Stabilization of 3-Helices in Macrocycles Using Dominant Rotor Methodology.

Stabilization of biologically relevant structural motifs has been a long-standing challenge. Here we show that atropisomeric dominant rotors can stabilize rare 3-helices in macrocycles. The target molecules were prepared using solid-phase peptide synthesis and subjected to extensive structural analysis.

Cell penetration of oxadiazole-containing macrocycles.

Passive membrane permeability is an important property in drug discovery and biological probe design. To elucidate the cell-penetrating ability of oxadiazole-containing (Odz) peptides, we employed the Chloroalkane Penetration Assay. The present study demonstrates that Odz cyclic peptides can be highly cell-penetrant depending on the position of specific side chains and the chloroalkane tag.

Identification of "Structural Pin" Interactions and their Significance for the Conformational Control of Macrocyclic Scaffolds.

While peptide macrocycles with rigidified conformations have proven to be useful in the design of chemical probes of protein targets, conformational flexibility and rapid interconversion can be equally vital for biological activity and favorable physicochemical properties. This study introduces the concept of "structural pin", which describes a hydrogen bond that is largely responsible for stabilizing the entire macrocycle backbone conformation. Structural analysis of macrocycles using nuclear magnetic resonance (NMR), molecular modelling and X-ray diffraction indicates that disruption of the structural pin can drastically influence the conformation of the entire ring, resulting in novel states with increased flexibility.

A Boron Scan of Ethyl Acetoacetate Leads to Versatile Building Blocks.

Discovered in the 19th century, ethyl acetoacetate has been central to the development of organic chemistry, including its pedagogy and applications. In this study, we present borylated derivatives of this venerable molecule. A boron handle has been installed at either - or -position of acetoacetate by homologation of acyl-MIDA (N-methyliminodiacetic acid) boronates with diazoacetates.

The Role of Attractive Non-Covalent Interactions in Peptide Macrocyclization.

The efficiency of macrocyclization reactions relies on the appropriate conformational preorganization of a linear precursor, ensuring that reactive ends are in spatial proximity prior to ring closure. Traditional peptide cyclization approaches that reduce the extent of terminal ion pairing often disfavor cyclization-conducive conformations and can lead to undesired cyclodimerization or oligomerization side reactions, particularly when they are performed without high dilution. To address this challenge, synthetic strategies that leverage attractive noncovalent interactions, such as zwitterionic attraction between chain termini during macrocyclization, offer a potential solution by reducing the entropic penalty associated with linear peptides adopting precyclization conformations.

Nitrilium ion trapping as a strategy to access structurally diverse heterobiaryl-containing peptide macrocycles.

Biaryl and heterobiaryl-containing cyclic peptides represent promising scaffolds for the development of bioactive molecules. The incorporation of heterobiaryl motifs continues to pose synthetic challenges, which is partially due to the difficulties in effecting late-stage metal-catalyzed cross-couplings. We report a new strategy to form heterobiaryls that is based on trapping nitrilium ions.

Teraryl Braces in Macrocycles: Synthesis and Conformational Landscape Remodeling of Peptides.

The three-dimensional structure of medium-sized cyclic peptides accounts for their biological activity and other important physiochemical properties. Despite significant advances in the past few decades, chemists' ability to fine-tune the structure, in particular, the backbone conformation, of short peptides made of canonical amino acids is still quite limited. Nature has shown that cross-linking the aromatic side chains of linear peptide precursors via enzyme catalysis can generate cyclophane-braced products with unusual structures and diverse activities.

β-Boron Effect Enables Regioselective and Stereospecific Electrophilic Addition to Alkenes.

Electrophilic addition to alkenes is a textbook-taught reaction, yet it is not always possible to control the regioselectivity of addition to unsymmetrical 1,2-disubstituted substrates. We report the observation and applications of the β-boron effect that accounts for high regioselectivity in electrophilic addition reactions to allylic MIDA (-methyliminodiacetic acid) boronates. While the well-established β-silicon effect bears partial resemblance to the observed reactivity, the silyl group is typically lost during functionalization.

A focus on the discovery of potent and selective cyclic peptide scaffolds for drug development.

In the past, cyclic peptide drugs were commonly discovered by isolation of natural products. However, recent efforts predominantly use high-throughput synthetic or genetically encoded libraries to find potent and selective hits against a range of challenging therapeutic targets. Kawamura (, 2022, , 3256-3262, https://doi.

Iminologous epoxide ring-closure.

The discovery of new reactions enables chemists to attain a better understanding of fundamental chemical reactivity and push the boundaries of organic synthesis. Our understanding and manipulation of high-energy states such as reactive conformations, intermediates, and transition structures contribute to this field. Herein we interrogate epoxide ring-closure by inserting the C[double bond, length as m-dash]N functionality into a well-known precursor to nucleophilic epoxide ring-closure.

Single Atom Ring Contraction of Peptide Macrocycles Using Cornforth Rearrangement.

Site-selective transformations of densely functionalized scaffolds have been a topic of intense interest in chemical synthesis. Herein we have repurposed the rarely used Cornforth rearrangement as a tool to effect a single-atom ring contraction in cyclic peptide backbones. Investigations into the kinetics of the rearrangement were carried out to understand the impact of electronic factors, ring size, and linker type on the reaction efficiency.

Navigating complex peptide structures using macrocycle conformational maps.

Identification of turn motifs that are stabilized by intramolecular hydrogen bonds can be useful in describing the conformation of peptide systems. However, this approach is somewhat insufficient for cyclic peptides because peptide regions that are not positioned within a hydrogen bond can be left with no description. Furthermore, non-regular secondary structures and other rarely-observed conformations can be left without detailed evaluation.

Property-Driven Development of Passively Permeable Macrocyclic Scaffolds Using Heterocycles.

Passive membrane permeability is a fundamental challenge in the development of bioactive macrocycles. To achieve this objective, chemists have resorted to various strategies, the most common of which is deployment of N-methylated amino acids and/or D-amino acids. Here we investigate the effect of heterocyclic grafts on the passive membrane permeability of macrocycles and report the structural consequences of iterative amino acid replacement by azole rings.

Improving the Kumada Catalyst Transfer Polymerization with Water-Scavenging Grignard Reagents.

Conjugated polymers have received widespread interest as optoelectronic materials. Recently, these macromolecules have been adopted for biologically relevant applications, such as sensors, imaging agents, and drug delivery vectors. A major limitation of the chemistry used to prepare these classes of compounds is that the resultant polymers themselves are not tolerant to water or are not inherently water-soluble.

Towards depeptidized aminoboronic acid derivatives through the use of borylated iminium ions.

Herein, we use α-boryl iminium intermediates to access progressively depeptidized branched β-aminoboronic acids that are functionalized with biologically relevant heterocycles. We investigate the interaction of these novel compounds with carbohydrates under physiological conditions and demonstrate their potential as synthetic building blocks.

Synthesis and Application of Constrained Amidoboronic Acids Using Amphoteric Boron-Containing Building Blocks.

Amidoboronic acid-containing peptidomimetics are an important class of scaffolds in chemistry and drug discovery. Despite increasing interest in boron-based enzyme inhibitors, constrained amidoboronic acids have received little attention due to the limited options available for their synthesis. We describe a new methodology to prepare both α- and β-amidoboronic acids that impose restrictions on backbone angles.

α-Aminoboronates: recent advances in their preparation and synthetic applications.

α-Aminoboronic acids and their derivatives are useful as bioactive agents. Thus far, three compounds containing an α-aminoboronate motif have been approved by the Food and Drug Administration (FDA) as protease inhibitors, and more are currently undergoing clinical trials. In addition, α-aminoboronic acids and their derivatives have found applications in organic synthesis, as α-aminomethylation reagents for the synthesis of chiral nitrogen-containing molecules, as nucleophiles for preparing valuable vicinal amino alcohols, and as bis-nucleophiles in the construction of valuable small molecule scaffolds.

Interrupted reactions in chemical synthesis.

Interrupted reactions reroute established processes to new and often unanticipated end points. Of particular interest are the cases in which a known reactive intermediate takes on a new reaction pathway, either because this pathway is lower in energy or because the conventional pathway is no longer available. Through analysis of documented cases, we aim to dissect the known interrupted reactions and trace their mechanistic origins.

Acyl metalloids: conformity and deviation from carbonyl reactivity.

Once considered as mere curiosities, acyl metalloids are now recognized for their utility in enabling chemical synthesis. This perspective considers the reactivity displayed by acylboron, -silicon, -germanium, and tellurium species. By highlighting the role of these species in various transformations, we demonstrate how differences between the comprising elements result in varied reaction outcomes.

Synthetic half-reactions.

This perspective on reactivity introduces Synthetic Half-Reactions (SHRs) as a way to analyze chemical transformations. SHRs denote either an uphill transformation leading to a higher energy state or a downhill transformation leading to a lower energy state. Using well-established processes, I show how the matching of different classes of SHRs offers a tool to classify chemical transformations.

Synthesis of Fluorinated Aminoalkylboronic Acids from Amphoteric α-Boryl Aldehydes.

Our ongoing search for underdeveloped functional group combinations has brought to light α-fluorinated aminoalkylboronic acids, a new class of molecules featuring the B-CF linkage. These compounds can now be generated from secondary amines and α-boryl aldehydes through electrophilic fluorination of boryl enamines or enamides. Fluorinated β-aminoalkylboronic acids show no signs of degradation under ambient conditions.

Acylboronates in Polarity-Reversed Generation of Acyl Palladium(II) Intermediates.

We report a catalytic cross-coupling process between aryl (pseudo)halides and boron-based acyl anion equivalents. This mode of acylboronate reactivity represents polarity reversal, which is supported by the observation of tetracoordinated boronate and acyl palladium(II) species by B, P NMR, and mass spectrometry. A broad scope of aliphatic and aromatic acylboronates has been examined, as well as a variety of aryl (pseudo)halides.

Two-Dimensional Barriers for Probing Conformational Shifts in Macrocycles.

We describe the development and use of composite two-dimensional barriers in macrocyclic backbones. These tunable constructs derive their mode of action from heterocyclic rearrangements. The Boulton-Katritzky reaction has been identified as a particularly versatile means to effect a composite barrier, allowing the examination of the influence of heterocycle translocation on conformation.

Illuminating the dark conformational space of macrocycles using dominant rotors.

Three-dimensional conformation is the primary determinant of molecular properties. The thermal energy available at room temperature typically equilibrates the accessible conformational states. Here, we introduce a method for isolating unique and previously understudied conformations of macrocycles.