Indole and azaindole halogenation catalyzed by the RebH enzyme variant 3-LSR utilizing co-purified reductase.

Biocatalytic C-H halogenation is becoming increasingly attractive due to excellent catalyst-controlled selectivity and environmentally benign reaction conditions. Significant efforts have been made on enzymatic halogenation of industrial arenes in a cost-effective manner. Here we report an unprecedented enzymatic halogenation of a panel of industrially important indole, azaindole and anthranilamide derivatives using a thermostable RebH variant without addition of any external flavin reductase enzyme.

Halogenation of Peptides and Proteins Using Engineered Tryptophan Halogenase Enzymes.

Halogenation of bioactive peptides via incorporation of non-natural amino acid derivatives during chemical synthesis is a common strategy to enhance functionality. Bacterial tyrptophan halogenases efficiently catalyze regiospecific halogenation of the free amino acid tryptophan, both in vitro and in vivo. Expansion of their substrate scope to peptides and proteins would facilitate highly-regulated post-synthesis/expression halogenation.

Engineered RebH Halogenase Variants Demonstrating a Specificity Switch from Tryptophan towards Novel Indole Compounds.

Activating industrially important aromatic hydrocarbons by installing halogen atoms is extremely important in organic synthesis and often improves the pharmacological properties of drug molecules. To this end, tryptophan halogenase enzymes are potentially valuable tools for regioselective halogenation of arenes, including various industrially important indole derivatives and similar scaffolds. Although endogenous enzymes show reasonable substrate scope towards indole compounds, their efficacy can often be improved by engineering.

A visible light-mediated, decarboxylative, desulfonylative Smiles rearrangement for general arylethylamine syntheses.

A decarboxylative, desulfonylative Smiles rearrangement is presented that employs activated-ester/energy transfer catalysis to decarboxylate β-amino acid derived starting materials at room-temperature under visible light irradiation. The radical Smiles rearrangement gives a range of biologically active arylethylamine products highly relevant to the pharmaceutical industry, chemical biology and materials science. The reaction is then applied to the synthesis of a chiral unnatural amino acid, 2-thienylalanine, used in the treatment of phenylketonuria.

Cobalt-Catalyzed Cross-Coupling Reactions of Aryl Triflates and Lithium Arylborates.

A catalyst system comprising CoCl/IAd·HBF enables the Suzuki-Miyaura cross-coupling reaction of a broad range of aryl triflates and arylboronic esters that are activated by -butyllithium.

Alkene Carboarylation through Catalyst-Free, Visible Light-Mediated Smiles Rearrangement.

A light-mediated Truce-Smiles arylative rearrangement is described that proceeds in the absence of any photocatalyst. The protocol creates two C-C bonds from simple starting materials, with the installation of an aryl ring and a difluoroacetate moiety across unactivated alkenes. The reaction proceeds via a radical mechanism, utilizing a light-mediated reduction of ethyl bromodifluoroacetate by N,N,N',N'-tetramethylethylenediamine (TMEDA) to set up intermolecular addition to an unactivated alkene, followed by Truce-Smiles rearrangement.

Ring-expanded N-heterocyclic carbenes as ligands in iron-catalysed cross-coupling reactions of arylmagnesium reagents and aryl chlorides.

The structure-activity relationship of expanded-ring N-heterocyclic carbenes (NHCs) in the iron-catalysed Kumada aryl-aryl coupling reaction was explored. This was achieved by comparing the catalytic performance of Fe-NHC catalysts generated in situ containing NHCs that differ in steric bulk. In particular, the influences of ring sizes (5-8) and N-aryl substituents were explored in terms of spectroscopic and structural features, which affect their %Vbur values.

Nickel-catalysed cyclopropanation of electron-deficient alkenes with diiodomethane and diethylzinc.

In the presence of a nickel catalyst, the cyclopropanation of electron-deficient alkenes with diiodomethane and diethylzinc is drastically accelerated. A wide range of cyclopropyl ketones, esters and amides can be accessed under these conditions.

Iron(ii) triflate/N-heterocyclic carbene-catalysed cross-coupling of arylmagnesiums with aryl chlorides and tosylates.

In comparison to iron(ii) halides, iron(ii) triflate exhibits a greater resistance towards reduction by p-tolylmagnesium bromide. This knowledge has led to the development of an iron(ii) triflate/N-heterocyclic carbene-catalysed cross-coupling system of aryl Grignard reagents with aryl chlorides and tosylates with high efficiency, even surpassing that of previously reported catalyst systems employing strongly coordinating counterions in some cases.

Mechanistic Evaluation of the Ni(IPr)-Catalyzed Cycloaddition of Alkynes and Nitriles to Afford Pyridines: Evidence for the Formation of a Key -Ni(IPr)(RCN) Intermediate.

A detailed mechanistic evaluation of the Ni(IPr)-catalyzed [2+2+2]-cycloaddition of diynes and nitriles was 2 conducted. Through kinetic analysis of these reactions, observed regioselectivities of the products, and stoichiometric reactions, Ni(IPr)-catalyzed cycloadditions of diynes and nitriles appear to proceed by a heterooxidative coupling mechanism, contrary to other common cycloaddition catalysts. Reaction profiles demonstrated strong dependence in nitrile, resulting in variable nitrile-dependent resting states.

Selective Kumada biaryl cross-coupling reaction enabled by an iron(III) alkoxide-N-heterocyclic carbene catalyst system.

A catalyst system comprising Fe2(O(t)Bu)6 and an N-heterocyclic carbene ligand enables efficient syntheses of (hetero)biaryls from the reactions of aryl Grignard reagents with a diverse spectrum of (hetero)aryl chlorides. Amongst the alkoxide and amide counterions investigated, tert-butoxide was the most effective in inhibiting the homocoupling of arylmagnesiums.

Cascade fluorofunctionalisation of 2,3-unsubstituted indoles by means of electrophilic fluorination.

Cascade fluorofunctionalisation of 2,3-unsubstituted indoles featuring the formation of C-C, C-F and C-O bonds via electrophilic fluorination using N-fluorobenzenesulfonimide is described. The use of an O-nucleophile tethered to the nitrogen of indoles enables the synthesis of polycyclic fluorinated indoline derivatives from simple precursors in 40-63% yields.

Regioselective copper-catalyzed carboxylation of allylboronates with carbon dioxide.

In the presence of a Cu(I)/NHC catalyst, the reactions of allylboronic pinacol esters with CO2 (1 atm) are highly regioselective, giving exclusively the more substituted β,γ-unsaturated carboxylic acids in most cases. A diverse array of substituted carboxylic acids can be prepared via this method, including compounds featuring all-carbon quaternary centers.

Direct conversion of indoles to 3,3-difluoro-2-oxindoles via electrophilic fluorination.

3,3-Difluoro-2-oxindoles can be obtained directly from indoles in moderate yields via electrophilic fluorination using N-fluorobenzenesulfonimide as a mild fluorinating reagent. The presence of tert-butyl hydroperoxide during the reaction, together with additional heating after quenching the reaction with triethylamine, is beneficial to the formation of the desired product.

The discovery of [Ni(NHC)RCN]2 species and their role as cycloaddition catalysts for the formation of pyridines.

The reaction of Ni(COD)(2), IPr, and nitrile affords dimeric [Ni(IPr)RCN](2) in high yields. X-ray analysis revealed these species display simultaneous η(1)- and η(2)-nitrile binding modes. These dimers are catalytically competent in the formation of pyridines from the cycloaddition of diynes and nitriles.

Copper-catalyzed alkene arylation with diaryliodonium salts.

Alkenes and arenes represent two classes of feedstock compounds whose union has fundamental importance to synthetic organic chemistry. We report a new approach to alkene arylation using diaryliodonium salts and Cu catalysis. Using a range of simple alkenes, we have shown that the product outcomes differ significantly from those commonly obtained by the Heck reaction.

Synthesis of biindolyls via palladium-catalyzed reactions.

An unprecedented synthesis of a range of high value homo- and heterobiindolyls is presented. The one-pot Miyaura borylation and subsequent Suzuki-Miyaura coupling sequence allows for the construction of the highly sterically congested C-C bond between two bromoindoles in modest to good overall yields.

A nickel-catalyzed route to pyridines.

A mild and general route for preparing pyridines from nitriles and diynes is described. Ni/imidazolyidene complexes were used to mediate cyclization alkynes and both aryl and alkyl nitriles at ambient temperature. In addition, the efficacy of this protocol allows for the preparation of a fused seven-membered pyridone and for intermolecular cyclizations.

N-heterocyclic carbenes as highly efficient catalysts for the cyclotrimerization of isocyanates.

[reaction: see text] A series of N-heterocyclic carbenes (NHCs) were evaluated as potential catalysts for the cyclotrimerization of isocyanates to afford isocyanurates. 1,3-Bis-(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene (SIPr) was found to be a highly efficient catalyst for the cyclotrimerization of a variety of isocyanates.

Nickel-catalyzed cycloaddition of alkynes and isocyanates.

A mild and general route for preparing 2-pyridones from isocyanates and diynes is described. Ni imidazolyidene complexes were used to mediate cyclizations between both internal and terminal diynes with aryl and alkyl isocyanates. In addition, the efficacy of this protocol allows for the preparation of a fused seven-membered pyridone and for three component cyclizations.

Reversible carboxylation of N-heterocyclic carbenes.

Spectroscopic analysis, thermogravimetric analysis, and crossover experiments performed on a series of imidazolium carboxylates revealed carboxylation was reversible with N-aryl substituted adducts.