CeCl3 catalyzed imino Diels-Alder reactions: hydrated vs anhydrous

Aza-Diels-Alder reaction is a straightforward way to synthesize useful nitrogen containing heterocyclic structures.1 In particular, the known reaction between imines and Danishefsky’s diene has proved to be an excellent way to obtain the 1,2-substituted-2,3-dihydropyridinone scaffold, widely present in bioactive small molecules and versatile building block for the synthesis of more complex structures.2 The reaction of Danishefsky’s diene with aromatic imines has been widely studied in last years, anyway less examples of the same reaction involving imines derived from aliphatic amines or aldehydes are present. For this reason the possibility to extend the potentiality of this reaction performing it on a large variety of imines was studied, under the Lewis acid promoting system CeCl3.7H2O/CuI, previously applied with success3 in many other synthetic methodologies. Imines 3 were prepared by direct condensation of aliphatic or aromatic amines and aldehydes and then the diene was added together with the catalyst, obtaining dihydropyridinones 4 with good to excellent yields in short reaction times. To extend the scope of this work, also imines derived from aminoacids were tested as dienophiles. The only moderate diastereoselectivity and the long time needed with some homochiral dienophiles prompted us to have a deeper insight into the mechanism, with the conclusion that the reaction proceed also through a slower competitive Mannich-Michael pathway, favoured by the presence of water in the catalyst. 1) Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099-6138. 2) Cant, A. A.; Sutherland, A. Synthesis 2012, 44, 1935-1950. 3) Bartoli, G.; Marcantoni, E.; Marcolini, M.; Sambri, L. Chem. Rev. 2010, 110, 6104-6143

An Efficient Lewis Acid Catalyzed Povarov Reaction for the One-Pot Stereocontrolled Synthesis of Polyfunctionalized Tetrahydroquinolines

An easy and efficient synthetic methodology for the one-pot stereocontrolled synthesis of tetrahydroquinolines through Lewis acid activated Povarov reaction is described. The protocol takes advantage of the very cheap, easy to handle, and environmentally friendly cerium trichloride as catalyst and allows to obtain either the anti- or the syn-isomer of the final tetrahydroquinoline with good selectivity, by performing the reaction in solvent or solventless conditions. The scope of the reaction is expanded to the one-pot synthesis of N-alkyltetrahydroquinolines through a very efficient iminium-Povarov approach. A deeper insight on the reaction system was provided by the study on the side reactions occurring in the reaction conditions and on the nature of the stereoselectivity

CeCl3 catalyzed imino Diels-Alder reactions: hydrated vs anhydrous

Aza-Diels-Alder reaction is a straightforward way to synthesize useful nitrogen containing heterocyclic structures.1 In particular, the known reaction between imines and Danishefsky’s diene has proved to be an excellent way to obtain the 1,2-substituted-2,3-dihydropyridinone scaffold, widely present in bioactive small molecules and versatile building block for the synthesis of more complex structures.2 The reaction of Danishefsky’s diene with aromatic imines has been widely studied in last years, anyway less examples of the same reaction involving imines derived from aliphatic amines or aldehydes are present. For this reason the possibility to extend the potentiality of this reaction performing it on a large variety of imines was studied, under the Lewis acid promoting system CeCl3.7H2O/CuI, previously applied with success3 in many other synthetic methodologies. Imines were prepared by direct condensation of aliphatic or aromatic amines and aldehydes and then the diene was added together with the catalyst, obtaining dihydropyridinones with good to excellent yields in short reaction times. To extend the scope of this work, also imines derived from aminoacids were tested as dienophiles.The only moderate diastereoselectivity and the long time needed with some homochiral dienophiles prompted us to have a deeper insight into the mechanism, with the conclusion that the reaction proceed also through a slower competitive Mannich-Michael pathway, favoured by the presence of water in the catalyst

Capsule-based automated synthesis for the efficient assembly of PROTAC like molecules

In recent years, the therapeutically beneficial degradation of proteins using PROteolysis Targeting Chimeras (PROTACs) has become an increasingly popular approach in drug discovery. However, the preparation of these larger than average, heavily functionalised molecules can be synthetically challenging and time-consuming, and experience in making and handling the final PROTACs and their precursors is not yet widespread. To overcome these challenges, an existing capsule-based automated synthesis console has been adapted and employed for the automated synthesis of PROTAC-like molecules. Reagent capsules containing a partial PROTAC reagent plus the reagents required for conjugation of the partial PROTAC to the target protein binder, as well as the materials for product isolation, were prepared in order to accelerate the process and simplify PROTAC synthesis. The use of these capsules, in combination with the automated synthesis console, has enabled the safe, automated preparation of a range of different PROTAC-like molecules bearing different linker and E3 ligase functionalities.ISSN:2635-098

An Integrated Console for Capsule-Based, Fully Automated Organic Synthesis

The current laboratory-based practice of organic synthesis renders automation difficult, suffers from safety and environmental hazards, and hampers the implementation of artificial intelligence guided drug discovery. Using a combination of innovative reagent design, hardware engineering, and a simple operating system we provide an instrument capable of executing complex organic reactions with prepacked capsules in a fully automated fashion. The machine conducts coupling reactions and delivers the purified products with minimal user involvement. Two of the most desirable reaction classes – the synthesis of saturated N-heterocycles and reductive amination – were implemented, along with multi-step sequences that provide drug-like organic molecules in a fully automated manner. We envision that this system will serve as a console for developers to provide synthetic methods as integrated, user-friendly packages for conducting organic synthesis in a safe and convenient fashion

Automated, Capsule-Based Suzuki–Miyaura Cross Couplings

The development of an automated process for Suzuki–Miyaura cross couplings is described, in which the complete reaction, workup, and product isolation are effected automatically with no user involvement, aside from loading of the starting materials and reaction capsule. This practical and simple method was successfully demonstrated to provide the desired biaryl products using a range of aryl bromides and boronic acids and is also effective for the late-stage functionalization of aryl halides in bioactive molecules