Biaryl Ether Research Articles

Macrocycles rapidly produced by multiple multicomponent reactions including bifunctional building blocks (MiBs)

Naturally occurring macrocycles often exhibit remarkable biological activities and, therefore, constitute an attractive starting point for diversity-oriented synthesis for lead discovery in drug development. Multicomponent reactions have been used for the introduction of chemical diversity in strategies towards macrocycle libraries, mostly by combinational synthesis of a linear precursor combined with a subsequent macrocyclization reaction. The Ugi reaction in particular may be used for the macrocyclization itself as well, and a library of natural product-like macrocycles can be constructed in a single step from simple precursors. The efficiency and versatility of both strategies is immense and is exemplarily illustrated by the construction of small libraries of cyclopeptide alkaloid derivatives and biaryl ether macrocycles. The syntheses of the latter compound group are examples of multiple multicomponent macrocyclizations including bifunctional building blocks (M3iB3 or MiB), of which the Ugi-MiBs and their variations are discussed in more detail.

A General and Efficient Protocol for the Synthesis of Biaryl Ethers from Aryl Silyl Ethers Using Cs2CO3.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The evolution of the matrix metalloproteinase inhibitor drug discovery program at abbott laboratories.

Matrix metalloproteinases (MMPs) have been implicated in several pathologies. At Abbott Laboratories, the matrix metalloproteinases inhibitor drug discovery program has focused on the discovery of a potent, selective, orally bioavailable MMP inhibitor for the treatment of cancer. The program evolved from early succinate-based inhibitors to utilizing in-house technology such as SAR by NMR to develop a novel class of biaryl hydroxamate MMP inhibitors. The metabolic instability of the biaryl hydroxamates led to the discovery of a new class of N-formylhydroxylamine (retrohydroxamate) biaryl ethers, exemplified by ABT-770 (16). Toxicity issues with this pre-clinical candidate led to the discovery of another novel class of retrohydroxamate MMP inhibitors, the phenoxyphenyl sulfones such as ABT-518 (19j). ABT-518 is a potent, orally bioavailable, selective inhibitor of MMP-2 and 9 over MMP-1 that has been evaluated in Phase I clinical trials in cancer patients.

Synthesis of a novel 14-membered highly constrained cyclic peptidic scaffold

The synthesis and NMR analysis of a novel highly constrained scaffold is described. The 14-membered macrocyclic ring structure was inspired by many medicinally relevant natural products that also contain the bi-aryl ether moiety. The synthesis required only commercially available starting materials and involved a base mediated SNAr cyclization. A conformational search was performed, which indicated a strong preference for a single conformation, which was consistent with observed ROE signals by NMR.

Rapid and Diverse Route to Natural Product‐Like Biaryl Ether Containing Macrocycles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A General and Efficient Protocol for the Synthesis of Biaryl Ethers from Aryl Silyl Ethers Using Cs2CO3

A general and efficient one-step procedure has been developed for the synthesis of biaryl ethers via direct coupling of electron-deficient arylhalides or aryl triflates to aryl t-butyldimethyl-silyl (TBS) ethers using Cs2CO3. The protocol was also applied to electron-rich arylhalides by addition of a catalytic amount of copper(I) iodide. The reaction is rapid and provides good to excellent yields.

Rapid and diverse route to natural product-like biaryl ether containing macrocycles

A two-step sequence involving an Ugi four-component reaction and an intramolecular nucleophilic aromatic substitution (S NAr) has been developed for the rapid access to biaryl-ether containing macrocycles. In the course of this study, we documented that ammonium chloride can promote the Ugi-4CR in non-polar aprotic solvent (toluene) without the interference of an alternative Passerini reaction. Solid phase synthesis of macrocycles by this two-step sequence was also developed using polymer (Wang resin) supported α-(4′-fluoro-3′-nitro)phenethyl isocyanoacetate as one of the inputs.

Aryl, Alkyl Bis-Silyl Ethers: Rapid Access to Monoprotected Aryl Alkyl and Biaryl Ethers.

For Abstract see ChemInform Abstract in Full Text.

Total synthesis of anti-HIV agent chloropeptin I.

A convergent diastereo- and enantioselective total synthesis of anti-HIV agent chloropeptin I is reported. Important features of the total synthesis include: (1) the use of Ti-catalyzed cyanide addition to imines to prepare a requisite amino acid moiety, (2) the discovery of the positive effect of MeOH in the Cu-mediated biaryl ether formation to afford one of the two macrocyclic peptide moieties, and (3) the discovery of the positive influence of collidine in the diastereoselective Pd-mediated cross-coupling to result in efficient formation of another macrocycle within this medicinally important molecule. This key step is performed in the presence of four unprotected phenols, two of which reside on dichlorophenylglycines.

Structural Determinants of Selective Thyromimetics

The thyromimetic GC-1 shows a preference for binding the beta form of the thyroid hormone receptor (TR). GC-1 was designed as an analogue of the thyromimetic DIMIT, which has a lower affinity for TR and is not selective. GC-1 has a methylene group linking its two aromatic rings and an oxyacetic acid polar side chain, while DIMIT has an ether oxygen linking its aromatic rings and an l-alanine polar side chain. The structural features of GC-1 that confer its greater affinity and selectivity compared to DIMIT were analyzed with the preparation of analogues that bear only one of their two different structural features. The analogue of GC-1 with a biaryl ether has selectivity comparable to that of GC-1, while the analogue of DIMIT with a methylene group linking its aromatic rings is only slightly selective. These results demonstrate that the oxyacetic acid side chain of GC-1 is critical in conferring TR-beta selectivity.

Aryl, Alkylbis-SilylEthers: Rapid Access to Monoprotected Aryl Alkyl and Biaryl Ethers

A simple one-pot procedure has been developed for the selective etherification of aryl silyl ethers in aryl, alkyl bis-silyl ethers to generate alkyl tert-butyldimethylsilyl-protected aryl alkyl ethers and biaryl ethers in good to excellent yields.

Critical Role of Diffraction Simulation in Establishing the Crystal and Molecular Structures of Poly(biaryl ether ketone)s

Molecular modeling and diffraction simulation studies of the biphenyl-based poly(ether ketone)s [O−Ar−Ar−O−Ar−CO−Ar−Ar−CO−Ar−]n (3) and [−O−Ar−Ar−CO−Ar−]n (4, Ar = 1,4-phenylene), coupled with data obtained from an oligomer single-crystal study, have enabled their crystal and molecular structures to be determined from X-ray powder data. A crystallographically disordered structure in which the ether and ketone linkages are distributed randomly over the bridging positions of the polymer chain is potentially available to both polymers and undoubtedly occurs in their random 1:2 copolymer (5). The disordered structure is monoclinic (rather than orthorhombic as has previously been proposed), in space group P21/b, with two chains per unit cell. Rietveld refinement of this structure for polymers 3 and 4, based on X-ray powder data, gave final agreement factors (Rwp) of 5.7% and 6.6%, respectively. Analysis of X-ray fiber data by diffraction simulation methods suggests that the disordered structure always predomin...

Application of ruthenium induced cyclization for construction of strained biaryl ether macrocyclic compounds

Synthesis of strained macrocyclic biaryl ethers of type 1 and 2 were accomplished using η 6-ruthenium-induced macroetherification. This novel application demonstrates the versatility of this method in construction of constrained macrocyclic biaryl ether ring systems.

ChemInform Abstract: A Rapid Access to Biaryl Ether Containing Macrocycles by Pairwise Use of Ugi 4CR and Intramolecular SNAr‐Based Cycloetherification.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Application of ruthenium-induced macrocyclization for the construction of macrocyclic depsipeptides.

The synthesis of a biaryl ether containing macrocyclic depsipeptide 1 was achieved in 6% overall yield. The desired macrocycle was constructed by cyclization of a phenol into eta(6)-ruthenium complex. The ruthenium metal was subsequently photolytically deprotected to obtain the macrocycle 1.

バンコマイシンの全合成研究 Ｋ．Ｃ．Ｎｉｃｏｌａｏｕ研究室に留学して

A number of valuable new synthetic strategies, such as the triazene-driven biaryl ether synthesis, have been developed during the total synthesis of vancomycin. Modern catalytic asymmetric reactions were employed for the construction of the required amino acid building blocks, which were then assembled to the appropriate peptide fragments, whose cyclization in the order A-B/C-O-D/D-O-E led to the framework of vancomycin aglycon. Sequential attachment of the required sugar moieties onto a suitably protected aglycon derivative, followed by deprotection, allowed the stereoselective total synthesis of the glycopeptide antibiotic vancomycin.

A rapid access to biaryl ether containing macrocycles by pairwise use of Ugi 4CR and intramolecular S(N)Ar-based cycloetherification.

[reaction: see text] From readily accessible starting materials, macrocycles with an endo aryl-aryl ether bond are synthesized in only two operations by combination of the Ugi four-component reaction and an intramolecular S(N)Ar reaction. The nitro group serves as an activator for the macrocyclization and provides a handle for the introduction of functional group diversity. A Ugi reaction promoted by ammonium chloride in aprotic solvent is documented for the first time.

ChemInform Abstract: Biaryl Ether Retrohydroxamates as Potent, Long‐Lived, Orally Bioavailable MMP Inhibitors.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Biaryl Ether Retrohydroxamates as Potent, Long-lived, Orally Bioavailable MMP Inhibitors

A novel series of biaryl ether reverse hydroxamate MMP inhibitors has been developed. These compounds are potent MMP-2 inhibitors with limited activity against MMP-1. Select members of this series exhibit excellent pharmacokinetic properties with long elimination half-lives (7 h) and high oral bioavailability (100%).

Atropisomerism, biphenyls and the Suzuki coupling: peptide antibiotics

The formidable synthetic challenge posed by the vancomycin class of glycopeptide antibiotics has only recently been met. Foremost among the difficulties associated with the synthesis of these molecules is the control of non-conventional stereochemical issues. These are a consequence of the molecules possessing biphenyl and biaryl ether linkages between amino acid residues situated within the constituent macrocycles. Among the keys to success is the availability of methods that allow the efficient formation of biaryl linkages between amino acid derivatives under mild conditions. Recent progress in the chemistry of the Suzuki coupling suggests that this constitutes a very powerful and general method for the synthesis of peptide biphenyls.