Unlocking Oxetane Potential: Modular Synthetic Platform for the Concise Synthesis of Acyclic Oligo-Isoprenoids and Terpenoids.

Terpenes occupy a unique place among the secondary metabolites due to their broad utility and extraordinary structural diversity. Their synthesis via polyene cyclization, either biomimetic or enzymatic, represents the cutting edge of modern synthetic chemistry. However, these endeavors have been inherently tied to the availability of natural and non-natural acyclic polyene starting materials. Herein, we report an oxetane-based platform for the modular construction of oxygenated polyolefins with precise geometric control. This "tail-to head" iterative method leverages the site-selective cross-metathesis of terminal olefins to form an alkylidene oxetane moiety and the regioselective ring opening of alkenyl-oxetanes for chain elongation. In addition, the unique and peculiar propensity of alkylidene oxetane fragment in various reactions was also revealed and exploited for site-selective functionalization, cyclization, and as a protecting group in polyenes.

Site-selective Photoredox-Catalyzed Late-stage Benzylic Hydrogen Isotope Exchange.

A highly regioselective visible light photoredox-catalyzed hydrogen isotope exchange (HIE) of benzylic positions in both simple and complex molecules is reported. The process follows a dual catalytic approach using an acridinium photocatalyst in combination with a thiol-based hydrogen atom transfer catalyst, while the use of D2O as an isotope source ensures operational simplicity and cost-effectiveness. High reactivity has been achieved for electron-rich benzylic positions. Moreover, targeted radical formation enables unprecedented selective HIE on intramolecular competing benzylic and alpha to heteroatom positions with moderate to excellent deuterium incorporation. The utility of the reaction was demonstrated on the late-stage HIE of several natural compounds and drug derivatives. Experimental studies and density functional theory (DFT) calculations suggested a single electron transfer (SET) mechanism followed by deprotonation to generate the benzylic radical, and revealed the importance of halogenated solvents or additives. Upon a weak complexation of the halogenated species to the substrate, an oxidation potential lowering effect is induced, as well as a stabilization of the radical-cation species through spin delocalization.

Enantioconvergent and Site-Selective Etherification of Carbohydrate Polyols through Chiral Copper Radical Catalysis.

Going beyond currently reported two electron transformations that formed the core backdrop of asymmetric catalytic site-selective carbohydrate polyol functionalizations, we herein report a seminal demonstration of an enantioconvergent copper catalyzed site-selective etherification of minimally protected saccharides through a single-electron radical pathway. Further, this strategy paves a rare strategy, through which a carboxamide scaffold that is present in some glycomimetics of pharmacological relevance, can be selectively introduced. In light of the burgeoning interest in chiral radical catalysis, and the virtual absence of such stereocontrol broadly in carbohydrate synthesis, our strategy showcased the unknown capability of chiral radical copper catalysis as a contemporary tool to address the formidable site-selectivity challenge on a remarkable palette of naturally occurring saccharides. When reducing sugars were employed, a further dynamic kinetic resolution type glycosylation can be activated by the catalytic system to selectively generate the challenging ß-O-glycosides.

Spirobipyridine Ligand Enabled Iridium-Catalyzed Site-Selective C-H Activation via Non-Covalent Interactions.

The selective borylation of specific C-H bonds in organic synthesis remains a formidable challenge. In this study, we present a novel spirobipyridine ligand that features a binaphthyl backbone. This ligand facilitates the iridium-catalyzed selective C-H borylation of benzene derivatives. The ligand is designed with "side-arm-wall" substituents that allow vicinal di- or multi-substituted benzene derivatives to approach metal center and effectively block other reactive sites by non-covalent interactions with substrates. The effectiveness of this strategy is demonstrated by the successful selective distal C-H activation of various alkaloids and its broad compatibility with functional groups.

Nanoparticles that Distinguish Chemical and Supramolecular Contexts of Lysine for Single-Site Functionalization of Protein.

Lysine is one of the most abundant residues on the surface of proteins and its site-selective functionalization is extremely challenging. The existing methods of functionalization rely on differential reactivities of lysine on a protein, making it impossible to label less reactive lysines selectively. We here report polymeric nanoparticles that mimic enzymes involved in the posttranslational modifications of proteins that distinguish the chemical and supramolecular contexts of a lysine and deliver the labeling reagent precisely to its ε amino group. The nanoparticles are prepared through molecular imprinting of cross-linkable surfactant micelles, plus an in situ, on-micelle derivatization of the peptide template prior to the imprinting. The procedures encode the polymeric nanoparticles with all the supramolecular information needed for sequence identification and precise labeling, allowing single-site functionalization of a predetermined lysine on the target protein in a mixture.

Photocatalytic Direct para-selective C-H Amination of Benzyl Alcohols: Selectivity Independent of Side Substituents.

Aminoarenes are important molecules for broad applications in nearly all modern industries that involve chemicals. Direct and site-selective C-H bond amination of arenes provides the most efficient and convenient method to prepare aminoarenes. A main challenge is to selectively install the amino group (or other functional groups) to the distal para-carbon of arenes (especially multi-substituted arenes) during the C-H bond functionalization events. Herein, we address this problem by designing a new strategy via a sequential radical dearomatization/radical amination/rearomatization process for para-selective amination of benzyl alcohols. The para-selectivity of our reaction is completely independent of the electronic and steric properties of the other substituents of the arene substrates. Aminoarenes with many substituents (up to full substitution) and diverse substitution patterns, including those difficult to synthesize previously, could be readily prepared using our protocols. Further exploration of the current strategy shall lead to other challenging C-H functionalization of arenes.

Binary Catalytic Hydrogen/Deuterium Exchange of Free α-Amino Acids and Derivatives.

The increasing demand for deuterium-labeled amino acids and derivatives has heightened interest in direct hydrogen/deuterium exchange reactions of free amino acids. Existing methods, including biocatalysis and metal catalysis, typically require expensive deuterium sources or excessive use of deuterium reagents and often struggle with site selectivity. In contrast, this binary catalysis system, employing benzaldehyde and Cs2CO3 in the presence of inexpensive D2O with minimal stoichiometric quantities, facilitates efficient hydrogen/deuterium exchange at the α-position of amino acids without the need for protecting groups in the polar aprotic solvent DMSO. The process is highly compatible with most natural and non-natural α-amino acids and derivatives, even those with potentially reactive functionalities. This advancement not only addresses the cost and efficiency concerns of existing methods but also significantly broadens the applicability and precision of deuterium labeling in biochemical research.

Iron-catalyzed C-7 Selective NH2 Amination of Indoles.

7-Aminoindoles are important synthetic intermediates to a broad range of bioactive molecules. Transition metal-catalyzed directed C-H amination is among the most straightforward route for their synthesis, whereas methods that could directly incorporate an NH2 group in a highly selective manner remains elusive. Moreover, there is still high demand for the development of earth-abundant metal catalysis for such attractive reactivity. We present here the first C-7 selective NH2 amination of indoles through a directed homolytic aromatic substitution (HAS) with iron-aminyl radical. The reaction exhibits broad substrate scope, tolerates variety of functional groups, and is readily scalable with catalyst loading down to 0.1 mol % and turnover number (TON) up to 4500.

Nickel-Based Catalysts for the Selective Monoarylation of Dichloropyridines: Ligand Effects and Mechanistic Insights.

This report describes a detailed study of Ni phosphine catalysts for the Suzuki-Miyaura coupling of dichloropyridines with halogen-containing (hetero)aryl boronic acids. With most phosphine ligands these transformations afford mixtures of mono- and diarylated cross-coupling products as well as competing oligomerization of the boronic acid. However, a ligand screen revealed that PPh2Me and PPh3 afford high yield and selectivity for monoarylation over diarylation as well as minimal competing oligomerization of the boronic acid. Several key observations were made regarding the selectivity of these reactions, including: (1) phosphine ligands that afford high selectivity for monoarylation fall within a narrow range of Tolman cone angles (between 136° and 157°); (2) more electron-rich trialkylphosphines afford predominantly diarylated products, while less-electron rich di- and triarylphosphines favor monoarylation; (3) diarylation proceeds via intramolecular oxidative addition; and (4) the solvent (MeCN) plays a crucial role in achieving high monoarylation selectivity. Experimental and DFT studies suggest that all these data can be explained based on the reactivity of a key intermediate: a Ni0-π complex of the monoarylated product. With larger, more electron-rich trialkylphosphine ligands, this π complex undergoes intramolecular oxidative addition faster than ligand substitution by the MeCN solvent, leading to selective diarylation. In contrast, with relatively small di- and triarylphosphine ligands, associative ligand substitution by MeCN is competitive with oxidative addition, resulting in selective formation of monoarylated products. The generality of this method is demonstrated with a variety of dichloropyridines and chloro-substituted aryl boronic acids. Furthermore, the optimal ligand (PPh2Me) and solvent (MeCN) are leveraged to achieve the Ni-catalyzed monoarylation of a broader set of dichloroarene substrates.

Asymmetric Pd/Organoboron-Catalyzed Site-Selective Carbohydrate Functionalization with Alkoxyallenes Involving Noncovalent Stereocontrol.

Herein, we demonstrate the robustness of a synergistic chiral Pd/organoboron system in tackling a challenging suite of site-, regio-, enantio- and diastereoselectivity issues across a considerable palette of biologically relevant carbohydrate polyols, when prochiral alkoxyallenes were employed as electrophiles. In view of the burgeoning role of noncovalent interactions (NCIs) in stereoselective carbohydrate synthesis, our mechanistic experiments and DFT modeling of the reaction path unexpectedly revealed that NCIs such as hydrogen bonding and CH-π interactions between the resting states of the Pd-π-allyl complex and the borinate saccharide are critically involved in the stereoselectivity control. Our strategy thus illuminates the untapped potential of harnessing NCIs in the context of transition metal catalysis to tackle stereoselectivity challenges in carbohydrate functionalization.