LongLarf

Everything is transient: The combination of a ruthenium catalyst with amines enables the C−H activation and deuteration of aromatic carbonyl compounds in a general manner. Using D₂O as a convenient source of deuterium, high deuteration levels were achieved and the application of this methodology for the preparation of deuterated pharmaceuticals was demonstrated.

Abstract

A novel ruthenium-catalyzed C−H activation methodology for hydrogen isotope exchange of aromatic carbonyl compounds is presented. In the presence of catalytic amounts of specific amine additives, a transient directing group is formed in situ, which directs selective deuteration. A high degree of deuteration is achieved for α-carbonyl and aromatic ortho-positions. In addition, appropriate choice of conditions allows for exclusive labeling of the α-carbonyl position while a procedure for the preparation of merely ortho-deuterated compounds is also reported. This methodology proceeds with good functional group tolerance and can be also applied for deuteration of pharmaceutical drugs. Mechanistic studies reveal a kinetic isotope effect of 2.2, showing that the C−H activation is likely the rate-determining step of the catalytic cycle. Using deuterium oxide as a cheap and convenient source of deuterium, the methodology presents a cost-efficient alternative to state-of-the-art iridium-catalyzed procedures.

Synlett
DOI: 10.1055/a-1458-5785

A transition-metal-free visible-light photoredox-catalyzed decarboxylative alkylation of the benzylic C(sp3)–H bonds of N-aryltetrahydroisoquinolines is reported. The method tolerates various functional groups and proceeds smoothly without requiring a stoichiometric oxidant. A preliminary mechanistic study indicated that a radical process is involved in the reaction.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

Enzymatic deprotection of a latent thiol under mild and physiological conditions expands the scope of classic thiol bioconjugation. New reaction schemes enable regioselective labeling and dual modifications for a variety of preparative applications and using the established and commercially available plethora of thiol-directed reagents.

Abstract

The thiol group of the cysteine side chain is arguably the most versatile chemical handle in proteins. To expand the scope of established and commercially available thiol bioconjugation reagents, we genetically encoded a second such functional moiety in form of a latent thiol group that can be unmasked under mild physiological conditions. Phenylacetamidomethyl (Phacm) protected homocysteine (HcP) was incorporated and its latent thiol group unmasked on purified proteins using penicillin G acylase (PGA). The enzymatic deprotection depends on steric accessibility, but can occur efficiently within minutes on exposed positions in flexible sequences. The freshly liberated thiol group does not require treatment with reducing agents. We demonstrate the potential of this approach for protein modification with conceptually new schemes for regioselective dual labeling, thiol bioconjugation in presence of a preserved disulfide bond and formation of a novel intramolecular thioether crosslink.

Nature Communications, Published online: 09 April 2021; doi:10.1038/s41467-021-22382-y

Optimized synthetic routes to pyridinium ions featuring two strongly π-donating R₃P=N− substituents are presented. These substituents cause severe disruption in aromaticity in these cations, and also impart exceptional reducing ability to the related bispyridinylidenes (neutral 2 e- donors). Preliminary reactivity studies show some enhanced reducing capabilities owing to the low redox potential of the bispyridinylidene.

Abstract

Optimized synthetic procedures for pyridinium ions featuring iminophosphorano (−N=PR₃; R=Ph, Cy) π-donor substituents in the 2- and 4- positions are described. Crystallographic and theoretical studies reveal that the strongly donating substituents severely polarize the π-electrons of the pyridyl ring at the expense of aromaticity. Moreover, the pyridinium ions are readily deprotonated to generate powerful bispyridinylidene (BPY) organic electron donors. Electrochemical studies show exceptionally low redox potentials for the two-electron BPY/BPY²⁺ couples, ranging from −1.71 V vs the saturated calomel electrode for 3PhPh (with four Ph₃P=N− groups) to −1.85 V for 3CyCy (with four Cy₃P=N− groups). These new compounds represent the most reducing neutral organic electron donors (OEDs) currently known. Some preliminary reductions involving 3CyCy showed enhanced capability owing to its low redox potential, such as the thermally activated reduction of an aryl chloride, but purification challenges were often encountered.

Metal-free dearomatization of N-heteroarenes is a well-known and powerful method to yield partially saturated N-heterocyclic building blocks. Yet, the use of sensitive reagents restricts the applicability in synthetic laboratories. Herein, we present a very mild and selective reduction of N-heteroarenes by amine borane to synthesize a broad variety of N-substituted 1,4- and 1,2-dihydropyridines.

Abstract

Dearomatization is an effective method to transform readily available N-heterocycles into partially saturated motifs. Manipulation of dihydro-derivatives holds great potential and provides access to a variety of semi-saturated N-heterocyclic building blocks. However, current strategies are limited in scope and the use of sensitive reagents restricts the applicability in synthetic laboratories. Herein, we report the synthesis of a broad variety of N-substituted 1,4- and 1,2-dihydropyridines by very mild and selective reduction with amine borane for the first time.

Nature Chemistry, Published online: 08 April 2021; doi:10.1038/s41557-021-00668-4

Mild methods to cleave the carbon-oxygen (C–O) bond in alkyl ethers could simplify chemical syntheses through the elaboration of these robust, readily available precursors. Here we report that dibromoboranes react with alkyl ethers in the presence of a nickel catalyst and zinc reductant to insert boron into the C–O bond. Subsequent reactivity can effect oxygen-to-nitrogen substitution or one-carbon homologation of cyclic ethers and more broadly streamline preparation of bioactive compounds. Mechanistic studies reveal a cleavage-then-rebound pathway via zinc/nickel tandem catalysis.

The development of dual catalytic systems mediated by light is on the rise. In particular, light-mediated N-heterocyclic carbene catalysis has recently experienced an exponential growth. This minireview gives an overview on the activation modes and synthetic opportunities that the combination of photoredox/NHC catalysis has to offer and discuss other approaches that do not require the use of an external photocatalyst.

Abstract

The combination of photocatalysis with other ground state catalytic systems have attracted much attention recently due to the enormous synthetic potential offered by a dual activation mode. The use of N-heterocyclic carbene (NHC) as organocatalysts emerged as an important synthetic tool. Its ability to harness umpolung reactivity by the formation of the Breslow intermediate has been employed in the synthesis of thousands of biologically important compounds. However, the available coupling partners are relatively restricted, and its combination with other catalytic systems might improve its synthetic versatility. Thus, merging photoredox and N-heterocyclic carbene (NHC) catalysis has emerged recently as a powerful strategy to develop new transformations and give access to a whole new branch of synthetic possibilities. This review compiles the NHC catalyzed methods mediated by light, either in the presence or absence of an external photocatalyst, that have been described so far, and aims to give an accurate overview of the potential of this activation mode.

A novel tandem catalytic route was developed for the selective production of 2-methyl piperidine (MP) or 6-methylpiperidin-2-one (MPO) from biomass-derived triacetic acid lactone (TAL), which opens the way for efficient production of piperidine and δ-lactam chemicals from renewable biomass.

Abstract

Piperidine and δ-Lactam chemicals have wide application, which are currently produced from fossil resource in industry. Production of this kind of chemicals from lignocellulosic biomass is of great importance, but is challenging and the reported routes give low yield. Herein, we demonstrate the strategy to synthesize 2-methyl piperidine (MP) and 6-methylpiperidin-2-one (MPO) from biomass-derived triacetic acid lactone (TAL) that is produced microbially from glucose. In this route, TAL was firstly converted into 4-hydroxy-6-methylpyridin-2(1H)-one (HMPO) through facile aminolysis, subsequently HMPO was selectively transformed into MP or MPO over Ru catalysts supported on beta zeolite (Ru/BEA-X, X is the molar ratio of Si to Al) via the tandem reaction. It was found that the yield of MP could reach 76.5 % over Ru/BEA-60 in t-BuOH, and the yield of MPO could be 78.5 % in dioxane. Systematic studies reveal that the excellent catalytic performance of Ru/BEA-60 was closely correlated with the cooperative effects between active metal and acidic zeolite with large pore geometries. The related reaction pathway was studied on the basis of control experiments.

Nature Communications, Published online: 06 April 2021; doi:10.1038/s41467-021-22292-z

Nature Chemistry, Published online: 05 April 2021; doi:10.1038/s41557-021-00657-7