analysis of a multicomponent molecular system. Herein, we will use a classic conformational "oddity", the anomeric effect, to discuss the value of identifying the key contributors to reactivity that can guide chemical predictions. After providing the background related to the relevant types of hyperconjugation and a brief historic outline of the origins of the anomeric effect, we outline variations of its patterns and provide illustrative examples for the role of the anomeric effect in structure, stability, and spectroscopic properties. We show that the complete hyperconjugative model remains superior in explaining the interplay between structure and reactivity. We will use recent controversies regarding the origin of the anomeric effect to start a deeper discussion relevant to any electronic effect. Why are such questions inherently controversial? How to describe a complex quantum system using a model that is "as simple as possible, but no simpler"? What is a fair test for such a model? Perhaps, instead of asking "who is right and who is wrong?" one should ask "why do we disagree?". Stereoelectronic thinking can reconcile quantum complexity with chemical intuition and build the conceptual bridge between structure and reactivity. Even when many factors contribute to the observed structural and conformational trends, electron delocalization is a dominating force when the electronic demand is high (i.e., bonds are breaking as molecules distort from their equilibrium geometries). In these situations, the role of orbital interactions increases to the extent where they can define reactivity. For example, negative hyperconjugation can unleash the "underutilized" stereoelectronic power of unshared electrons (i.e., the lone pairs) to stabilize a developing positive charge at an anomeric carbon. This analysis paves the way for the broader discussion of the omnipresent importance of negative hyperconjugation in oxygen-containing functional groups. From that point of view, the stereoelectronic component of the anomeric effect plays a unique role in guiding reaction design.

Stereoelectronic power of oxygen in control of chemical reactivity: the anomeric effect is not alone.

Although carbon is the central element of organic chemistry, oxygen is the central element of stereoelectronic control in organic chemistry. Generally, a molecule with a C-O bond has both a strong donor (a lone pair) and a strong acceptor (e.g., a σ*C-O orbital), a combination that provides opportunities to influence chemical transformations at both ends of the electron demand spectrum. Oxygen is a stereoelectronic chameleon that adapts to the varying situations in radical, cationic, anionic, and metal-mediated transformations. Arguably, the most historically important stereoelectronic effect is the anomeric effect (AE), i.e., the axial preference of acceptor groups at the anomeric position of sugars. Although AE is generally attributed to hyperconjugative interactions of σ-acceptors with a lone pair at oxygen (negative hyperconjugation), recent literature reports suggested alternative explanations. In this context, it is timely to evaluate the fundamental connections between the AE and a broad variety of O-functional groups. Such connections illustrate the general role of hyperconjugation with oxygen lone pairs in reactivity. Lessons from the AE can be used as the conceptual framework for organizing disjointed observations into a logical body of knowledge. In contrast, neglect of hyperconjugation can be deeply misleading as it removes the stereoelectronic cornerstone on which, as we show in this review, the chemistry of organic oxygen functionalities is largely based. As negative hyperconjugation releases the "underutilized" stereoelectronic power of unshared electrons (the lone pairs) for the stabilization of a developing positive charge, the role of orbital interactions increases when the electronic demand is high and molecules distort from their equilibrium geometries. From this perspective, hyperconjugative anomeric interactions play a unique role in guiding reaction design. In this manuscript, we discuss the reactivity of organic O-functionalities, outline variations in the possible hyperconjugative patterns, and showcase the vast implications of AE for the structure and reactivity. On our journey through a variety of O-containing organic functional groups, from textbook to exotic, we will illustrate how this knowledge can predict chemical reactivity and unlock new useful synthetic transformations.

Marriage of Peroxides and Nitrogen Heterocycles: Selective Three-Component Assembly, Peroxide-Preserving Rearrangement, and Stereoelectronic Source of Unusual Stability of Bridged Azaozonides.

Stable bridged azaozonides can be selectively assembled via a catalyst-free three-component condensation of 1,5-diketones, hydrogen peroxide, and an NH-group source such as aqueous ammonia or ammonium salts. This procedure is scalable and can produce gram quantities of bicyclic stereochemically rich heterocycles. The new azaozonides are thermally stable and can be stored at room temperature for several months without decomposition and for at least 1 year at -10 °C. The chemical stability of azaozonides was explored for their subsequent selective transformations including the first example of an aminoperoxide rearrangement that preserves the peroxide group. The amino group in aminoperoxides has remarkably low nucleophilicity and does not participate in the usual amine alkylation and acylation reactions. These observations and the 15 pKa units decrease in basicity in comparison with a typical dialkyl amine are attributed to the strong hyperconjugative nN→σ*C-O interaction with the two antiperiplanar C-O bonds. Due to the weakness of the complementary nO→σ*C-N donation from the peroxide oxygens (a consequence of "inverse α-effect"), this interaction depletes electron density from the NH moiety, protects it from oxidation, and makes it similar in properties to an amide.

How to Build Rigid Oxygen-Rich Tricyclic Heterocycles from Triketones and Hydrogen Peroxide: Control of Dynamic Covalent Chemistry with Inverse α-Effect.

We describe an efficient one-pot procedure that "folds" acyclic triketones into structurally complex, pharmaceutically relevant tricyclic systems that combine high oxygen content with unusual stability. In particular, ß,γ'-triketones are converted into three-dimensional polycyclic peroxides in the presence of H2O2 under acid catalysis. These transformations are fueled by stereoelectronic frustration of H2O2, the parent peroxide, where the lone pairs of oxygen are not involved in strongly stabilizing orbital interactions. Computational analysis reveals how this frustration is relieved in the tricyclic peroxide products, where strongly stabilizing anomeric nO→σC-O* interactions are activated. The calculated potential energy surfaces for these transformations combine labile, dynamically formed cationic species with deeply stabilized intermediate structures that correspond to the introduction of one, two, or three peroxide moieties. Paradoxically, as the thermodynamic stability of the peroxide products increases along this reaction cascade, the kinetic barriers for their formation increase as well. This feature of the reaction potential energy surface, which allows separation of mono- and bis-peroxide tricyclic products, also explains why formation of the most stable tris-peroxide is the least kinetically viable and is not observed experimentally. Such unique behavior can be explained through the "inverse α-effect", a new stereoelectronic phenomenon with many conceptual implications for the development of organic functional group chemistry.