Concept: Cascade reaction
‘Dibal'lin’ on a budget: The enantioselective total syntheses of transtaganolides A-D are rapidly achieved by a highly diastereoselective Ireland-Claisen/Diels-Alder cascade reaction of an enantioenriched geraniol derivative. Based on X-ray diffraction data, the absolute configuration of these metabolites is established and discussed within the context of existing biosynthetic hypotheses.
A one-step, transition-metal-free protocol, involving facile post-treatment, for the regioselective synthesis of 1,3-diazaheterocycle fused [1,2-a][1,8]naphthyridine derivatives () from 2-chloroquinoline-3-carbaldehydes (ClQuAlds) () and heterocyclic ketene aminals (HKAs) () was developed via a joint experimental-computational approach. The computational prediction of the reactivity of two series of synthons was applied in the process of optimizing the reaction conditions, which relied on density functional theory (DFT) calculations together with concepts of frontier molecular orbital (FMO) theory and quantitative structure-reactivity relationship (QSRR) presumptions. The combined results enabled the proposal of a pre-synthetic prediction of global reactivity. The fully consistent results of the synthetic experiments with the in silico evaluation confirmed the rationality, effectiveness, and practicability of the new strategy. Notably, the joint method is not limited to the laboratory, but has applications ranging from routine to industry. This approach is likely to yield numerous insights to accelerate HKA-related synthetic chemistry that can be extended to numerous heterocycles. It thus opens up a novel entry towards rapidly investigating the reactivity of novel synthons with unique properties, a further step towards exploiting cascade reactions by avoiding the futile waste of time and resources.
A five-step total synthesis of (±)-verrubenzospirolactone has been achieved using a biomimetic, intramolecular Diels-Alder reaction of a 2H-chromene to form two rings and four stereocenters in the final step. This Diels-Alder reaction occurs spontaneously at 30 °C “on-water”, and thus suggests that it is likely to be non-enzymatic in nature. The structure of (±)-verrubenzospirolactone was also used to inspire a quadruple cascade reaction to generate seven stereocenters, four rings, three C-C bonds, and two C-O bonds in one step.
An unprecedented gold-catalyzed cycloisomerization/1,5-H migration/Diels-Alder reaction cascade has been developed that enables the rapid construction of complex nitrogen polycyclic compounds. This one-pot, three-step cascade reaction offers good yields of the products and is promoted by a single gold catalyst under very mild conditions.
Hierarchical self-assembly is used to fabricate bio-catalytically active, self-supporting protein-polymer surfactant films capable of sustaining two- or three-enzyme cascade reactions.
A novel diazo-cascade approach has been developed for the synthesis of nine-membered oxacycles utilizing readily accessible β-hydroxy vinyl ketones and vinyl diazo esters. The Rh(II)-catalyzed cascade reaction begins with carbene O-H insertion followed by an intramolecular aldol cyclization to provide a substituted tetrahydrofuran intermediate that undergoes an oxy-Cope rearrangement to provide functionalized nine-membered oxacycles with complete stereoselectivity.
A Michael-Mannich-hemiaminalization-dehydration cascade reaction was developed for the construction of spirooxindole benzoquinolizine derivatives. Additionally, spirooxindole benzoindolizidine was prepared conveniently through a ring-contracted rearrangement reaction from spirooxindole benzoquinolizine.
A combination of metal- and organo-catalysts sequentially catalyzing the Friedel-Crafts/aldol tandem reaction between 3-pyrrolyl-oxindoles and isatin-derived β,γ-unsaturated α-ketoesters has been reported, which leads to two types of diastereomeric enantio-enriched bispirooxindoles with three quaternary stereocentres and synthetically valuable functional groups in high yields with excellent enantioselectivity and diastereoselectivity.
Enzyme-filled polystyrene-b-poly(3-(isocyano-L-alanyl-aminoethyl)thiophene) (PS-b-PIAT) nanoreactors are encapsulated together with free enzymes and substrates in a larger polybutadiene-b-poly(ethylene oxide) (PB-b-PEO) polymersome, forming a multicompartmentalized structure, which shows structural resemblance to the cell and its organelles. An original cofactor-dependent three-enzyme cascade reaction is performed, using either compatible or incompatible enzymes, which takes place across multiple compartments.
Bridged bicyclic metallacyclopentenes generated from the [4+2] cycloaddition of metallacyclopentadienes with alkenes have been proposed as reactive intermediates in the course of [2+2+2] annulation reactions. Recently a collection of alkoxide-directed Ti-mediated [2+2+2] annulation reactions have been discovered for the synthesis of densely functionalized hydrindanes, where the bridged bicyclic metallacyclopentenes from intramolecular [4+2] were treated as fleeting intermediates en route to cyclohexadiene products by formal cheletropic extrusion of Ti(Oi-Pr)2. In studies aimed at understanding the course of these organometallic cascade reactions it was later discovered that these bridged bicyclic intermediates can be trapped by various elimination processes. Here, we have realized metallacycle-mediated annulation reactions for the assembly of angularly substituted decalins - structural motifs that are ubiquitous in natural products and molecules of pharmaceutical relevance. In addition to defining the basic annulation reaction we have discovered a surprising stability associated with the complex organometallic intermediates generated in the course of this coupling process and document here the ability to control the fate of this species. Ligand-induced cheletropic extrusion of the titanium center delivers cyclohexadiene-containing products, while several distinct protonation events have been identified to realize polycyclic products that contain three new stereocenters (one of which is the angular quaternary center that is a hallmark of alkoxide-directed titanium-mediated [2+2+2] annulation reactions). Examples of this metallacycle-mediated annulation reaction are provided to demonstrate that a range of stereodefined fused bicyclo[4.4.0]-decanes are accessible, including those that contain aromatic and aliphatic substituents, and an empirical model is presented to accompany the observations made.