Strong and confined imidodiphosphorimidate (IDPi) catalysts enable highly enantioselective substitutions of cyclic, aliphatic hemiaminal ethers with enol silanes. 2‐Substituted pyrrolidines, ...piperidines, and azepanes are obtained with high enantioselectivities, and the method displays a broad tolerance of various enol silane nucleophiles. Several natural products can be accessed using this methodology. Mechanistic studies support the intermediacy of non‐stabilized, cyclic N‐(exo‐acyl)iminium ions, paired with the confined chiral counteranion. Computational studies suggest transition states that explain the observed enantioselectivity.
Saturated nitrogen heterocycles are essential pharmacophores in drugs and natural products, and general methods for their enantioselective synthesis are still highly sought after. A new direct approach utilizing hemiaminal methyl ethers as N‐acyliminium precursors for the enantioselective preparation of cyclic, aliphatic and 2‐subsituted pyrrolidines, piperidines and azepanes has been achieved.
During the last 20 years, organocatalysis has significantly advanced as a field. Thanks to contributions from hundreds of groups and companies around the world, the area has risen from a few ...mechanistically ill-defined niche reactions, to one of the most vibrant and innovative fields in chemistry, providing several well-defined generic activation modes for selective catalysis. Organocatalysis is also on the rise in industrial settings, especially for the production of enantiomers, which are of use in fine chemistry, pharma, crop-protection, and fragrance chemistry. Here we will look at some of the specific elements of organocatalysis that we think are particularly attractive and contribute to this successful development.
An interrupted Pummerer/nickel‐catalysed cross‐coupling strategy has been developed and used in the elaboration of styrenes. The operationally simple method can be carried out as a one‐pot process, ...involves the direct formation of stable alkenyl sulfonium salt intermediates, utilises a commercially available sulfoxide, catalyst, and ligand, operates at ambient temperature, accommodates sp‐, sp2‐, and sp3‐hybridised organozinc coupling partners, and delivers functionalised styrene products in high yields over two steps. An interrupted Pummerer/cyclisation approach has also been used to access carbo‐ and heterocyclic alkenyl sulfonium salts for cross‐coupling.
Feel free to interrupt: Styrenes were activated under metal‐free conditions by an interrupted Pummerer process. The resulting stable alkenyl sulfonium salts underwent nickel‐catalysed cross‐coupling under simple, mild conditions. The versatile sequence could be carried out as a one‐pot process with a range of organozinc partners to form di‐, tri‐, and tetrasubstituted alkene products.
Since early 2020, scientists have strived to find an effective solution to fight SARS‐CoV‐2, in particular by developing reliable vaccines that inhibit the spread of the disease and repurposing drugs ...for combatting its effects on the human body. The antiviral prodrug Remdesivir is still the most widely used therapeutic during the early stages of the infection. However, the current synthetic routes rely on the use of protecting groups, air‐sensitive reagents, and cryogenic conditions, thus impeding a cost‐efficient supply to patients. We have, therefore, focused on the development of a straightforward, direct addition of (hetero)arenes to unprotected sugars. Here we report a silylium‐catalyzed and completely stereoselective C‐glycosylation that initially yields the open‐chain polyols, which can be selectively cyclized to provide either the kinetic α‐furanose or the thermodynamically favored β‐anomer. The method significantly expedites the synthesis of Remdesivir precursor GS‐441524 after a subsequent Mn‐catalyzed C−H oxidation and deoxycyanation.
A straightforward, direct addition of (hetero)arenes to unprotected sugars is presented. A silylium‐catalyzed and completely stereoselective C‐glycosylation initially yields the open‐chain polyols, which are cyclized to provide either the kinetic α‐furanose or the thermodynamically favored β‐anomer. The utility of the method is showcased in the synthesis of Remdesivir precursor GS‐441524 by a subsequent Mn‐catalyzed C−H oxidation and deoxycyanation.
A sulfur-directed Fe(iii)-mediated ortho C-H coupling of arenes with unactivated terminal alkenes gives products of regioselective alkene chloroarylation. The novel mechanism involves ...redox-activation of the arene partner and alkene addition to the resultant aryl radical cation.
A novel route to medicinally-relevant dihydrobenzofurans utilises a sulfur-directed C-H ortho-coupling of arenes and unactivated terminal alkenes mediated by iron, and a palladium-catalysed ...deallylation/heterocyclisation sequence. The iron-mediated coupling affords linear products of alkene chloroarylation in good yield and with complete regioselectivity. The coupling likely proceeds by redox-activation of the arene partner by iron(iii) and alkene addition to the resultant radical cation.
Seit Beginn des Jahres 2020 wird nach einer effektiven Lösung im Kampf gegen SARS‐CoV‐2 gesucht, vor allem durch Entwicklung verlässlicher Impfstoffe, welche die Verbreitung des Virus verhindern, und ...durch die Untersuchung bereits für andere Indikationen zugelassener Wirkstoffe. Diesbezüglich ist die Anwendung der antiviralen Prodrug Remdesivir immer noch am weitesten verbreitet, allerdings beschränkt sich die Synthese auf Schutzgruppen, sauerstoffsensitive Reagenzien und kryogene Temperaturen, weshalb eine kosteneffiziente Herstellung nicht immer gewährleistet werden kann. Um zur Lösung dieses Problems beizutragen, konzentrierten wir uns auf die Entwicklung einer direkten Addition von (Hetero)arenen an ungeschützte Zucker. Hier berichten wir von einer silyliumkatalysierten und vollkommen stereoselektiven C‐Glykosylierung, die zunächst offenkettige Polyole liefert, welche schließlich durch Cyclisierung unter kinetischer oder thermodynamischer Kontrolle zur α‐ oder β‐Furanose umgesetzt werden. Die Methode ermöglicht raschen Zugang zu Remdesivir‐Intermediat GS‐441524 nach anschließender Mn‐katalysierter C−H‐Oxidation sowie Deoxycyanierung.
Wir präsentieren eine direkte Addition von (Hetero)arenen an ungeschützte Zucker. Eine silyliumkatalysierte und vollständig stereoselektive C‐Glykosylierung ergibt zunächst offenkettige Polyole, die schließlich durch Cyclisierung unter kinetischer oder thermodynamischer Kontrolle zur α‐ oder β‐Furanose umgesetzt werden. Die Nützlichkeit der Methode wird demonstriert anhand der Synthese des Remdesivir‐Precursors GS‐441524 durch anschließende Mn‐katalysierte C−H‐Oxidation und Deoxycyanierung.
An interrupted Pummerer/nickel‐catalysed cross‐coupling strategy has been developed and used in the elaboration of styrenes. The operationally simple method can be carried out as a one‐pot process, ...involves the direct formation of stable alkenyl sulfonium salt intermediates, utilises a commercially available sulfoxide, catalyst, and ligand, operates at ambient temperature, accommodates sp‐, sp2‐, and sp3‐hybridised organozinc coupling partners, and delivers functionalised styrene products in high yields over two steps. An interrupted Pummerer/cyclisation approach has also been used to access carbo‐ and heterocyclic alkenyl sulfonium salts for cross‐coupling.
Synthese mit Unterbrechung: Styrole werden unter metallfreien Bedingungen mithilfe eines unterbrochenen Pummerer‐Prozesses aktiviert, und die resultierenden stabilen Alkenylsulfoniumsalze gehen eine Nickel‐katalysierte Kreuzkupplung unter milden Bedingungen ein. Die vielseitige Sequenz wurde als Eintopfreaktion mit einer Bandbreite von Organozink‐Partnern unter Bildung von di‐, tri‐ und tetrasubstituierten Alkenen durchgeführt.
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