Enantioselective Aziridination of Unactivated Terminal Alkenes Using a Planar Chiral Rh(III) Indenyl Catalyst.

Chiral aziridines are important structural motifs found in natural products and various target molecules. They serve as versatile building blocks for the synthesis of chiral amines. While advances in catalyst design have enabled robust methods for enantioselective aziridination of activated olefins, simple and abundant alkyl-substituted olefins pose a significant challenge. In this work, we introduce a novel approach utilizing a planar chiral rhodium indenyl catalyst to facilitate the enantioselective aziridination of unactivated alkenes. This transformation exhibits a remarkable degree of functional group tolerance and displays excellent chemoselectivity favoring unactivated alkenes over their activated counterparts, delivering a wide range of enantioenriched high-value chiral aziridines. Computational studies unveil a stepwise aziridination mechanism in which alkene migratory insertion plays a central role. This process results in the formation of a strained four-membered metallacycle and serves as both the enantio- and rate-determining steps in the overall reaction.

Synthesis, stereochemical assignment, and enantioselective catalytic activity of late transition metal planar chiral complexes.

Planar chirality is an important form of molecular chirality that can be utilized to induce enantioselectivity when incorporated into transition metal catalysts. However, due to synthetic constraints, the use of late transition metal planar chiral complexes to conduct enantioselective transformations has been limited. Additionally, the published methods surrounding the stereochemical assignment of planar chiral compounds are sometimes conflicting, making proper assignment difficult. This review aims to provide clarity on the methods available to assign planar chirality and provide an overview on the synthesis and use of late transition metal planar chiral complexes as enantioselective catalysts.

Chemical Modifications to Enhance the Drug Properties of a VIP Receptor Antagonist (ANT) Peptide.

Antagonist peptides (ANTs) of vasoactive intestinal polypeptide receptors (VIP-Rs) are shown to enhance T cell activation and proliferation in vitro, as well as improving T cell-dependent anti-tumor response in acute myeloid leukemia (AML) murine models. However, peptide therapeutics often suffer from poor metabolic stability and exhibit a short half-life/fast elimination in vivo. In this study, we describe efforts to enhance the drug properties of ANTs via chemical modifications. The lead antagonist (ANT308) is derivatized with the following modifications: N-terminus acetylation, peptide stapling, and PEGylation. Acetylated ANT308 exhibits diminished T cell activation in vitro, indicating that N-terminus conservation is critical for antagonist activity. The replacement of residues 13 and 17 with cysteine to accommodate a chemical staple results in diminished survival using the modified peptide to treat mice with AML. However, the incorporation of the constraint increases survival and reduces tumor burden relative to its unstapled counterpart. Notably, PEGylation has a significant positive effect, with fewer doses of PEGylated ANT308 needed to achieve comparable overall survival and tumor burden in leukemic mice dosed with the parenteral ANT308 peptide, suggesting that polyethylene glycol (PEG) incorporation enhances longevity, and thus the antagonist activity of ANT308.

Switchable Regioselective 6-endo or 5-exo Radical Cyclization via Photoredox Catalysis.

Controlling the regioselectivity of radical cyclizations to favor the 6-endo mode over its kinetically preferred 5-exo counterpart is difficult without introducing substrate prefunctionalization. To address this challenge, we have developed a simple method for reagent controlled regioselective radical cyclization of halogenated N-heterocycles onto pendant olefins. Radical generation occurs under mild photoredox conditions with control of the regioselectivity governed by the rate of hydrogen atom transfer (HAT). Utilizing a polarity-matched thiol-based HAT agent promotes the highly selective formation of the 5-exo cyclization product. Conversely, limiting the solubility of the HAT reagent Hantzsch ester (HEH) leads to selective formation of the thermodynamically favored 6-endo product. This occurs through an initial 5-exo cyclization, with the resulting alkyl radical intermediate undergoing neophyl rearrangement to form the 6-endo product. Development of this switchable catalysis strategy allows for two modes of divergent reactivity to form either the 6-endo or 5-exo product, generating fused N-heteroaromatic/saturated ring systems.

Synthesis of Ribosomally Synthesized and Post-Translationally Modified Peptides Containing C-C Cross-Links.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are known for their macrocyclic structures, which impart unique biological activity. One rapidly emerging subclass of RiPP natural products contains macrocyclic C-C cross-links between two amino acid side chains. These linkages, often biosynthetically formed by a single rSAM or P450 enzyme, introduce significant structural and synthetic complexity to the molecules. While nature utilizes elegant mechanisms to produce C-C cross-linked RiPPs, synthetic tools are only able to access a portion of these biologically relevant natural products. This review provides an overview of the structures in this subclass as well as a discussion on their chemical syntheses.

Synthetic Routes for Heteroatom-Containing Alkylated/Arylated Polycyclic Aromatic Hydrocarbons.

Synthetic routes for heteroatom-containing polycyclic aromatic hydrocarbons (H-PAHs) with alkyl and aryl substitution are demonstrated. Three H-PAHs, including heteroatom-containing rubicenes (H-rubicenes), angular-benzothiophenes (ABTs), and indenothiophene (IDTs) were successfully synthesized by two key steps, including polysubstituted olefin formation and cyclization. Specifically, ABT and H-rubicenes were comprehensively investigated by single-crystal X-ray diffraction, NMR spectroscopy, UV-vis absorption, cyclic voltammetry, transient absorption, and single-crystal OFET measurements.

The Mechanism of Rhodium-Catalyzed Allylic C-H Amination.

Herein, the mechanism of catalytic allylic C-H amination reactions promoted by Cp*Rh complexes is reported. Reaction kinetics experiments, stoichiometric studies, and DFT calculations demonstrate that the allylic C-H activation to generate a Cp*Rh(π-allyl) complex is viable under mild reaction conditions. The role of external oxidants in the catalytic cycle is elucidated. Quantum mechanical calculations, stoichiometric reactions, and cyclic voltammetry experiments concomitantly support an oxidatively induced reductive elimination process of the allyl fragment with an acetate ligand proceeding through a Rh(IV) intermediate. Stoichiometric oxidation and bulk electrolysis of the proposed π-allyl intermediate are also reported to support these analyses. Lastly, evidence supporting the amination of an allylic acetate intermediate is presented. We show that Cp*Rh(III)2+ behaves as a Lewis acid catalyst to complete the allylic amination reaction.

Designing a Planar Chiral Rhodium Indenyl Catalyst for Regio- and Enantioselective Allylic C-H Amidation.

Chiral variants of group IX Cp and Cp* catalysts are well established and catalyze a broad range of reactions with high levels of enantioselectivity. Enantiocontrol in these systems results from ligand design that focuses on appropriate steric blocking. Herein we report the development of a new planar chiral indenyl rhodium complex for enantioselective C-H functionalization catalysis. The ligand design is based on establishing electronic asymmetry in the catalyst, to control enantioselectivity during the reactions. The complex is easily synthesized from commercially available starting materials and is capable of catalyzing the asymmetric allylic C-H amidation of unactivated olefins, delivering a wide range of high-value enantioenriched allylic amide products in good yields with excellent regio- and enantioselectivity. Computational studies suggest that C-H cleavage is rate- and enantio-determining, while reductive C-N coupling from the RhV-nitrenoid intermediate is regio-determining.

Regioselective Cp*Ir(III)-Catalyzed Allylic C-H Sulfamidation of Allylbenzene Derivatives.

In this study we report the development of the regioselective Cp*Ir(III)-catalyzed allylic C-H sulfamidation of allylbenzene derivatives, using azides as the nitrogen source. The reaction putatively proceeds through a Cp*Ir(III)-π-allyl intermediate and demonstrates exclusive regioselectivity for the branched position of the π-allyl. The reaction performs well on electron-rich and electron-deficient allylbenzene derivatives and is tolerant of a wide range of functional groups, including carbamates, esters, and ketones. The proposed mechanism for this reaction proceeds via C-N reductive elimination from a Cp*Ir(V) nitrenoid complex at the branched position of the π-allyl.

Recent Developments in C-H Activation for Materials Science in the Center for Selective C-H Activation.

Abstract: Organic electronics is a rapidly growing field driven in large part by the synthesis of ∏-conjugated molecules and polymers. Traditional aryl cross-coupling reactions such as the Stille and Suzuki have been used extensively in the synthesis of ∏-conjugated molecules and polymers, but the synthesis of intermediates necessary for traditional cross-couplings can include multiple steps with toxic and hazardous reagents. Direct arylation through C-H bond activation has the potential to reduce the number of steps and hazards while being more atom-economical. Within the Center for Selective C-H Functionalization (CCHF), we have been developing C-H activation methodology for the synthesis of ∏-conjugated materials of interest, including direct arylation of difficult-to-functionalize electron acceptor intermediates and living polymerization of ∏-conjugated polymers through C-H activation.

Intermolecular Allylic C-H Etherification of Internal Olefins.

Herein we report on the development of an oxidative allylic C-H etherification reaction, utilizing internal olefins and alcohols as simple precursors. Key advances include the use of RhCp* complexes to promote the allylic C-H functionalization of internal olefins and the compatibility of the oxidative conditions with oxidatively sensitive alcohols, enabling the direct etherification reaction. Preliminary mechanistic studies, consistent with C-H functionalization as the rate determining step, are presented.

Stereochemical Complexity in Oxocarbenium-Ion-Initiated Cascade Annulations for the Synthesis of the ABCD Core of Mattogrossine.

Mattogrossine is an indole alkaloid isolated from Strychnos mattogrossensis that contains an unusual tetrahydrofuran ring with a concomitant hemiacetal in its structure. While tetrahydrofuran intermediates have been used in the synthesis of other strychnos alkaloids, no investigations have been performed into the synthesis of alkaloids containing this structure. We have developed an oxocarbenium-ion-initiated cascade annulation that provides us access to the ABCD ring structure of mattogrossine.

Synthesis and C-H Functionalization Chemistry of Thiazole-Semicoronenediimides (TsCDIs) and -Coronenediimides (TCDIs).

Coronenediimide (CDI) derivatives have a planar structure, a reasonably high electron affinity, and a rigid and extended delocalized π-system. Therefore, this core and variants thereof may be promising building blocks for the synthesis of electron transport materials. Herein, we have synthesized thiazole-semicoronenediimides (TsCDIs) and -coronenediimides (TCDIs) by a two-step process from a perylenediimide (PDI) precursor. Conditions for C-H arylation and heteroarylation of the thiazole moiety of this core were developed and were successfully used for the synthesis of dimer, triad, and polymeric materials. The optical and electrochemical properties of these materials and their monomers were examined as a function of side-chain modification and π-extension. With their broad optical absorption and low reduction potentials, these materials could be candidates as organic semiconductors for applications in OFETs and as nonfullerene acceptors.

Regioselective Intermolecular Allylic C-H Amination of Disubstituted Olefins via Rhodium/π-Allyl Intermediates.

A method for catalytic intermolecular allylic C-H amination of trans-disubstituted olefins is reported. The reaction is efficient for a range of common nitrogen nucleophiles bearing one electron-withdrawing group, and proceeds under mild reaction conditions. Good levels of regioselectivity are observed for a wide range of electronically diverse trans-ß-alkyl styrene substrates.

KO(t)Bu-Initiated Aryl C-H Iodination: A Powerful Tool for the Synthesis of High Electron Affinity Compounds.

An efficient iodination reaction of electron-deficient heterocycles is described. The reaction utilizes KO(t)Bu as an initiator and likely proceeds by a radical anion propagation mechanism. This new methodology is particularly effective for functionalization of building blocks for electron transport materials. Its utility is demonstrated with the synthesis of a new perylenediimide-thiazole non-fullerene acceptor capable of delivering a power conversion efficiency of 4.5% in a bulk-heterojunction organic solar cell.

Ir-Catalyzed enantioselective group transfer reactions.

Recently, several novel iridium complexes have been shown to catalyse group transfer reactions in a highly selective fashion. Rhodium complexes, and in particular dirhodium tetracarboxylate salts, have proven to be a remarkably useful class of catalysts for these reactions through several decades of development. Recent results suggest that iridium may offer opportunities to address challenges in this chemistry and provide complementary reactivity patterns. This tutorial review outlines the recent developments in Ir-catalyzed enantioselective group transfer chemistry with highlights on examples which display this unique reactivity.

A C-H functionalization protocol for the direct synthesis of benzobisthiazole derivatives.

Benzobisthiazole and thiazolothiazole derivatives are useful components in a variety of organic electronics devices resulting from their absorption, electroluminescence, and charge-transport properties. A convenient synthesis of these molecules via palladium/copper cocatalyzed C-H bond functionalization is described. Reaction conditions were optimized in a bromobenzene/benzobisthiazole system that allowed for the one-pot functionalization of both thioimidate positions of benzobisthiazole. The extension of this methodology to the synthesis of cruciform architectures and the functionalization of thiazolothiazole is also described.

Photoredox-Driven Three-Component Coupling of Aryl Halides, Olefins, and O2.

Modern organic synthesis requires methodologies that bring together abundant feedstock chemicals in a mild and efficient manner. To aid in this effort, we have developed a multicomponent radical hydroxyarylation reaction that utilizes aryl halides, olefins, and O2 as the reaction components. Crucial to this advance was an oxidative, rather than a reductive, approach to aryl radical generation, which enables reaction tolerance to O2. This methodology displays a broad functional group tolerance with a variety of functionalized aryl halides and a broad array of olefins. Development of this methodology enables rapid access to biologically relevant hydroxyaryl products from simple, commercially available starting materials.

Defluoroalkylation of Trifluoromethylarenes with Hydrazones: Rapid Access to Benzylic Difluoroarylethylamines.

Here, we report an efficient and modular approach toward the formation of difluorinated arylethylamines from simple aldehyde-derived N,N-dialkylhydrazones and trifluoromethylarenes (CF3-arenes). This method relies on selective C-F bond cleavage via reduction of the CF3-arene. We show that a diverse set of CF3-arenes and CF3-heteroarenes react smoothly with a range of aryl and alkyl hydrazones. The ß-difluorobenzylic hydrazine product can be selectively cleaved to form the corresponding benzylic difluoroarylethylamines.

Rhodium catalyzed allene amination: diastereoselective synthesis of aminocyclopropanes via a 2-amidoallylcation intermediate.

The interaction of a sulfamate ester derived metallonitrene with an allene generates a versatile intermediate with 2-amidoallylcation-like reactivity, capable of rearranging to give highly substituted iminocyclopropanes or acting as a novel dipolar species engaging external dipolarophiles.