Asymmetric synthesis of antimicrotubule biaryl hybrids of allocolchicine and steganacin

The asymmetric synthesis of novel axially chiral biaryl compounds 5 a-f containing a seven- or eight-membered heterocyclic medium ring is described. These molecules can be considered to be structural hybrids of allocolchicine- and steganacin-type natural products. The synthesis featured an atropo-diastereoselective biaryl Suzuki coupling in which a benzylic stereocenter efficiently transferred its stereochemical information to the biaryl axis. The coupling conditions were optimized, and two biphenylphosphane ligands (DavePhos and S-Phos) were found to give the highest yields and diastereoselectivities. A three-element stereochemical model was proposed to explain the observed diastereoselectivities. In a second key step, the medium ring of the target molecules was formed by a stereoselective S(N)1-type cyclodehydration that probably involved a configurationally stable carbocationic intermediate, as supported by calculations. Alternatively, S(N)2-type cyclizations were employed on the same Suzuki coupling products to give the target molecules in a stereodivergent or stereoconvergent manner. These cyclization methods furnished the target hybrid analogues 5 a-f with ee values above 94 %. All analogues were evaluated as antimicrotubule agents and against a panel of cancer-cell lines using colchicine (1) and N-acetylcolchinol (3) as references. Promising activities were found for R,aR-configured compounds 5 a, b and 5 f; in particular, ethyl analogue 5 b showed a twofold antimicrotubule activity relative to colchicine.     

Microwave-assisted transition-metal-catalyzed synthesis of N-shifted and ring-expanded buflavine analogues

Two novel and efficient strategies for the synthesis of hitherto unknown N-shifted and ring-expanded buflavine analogues are presented. Construction of the medium-sized ring system of the title molecules, a difficult task due to the high activation energy needed for the ring-closure with the additional rigidity imposed by the biaryl skeleton, was achieved by using Suzuki-Miyaura biaryl coupling and a ring-closing metathesis reaction as the key steps. The combination of a second-generation Grubbs catalyst and microwave irradiation proved to be highly useful in generating the otherwise difficult to obtain medium-sized ring system of the buflavine analogues.     

Seven- and eight-membered heterocyclic biaryl synthesis through a metal-free oxidative coupling reaction

A metal-free intramolecular biaryl coupling mediated by DDQ and BF₃·OEt₂ was developed. The reaction proceeds smoothly at room temperature to give seven- and eight-membered heterocyclic biaryl compounds in up to 95% yields. Only 1 equiv of DDQ sufficed for the reaction, obviating the use of a large excess of oxidants and undesired chlorination pathway in metal-mediated process.     

Comparison of facially amphiphilic biaryl dendrimers with classical amphiphilic ones using protein surface recognition as the tool

Facially amphiphilic biaryl dendrimers are compared with the more classical benzyl ether amphiphilic dendrimers for molecular recognition, using protein binding as the probe. The protein used for the proposed study is chymotrypsin (ChT). A generation-dependent binding affinity was observed with the benzyl ether dendrimers, while the affinities were independent of generation in the case of the biaryl dendrimers. Similarly, although the ligands incorporated in both dendrons are the same, the biaryl dendrimers are able to bind more proteins compared to the benzyl ether dendrimers. For example, G3-dendron of biaryl dendrimer can bind six molecules of chymotrypsin, whereas G3-analogue of benzyl ether dendrimers can bind only three molecules of chymotrypsin. This result is consistent with our hypothesis that the internal layers of the facially amphiphilic biaryl dendrons are solvent-exposed and accessible for recognition. In addition, the systematic size differences in dendrons were also used to gain insights into the substrate selectivity that the enzyme gains upon binding to a ligand scaffold.     

Palladium-catalyzed benzoin-mediated redox process leading to biaryls from aryl halides

An expedient synthetic procedure of biaryl derivatives was developed using a palladium-catalyzed, benzoin-mediated redox process from aryl halides. Various biaryls were synthesized in good yields in short time.     

Solid-phase synthesis of biaryl cyclic peptides by borylation and microwave-assisted intramolecular Suzuki-Miyaura reaction

Miyaura borylation and Suzuki-Miyaura cross-coupling have been combined to set up an efficient strategy for the solid-phase synthesis of biaryl cyclic peptides. The Miyaura borylation was the key step in obtaining the linear peptidyl resin precursor containing both the boronate and the halogenated derivative of an aromatic amino acid. The Suzuki-Miyaura macrocyclization was performed under microwave irradiation leading to biaryl cyclic peptides of different ring sizes.     

Synthesis and characterization of a functionalized chiral biaryl capable of exhibiting unidirectional bond rotation

A class of chiral biaryl molecules that have been designed to undergo unidirectional rotation about the aryl–aryl bond may show promise for future application in the area of synthetic molecular motors. These asymmetric molecules should be capable of channeling chemical energy into repeated 360° rotation in one direction. Herein we report the synthesis and characterization of one such biaryl molecule (1).     

The Biocatalytic Repertoire of Natural Biaryl Formation

The catalytic and selective construction of carbon–carbon bonds for the generation of complex molecules is one of the most important tasks in organic chemistry. This was clearly highlighted by the 2010 Nobel Prize in Chemistry, which was awarded for the development of Pd‐catalyzed cross‐coupling reactions. The underlying concept of cross‐linking building blocks to generate molecular complexity can also be widely found in natural product biosynthesis. Impressive examples for such natural cross‐coupling reactions are biosynthetic processes for the assembly of biaryl moieties in natural products—highly efficient enzymatic reactions that often achieve synthetically yet unmatched selectivities. This Minireview highlights selected examples that showcase these fascinating biotransformations.     

A new and direct approach to functionalized biaryl α-ketophosphonic acids via aqueous Suzuki coupling on solid support

A new method for the synthesis of functionalized biaryl α-ketophosphonic acids has been developed. The key step involves the use of sodium bromobenzoyl phosphonates to react with polymer-bound boronic acids via microwave-assisted aqueous Suzuki coupling. This approach provides rapid access to a wide range of diverse biaryl analogues containing an α-ketophosphonic acid moiety.     

Heck, direct arylation, and hydrogenation: two or three sequential reactions from a single catalyst

Palladium-catalyzed tandem multifunctional reactions leading to the synthesis of substituted biaryl molecules have been developed including tandem Heck-direct arylation and tandem-sequential Heck-direct arylation-hydrogenation. These reactions occur in good yield and have been employed in the synthesis of a cytotoxic biaryl compound.     

Efficient synthesis of substituted biaryl anilines and biaryl phenols via a Suzuki cross-coupling reaction

An efficient synthesis of biaryl building blocks with multiple point diversities via a Suzuki cross-coupling reaction using a commercially available preformed Pd catalyst 1 was reported. Substituted biaryl anilines and phenols were obtained in one step from commercially available aryl halides.     

New two-step sequence involving a hetero-Diels-Alder and a nonphenolic oxidative coupling reaction: a convergent access to analogs of steganacin

A new family of analogs of steganacin, an important antimitotic compound, was accessed. It takes advantage of a completely stereoselective sequence of two key steps. The central dihydropyrane core is built by a highly diastereoselective and facially controlled hetero-Diels-Alder reaction. It is followed by a nonphenolic biaryl oxidative coupling with a complete atropo-stereoselectivity. It leads to a quick way to form cyclic biaryl lignans.     

Easily prepared air- and moisture-stable Pd-NHC (NHC=N-heterocyclic carbene) complexes: a reliable, user-friendly, highly active palladium precatalyst for the Suzuki-Miyaura reaction

The synthesis of NHC-PdCl(2)-3-chloropyridine (NHC=N-heterocyclic carbene) complexes from readily available starting materials in air is described. The 2,6-diisopropylphenyl derivative was found to be highly catalytically active in alkyl-alkyl Suzuki and Negishi cross-coupling reactions. The synthesis, ease-of-use, and activity of this complex are substantial improvements over in situ catalyst generation and all current Pd-NHC complexes. The utilization of complex 4 led to the development of a reliable, easily employed Suzuki-Miyama protocol. Employing various reaction conditions allowed a large array of hindered biaryl and drug-like heteroaromatic compounds to be synthesized without difficulty.     

Synthesis of a (piperazin-1-ylmethyl)biaryl library via microwave-mediated Suzuki-Miyaura cross-couplings

Boc-protected (piperazin-1-ylmethyl)biaryls have been synthesised from (Boc-piperazin-1-ylmethyl)phenylboronic acid pinacol esters via a microwave-mediated Suzuki-Miyaura coupling with aryl bromides viz. 1-bromo-, 2-, 3- or 4-nitrobenzene or 2-bromo-5-nitropyridine. Judicial removal of the protecting group on the piperazine, or facile reduction of the nitro group on the biaryl system enabled the manipulation of two points of functionality in order to diversify the scope of the resulting biaryl library.     

Microwave-assisted direct biaryl coupling: first application to the synthesis of aporphines

We have investigated the use of microwaves in a direct biaryl coupling reaction for the synthesis of analogs of the aporphine alkaloid nantenine. Our study shows that the aporphine core may be rapidly accessed from benzyl-tetrahydroisoquinoline substrates with this method. This is the first report of a microwave-assisted direct biaryl coupling reaction in the synthesis of aporphine molecules.     

Efficient Synthesis of Diaryl Ketones by Nickel‐Catalyzed Negishi Cross‐Coupling of Amides by Carbon–Nitrogen Bond Cleavage at Room Temperature Accelerated by a Solvent Effect

The first Negishi cross‐coupling of amides for the synthesis of versatile diaryl ketones by selective C?N bond activation under exceedingly mild conditions is reported. The cross‐coupling was accomplished with bench‐stable, inexpensive precatalyst [Ni(PPh₃)₂Cl₂] that shows high functional‐group tolerance and enables the synthesis of highly functionalized diaryl ketone motifs. The coupling occurred with excellent chemoselectivity favoring the ketone (cf. biaryl) products. Notably, this process represents the mildest conditions for amide N?C bond activation accomplished to date (room temperature, <10 min). Considering the versatile role of polyfunctional biaryl ketone linchpins in modern organic synthesis, availability, and excellent functional‐group tolerance of organozinc reagents, this strategy provides a new platform for amide N?C bond/organozinc cross‐coupling under mild conditions.     

The coupling of aryl halides in the ionic liquid [bmim]PF6

Several aryl halides have been coupled using the zero valent nickel catalyst [(PPh₃)_nNi(0)], to give the biaryl in moderate to good yield, employing the ionic liquid [bmim]PF₆. The ionic liquid and catalyst were recycled after extraction of the biaryl.     

First total synthesis of tenuifolin via PIFA mediated oxidative biaryl coupling

The first total synthesis of a sesquiterpenoid, tenuifolin, was achieved in seven linear steps. Phenyliodine(III) bis(trifluoacetate) (PIFA) mediated oxidative biaryl coupling was employed as a key step to construct the central seven-membered ring with a double bond. The double bond formation was also exploited.     

Carrier Protein-Free Enzymatic Biaryl Coupling in Arylomycin A2 Assembly and Structure of the Cytochrome P450 AryC**

The arylomycin antibiotics are potent inhibitors of bacterial type I signal peptidase. These lipohexapeptides contain a biaryl structural motif reminiscent of glycopeptide antibiotics. We herein describe the functional and structural evaluation of AryC, the cytochrome P450 performing biaryl coupling in biosynthetic arylomycin assembly. Unlike its enzymatic counterparts in glycopeptide biosynthesis, AryC converts free substrates without the requirement of any protein interaction partner, likely enabled by a strongly hydrophobic cavity at the surface of AryC pointing to the substrate tunnel. This activity enables chemo-enzymatic assembly of arylomycin A2 that combines the advantages of liquid- and solid-phase peptide synthesis with late-stage enzymatic cross-coupling. The reactivity of AryC is unprecedented in cytochrome P450-mediated biaryl construction in non-ribosomal peptides, in which peptidyl carrier protein (PCP)-tethering so far was shown crucial both in vivo and in vitro.     

Palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of organoboronic acids with N-protected 4-iodophenyl alanine linked isoxazoles

Suzuki-Miyaura coupling reaction of N-protected 4-iodopheyl alanine isoxazoles with arylboronic acids, catalyzed by palladium, efficiently produce benzyl-N-(4-bipheyl)-2-(3-methyl-5(E)-2-aryl-1-ethenyl-4- isoxazolyl)-amino-2-oxoethyl) carba-mates in good yields. This process is first of its kind to construct carbon-carbon bond formation having biaryl motif on amino acid linked isoxazole moiety.