Borane-Trimethylamine Complex: A Versatile Reagent in Organic Synthesis.

Borane-trimethylamine complex (Me3N·BH3; BTM) is the most stable of the amine-borane complexes that are commercially available, and it is cost-effective. It is a valuable reagent in organic chemistry with applications in the reduction of carbonyl groups and carbon-nitrogen double bond reduction, with considerable examples in the reduction of oximes, hydrazones and azines. The transfer hydrogenation of aromatic N-heterocycles and the selective N-monomethylation of primary anilines are further examples of recent applications, whereas the reduction of nitrobenzenes to anilines and the reductive deprotection of N-tritylamines are useful tools in the organic synthesis. Moreover, BTM is the main reagent in the regioselective cleavage of cyclic acetals, a reaction of great importance for carbohydrate chemistry. Recent innovative applications of BTM, such as CO2 utilization as feedstock and radical chemistry by photocatalysis, have extended their usefulness in new reactions. The present review is focused on the applications of borane-trimethylamine complex as a reagent in organic synthesis and has not been covered in previous reviews regarding amine-borane complexes.

Catalytic C3 aza-alkylation of indoles.

The aza-alkylation reaction at indole's C3 position allows the introduction of a differently substituted aminomethyl group, with the formation of a new stereogenic centre. The reaction involves essentially three different partners: an indole, aldehyde and amine. The formation of the reactive iminium species can be catalyzed by metals, Brønsted acids, Lewis acids or organocatalysts. The stereoselective reaction is feasible with satisfactory outcomes. This review summarizes the recent (2000-2019) meaningful papers in which the in-depth study and exploitation of this reactivity are reported.

Total Synthesis of (-)-Anaferine: A Further Ramification in a Diversity-Oriented Approach.

The piperidine ring is a widespread motif in several natural bioactive alkaloids of both vegetal and marine origin. In the last years, a diversity-oriented synthetic (DOS) approach, aimed at the generation of a library of piperidine-based derivatives, was developed in our research group, employing commercially available 2-piperidine ethanol as a versatile precursor. Here, we report the exploration of another ramification of our DOS approach, that led us to the stereoselective total synthesis of (-)-anaferine, a bis-piperidine alkaloid present in Withania somnifera extract. This natural product was obtained in 9% overall yield over 13 steps, starting from a key homoallylic alcohol previously synthesised in our laboratory. Therefore, the collection of piperidine-derivatives accessible from 2-piperidine ethanol was enriched with a new, diverse scaffold.

Correction: Self-assembled 4-(1,2-diphenylbut-1-en-1-yl)aniline based nanoparticles: podophyllotoxin and aloin as building blocks.

Correction for 'Self-assembled 4-(1,2-diphenylbut-1-en-1-yl)aniline based nanoparticles: podophyllotoxin and aloin as building blocks' by Gaia Fumagalli, et al., Org. Biomol. Chem., 2017, DOI: 10.1039/c6ob02591a.

Self-assembled 4-(1,2-diphenylbut-1-en-1-yl)aniline based nanoparticles: podophyllotoxin and aloin as building blocks.

The ability of 4-(1,2-diphenylbut-1-en-1-yl)aniline as a self-assembly inducer is reported. The conjugation of this moiety with aloin or podophyllotoxin resulted in spherical nanoparticles that were characterized by Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM) and NanoSight technology. A preliminary biological evaluation on two cancer cell lines is reported.

Enzymatic Kinetic Resolution of 2-Piperidineethanol for the Enantioselective Targeted and Diversity Oriented Synthesis.

2-Piperidineethanol (1) and its corresponding N-protected aldehyde (2) were used for the synthesis of several natural and synthetic compounds. The existence of a stereocenter at position 2 of the piperidine skeleton and the presence of an easily-functionalized group, such as the alcohol, set 1 as a valuable starting material for enantioselective synthesis. Herein, are presented both synthetic and enzymatic methods for the resolution of the racemic 1, as well as an overview of synthesized natural products starting from the enantiopure 1.

2-Hydroxyoleic Acid as a Self-Assembly Inducer for Anti-Cancer Drug-Centered Nanoparticles.

A potent nontoxic antitumor drug, 2-hydroxyoleic acid (6, 2OHOA) used for membrane lipid therapy, was selected as a self-assembly inducer due to its ability to form nanoparticles (NPs) in water. For this purpose, it was conjugated with a series of anticancer drugs through a disulfide-containing linker to enhance cell penetration and to secure drug release inside the cell. The antiproliferative evaluation of the synthesized NP formulations against three human tumor cell lines (biphasic mesothelioma MSTO-211H, colorectal adenocarcinoma HT-29, and glioblastoma LN-229) showed that nanoassemblies 16-22a,bNPs exhibit antiproliferative activity at micromolar and submicromolar concentrations. Furthermore, the ability of the disulfide-containing linker to promote cellular effects was confirmed for most nanoformulations. Finally, 17bNP induced intracellular ROS increase in glioblastoma LN-229 cells similarly to free drug 8, and such elevated production was decreased by pretreatment with the antioxidant N-acetylcysteine. Also, nanoformulations 18bNP and 21bNP confirmed the mechanism of action of the free drugs.

Self-assembling Releasable Thiocolchicine-Diphenylbutenylaniline Conjugates.

The design and the synthesis of new self-assembling conjugates is reported. The target compounds are characterized by the presence of a self-immolative linker that secures a controlled release induced by lipase cleavage. 4-(1,2-Diphenylbut-1-en-1-yl)aniline is used as a self-assembling inducer and amino-thiocolchicine as prototype of drug. The release of thiocolchicine derivative has been demonstrated in vitro in the presence of porcine pancreatic lipase and Celite-supported lipase. The formation of nanoparticles is confirmed by dynamic light scattering, atomic force microscopy, and fluorescence microscopy. The antiproliferative activity has been proved on two human cancer cell lines.

The 1,2,3-triazole ring as a bioisostere in medicinal chemistry.

1,2,3-Triazole is a well-known scaffold that has a widespread occurrence in different compounds characterized by several bioactivities, such as antimicrobial, antiviral, and antitumor effects. Moreover, the structural features of 1,2,3-triazole enable it to mimic different functional groups, justifying its wide use as a bioisostere for the synthesis of new active molecules. Here, we provide an overview of the 1,2,3-triazole ring as a bioisostere for the design of drug analogs, highlighting relevant recent examples.

Chalcone Derivatives Activate and Desensitize the Transient Receptor Potential Ankyrin 1 Cation Channel, Subfamily A, Member 1 TRPA1 Ion Channel: Structure-Activity Relationships in vitro and Anti-Nociceptive and Anti-inflammatory Activity in vivo.

Eleven compounds belonging to the chalcone family were tested for their ability to activate and subsequently desensitize the rat transient receptor potential ankyrin 1 cation channel, subfamily A, member 1 (TRPA1) in a heterologous expression system. Four of the tested compounds were more potent than the TRPA1 agonist mustard oil, and showed also a strong desensitizing effect. Some chalcone compounds were not pungent in the eye-wiping assay and quite remarkably inhibited in a long-lasting and dose-dependent manner the pain response in the formalin test. Chalcones can be considered as novel candidates for the development of antihyperalgesic preparations based on TRPA1 desensitization.

Synthesis of N,N-Dialkyl-N'-arylhydrazines via palladium-catalyzed N-arylation by using N,N-dialkylhydrazines/2LiCl adducts.

[reaction: see text] The reaction of N,N-dialkylhydrazine/2LiCl adducts with aryl bromides in the presence of Pd(2)(dba)(3) as the palladium source, Xantphos or X-phos as the ligands, toluene as the solvent, and NaOBu-t as the base provides an efficient route to N,N-dialkyl-N'-arylhydrazines. Best results were obtained by using N,N-dialkylhydrazine/2LiCl adducts prepared in situ, omitting their isolation.

Cyclopamine-Paclitaxel-Containing Nanoparticles: Internalization in Cells Detected by Confocal and Super-Resolution Microscopy.

Cyclopamine- and paclitaxel-containing hetero-nanoparticles generated by self-assembly show combined efficacy in the treatment of three different cancer cell lines. The use of ternary combination with the addition of a dye-squalene conjugate secured the obtainment of fluorescent nanoparticles that permitted the observation of the cellular internalization by confocal microscopy and super-resolution dSTORM (direct stochastic optical reconstruction microscopy).

New methodologies for the oxidation of Fischer carbene complexes: synthesis of hydrazides.

[reaction: see text] We report new, high-yield methodologies for oxidizing Fischer carbenes, particularly hydrazinocarbene complexes. The reagents traditionally used to oxidize Fischer carbenes have failed because of the stability of hydrazinocarbene complexes and the easy oxidation of formed hydrazides in the reaction conditions. The three newly developed methodologies are very mild, fast, efficient, and complementary. Differently functionalized hydrazinocarbene complexes can be oxidized to afford new hydrazides.

Synthesis of chiral chromium tricarbonyl labeled thymine PNA monomers via the Ugi reaction.

[reaction: see text] Ugi condensation was used to synthesize the first examples of chiral racemic Ar.Cr(CO)(3) labeled peptide nucleic acid (PNA) monomers bearing the organometallic moiety linked to the alpha-carbon of the glycine unit.

Highly enantioselective approach to geminal bisphosphonates by organocatalyzed Michael-type addition of beta-ketoesters.

A valuable organocatalyzed protocol has been developed for the asymmetric synthesis of bisphosphonate derivatives, a class of pharmaceutically important molecules. Cheap and commercially available dihydroquinine effectively catalyzed conjugate additions of cyclic beta-ketoesters to ethylidenebisphosphonate esters, leading to optically active geminal bisphosphonates, bearing an all-carbon substituted quaternary stereocenter, in high yields and enantioselectivities of up to 99 % ee. Further elaborations of Michael adducts to the corresponding bisphosphonic acids or vinyl phosphonates have also been successfully performed, with conservation of optical purity.

Asymmetric aza-Michael reactions catalyzed by cinchona alkaloids.

The organocatalysed asymmetric aza-Michael addition of hydrazones to cyclic enones has been achieved in good yield and stereoselection using cheap and commercially available cinchona alkaloids as catalysts. A systematic study of the influence of the structure of the enone on the stereoselectivity was carried out, leading to optically active products with up to 77% ee. The products can be recrystallized to give nearly enantiopure products, and furthermore it was shown that the products could be reduced to the corresponding 1,3-benzylidenehydrazino alcohol derivatives with high diastereoselectivity.