Synthesis of substituted asymmetrical biphenyl amino esters as alpha helix mimetics

As part of our ongoing project to develop new molecular probes for estrogen receptor-alpha, we are exploring the utility of internally-substituted asymmetric biphenyls as a proteomimetic scaffold. In this study, we describe synthetic methods for preparing the requisite substituted-bromophenol precursors, their further elaboration, and the subsequent Suzuki–Miyaura coupling of these sterically-hindered and electronically-rich aromatic systems. The results provide an efficient route with which to generate further libraries of novel asymmetric biphenyl compounds as potential proteomimetics.     

Sequential palladium-catalysed C- and N-arylation reactions as a practical and general protocol for the synthesis of the first series of oxcarbazepine analogues

The first series of oxcarbazepine analogues, starting from readily-available materials and through a high-yielding five-step sequence based on palladium catalysis, is reported. The so-obtained compounds incorporate not only a variety of substituents in both of the aryl rings comprising the framework of an oxcarbazepine, but also involve the more challenging palladium-catalysed coupling of a number of heteroaromatic substrates. The addition of small amounts of water in some of the metal-catalysed processes showed a beneficial effect, highly increasing the selectivity of such reactions.     

Palladium-catalyzed double cross-coupling reaction of 1,2-bis(pinacolatoboryl)alkenes and -arenes with 2,2′-dibromobiaryls: annulative approach to functionalized polycyclic aromatic hydrocarbons

This study demonstrates that the double cross-coupling reaction of 1,2-bis(pinacolatoboryl)alkenes and -arenes with 2,2′-dibromobiaryls proceeds smoothly with the aid of a catalytic amount of Pd(PPh₃)₄ in the presence of excess base to give a variety of polycyclic aromatic hydrocarbons, such as phenanthrenes, [5]helicene, dithienobenzenes, triphenylenes, dibenzo[g,p]chrysenes, and triphenyleno[1,2-b:4,3-b′]dithiophenes in good to high yields. It is noteworthy that the annulations using 2,2′-dibromooctafluorobiphenyl as an electrophile furnish the otherwise difficult to synthesize octafluorophenanthrenes and semi-fluorinated dibenzo[g,p]chrysenes in high yields.     

5,6-Dihydropyrrolo[2,1-b]isoquinolines as scaffolds for synthesis of lamellarin analogues

Efficient modular synthetic routes to open chain marine alkaloids such as lamellarins have been developed. 5,6-Dihydropyrrolo[2,1-b]isoquinoline scaffolds were prepared, and protocols enabling regioselective bromination followed by Suzuki cross-coupling were established for the introduction of aryl groups onto the 2- and 3-positions.     

Metal assisted synthesis of mono and diamino substituted pyridines

A microwave assisted Buchwald-Hartwig amination protocol is reported for a series of dihalopyridine precursors. Using this procedure, selective substitution of one halogen by aryl or alkylamines is possible in very short time, usually 30 min. Mild base (K₂CO₃) can be used successfully, which broadens the substrate scope. The second halogen can then be substituted using alkylamines under nucleophilic substitution condition or via a Suzuki-Miyaura cross-coupling reaction. The target compounds are potential inducers of cardiomyogenesis as innovative approach in regenerative medicine.     

Practical synthesis of pinacolborane for one-pot synthesis of unsymmetrical biaryls via aromatic C-H borylation-cross-coupling sequence

A method for practical preparation of pinacolborane from borane-diethylaniline and pinacol was newly developed. Aromatic C-H borylation of arenes with pinacolborane or bis(pinacolato)diboron catalyzed by 1/2[Ir(OMe)(COD)]₂-(4,4′-di-tert-butyl-2,2′-bipyridine) at 25 °C in hexane to give arylboronic esters was directly followed by cross-coupling with aromatic bromides at 60 °C in the presence of PdCl₂(dppf) (3.0 mol %) and K₃PO₄ in DMF. This one-pot, two-step procedure provided a variety of unsymmetrical biaryls in high yields.     

Sequential and domino Sonogashira coupling: Efficient tools for the synthesis of diarylalkynes

The Sonogashira coupling reaction of aryl halides with a masked acetylene, leading to the formation of diarylethynes is reviewed. The process is either run in a sequential coupling-deprotection-coupling manner, or sometimes it is carried out in one-pot, a reaction we coined domino coupling. The procedures were also extended to the synthesis of compound libraries.     

Solid-phase parallel synthesis of 1,3,4-oxadiazole based peptidomimetic library as a potential modulator of protein-protein interactions

Design and solid phase synthesis of the 1,3,4-oxadiazole based peptidomimetic library is presented. Library synthesis starts from the coupling of the thiosemicarbazide resin with Fmoc-protected amino acid following desulfurative cyclization to 1,3,4-oxadiazoles. Following substitution of the secondary amine with the 3-nitrobenzoyl functional group and its further reduction were performed. Thus, the functionalization with amino acids could be performed on both sides of the core skeleton. After diversification and cleavage from the resin using TFA: DCM cleavage cocktail, an enantiopure library of compounds was obtained. Further evaluation of physicochemical properties was performed.     

Revisiting the Hirao cross-coupling: improved synthesis of aryl and heteroaryl phosphonates

The palladium-catalyzed cross-coupling of dialkylphosphite with aromatic electrophiles (Hirao coupling) was re-investigated. Some limitations in terms of palladium loadings and substrate reactivity are alleviated with the use of Pd(OAc)₂ complexed to 1,1′-bis(diphenylphosphino)ferrocene (dppf) as a ligand. Various aryl and heteroaryl halides are employed to deliver both known and novel substituted phosphonates. The first examples of aryl chloride couplings are also reported.     

Divergent synthesis of arylated pyridin-2(1H)-one derivatives via metal-catalysed cross-coupling processes

1,5-Di(hetero)arylated-pyridin-2(1H)-one derivatives have been readily obtained in good yields starting from 2-fluoro-5-pyridylboronic acid. The sequence comprises three steps: (i) palladium-catalysed Suzuki-Miyaura reaction; (ii) base-catalysed hydrolysis; (iii) copper-catalysed C-N coupling. X-ray crystal structures are reported for selected pyridin-2(1H)-one derivatives. These compounds are of interest as new scaffolds for drug discovery.     

Vinyl nosylates as partner in copper and silver co-catalyzed Sonogashira cross-coupling reactions

Vinyl nosylates, readily obtained from β-dicarbonyl derivatives, could be efficiently engaged in Sonogashira cross-coupling reactions, either cocatalyzed by copper or silver salts. The para-nitrobenzenesulfonate (nosylate) group allows this coupling to be performed under very mild conditions (room temperature). These new leaving group and mild conditions could be applied to the synthesis of acetylenic coumarinyl derivatives and to the total synthesis of an acetylenic monoterpene natural product, named cleviolide.     

A general synthesis of diversely substituted indazoles and hetero-aromatic derivatives from o-halo-(het)arylaldehydes or -phenones

A set of variously substituted indazoles and hetero-aromatic derivatives were synthesized from o-halo-(het)arylaldehydes using a palladium catalyzed amination followed by cyclization. Starting from phenones, this process was extended to give 3-substituted indazoles. Moreover, N-1-substituted-indazoles can be reached by this strategy using an optional selective N-1-alkylation step during the process. This methodology offers a general and easy route for the synthesis of regioselectively substituted indazoles.     

Efficient synthesis of racemic and chiral alkenyl sulfoxides by palladium-catalyzed Suzuki coupling

Alkenyl sulfoxide derivatives are obtained in high yields through a palladium-catalyzed Suzuki/Miyaura cross-coupling reaction of racemic and chiral 1-halo sulfoxides with aryl and alkenyl boronic acids. Chiral substrates react with no loss of optical purity and high optical yields. The reaction takes place with different palladium catalysts, such as Pd(PPh₃)₄ or Pd(OAc)₂/DABCO. Although nitrogen ligands like DABCO lead to an active palladium catalyst, they are less effective than the phosphine ones.     

Building block synthesis of predominantly (E) symmetrical and unsymmetrical 1,2-difluorostilbenes from 1,2-dibromo-1,2-difluoroethene

An efficient synthesis of predominantly (E) symmetrical or unsymmetrical 1,2-difluorostilbenes based on the Suzuki–Miyaura palladium-catalyzed cross-coupling reaction of arylboronic acids with predominantly (E)-1,2-dibromo-1,2-difluoroethene in the presence of Cs₂CO₃ in toluene is described. The reaction preserved the stereochemistry of the building block and performed in good yield independently of the electron-withdrawing or electron-donating character of the substituents.     

Palladium-catalyzed coupling reactions towards the synthesis of well-defined thiophene-oligomers

Heck- and Ullmann-type palladium-catalyzed reactions were used in order to perform the synthesis of 3′,4″-dioctyl-2,2′,5′2″,5″,2′″-tetrathienyl. The desired oligothiophene was synthesized in five steps with a total yield of 38% by a Heck-type reaction of bromo-derivatives and a yield of 45% by an Ullmann-type reaction of iodo-precursors.     

Design and synthesis of alpha-helical peptides and mimetics

The alpha-helix is the most abundant secondary structural element in proteins and is an important structural domain for mediating protein-protein and protein-nucleic acid interactions. Strategies for the rational design and synthesis of alpha-helix mimetics have not matured as well as other secondary structure mimetics such as strands and turns. This perspective will focus on developments in the design, synthesis and applications of alpha-helices and mimetics, particularly in the last 5 years. Examples where synthetic compounds have delivered promising biological results will be highlighted as well as opportunities for the design of mimetics of the type I alpha-helical antifreeze proteins.     

Design and synthesis of novel 1,4-benzodiazepine surrogates as potential CCKA and CCKB antagonists via palladium-catalyzed three-component cascade reactions

Structurally diverse novel 1,4-benzodiazepine analogues related to selective CCKA antagonist MK-329, and CCKB antagonists L-365,260 and YM022 are prepared via palladium-catalyzed three component domino reactions involving allenylation-carbonylation-anion capture in one-pot cascade protocol in good to excellent yields.     

Macrocyclic peptides as regulators of protein-protein interactions

Protein-protein interactions are attractive but challenging targets for drug discovery. Recent technological progress and examples using macrocyclic peptides as protein interaction modulators are reviewed.     

Chemoselective Suzuki-Miyaura reactions of 4-bromo-3-O-triflyl-estrone. Synthesis and atropisomerism of arylated estrones

4-Bromo-3-O-triflyl-estrone has been synthesized in 2 steps from estrone and was successfully employed in chemoselective palladium catalysed Suzuki-Miyaura reactions. Mono- and bis-arylations were carried out selectively by variation of ligands and solvents. Overall 19 derivatives of mono- and bis-arylated estrones were synthesized under optimized conditions in high yields. Various products showed atropisomerism which was studied in detail by NMR spectroscopy.     

Transition metal catalyzed cross-coupling of aryl Grignard reagents with aryl fluorides via Pd- or Ni-activation of the C-F bond: an efficient synthesis of unsymmetrical biaryls - application of microwave technology in ligand and catalyst screening

Biaryl compounds are prevalent in both nature and in active pharmaceutical ingredients. The palladium and nickel catalyzed cross-coupling of aryl Grignard reagents with aryl fluorides reported herein affords moderate to excellent yields of the corresponding unsymmetrical biaryls. In addition, the first example of a biaryl cross-coupling utilizing unactivated aryl fluorides under phosphine free palladium conditions is reported. Microwave technology allowed rapid optimization of catalyst systems, which identified several ligands for this cross-coupling reaction.