Biaryl Couplings Research Articles

Development of a P450 Fusion Enzyme for Biaryl Coupling in Yeast.

Despite the diverse and potent bioactivities displayed by axially chiral biaryl natural products, their application in drug discovery is limited by restricted access to these complex molecular scaffolds. In particular, fundamental challenges remain in controlling the site- and atroposelectivity in biaryl coupling reactions. In contrast, Nature has a wealth of biosynthetic enzymes that catalyze biaryl coupling reactions with catalyst-controlled selectivity. In particular, a growing subset of fungal P450s have been identified to catalyze site- and atroposelective biaryl couplings. Herein, we optimize a whole-cell biocatalytic platform in Pichia pastoris to synthesize biaryl molecules through the recombinant production of the fungal P450 KtnC. Moreover, engineering redox self-sufficient fusion enzymes further improves the efficiency of the system. Altogether, this work provides a platform for biaryl coupling reactions in yeast that can be applied to engineering a currently underexplored pool of fungal P450s into selective biocatalysts for the synthesis of complex biaryl compounds.

A Review on Oxidative Gold‐Catalyzed C‐H Arylation of Arenes – Challenges and Opportunities

Cross‐coupling strategies have become essential in modern organic synthesis. While palladium has historically dominated this field, other transition metals have arisen as potent and orthogonal alternatives. Gold, typically thought of as just a Lewis acid, has recently demonstrated redox chemistry in several cross‐coupling reactions using an external oxidant. One of these branches, oxidative C–H functionalizations, has made significant advances in recent years. Herein, we discuss the discovery and development of gold catalysis in this realm with particular focus on improvements in scope and mechanistic understandings in relation to biaryl couplings.

Acyclic, Linear Oligo-meta-phenylenes as Multipotent Base Materials for Highly Efficient Single-layer Organic Light-emitting Devices.

Oligo-meta-phenylenes have been designed and synthesized as multipotent base materials of single-layer organic light-emitting devices. Simple molecular structures of oligo-meta-phenylenes composed of linear phenylene arrays benefited from the wealth of modern reactions available for biaryl couplings and were concisely synthesized in a series. Structure-performance relationship studies with the first seven congeners revealed key features important for the multipotent materials in single-layer devices. As a result, highly efficient phosphorescent electroluminescence was made possible in a highly simplified device architecture comprising one-region, single-layer configurations. Detailed investigations with hole-only devices disclosed that the hole mobility was effectively retarded by potent materials, which should facilitate hole/electron recombination for electroluminescence.

Iron‐Catalyzed Room Temperature Cross‐Couplings of Bromophenols with Aryl Grignard Reagents

AbstractHerein we report a room temperature Fe‐catalyzed coupling reaction of various bromophenols with aryl Grignard reagents, which exhibits a wide substrate scope and high functional group tolerance. For the first time, the combination of simple Fe(acac)3/PBu3/Ti(OEt)4 has been used as an effective catalyst for the biaryl couplings of bromophenols or their Na or K salts with debromination and etherification side reactions being well suppressed. Various biphenols including natural product garcibiphenyl C as well as pharmaceutical diflunisal and its ethyl ester were facilely synthesized using the present protocol.magnified image

Phenolate Enabled General and Selective Fe/Ti Cocatalyzed Biaryl Cross-Couplings between Aryl Halides and Aryl Grignard Reagents.

The serendipitous addition of a phenolate to FeCl3/TMEDA/Ti(OEt)4 enables a strong Fe/Ti cooperativity that can efficiently catalyze a general and selective biaryl-coupling reaction. In the absence of phosphine or NHC ligands, various aryl chlorides, bromides, and iodides can couple with a variety of common and Knochel-type aryl Grignard reagents. A wide range of sensitive functional groups in either coupling partner can be tolerated. This bimetallic cocatalysis not only remarkably extends the scope of Fe-catalyzed biaryl couplings but also provides a solution to the problem of functional group compatibility of Grignard reagents.

Iron-catalysed substrate-directed Suzuki biaryl cross-coupling

Although the replacement of ubiquitous palladium catalysts with more sustainable iron-based analogues continues apace, the simple biaryl Suzuki cross-coupling reaction remains stubbornly elusive. It appears that the main issue hampering the reaction is activation of the aryl halide C–X bond. Here we show that a simple N-pyrrole amide and related directing groups on the aryl halide substrates facilitate this process by transient π-coordination to the iron centre. This allows iron-catalysed Suzuki biaryl cross-coupling to proceed, under mild conditions, with alkyllithium-activated aryl pinacol boronic esters. Cross-coupling of aryl compounds is one of the most powerful carbon–carbon bond forming reactions available, and typically involves the use of expensive and scarce palladium salts. Here Bedford and co-workers show that iron can be an effective catalyst for Suzuki biaryl couplings.

Iron-catalysed Suzuki biaryl couplings

Although the replacement of palladium with iron in metal-catalysed cross-couplings continues apace, the Suzuki synthesis of biaryls — arguably the most widely used class of such C–C bond formations — has remained elusive. Now, by use of a π-coordinating directing group, another step has been taken toward iron-catalysed Suzuki reactions.

A Planar‐Chiral Phosphino(alkenyl)ferrocene for Suzuki–Miyaura C–C Coupling Reactions (Eur. J. Org. Chem. 30/2014)

The cover picture shows the graphical representation of a planar-chiral phosphino(alkenyl)ferrocene in a fictional pass in the Erzgebirge (Ore Mountains) at the junction of two paths. The article by H. Lang et al. on p. 6676 ff describes the use of this compound for the atropselective synthesis of sterically congested biaryls by a Suzuki–Miyaura coupling. One of these biaryls is depicted in the back of the cartoon. This research is motivated by the fact that the synthesis of sterically congested biaryls and atropselective biaryl couplings are almost exclusively considered as individual topics. In this respect, the ferrocene unit is excellently suited to combine these two fields exerting the intrinsic chirality of 1,2-heterodisubstituted ferrocenes. Investigations demonstrating proof of principle are presented in this article. Reference to Chemnitz, the hometown of the authors, is made by the colourful chimney, the newest landmark in the region, which is the highest building in Saxony.

ChemInform Abstract: Selective Co/Ti Cooperatively Catalyzed Biaryl Couplings of Aryl Halides with Aryl Metal Reagents.

Various aryl bromides or chlorides, including those bearing a free COOH, OH, CONHR, and SO2NHR group, coupled with aryl magnesium or lithium reagents in the presence of 7.5 mol % CoCl2/15 mol % PBu3 and substoichiometric Ti(OEt)4 (40 mol % to ArM) at room temperature in high yields with high chemo- and regioslectivity. This simple reaction represents the first example of Co/Ti cooperative catalysis which plays a key role in suppressing undesired homocouplings.

Copper-Mediated Direct Arylation of Azole Compounds

This account briefly summarizes recent development of copper-mediated direct arylations of 1,3-azole compounds by our group. Various azoles undergo the direct arylation with aryl iodides in the presence of CuI and an appropriate base to afford the corresponding heterobiaryls. On the other hand, Cu(OAc)2 enables more challenging dehydrogenative biaryl couplings via twofold C–H cleavage of starting arenes, providing the most straightforward and ultimately ideal approach to the biaryl motif. Moreover, an annulative dehydrogenative coupling with o-alkynylphenols and anilines is also possible under CuF2-mediated conditions to form azole-benzofuran and -indole conjugations directly. All the reactions proceed effectively without any precious transition metal catalysts such as palladium, rhodium, and ruthenium.

Development of Efficient Asymmetric Suzuki-Miyaura Cross-Coupling and Applications in Synthesis

A series of structurally rigid, sterically bulky biaryl monophosphorus ligands were designed and synthesized to investigate the reactivity and stereoselectivity of asymmetric Suzuki-Miyaura cross-coupling reaction. High efficiencies were achieved in sterically demanding cross-couplings for the synthesis of tetra-ortho-substituted biaryls with various functional- ities. Sterically demanding aryl-alkyl Suzuki-Miyaura couplings between di-ortho-substituted aryl halides and secondary al- kylboronic acids were also successful. In achieving efficient asymmetric Suzuki-Miyaura coupling, we implemented a new concept by employment of a chiral biaryl monophosphorus ligand developed in the group as well as utilization of a secondary interaction between two coupling partner. Using a π-π interaction of a benzooxazolidinone substituent with one aryl partner, we developed enantioselective biaryl couplings containing ortho-carbonyl substituents. High enantioselectivities were also achieved in biaryl coupling containing ortho-oxy substituents by utilizing a polar-π interaction between a polar bis(2- oxo-3-oxazolidinyl)phosphonic (BOP) substituent and one aryl partner. The methodology enabled us for the first time to im- plement efficient asymmetric Suzuki-Miyaura coupling in total synthesis and accomplish the syntheses of chiral biaryl natural products korupensamines A and B, ultimately a concise and stereoselective synthesis of michellamine B. Keywords monophosphorus ligand; sterically demanding; Suzuki-Miyaura coupling; secondary interaction; total synthesis

Selective Co/Ti Cooperatively Catalyzed Biaryl Couplings of Aryl Halides with Aryl Metal Reagents

Various aryl bromides or chlorides, including those bearing a free COOH, OH, CONHR, and SO2NHR group, coupled with aryl magnesium or lithium reagents in the presence of 7.5 mol % CoCl2/15 mol % PBu3 and substoichiometric Ti(OEt)4 (40 mol % to ArM) at room temperature in high yields with high chemo- and regioslectivity. This simple reaction represents the first example of Co/Ti cooperative catalysis which plays a key role in suppressing undesired homocouplings.

ChemInform Abstract: Highly Efficient Carbazolyl‐Derived Phosphine Ligands: Application to Sterically Hindered Biaryl Couplings.

AbstractA novel carbazolyl‐containing phosphine ligand is prepared and successfully applied in the Suzuki—Miyaura coupling reaction.

Highly efficient carbazolyl-derived phosphine ligands: application to sterically hindered biaryl couplings

A new family of phosphine ligands bearing a bulky carbazolyl scaffold is described. With the combination of ligand 2a and Pd(OAc)(2), difficult tri-ortho-substituted biaryl couplings are accomplished smoothly. In particular, the catalyst loading as low as 0.02 mol% of Pd for non-activated 2,6-disubstituted aryl chloride coupling can be achieved.

A General Palladium Catalyst System for Suzuki−Miyaura Coupling of Potassium Aryltrifluoroborates and Aryl Mesylates

The first general examples of palladium-catalyzed Suzuki-type cross-coupling of aryl and heteroaryl mesylates with potassium aryl and heteroaryltrifluoroborates are presented. In addition to biaryl couplings, the cross-coupling reactions of aryl mesylates with alkyl and vinyltrifluoroborate salts have also been successfully accomplished.

A Convenient Catalyst for Aqueous and Protein Suzuki−Miyaura Cross-Coupling

A phosphine-free palladium catalyst for aqueous Suzuki-Miyaura cross-coupling is presented. The catalyst is active enough to mediate hindered, ortho-substituted biaryl couplings but mild enough for use on peptides and proteins. The Suzuki-Miyaura couplings on protein substrates are the first to proceed in useful conversions. Notably, hydrophobic aryl and vinyl groups can be transferred to the protein surface without the aid of organic solvent since the aryl- and vinylboronic acids used in the coupling are water-soluble as borate salts. The convenience and activity of this catalyst prompts use in both general synthesis and bioconjugation.

Palladium Catalysts Supported on Mesoporous Molecular Sieves Bearing Nitrogen Donor Groups: Preparation and Use in Heck and Suzuki CC Bond‐Forming Reactions

A series of supported catalysts is prepared by treatment of SBA-15-type mesoporous molecular sieve bearing [triple chemical bond]SiCH(2)CH(2)CH(2)NHCH(2)CH(2)NEt(2) groups with palladium(II) acetate. These catalysts are studied in Suzuki biaryl couplings and in Heck reactions to establish the influence of metal loading and innocent surface modifications (trimethylsilylation). The Suzuki reaction proceeded efficiently with model and practically relevant substrates; the catalyst performance increasing with an increasing degree of metalation (decreasing N/Pd ratio). Catalyst poisoning tests revealed that the reaction takes place in the liquid phase with the catalyst serving as a reservoir of active metal species and also as a stabilizing support once the reaction is performed. In the Heck reactions, on the other hand, the catalyst performance strongly changed with the reaction temperature and with the N/Pd ratio. The material with the lowest metal loading (0.01 mmol palladium per gram of material, N/Pd ratio ca. 100:1) proved particularly attractive in the Heck coupling, being highly active at elevated temperatures, recyclable, and capable of acting as a bifunctional catalyst (i.e., functioning without any external base.

Total synthesis of chiral biaryl natural products by asymmetric biaryl coupling

This tutorial review highlights the use of catalytic asymmetric 2-naphthol couplings in total synthesis. The types of chirality, chiral biaryl natural products, prior approaches to chiral biaryl natural products, and other catalytic asymmetric biaryl couplings are outlined. The three main categories of chiral catalysts for 2-naphthol coupling (Cu, V, Fe) are described with discussion of their limitations and advantages. Applications of the copper catalyzed couplings in biomimetic syntheses are discussed including nigerone, hypocrellin, calphostin D, phleichrome, and cercosporin.

Enantioselective Reduction of Biaryl Lactones via DKR

Chiral biaryl compounds are typically accessed by biaryl couplings followed by a resolution; a challenging approach in cases of hindered ortho-substituted aryl partners. The above strategy is advantageous since the biaryl coupling is effected on intramolecular aryl partners tethered by an ester function. The racemic atropisomer mixture is submitted to a dynamic kinetic resolution (DKR) where asymmetric reduction occurs at a temperature where rapid isomerization of the atropisomers can take place. Reduction of the matched atropisomer fully converts the racemic mixture into the desired enantiomer of the biaryl compound in high enantiomeric ecxess.

The Synthesis of Heterocyclic Compounds with Hypervalent Organoiodine Reagents

AbstractFor Abstract see ChemInform Abstract in Full Text.