Direct synthesis of the arylboronic acid analogues of phenylglycine via microwave-assisted four-component Ugi reaction

A four-component Ugi reaction (Ugi-4CR) utilizing formylphenyl boronic acids under mild condition was developed for the synthesis of arylboronic acid analogs. The reactions were performed in methanol and accelerated by microwave irradiation, which makes this strategy suitable for constructing boronic-containing chemical libraries. Two of the synthesized analogs were found to have cytotoxic activity against HepG2, MDA-MB231, and A549 cancer cell lines, demonstrating the potential application of this approach in developing novel boron-containing pharmaceuticals.     

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.     

Planar Antiaromatic Core-Modified 24π Hexaphyrin(1.0.1.0.1.0) and 32π Octaphyrin(1.0.1.0.1.0.1.0) Bearing Alternate Hybrid Diheterole Units

The Lewis acid catalyzed self-condensation of hybrid diheterole (furan-pyrrole and thiophene-pyrrole) precursors has afforded novel Hückel antiaromatic 24π hexaphyrin(1.0.1.0.1.0) and 32π octaphyrin(1.0.1.0.1.0.1.0) structures without β-annulated bridges. Single-crystal X-ray diffraction analysis of the hybrid porphyrinoids ( S₃N₃-ox and O₄N₄-ox ) revealed a nearly planar conformation and the ¹H NMR spectra suggest the presence of paratropic ring currents. These antiaromatic macrocycles show characteristic optical features and underwent reversible two-electron reduction to Hückel aromatic 26π- and 34π-electron species, respectively, as is evident from the results of spectroscopic and theoretical studies (nucleus-independent chemical shift (NICS) and anisotropy of the current-induced density (ACID) calculations). The incorporation of hybrid diheteroles alternately into expanded porphyrin skeletons provides a novel approach to the fine-tuning of the electronic structures of planar antiaromatic macrocycles.     

Palladium- and copper-catalyzed synthesis of medium- and large-sized ring-fused dihydroazaphenanthrenes and 1,4-benzodiazepine-2,5-diones. control of reaction pathway by metal-switching

Methods for the synthesis of dihydroazaphenanthrene fused to macrocycles (2) and medium-ring heterocycles (4), as well as 1,4-benzodiazepine-2,5-diones (5), are developed. A distinctly different catalytic property of palladium and copper catalysts was uncovered that leads to the development of a divergent synthesis of two different heterocyclic scaffolds from the same starting materials, simply by metal-switching. Thus, starting from linear amide 3, palladium acetate triggers a domino intramolecular N-arylation/C-H activation/aryl-aryl bond-forming process to provide 4, while copper iodide promotes only the intramolecular N-arylation reaction leading to 5. In combination with the Ugi multicomponent reaction (Ugi-4CR) for the preparation of the linear amides, a two-step synthesis of either the 5,6-dihydro-8H-5,7a-diazacyclohepta[jk]phenanthrene-4,7-dione (4) or 1,4-benzodiazepine-2,5-diones (5), by appropriate choice of metal catalyst, is subsequently developed from very simple starting materials.     

Schiff base macrocycles containing pyrroles and pyrazoles

A double nucleophilic substitution reaction of 3,5-bis(chloromethyl)pyrazole with pyrroles generates a novel pyrrole-pyrazole hybrid building block, the pyrazole analogue to tripyrrane. Vilsmeier-Haack formylation produces the corresponding dialdehyde, which was used in the formation of a series of nonaromatic Schiff base macrocycles. NMR and UV/Vis spectroscopy and single-crystal diffractometry were used to characterize the novel macrocycles. The solid-state structures of select free bases and protonated members of this class of macrocycles display a range of intra- and intermolecular hydrogen-bonding patterns that suggest their use in molecular-recognition systems. They also contain an acid-sensitive chromophore. Their acid-base and anion-recognition properties were ascertained; alas, only modest anion-selective spectroscopic signatures could be detected by using UV/Vis and (1)H NMR spectroscopy. The macrocycles proved resistant toward oxidation to their aromatic congeners. The pyrrole-pyrazole building blocks presented are potentially useful for the synthesis of a range of pyrazole analogues of all-pyrrole macrocycles.     

Synthesis of orthogonally protected cyclic homooligomers from sugar amino acids

Two new families of orthogonally protected cyclic homooligomers with two to four sugar units were synthesized from pyranoid sugar amino acids. Cyclic oligomers composed of amide-linked sugar amino acids (1-3) were prepared by cyclization of linear oligomers of the novel orthogonally protected pyranoid sugar amino acid 12 using a solution-phase coupling method. These orthogonally protected cyclic molecules can be selectively or fully deprotected, affording the macrocycles ready to further functionalization. The straightforward reduction of the amide bonds in the cyclic oligomers 1-3 gave the corresponding amine-linked macrocycles 4-6. This kind of amine-linked carbohydrate-based cyclic oligomer has never been reported before. These flexible molecular receptors could be studied as molecular hosts for molecular, cationic, and anionic recognition. Conformational analysis by molecular modeling (AM1) showed that all of the deprotected cyclic trimers and tetramers preferred a (4)C(1) chair conformation with oxygen atoms of the sugar ring located on the interior of the cavity and the secondary hydroxyl groups outward. In the amide-linked macrocycles, all of the amide bonds are in s-trans conformation. The estimated size of the internal cavity is about 4.5 A for the cyclic trimer and 6.9 A for the cyclic tetramer. The amine-linked macrocycles displayed similar conformational behavior with a slight decrease in internal cavity.     

A biomimetic approach for polyfunctional secocholanes: tuning flexibility and functionality on peptidic and macrocyclic scaffolds derived from bile acids

Bile acids are important scaffolds in medicinal and supramolecular chemistry. However, the use of seco bile acids, i.e., bile acids with opened rings, as cores or building blocks for the assembly of complex peptide conjugates or macrocycles has remained elusive so far. A biomimetic approach to secocholanes, based on an oxidative ring-expansion/ring-opening sequence, offers efficient access to novel structures with tunable flexibility and functionality. The process preserves selected portions of the original stereochemical and functional information of the steroid, while additional structural elements are incorporated in further (diversity-generating) steps. The potential of these building blocks for peptide and macrocycle chemistry is exemplified by the attachment of relevant alpha-amino acids and by the production of various complex macrocycles obtained by conventional (e.g., macrolactonization and macrolactamization) and multicomponent (e.g., Ugi four-component) macrocyclizations. This combination of secocholanic skeleton manipulation with, e.g., varied types of macrocyclization protocols, produces high levels of skeletal diversity and complexity. Therefore, this approach may have applicability either for the synthesis of biologically active ligands or as artificial receptors ("hosts").     

Quantifizierung von Taurin- und Glycinkonjugaten von Cholans?uren mittels Ionenpaarchromatographie an RP-Materialien

Ohne Zusammenfassung

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Quantification of taurine- and glycine-conjugates of cholanic acids by ion pair chromatography on RP materials

     

Propylphosphonic anhydride (T3P®) mediated synthesis of 3-oxoisoindoline-1-carboxamides from 2-formylbenzoic acid,amines, and isocyanides. Preparation of isoindolinone alkaloids

Propylphosphonic anhydride (T3P®) was successfully applied to the synthesis of an isoindolinone library by the utilization of an Ugi four-center, three-component reaction (Ugi-4C-3CR). The use of T3P® significantly shortened the required reaction time and the corresponding products were obtained in good to high yields. Moreover, a side-reaction was observed when phenylethylamine derivatives and tryptamine were used as the amine component. The latter reaction was applied to the microwave-assisted, one-pot synthesis of the isoquinoline alkaloid (±)-nuevamine. Surprisingly, the traditional Ugi four-component reaction (Ugi-4CR) was unsuccessful in the presence of T3P®. In this case an α-amino amide was produced excluding the carboxylic acid from the multicomponent reaction.     

Synthesis of steroid-biaryl ether hybrid macrocycles with high skeletal and side chain variability by multiple multicomponent macrocyclization including bifunctional building blocks

Utilizing the multiple multicomponent macrocyclization including bifunctional building blocks (MiB) strategy, a library of nonracemic, nonrepetitive peptoid-containing steroid-biaryl ether hybrid macrocycles was built. Up to 16 new bonds, including those of the macrocyclization, can be formed in one pot simultaneously while introducing varied elements of diversity. Functional diversity is generated primarily by choosing Ugi-reactive functional building blocks, bearing the respective recognition or catalytic motifs. These appear attached to the peptoid backbone of the macrocyclic cavity, similar to side chains of amino acids found in enzyme active sites. Likewise, skeletal diversity is based on the variation of defined bifunctional building blocks which allow the parallel formation of macrocyclic cavities that are highly diverse in shape and size and thus perspectively in function. This straightforward approach is suitable to generate multifunctional macrocycles for applications in catalysis, supramolecular, or biological chemistry.     

An asymmetric Ugi three-component reaction induced by chiral cyclic imines: synthesis of morpholin- or piperazine-keto-carboxamide derivatives

A series of chiral 5,6-dihydro-1,4-oxazin-2-one substrates, as preformed cyclic aldimines and ketoimines, were employed to develop a new asymmetric Ugi three-component reaction for the first time. The Ugi reaction of the imines, isocyanides, and carboxylic acids opens an efficient access to novel morpholin-2-one-3-carboxamide compounds. The chiral imines showed promising stereoinduction for the new chiral center of the Ugi products, and predominant trans-isomers were obtained in the most cases. Addition of some Lewis acids or proton acids could improve the diastereoselectivity further but usually led to a drop in total yield. The Ugi-3CR could be extended to the stereoselective synthesis of ketopiperazine-2-carboxamide derivatives.     

Anion and carboxylic acid binding to monotopic and ditopic amidopyridine macrocycles

Binding of inorganic anions, carboxylic acids, and tetraalkylammonium carboxylates by macrocyclic compounds of different size was studied by NMR in DMSO-d6. It has been shown that at least a 15-membered ring is necessary for successful recognition of fluoride. Larger macrocycles were shown to bind HSO4(-), H2PO4(-), Cl(-), and carboxylic acid salts. Effects of binding topicity are discussed. The 30-membered macrocycles 4 and 4m selectively bind substrates that are size- and shape-complementary: maximum binding is observed for dicarboxylic acids and dicarboxylates with four-carbon chains, and the binding constant for association of fumaric acid and 4 is ca. 5 orders of magnitude higher than that of maleic acid. The 30-membered macrocycle 4m showed selectivity toward alpha-ketocarboxylic acids. Secondary amino groups were not crucial for binding of fluoride to the macrocycles; however, they proved to be very important for selectivity and strength of carboxylic acid binding. The X-ray structure of the adduct of 4 and nitrobenzoic acid confirmed the guest H-bonding with both the amide and the secondary amino groups of the 30-membered macrocyclic host.     

Palladium-catalyzed stereoselective synthesis of 3-(aminomethylene)-oxindoles

An efficient palladium-catalyzed protocol for the stereoselective synthesis of 3-(aminoarylmethylene)-oxindoles has been developed. In this approach, Ugi-4-component reaction adducts were used as starting materials for carbopalladative cyclization-Buchwald reaction sequences.     

A bidirectional access to novel thiadiazine hybrid molecules by double multicomponent reactions

In an attempt to further exploit multicomponent reactions in the field of hybrid heterocyclic molecules, we describe a bidirectional approach for the synthesis of novel 1,3,5-thiadiazine-peptides molecules. The process relies on the execution of two Ugi reactions between dicarboxy-functionalized 1,3,5-thiadiazine with different amines and isocyanides. An alternative strategy relying on a sequential multicomponent macrocyclization procedure was also developed to afford thiadiazine peptide-like macrocycles. Both methods showed great chemical efficiency and versatility.     

Two‐Step Synthesis of Complex Artificial Macrocyclic Compounds

The design and synthesis of head‐to‐tail linked artificial macrocycles using the Ugi‐reaction has been developed. This synthetic approach of just two steps is unprecedented, short, efficient and works over a wide range of medium (8–11) and macrocyclic (≥12) loop sizes. The substrate scope and functional group tolerance is exceptional. Using this approach, we have synthesized 39 novel macrocycles by two or even one single synthetic operation. The properties of our macrocycles are discussed with respect to their potential to bind to biological targets that are not druggable by conventional, drug‐like compounds. As an application of these artificial macrocycles we highlight potent p53–MDM2 antagonism.     

Structural diversity of metal–organic frameworks via employment of azamacrocycles as a building block

Research on incorporating macrocycles into metal–organic frameworks (MOFs) has been performed intensively due to the opportunities afforded by merging a merit of macrocycles with MOF chemistry, which lead to novel hybrid materials for potential application. Among the numerous kinds of macrocycles, azamacrocycles are used as traditional and popular chelating agents in supramolecular coordination chemistry, because they are very easily functionalized by joining pendant arms and possess a strong propensity to complex metal cations, accounting for the amine functionalities. With this as background, many types of azamacrocyclic MOFs have been synthesized, granting compositionally and topologically new MOFs. The macrocyclic rings can serve as additional adsorption sites or catalytic sites, and the pendant arms on the macrocycles can also play versatile roles such as structure-directing agents, pore-decorating moieties, or rotatable molecular gates for opening/closing pores. In this review, we comprehensively discuss the syntheses, structures, and features of azamacrocyclic MOFs reported to date. Based on representative studies, advantages of these compounds are described, such as how the azamacrocycles increase the structural diversity and complexity of the MOFs and induce novel structural properties within the architectures.     

Binuclear ruthenium macrocycles formed via the weak-link approach

The "weak-link approach" for the synthesis of metallomacrocycles has been used to synthesize a series of novel Ru(II) macrocycles in high yield. RuCl2(PPh3)3 has been reacted with two different phosphino-alkyl-ether hemilabile ligands, 1,4-(PPh2(CH2)2O)2C6H4 and 1,4-(PPh2(CH2)2OCH2)2C6H4. The hemilabile bidentate ligand coordinates to Ru(II) centers through both the P and O atoms to form bimetallic "condensed intermediates". The weak Ru-O bonds have been selectively cleaved with CO, 1,2-diaminopropane, and pyridine to yield large open macrocycles. This is the first example of the weak-link approach employed to synthesize macrocycles with Ru, and metal centers in general that have more than four coordination sites.     

Skeletal Rearrangement of Twisted Thia‐Norhexaphyrin: Multiply Annulated Polypyrrolic Aromatic Macrocycles

A hybrid thia‐norhexaphyrin comprising a directly linked N‐confused pyrrole and thiophene unit ( 1 ) revealed unique macrocycle transformations to afford multiply inner‐annulated aromatic macrocycles. Oxidation with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone triggered a cleavage of the C?S bond of the thiophene unit, accompanied with skeletal rearrangement to afford unique π‐conjugated products: a thiopyrrolo‐pentaphyrin embedded with a pyrrolo[1,2]isothiazole ( 2 ), a sulfur‐free pentaphyrin incorporating an indolizine moiety ( 3 ), and a thiopyranyltriphyrinoid containing a 2H‐thiopyran unit ( 4 ). Furthermore, 2 underwent desulfurization reactions to afford a fused pentaphyrin containing a pyrrolizine moiety ( 5 ) under mild conditions. Using expanded porphyrin scaffolds, oxidative thiophene cleavage and desulfurization of the hitherto unknown N‐confused core‐modified macrocycles would be a practical approach for developing unique polypyrrolic aromatic macrocycles.     

Participation of ethyl 3-formylindole-2-carboxylate with the Ugi four-component condensation reaction

Multicomponent condensation of ethyl 3-formylindole 2-carboxylate, amines, isocyanide and (S)-N-boc-alanine or (S)-N-boc-serine is described. This Ugi four-component condensation (Ugi-4CC) reaction yielded a series of novel dipeptides containing an indolyl moiety. These compounds exhibit potential biological activity.     

Macrocyclic depolymerization of arylene-ethynylene copolymers: a dynamic combinatorial method

A dynamic combinatorial approach for the synthesis of arylene ethynylene macrocycles (AEMs) from linear polymers is described. By using readily available carbazolyl-ethynylene copolymers as starting materials we obtained a number of novel macrocycles that would be difficult to prepare by traditional methods.