Acetaldehyde in the Enders triple cascade reaction via acetaldehyde dimethyl acetal.

Asymmetric organocatalyzed multicomponent reactions represent an important toolbox in the field of organic synthesis to build complex scaffolds starting from simple starting materials. The Enders three-component cascade reaction was a cornerstone in the field and a plethora of organocatalyzed cascade reactions followed. However, acetaldehyde was not shown as a successful reaction partner, probably because of its high reactivity. Herein, we report the Enders-type cascade reaction using acetaldehyde dimethyl acetal, as a masked form of acetaldehyde. This strategy directly converts acetaldehyde, nitroalkenes and enals into stereochemically dense cyclohexenals in good yield and excellent enantioselectivity.

Synergistic Strategies in Aminocatalysis.

Synergistic catalysis offers the unique possibility of simultaneous activation of both the nucleophile and the electrophile in a reaction. A requirement for this strategy is the stability of the active species towards the reaction conditions and the two concerted catalytic cycles. Since the beginning of the century, aminocatalysis has been established as a platform for the stereoselective activation of carbonyl compounds through HOMO-raising or LUMO-lowering. The burgeoning era of aminocatalysis has been driven by a deep understanding of these activation and stereoinduction modes, thanks to the introduction of versatile and privileged chiral amines. The aim of this review is to cover recent developments in synergistic strategies involving aminocatalysis in combination with organo-, metal-, photo-, and electro-catalysis, focusing on the evolution of privileged aminocatalysts architectures.

DoE-Driven Development of an Organocatalytic Enantioselective Addition of Acetaldehyde to Nitrostyrenes in Water.

The development of an enantioselective enamine-catalysed addition of masked acetaldehyde to nitroalkenes via a rational approach helped to move away from the use of chloroform. The presented research allows the use of water as a reaction medium, therefore improving the industrial relevance of a protocol to access very important pharmaceutical intermediates. Critical to the success is the use of chemometrics-assisted 'Design of Experiments' (DoE) optimisation during the development of the presented new synthetic approach, which allows to investigate the chemical space in a rational way.

Photoredox Cross-Dehydrogenative Coupling of N-Aryl Glycines Mediated by Mesoporous Graphitic Carbon Nitride: An Environmentally Friendly Approach to the Synthesis of Non-Proteinogenic α-Amino Acids (NPAAs) Decorated with Indoles.

Indole-decorated glycine derivatives are prepared through an environmentally benign cross-dehydrogenative coupling between N-aryl glycine analogues and indoles (yield of ≤81%). Merging heterogeneous organocatalysis and photocatalysis, C-H functionalization has been achieved by selective C-2 oxidation of N-aryl glycines to afford the electrophilic imine followed by Friedel-Crafts alkylation with indole. The sustainability of the process has been taken into account in the reaction design through the implementation of a metal-free recyclable heterogeneous photocatalyst and a green reaction medium. Scale-up of the benchmark reaction (gram scale, yield of 69%) and recycling experiments (over seven runs without a loss of efficiency) have been performed to prove the robustness of the protocol. Finally, mechanistic studies were conducted employing electron paramagnetic resonance spectroscopy to unveil the roles of the photocatalyst and oxygen in the formation of odd-electron species.

Continuous-Flow Synthesis of Arylthio-Cyclopropyl Carbonyl Compounds.

The straightforward, continuous-flow synthesis of cyclopropyl carbaldehydes and ketones has been developed starting from 2-hydroxycyclobutanones and aryl thiols. This acid-catalyzed mediated procedure allows access to the multigram and easily scalable synthesis of cyclopropyl adducts under mild conditions, using reusable Amberlyst-35 as a catalyst. The resins, suitably ground and used for filling steel columns, have been characterized via TGA, ATR, SEM and BET analyses to describe the physical-chemical properties of the packed bed and the continuous-flow system in detail. To highlight the synthetic versatility of the arylthiocyclopropyl carbonyl compounds, a series of selective oxidation reactions have been performed to access sulfoxide and sulfone carbaldehyde cyclopropanes, oxiranes and carboxylic acid derivatives.

π-Extended Polyaromatic Hydrocarbons by Sustainable Alkyne Annulations through Double C-H/N-H Activation.

The widespread applications of substituted diketopyrrolopyrroles (DPPs) call for the development of efficient methods for their modular assembly. Herein, we present a π-expansion strategy for polyaromatic hydrocarbons (PAHs) by C-H activation in a sustainable fashion. Thus, twofold C-H/N-H activations were accomplished by versatile ruthenium(II)carboxylate catalysis, providing step-economical access to diversely decorated fluorogenic DPPs that was merged with late-stage palladium-catalyzed C-H arylation on the thus-assembled DPP motif.

Enantioselective C-H Activation with Earth-Abundant 3d Transition Metals.

Molecular syntheses largely rely on time- and labour-intensive prefunctionalization strategies. In contrast, C-H activation represents an increasingly powerful approach that avoids lengthy syntheses of prefunctionalized substrates, with great potential for drug discovery, the pharmaceutical industry, material sciences, and crop protection, among others. The enantioselective functionalization of omnipresent C-H bonds has emerged as a transformative tool for the step- and atom-economical generation of chiral molecular complexity. However, this rapidly growing research area remains dominated by noble transition metals, prominently featuring toxic palladium, iridium and rhodium catalysts. Indeed, despite significant achievements, the use of inexpensive and sustainable 3d metals in asymmetric C-H activations is still clearly in its infancy. Herein, we discuss the remarkable recent progress in enantioselective transformations via organometallic C-H activation by 3d base metals up to April 2019.

Enantioselective Cobalt(III)-Catalyzed C-H Activation Enabled by Chiral Carboxylic Acid Cooperation.

The enantioselective cobalt(III)-catalyzed C-H alkylation was achieved through the design of a novel chiral acid. The cobalt(III)-catalyzed enantioselective C-H activation was characterized by high position-, regio- and enantio-control under exceedingly mild reaction conditions. Thereby, the robust cooperative cobalt(III) catalysis proved tolerant of valuable electrophilic functional groups, including hydroxyl, bromo, and iodo substituents. Mechanistic studies revealed a considerable additive effect on kinetics and on a negative non-linear-effect.

Synergistic Manganese(I) C-H Activation Catalysis in Continuous Flow: Chemoselective Hydroarylation.

Chemoselective hydroarylations were accomplished by a novel synergistic Brønsted acid/manganese(I)-catalyzed C-H activation manifold. Thus, alkynes bearing O-leaving groups could, for the first time, be employed for C-H alkenylations without concurrent ß-O elimination, thereby setting the stage for versatile late-stage diversifications. Also described is the first manganese-catalyzed C-H activation in continuous flow, thus enabling efficient hydroarylations within only 20 minutes.

Towards high-performance Lewis acid organocatalysis.

The combination of Lewis acid organocatalysis and internal hydrogen-bond assistance was used to develop a new type of highly active disulfonimide catalyst. The increased Lewis acidity was documented by activity comparisons as well as theoretical investigations. Finally, the potential of the hydrogen-bond-assisted disulfonimide catalyst was demonstrated by its application in an enantioselective transformation.

Piers-Rubinsztajn reaction to unlock an 8-step synthesis of 7-hydroxy cannabidiol.

A scalable synthesis of 7-hydroxy cannabidiol (7-OH CBD), a primary metabolite of (-)-cannabidiol (CBD), is highly desirable, from an industrial point of view, to enable future clinical trials. A Piers-Rubinsztajn reaction was key to enable a mild deprotection and a concise synthesis of 7-OH CBD from commercially available CBD, in 31% overall yield.

Organocatalytic asymmetric Friedel-Crafts alkylation of indoles with simple alpha,beta-unsaturated ketones.

[structure: see text]. The first general and highly enantioselective organocatalytic Friedel-Crafts alkylation of indoles with simple alpha,beta-unsaturated ketones has been accomplished. Central to these studies has been the identification of a new catalyst amine salt, in which both the cation and the anion are chiral, that exhibits high reactivity and selectivity for iminium ion catalysis.

Asymmetric catalytic aziridination of cyclic enones.

The first catalytic method for the asymmetric aziridination of cyclic enones is described. The presented organocatalytic strategy is based on the use of an easily available organocatalyst that is able to convert a wide range of cyclic enones into the desired aziridines with very high enantiomeric purity and good chemical yield. Such a method may very well open up new opportunities to stereoselectively prepare complex chiral molecules that possess an indane moiety, a framework that is found in a large number of bioactive and pharmaceutically important molecules.