Advances in Palladium-Catalyzed Cascade Cyclizations

The past decades in organic chemistry have witnessed significant improvements in synthetic efficiency as a result of considerable progress in cascade reactions, tandem reactions, and related one-pot processes. These methods are less time-consuming and produce less waste compared to the classical stepwise approach. However, cascade chemistry requires a more careful design and compatible reaction types for success. Palladium-catalyzed cross-coupling reactions, with their well understood multistep catalytic cycles, form a promising basis for the design of cascade reactions. Furthermore, they are compatible with a range of functional groups and can be combined with a range of secondary transformations. The resulting palladium-catalyzed cascade reactions have provided access to a plethora of complex small molecules of high medicinal relevance. This review provides an overview of the developments in palladium-catalyzed cascade reactions since 2011, classified according to the initiation, propagation, and termination steps comprising the palladium cascade reactions. This classification should assist the reader and may provide inspiration for the design of new cascade reactions. (Figure presented.)

Total Synthesis of Aspidosperma and Strychnos Alkaloids through Indole Dearomatization

Monoterpenoid indole alkaloids are the major class of tryptamine-derived alkaloids found in nature. Together with their structural complexity, this has attracted great interest from synthetic organic chemists. In this Review, the syntheses of Aspidosperma and Strychnos alkaloids through dearomatization of indoles are discussed

Base Metal Catalyzed Isocyanide Insertions

Isocyanides are diverse C1 building blocks considering their potential to react with nucleophiles, electrophiles, and radicals. Therefore, perhaps not surprisingly, isocyanides are highly valuable as inputs for multicomponent reactions (MCRs) and other one-pot cascade processes. In the field of organometallic chemistry, isocyanides typically serve as ligands for transition metals. The coordination of isocyanides to metal centers alters the electronic distribution of the isocyano moiety, and reaction pathways can therefore be accessed that are not possible in the absence of the metal. The tunable reactivity of the isocyanide functional group by transition metals has evolved into numerous useful applications. Especially palladium-catalyzed isocyanide insertion processes have emerged as powerful reactions in the past decade. However, reports on the use of earth-abundant and cheap base metals in these types of transformations are scarce and have received far less attention. In this Minireview, we focus on these emerging base metal catalyzed reactions and highlight their potential in synthetic organic chemistry. Although mechanistic studies are still scarce, we discuss distinct proposed catalytic cycles and categorize the literature according to 1) the (hetero)atom bound to and 2) the type of bonding with the transition metal in which the (formal) insertion occurs

Iodospirocyclization of Tryptamine-Derived Isocyanides:Formal Total Synthesis of Aspidofractinine

The N-iodosuccinimide-mediated spirocyclization of tryptamine-derived isocyanides to generate spiroindolenines is reported. The products contain both an imine and an imidoyl iodide as flexible handles for follow-up chemistry. Nucleophilic addition typically occurs chemoselectively on the imine moiety with complete diastereoselectivity, providing opportunities for the construction of complex molecular frameworks. The synthetic potential of the method was showcased in the formal total synthesis of (±)-aspidofractinine

Multicomponent Synthesis of 3,6-Dihydro-2H-1,3-thiazine-2-thiones

Non-fused 3,6-dihydro-2H-1,3-thiazine-2-thiones constitute a so far rather unexplored class of compounds, with the latest report dating back more than two decades. Thiazine-2-thiones contain an endocyclic dithiocarbamate group, which is often found in pesticides, in substrates for radical chemistry and in synthetic intermediates towards thioureas and amidines. We now report the multicomponent reaction (MCR) of in situ-generated 1-azadienes with carbon disulfide. With this reaction, a one-step protocol towards the potentially interesting 3,6-dihydro-2H-1,3-thiazine-2-thiones was established and a small library was synthesized

Synthesis of tetracyclic spiroindolines by an interrupted Bischler-Napieralski reaction: total synthesis of akuammicine

Judicious substrate design allows interruption of the classical Bischler-Napieralski reaction, providing access to a range of diversely substituted tetracyclic spiroindolines. These complex polycyclic scaffolds are valuable building blocks for the construction of indole alkaloids, as showcased in a concise total synthesis of (±)-akuammicine