James Sanderson

A variety of N‐methylated peptides were synthesized in high yield without severe racemization via the generation of acylN‐methylimidazolium cations. Brønsted acids dramatically accelerated the reaction. The developed amidation reaction enabled the synthesis of a bulky peptide in higher yield and shorter reaction time in comparison with conventional amidation reactions. The first total synthesis of pterulamides I–IV was also achieved.

Abstract

The development of a robust amide‐bond formation remains a critical aspect of N‐methylated peptide synthesis. In this study, we synthesized a variety of dipeptides in high yields, without severe racemization, from equivalent amounts of amino acids. Highly reactive N‐methylimidazolium cation species were generated in situ to accelerate the amidation. The key to success was the addition of a strong Brønsted acid. The developed amidation enabled the synthesis of a bulky peptide with a higher yield in a shorter amount of time compared with the results of conventional amidation. In addition, the amidation can be performed by using either a microflow reactor or a conventional flask. The first total synthesis of naturally occurring bulky N‐methylated peptides, pterulamides I–IV, was achieved. Based on experimental results and theoretical calculations, we speculated that a Brønsted acid would accelerate the rate‐limiting generation of acyl imidazolium cations from mixed carbonic anhydrides.

A photo‐organo‐iron‐catalyzed cyclotrimerization of alkynes has been developed that involves photoredox activation of a simple iron catalyst. The reaction operates under very mild conditions (visible light, 20 °C, 1 h) with 1–2 mol % loading of the triple catalyst system (organic dye, amine, and FeCl₂).

Abstract

Successful combinations of visible‐light photocatalysis with metal catalysis have recently enabled the development of hitherto unknown chemical reactions. Dual mechanisms from merging metal‐free photocatalysts and earth‐abundant metal catalysts are still in their infancy. We report a photo‐organo‐iron‐catalyzed cyclotrimerization of alkynes by photoredox activation of a ligand‐free Fe catalyst. The reaction operates under very mild conditions (visible light, 20 °C, 1 h) with 1–2 mol % loading of the three catalysts (dye, amine, FeCl₂).

A transition‐metal‐free method for the synthesis of α‐branched amines from tertiary carboxamides and lactams with carbon‐centered nucleophiles has been developed. This scalable process relies on the controlled reduction of tertiary amides by NaH/NaI composite, in situ treatment of the resulting anionic hemiaminal with trimethylsilyl chloride, and subsequent coupling with nucleophilic reagents including Grignard reagents and tetrabutylammonium cyanide.

Abstract

A new method for the synthesis of α‐branched amines by reductive functionalization of tertiary carboxamides and lactams is described. The process relies on the efficient and controlled reduction of tertiary amides by a sodium hydride/sodium iodide composite, in situ treatment of the resulting anionic hemiaminal with trimethylsilyl chloride and subsequent coupling with nucleophilic reagents including Grignard reagents and tetrabutylammonium cyanide. The new method exhibits broad functional‐group compatibility, operates under transition‐metal‐free reaction conditions, and is suitable for various synthetic applications on both sub‐millimole and on multigram scales.

Nature, Published online: 20 April 2020; doi:10.1038/d41586-020-01144-8

Inspired by the Sonogashira reaction, important progress has been made in the area of dual catalysis by using a combination of palladium and copper catalysts. In this Minireview on https://doi.org/10.1002/chem.201904495page 4895 ff., Y. Wu, X. Huo, and W. Zhang summarize the developments of Pd/Cu catalyst systems based on their ability to catalyzed specific reactions: 1) palladium chemistry involving allylic substitution, propargyl substitution, carbonylative coupling, and domino reaction; 2) copper chemistry involving C−H activation, decarboxylation, Cu−B, Cu−H, Cu−Si, and Cu−enolates.

The conversion of carboxylic acids into ketones using combined photoredox/ N‐heterocyclic carbene (NHC) catalysis has been developed. In situ activation of a carboxylic acid followed by generation of an acyl azolium allows productive radical–radical coupling to afford ketones in good to excellent yields. This single‐electron, reductive alkylation was applied in the late‐stage functionalization of various pharmaceutical compounds.

Abstract

As a key element in the construction of complex organic scaffolds, the formation of C−C bonds remains a challenge in the field of synthetic organic chemistry. Recent advancements in single‐electron chemistry have enabled new methods for the formation of various C−C bonds. Disclosed herein is the development of a novel single‐electron reduction of acyl azoliums for the formation of ketones from carboxylic acids. Facile construction of the acyl azolium in situ followed by a radical–radical coupling was made possible merging N‐heterocyclic carbene (NHC) and photoredox catalysis. The utility of this protocol in synthesis was showcased in the late‐stage functionalization of a variety of pharmaceutical compounds. Preliminary investigations using chiral NHCs demonstrate that enantioselectivity can be achieved, showcasing the advantages of this protocol over alternative methodologies.

Organic halides are important building blocks in synthesis, but their use in (photo)redox chemistry is limited by their low reduction potentials. Halogen-atom transfer remains the most reliable approach to exploit these substrates in radical processes despite its requirement for hazardous reagents and initiators such as tributyltin hydride. In this study, we demonstrate that α-aminoalkyl radicals, easily accessible from simple amines, promote the homolytic activation of carbon-halogen bonds with a reactivity profile mirroring that of classical tin radicals. This strategy conveniently engages alkyl and aryl halides in a wide range of redox transformations to construct sp³-sp³, sp³-sp², and sp²-sp² carbon-carbon bonds under mild conditions with high chemoselectivity.

CRISPR-Cas9 gene editing provides a powerful tool to enhance the natural ability of human T cells to fight cancer. We report a first-in-human phase 1 clinical trial to test the safety and feasibility of multiplex CRISPR-Cas9 editing to engineer T cells in three patients with refractory cancer. Two genes encoding the endogenous T cell receptor (TCR) chains, TCRα (TRAC) and TCRβ (TRBC), were deleted in T cells to reduce TCR mispairing and to enhance the expression of a synthetic, cancer-specific TCR transgene (NY-ESO-1). Removal of a third gene encoding programmed cell death protein 1 (PD-1; PDCD1), was performed to improve antitumor immunity. Adoptive transfer of engineered T cells into patients resulted in durable engraftment with edits at all three genomic loci. Although chromosomal translocations were detected, the frequency decreased over time. Modified T cells persisted for up to 9 months, suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of CRISPR gene editing for cancer immunotherapy.

Recent groundbreaking studies on organoferrates have demonstrated that coordinatively unsaturated three‐coordinate σ‐alkylferrates are active catalysts in Fe‐catalyzed cross‐couplings with Grignard reagents and that pronounced solvent and counterion effects dictate metalate speciation and catalyst activity. Thanks to modern spectroscopic methods, sensitive catalyst intermediates could be analyzed.

Silaboration of [1.1.1]propellane enabled direct introduction of B and Si functional groups onto the bicyclo[1.1.1]pentane (BCP) scaffold in high yield under mild, additive‐free conditions. The silaborated BCP can be obtained on a gram scale in a single step without the need for column chromatography purification, and is storable and easy to handle, providing a versatile synthetic intermediate for BCP derivatives.

Abstract

The silaboration of [1.1.1]propellane enables direct introduction of B and Si functional groups onto the bicyclo[1.1.1]pentane (BCP) scaffold in high yield under mild, additive‐free conditions. The silaborated BCP can be obtained on a gram‐scale in a single step without the need for column‐chromatographic purification, and is storable and easy to handle, providing a versatile synthetic intermediate for BCP derivatives. We also describe various conversions of the C−B/C−Si bonds on the BCP scaffold, including development of a modified Suzuki–Miyaura cross‐coupling reaction at the highly sterically hindered bridgehead sp³ carbon center of the BCP skeleton using a combination of highly activated BCP boronic esters, copper(I) oxide, and a PdCl₂(dppf) catalyst system.

Synthesis of a diverse range of heterobiaryls has been achieved by a transition‐metal‐free sp²–sp² cross‐coupling strategy using lithiated heterocycle, aryl or heteroaryl boronic ester and an electrophilic halogen source (see scheme).

Abstract

The synthesis of a diverse range of heterobiaryls has been achieved by a transition‐metal‐free sp²–sp² cross‐coupling strategy using lithiated heterocycle, aryl or heteroaryl boronic ester and an electrophilic halogen source. The construction of heterobiaryls was carried out through electrophilic activation of the aryl–heteroaryl boronate complex, which triggered 1,2‐migration from boron to the carbon atom. Subsequent oxidation of the intermediate boronic ester afforded heterobiaryls in good yield. A comprehensive ¹¹B NMR study has been conducted to support the mechanism. The cross coupling between two nucleophilic cross coupling partners without transition metals reveals a reliable manifold to procure heterobiaryls in good yields. Various heterocycles like furan, thiophene, benzofuran, benzothiophene, and indole are well tolerated. Finally, we have successfully demonstrated the gram scale synthesis of the intermediates for an anticancer drug and OLED material using our methodology.

The main‐group age: The past decade has revealed main‐group‐element compounds that display transition‐metal‐like reactivity in stoichiometric and even catalytic transformations. Cornella and co‐workers have now reported a bismuth complex that catalyzes fluoroarene formation from aryl boronate esters, a reaction that is almost unprecedented in transition‐metal catalysis.

A cheap Co‐upling: A cobalt‐catalyzed cross‐coupling reaction of functionalized primary and secondary alkylzinc reagents with a variety of aryl and heteroaryl halides is described. Cross‐coupling reactions using secondary cyclohexylzinc reagents proceed in a highly diastereoselective fashion furnishing the corresponding products in up to 98:2 d.r. The procedure enables the coupling of alkynyl bromides with primary and secondary zinc reagents.

Abstract

A combination of 10 % CoCl₂ and 20 % 2,2′‐bipyridine ligands enables cross‐coupling of functionalized primary and secondary alkylzinc reagents with various (hetero)aryl halides. Couplings with 1,3‐ and 1,4‐substituted cycloalkylzinc reagents proceeded diastereoselectively leading to functionalized heterocycles with high diastereoselectivities of up to 98:2. Furthermore, alkynyl bromides react with primary and secondary alkylzinc reagents providing the alkylated alkynes.

Photoredox Catalysis (PRC) and Synthetic Organic Electrochemistry (SOE) are often considered competing technologies in organic synthesis and their fusion has been largely overlooked. We review state‐of‐the‐art synthetic organic photoelectrochemistry, grouping examples into three categories: 1) electrochemically‐mediated PhotoRedox Catalysis (e‐PRC), 2) decoupled PhotoElectrochemistry (dPEC) and 3) interfacial PhotoElectrochemistry (iPEC). Such synergies prove beneficial not only for synthetic ‘greenness’ and chemical selectivity, but also in the accumulation of energy for accessing super‐oxidizing or reducing single‐electron‐transfer (SET) agents. Opportunities and challenges in this emerging and exciting field are discussed.