Transition Metals Catalysis in C-C and C-Heteroatom Bonds Forming Reactions

Transition metals catalysis represents an important and versatile tool for the organic synthesis. Indeed its use is associated with several advantages in terms of reaction selectivity, and “atom economy”. In the last decade the growing utilization of transition metals catalysis has deeply influenced and modified the design of heterocyclic synthesis as testified by the wide amount of studies on the palladium-catalyzed cross-coupling reaction that in 2010 led Prof. Richard F. Heck (University of Delaware, USA), Prof. Ei-ichi Negishi (Purdue University, USA) and Prof. Akira Suzuki (Hokkaido University, Japan) to achieve the Nobel Prize for Chemistry. In this context, during my doctorate activity, we investigated the construction of heterocyclic rings and the production of derivatives of heterocyclic compounds of biological interest through palladium, copper and gold catalyzed reactions. As part of our studies on the palladium catalysis we developed several synthetic strategy for the construction of different classes of compounds such us functionalized 2,3-dihydrofurans, substituted 2,3-substituted quinolin-4-(1H)-ones, dibenzo[a,c]carbazoles, 2-amino ketones and aryl sulfones. Then, the economic attractiveness of copper-based methods and the growing interest in copper-catalyzed syntheses stimulated us to investigate some copper-catalyzed protocol. In this area we studied the oxidation reaction of the 1,2-diarylethanones and the cyclization reaction of the N-(2-bromoaryl)enaminones to obtain 2,4-diarylbenzo[b][1,4]oxazepines. Finally, using gold complexes we developed a new sinthetical approach to 2,4-diaryl-2,3- dihydro-1H-benzo[b][1,4]diazepines

Palladium-Catalyzed Cascade Approach to 12-(Aryl)indolo[1,2- c ]quin­azolin-6(5 H )-ones

A straightforward one-pot approach to the synthesis of challenging 12-arylindolo[1,2-c]quinazolin-6(5H)-ones is described. Starting from readily available o-(o-aminophenylethynyl)trifluoroacetanilides, palladium-catalyzed aminoarylation of the triple bond with ArI, ArBr, and ArN2 +BF4 – is followed by cyclization of the resulting N-trifluoro­acetyl-2-(o-aminophenyl)-3-aryl indole. This sequential reaction provides the title compounds by means of a rare elimination of trifluoromethane

Palladium-Catalyzed Synthesis of 6-aryl Dopamine Derivatives

Dopamine is a key neurotransmitter involved in a series of biologically relevant processes and its derivatives have sparked significant interest as intriguing synthetic targets. This class of compounds is indeed not only considerable for the potential biological activities but is also promising for diverse applications in material science. In light of this, our research was focused on the synthesis of 6-aryldopamine derivatives starting from 4-(2-aminoethyl)phenol through a sequential protocol, whose main steps are hydroxylation, halogenation, and Suzuki cross-coupling. Our method demonstrated versatility, efficiency, and compatibility with various functional groups, including aldehydes, ketones, esters, ethers, and fluorine

Molecular recognition of the HPLC Whelk-O1 selector towards the conformational enantiomers of nevirapine and oxcarbazepine

The presence of stereogenic elements is a common feature in pharmaceutical compounds, and affording optically pure stereoisomers is a frequent issue in drug design. In this context, the study of the chiral molecular recognition mechanism fundamentally supports the understanding and optimization of chromatographic separations with chiral stationary phases. We investigated, with molecular docking, the interactions between the chiral HPLC selector Whelk-O1 and the stereoisomers of two bioactive compounds, the antiviral Nevirapine and the anticonvulsant Oxcarbazepine, both characterized by two stereolabile conformational enantiomers. The presence of fast-exchange enantiomers and the rate of the interconversion process were studied using low temperature enantioselective HPLC and VT-NMR with Whelk-O1 applied as chiral solvating agent. The values of the energetic barriers of interconversion indicate, for the single enantiomers of both compounds, half-lives sufficiently long enough to allow their separation only at critically sub-ambient temperatures. The chiral selector Whelk-O1 performed as a strongly selective discriminating agent both when applied as a chiral stationary phase (CSP) in HPLC and as CSA in NMR spectroscopy

Experimental Results and Mechanistic Insights on the Reactions of Indolylmethyl Acetates with Soft Carbon Pronucleophiles

The palladium-catalyzed reaction of N-protected 2-indolylmethyl acetates with soft carbon pronucleophiles is described. Besides the formation of the expected coupling reaction at the C1 ' position, unprecedented attack at the C3 position of the plausible eta(3)-indolyl-palladium intermediate has been observed, and the selectivity control C1 '/C3 seems to depend on the nature of the protecting group and ligand. The reactivity of 3-indolylmethyl acetates has also been also investigated. Quantum chemical calculations support the experimental results

A unique high-diversity natural product collection as a reservoir of new therapeutic leads

Plants represent a rich source of structurally diverse secondary metabolites, which can be exploited in the development of new clinically important compounds. Indeed, due to their biodiversity, medicinal plants represent the largest library of compounds that has ever existed. To date less than 1% of this vast biodiversity has been exploited in drug discovery, due to several factors, including the lack of an appropriate multidisciplinary perspective. Here we review the successful application of computer-aided methods in screening a unique and high-diversity in house collection library composed of around 1000 individual natural products, isolated mainly from indigenous plants collected in biodiversity-rich countries, especially of the tropics and subtropics, and enlarged with their semi-synthetic and synthetic derivatives, as well as plant material extracts, up to around 2000 components. During the last ten years, the in house library has provided several lead compounds that have been developed, and in some cases patented, as anticancer and antimicrobial agents. The main classes of the library are described, including (but not limited to) alkaloids, terpenoids, Diels–Alder-type adducts, isoflavones, chalcones, and cannabinoids. The main focus is on the chemical characteristics and biological activity of these identified compounds, with particular attention being given to those currently under patent or in the preclinical phase. We also assess the use of computer-aided methods in screening this unique and diverse in house collection of natural products that, over the last ten years, has provided some lead compounds that have been developed, and in some cases patented, as anticancer and antimicrobial agents. Finally, this review highlights the potential use of plant food extracts as a source of nutraceuticals and functional foods. The multidisciplinary approach described herein may further motivate research groups involved in natural product chemistry to potentially benefit from a limitless source of novel bioactive compounds

Immobilization of Lathyrus cicera Amine Oxidase on Magnetic Microparticles for Biocatalytic Applications

Amine oxidases are enzymes belonging to the class of oxidoreductases that are widespread, from bacteria to humans. The amine oxidase from Lathyrus cicera has recently appeared in the landscape of biocatalysis, showing good potential in the green synthesis of aldehydes. This enzyme catalyzes the oxidative deamination of a wide range of primary amines into the corresponding aldehydes but its use as a biocatalyst is challenging due to the possible inactivation that might occur at high product concentrations. Here, we show that the enzyme’s performance can be greatly improved by immobilization on solid supports. The best results are achieved using amino-functionalized magnetic microparticles: the immobilized enzyme retains its activity, greatly improves its thermostability (4 h at 75 ◦C), and can be recycled up to 8 times with a set of aromatic ethylamines. After the last reaction cycle, the overall conversion is about 90% for all tested substrates, with an aldehyde production ranging between 100 and 270 mg depending on the substrate used. As a proof concept, one of the aldehydes thus produced was successfully used for the biomimetic synthesis of a non-natural benzylisoquinoline alkaloid

Construction of the 1,5-benzodiazepine skeleton from o-phenylendiamine and propargylic alcohols via a domino gold-catalyzed hydroamination/cyclization process

The gold-catalyzed reaction of o-phenylendiamine with propargylic alcohols affords 1,5-benzodiazepines bearing different substituents on the 2 and 4 positions. The method allows even for the selective preparation of 4-substituted 1,5-benzodiazepine derivatives

Dibenzo[a,c]carbazoles from 2-(2-bromoaryl)-3-arylindoles via a palladium-catalyzed intramolecular C-H functionalization/C-C bond formation process

The palladium-catalyzed cyclization of 2-(2-bromoaryl)-3-arylindoles provides a new versatile approach to dibenzo[a,c]carbazoles. The reaction tolerates a variety of useful substituents including chloro, nitro, ether, cyano, keto, and ester groups

Asymmetric Hydroarylation Reactions Catalyzed by Transition Metals: Last 10 Years in a Mini Review

Hydroarylation reactions play a pivotal role in organic chemistry due to their versatility and efficiency. In the last 10 years, the scientific production around this reaction has been very high, but in its asymmetric version, the results are less. In this mini review, selected literature examples are considered to draw attention to directions of the asymmetric hydroarylation reaction mediated by transition metal catalysts. The selected works were grouped in two main sections. In the first, we reported examples relating the narrower definition of hydroarylation, namely the metal-catalyzed processes where inactivated aryl moiety undergoes a direct functionalization via insertion of an unsaturated compound. In the second part, hydroarylation reactions take place with the use of pre-activated aryl substrates, usually aryl-iodides or aryl-boronated