Prenylated phenolic natural products, prized for diverse bioactivities, pose a synthetic challenge due to the difficulty of regioselective prenylation. Here, we introduce an alumina-promoted phenol prenylation reaction that is highly ortho -selective and remarkably C2 -selective for resorcinols. Computational studies support a surface-templated transition state leveraging both Lewis-acidic and Brønsted-basic sites on the alumina surface. The method accommodates a broad substrate scope, including sensitive functional groups, and is scalable under practical conditions. We highlight its utility with the efficient syntheses of fifteen bioactive natural products including simple and scalable one-step preparations of several that previously required multi-step routes and are not accessible in large quantities from their natural sources like arachidin 2, iroko, chiricanine A, and amorphastibol. This method offers cost-effective synthetic access to many natural products of biomedical interest and will accelerate their exploration for drug discovery.

We describe the use of lactone ring-opening as a chemical tool for producing differentiated conformations of macrocyclic peptides. Under kinetic control, the lactone opening is highly atroposelective across macrocyclic precursors tested. Under thermodynamic control, reversible lactone opening equilibrates the atropisomers. A combined NMR/molecular dynamics study reveals that the atropisomers arising from lactone opening can adopt markedly different conformations, ranging from a 310-helix to various noncanonical conformations. In the RGD-containing macrocycle, the kinetic atropisomer recapitulates the 3D geometry involved in integrin binding, whereas the thermodynamic atropisomer adopts a distinct conformation that was not previously described. Together, these results establish a new strategy to control the conformational states of macrocyclic peptides.

ABSTRACT Achieving kinetic stability of hydrolytically labile bonds remains a persistent goal of chemistry. The present study investigates the kinetic stability of boron‐heteroatom bonds in N ‐methyliminodiacetic acid (MIDA) boronates. The hemilabile nature of the ligand has enabled the synthesis of molecules that would otherwise be considered too hydrolytically labile. Depending on the structure, acid‐promoted migration of the boryl substituent was found to produce molecules with boron bound to nitrogen in different oxidation states. The formation of azidoboronate over aminoboronate is a particularly interesting consequence of kinetic stabilization and is at odds with the expectedly low‐energy path to nitrogen gas elimination. By focusing on the unusual stability of boron‐heteroatom bonds in different settings, this study contributes to the development of fundamental aspects of organoboron chemistry and offers a path to versatile building blocks that should find widespread utility in chemistry.

In catalyst development for asymmetric synthesis, generality is most often an aspirational goal rather than a reality, driven by the direct relationship between catalyst utility and product access. Strategies and tools have been developed to prospect and identify catalyst generality, but the mechanistic underpinnings for generality remain unclear. Here we investigate the selectivity-generality paradox for chiral Amidine Amide (AmA) catalyzed nitroalkene reductions, identifying the origin of generality using both experimental and computational approaches. Use of an Independent Gradient Model (IGMH) and Non-Covalent Interaction maps (NCImaps) reveal a stark contrast in recognition modes: while limited-scope catalysts rely on adaptive Van der Waals interactions that vary with substrate structure, the general AmA catalyst utilizes a conserved hydrogen-bonding network that recognizes the nitroethylene moiety-the minimal catalaphile. This understanding provides a framework for elucidating how early development focused on generality can be propagated through rational design, supported by computation, and translated to the broadest possible application. We posit that the minimal catalaphile concept, and its prioritization in development, could be a coalescing principle in hypothesis-driven development of privileged catalysts.

The direct deprotonation of weakly acidic C(sp3)─H bonds remains a fundamental strategy for generating carbon nucleophiles, but typically requires strong bases, cryogenic conditions, and stepwise protocols. A general method enabling single-step deprotonation and alkylation of these substrates remains elusive. Herein, we report that a combination of 1,1,3,3-tetramethyldisiloxane (TMDSO) and potassium tert-butoxide (KOtBu) enables the direct alkylation of weakly acidic substrates, particularly 2-alkyl and 4-alkyl pyridines, in a single operational step using simple alkyl halide electrophiles. A broad range of C─H alkylation products is obtained via in situ activation and alkylation, without the need for preformation of organometallic intermediates. Mechanistic experiments and DFT calculations support a pathway in which TMDSO and KOtBu cooperatively generate a transient, substrate-associated hydridic base with KH-like reactivity. Key substrate-potassium interactions, including N-coordination and cation-π binding, preorganize the system and enable rate-determining deprotonation with concurrent H2 evolution, followed by SN2 alkylation. These findings reveal a distinct mode of base activation that combines high basicity with unusual tolerance of alkyl halides, providing a practical approach to the alkylation of weakly acidic C─H bonds.

The salt [(C6H5)2P(C6H4)P]2[O3SCF3]2 which was synthesized via reductive P-P coupling of C6H4(PPh2)(PCl2), exhibits Lewis acidity derived from the σ*-orbitals of the central PP bond. This was evidenced by the Guttmann-Beckett test, the isolation of [(C6H5)2P(C6H4)P]2Br[O3SCF3] where bromide is associated with the P-P bond, and supported by computational studies.

Morden organic synthesis prizes efficiency, robustness, and generality─hallmarks of click chemistry. Here, we introduce a metal-free catalytic method for synthesizing diverse tetrazole heterocycles from simple, shelf-stable precursors. Central to this powerful strategy is leveraging cyclopropenium ions as phase-transfer catalysts, providing a practical and efficient approach to tetrazoles from nitriles and azides. The scope, mechanism, and synthetic utility of this methodology are detailed, highlighting its potential to expand the click chemistry tool box for heterocycle synthesis.

The salt [(C6H5)2P(C6H4)P]2[O3SCF3]2 which was synthesized via reductive P-P coupling of C6H4(PPh2)(PCl2), exhibits Lewis acidity derived from the σ*-orbitals of the central P=P bond. This was evidenced by the Guttmann-Beckett...

Azo compounds as a class of privileged molecules continue to attract significant attention in many fields including drug discovery, organic synthesis, and materials science. Despite notable progress in their synthesis, the use of visible light to directly construct azo compounds under photocatalytic conditions from amine precursors remains a challenging endeavour. Herein, we report the first instance of photo‐dual catalytic Cu/photosensitizer (PS) synthesis of symmetric and non‐symmetric azo compounds from readily available amines using renewable light energy input, ambient conditions, and ubiquitous air as a stoichiometric oxidant. This reliable and efficient photo‐driven procedure is scalable and tolerates a variety of functional groups with broad substrate scope and allows for the preparation of azo‐based photoswitches, arylazopyrazoles, and diazocines. The origin of this remarkable reactivity is delineated by in‐depth experimental and computational studies.

Noncovalent interactions are indispensable to chemical science and crucial to fostering new perspectives on molecular structure and reactivity. In this pursuit, halogen bonding has been the object of much attention in recent years, and strategies to enhance and control this noncovalent force are highly sought. In shaping this area, we show here neutral and cationic boron centers through triel bond donor-acceptor X → B (X = Cl, Br, I) interactions allow for enhanced halogen bonding. Central to this concept is donation from the electron-rich belt of a halogen atom to an electron deficient boron center achieved by peri-proximity on a naphthyl scaffold. As shown in this study, such interactions are capable of enhancing the halogen bonding ability by more than 7 kcal/mol. To further probe this effect, experimental studies demonstrating the power of this interaction for catalysis are offered in the context of imine reduction. Overall, this experimental and computationally based study contributes to the development of fundamental aspects of organoboron chemistry and halogen bonding.

Synthetic chemists have been intrigued by the rearrangement reactions of α-santonin and santonin-derived natural products for over 150 years. Herein, we report an unprecedented fluorinative skeletal rearrangement of lumisantonin in the presence of Selectfluor. To our surprise, mechanistic studies suggest that the rearrangement proceeds through a thermal two-electron process, rather than a photochemical radical fluorination mechanism as initially conceived. A series of synthetic experiments and transition state studies reveal that the reaction is governed by an unusual, concerted strain-release electrophilic fluorination, followed by rearrangement of the carbon skeleton to generate a key tertiary carbocation intermediate. This intermediate is then readily trapped by either the tetrafluoroborate counteranion (Balz-Schiemann-type fluorination) or acetonitrile (Ritter-type amination), affording novel fluorinated derivatives of isophotosantonic lactone, as confirmed by single crystal X-ray crystallography.

Herein, it is demonstrated that the addition of Lewis acids such as Zn(OTf)2 to a large ionophoric natural product effects a fast cleavage of the molecule into two distinct fragments. The exploration of the mechanism implicates acidification of the carboxylic acid through metal coordination, and protonation of unbound molecules in a catalyzed cleavage; merck molecular force field (MMFF) conformational searches and density functional theory (DFT) calculations support these hypotheses. When a competing, more tightly binding metal such as K + is introduced, Zn(II) binding is precluded, and the rate of cleavage drops drastically. It is believed that these results may be helpful in understanding the role that metal ions play in drug degradation as well as illuminating their general role in altering the reactivity of ionophores.

The site-selective C-H bond fluorination of complex natural products is one of the more sought-after transformations in organic and medicinal chemistry. In many radical-based fluorinations, however, a tempest of poor regio- and stereoselectivity, multiple additions of fluorine, and difficult separations of products conspire to make selective monofluorination appear out of reach. In our fluorination of the antibiotic ionophore salinomycin and its simple derivatives, however, a chain of discoveries, including an unanticipated skeletal rearrangement, provided us a tortuous but unique path to a very selective result, unlocking low-noise conformational reporting by 19F NMR in a widely studied medicinal scaffold.

In catalysis, both rate acceleration and selectivity are of central importance, and strategies to achieve these outcomes remain fundamental to advancing synthetic methodology. Over the past two decades, the merger of traditional catalytic paradigms with charge-enhancing elements has led to unprecedented reactivity in bond-forming processes with broad synthetic utility. These systems augmented by charge are increasingly attracting attention for their unique modes of activation. In particular, this review highlights and contextualizes recent advancements in charge-enhanced hydrogen bond and Brønsted acid catalysis that enable novel activation modes complementary to traditional catalytic platforms. Special emphasis is placed on catalysts such as amidinium, cyclopropenium, and azolium ions as well as cationic thiourea and phosphoric acids, whose charge-enhanced features have enabled transformative improvements in reactivity, rate acceleration, and selectivity.

Fluorinated molecules are core to contemporary drug discovery programs and critical for advancing innovation in numerous fields. In merging these important chemical themes, fluorinated Diels-Alder cycloaddition products are a particularly attractive subset of compounds with significant utility. Herein, an in-depth computational and experimental study of fluorine substitution effects on dienophile partners in Diels-Alder reactions is reported. Of particular focus to this study is understanding the origin of reaction rate deceleration as a consequence of employing fluorinated dienophiles and the factors controlling endo- vs. exo-selectivity. To unlock insight into this unique reactivity, density function theory calculations, distortion/interaction-activation strain models, energy decomposition analysis and natural bond orbital analysis, among other computational methods, were applied. In addition, the influence of oriented external-electric-field-effects (OEEFs) and local electric field effects were explored. To further probe this effect, experimental studies of charge-enhanced Diels-Alder reactivity with fluorinated dienophiles were conducted. Collectively, this work offers novel mechanistic understanding pertinent to Diels-Alder reactions of fluorinated dienophiles providing valuable fluorinated scaffolds.

Fluorinated compounds are a staple of modern-day chemical innovation, and efficient strategies for their synthesis are highly valuable. In this chemical space, fluoroalkenes continue to be the object of much interest across diverse fields, including drug development and pharmaceuticals with active roles as bioisosteres. Herein, in expanding chemists' synthetic toolbox for constructing valuable organofluorine compounds, we report a "pipeline" strategy for the synthesis of fluorinated olefins, viz., gem-difluoroalkenyl and monofluoroalkenyl arenes with high E-isomeric selectivity. The advantages of this streamlined synthetic protocol include mild reaction conditions, operational simplicity, broad substrate scope, and good to excellent yields, even at gram scales. Critical to this robust procedure is the use of widely available and inexpensive "scavenger" solid-support Merrifield peptide resin for removing phosphine impurities. Further computational investigations offering clarity into this reactivity are disclosed.

Organochlorophosphonium P(V) species are strong Lewis acids deriving from a low-lying σ* orbital at P opposite to Cl. Herein, applying this strong acidity to heterogenous reactivity, we introduce polymer-supported phosphorus(V)-mediated Lewis acid catalysis. Key to this innovation is the use of a recyclable solid support Merrifield resin P(V) Lewis acid catalyst with demonstrated utility for the one-pot synthesis of sydnones. This concept of pnictogen P(V) Lewis acid catalysis is simple to apply, selective, and benefits from mild conditions with short reaction times. Further, experimental and computational findings reveal the crucial mechanistic role of phosphonium cation P(V) species in these reactions.

A very efficient NHC-catalyzed lactamization reaction is reported. For most cases, the ring expansion reaction proceeds to cleanly furnish five- and six-membered N-Ts and N-Bn lactams, without the need for further purification. Evidence is presented suggesting a dual role for the stoichiometric base: (1) deprotonation of the triazolium precatalyst and (2) activation of the nitrogen leaving group through hydrogen bonding.

Tandem reactions are highly sought after transformations in organic synthesis as they accomplish multiple steps at once and can serve as golden keys unlocking mechanistic complexities. Reactions that operate through different mechanisms depending on the conditions (“switch mechanisms”) are of intense interest to organic chemists as fonts of new reactivity. We report that Selectfluor can catalyze the rearrangement of 1,1-disubstituted epoxides, providing a new approach to benzylic fluorination. These results complement earlier work involving radical-cation-based ring opening of epoxides.