Pnictogen-bonding catalysis: brevetoxin-type polyether cyclizations.

Pnictogen-bond donors are attractive for use in catalysis because of deep σ holes, high multivalency, rich hypervalency, and chiral binding pockets. We here report natural product inspired epoxide-opening polyether cyclizations catalyzed by fluoroarylated Sb(v) > Sb(iii) > Bi > Sn > Ge. The distinctive characteristic found for pnictogen-bonding catalysis is the breaking of the Baldwin rules, that is selective endo cyclization into the trans-fused ladder oligomers known from the brevetoxins. Moreover, tris(3,4,5-trifluorophenyl)stibines and their hypervalent stiborane catecholates afford different anti-Baldwin stereoselectivity. Lewis (SbCl3), Brønsted (AcOH) and π acids fail to provide similar access to these forbidden rings. Like hydrogen-bonding catalysis differs from Brønsted acid catalysis, pnictogen-bonding catalysis thus emerges as the supramolecular counterpart of covalent Lewis acid catalysis.

Pnictogen-Bonding Catalysis: An Interactive Tool to Uncover Unorthodox Mechanisms in Polyether Cascade Cyclizations.

Pnictogen-bonding catalysis and supramolecular σ-hole catalysis in general is currently being introduced as the non-covalent counterpart of covalent Lewis acid catalysis. With access to anti-Baldwin cyclizations identified as unique characteristic, pnictogen-bonding catalysis appeared promising to elucidate one of the hidden enigmas of brevetoxin-type epoxide opening polyether cascade cyclizations, that is the cyclization of certain trans epoxides into cis-fused rings. In principle, a shift from SN 2- to SN 1-type mechanisms could suffice to rationalize this inversion of configuration. However, the same inversion could be explained by a completely different mechanism: Ring opening with C-C bond cleavage into a branched hydroxy-5-enal and the corresponding cyclic hemiacetal, followed by cascade cyclization under conformational control, including stereoselective C-C bond formation. In this report, a pnictogen-bonding supramolecular SbV catalyst is used to demonstrate that this unorthodox polyether cascade cyclization mechanism occurs.

Polyether Natural Product Inspired Cascade Cyclizations: Autocatalysis on π-Acidic Aromatic Surfaces.

Anion-π catalysis functions by stabilizing anionic transition states on aromatic π surfaces, thus providing a new approach to molecular transformation. The delocalized nature of anion-π interactions suggests that they serve best in stabilizing long-distance charge displacements. Aiming therefore for an anionic cascade reaction that is as charismatic as the steroid cyclization is for conventional cation-π biocatalysis, reported here is the anion-π-catalyzed epoxide-opening ether cyclizations of oligomers. Only on π-acidic aromatic surfaces having a positive quadrupole moment, such as hexafluorobenzene to naphthalenediimides, do these polyether cascade cyclizations proceed with exceptionally high autocatalysis (rate enhancements kauto /kcat >104 m-1 ). This distinctive characteristic adds complexity to reaction mechanisms (Goldilocks-type substrate concentration dependence, entropy-centered substrate destabilization) and opens intriguing perspectives for future developments.

Primary Anion-π Catalysis of Epoxide-Opening Ether Cyclization into Rings of Different Sizes: Access to New Reactivity.

The concept of anion-π catalysis focuses on the stabilization of anionic transition states on aromatic π surfaces. Recently, we demonstrated the occurrence of epoxide-opening ether cyclizations on aromatic π surfaces. Although the reaction proceeded through unconventional mechanisms, the obtained products are the same as those from conventional Brønsted acid catalysis, and in agreement with the Baldwin selectivity rules. Different mechanisms, however, should ultimately lead to new products, a promise anion-π catalysis has been reluctant to live up to. Herein, we report non-trivial reactions that work with anion-π catalysis, but not with Brønsted acids, under comparable conditions. Namely, we show that the anion-π templated autocatalysis and epoxide opening with alcoholate-π interactions can provide access to unconventional ring chemistry. For smaller rings, anion-π catalysis affords anti-Baldwin oxolanes, 2-oxabicyclo[3.3.0]octanes, and the expansion of Baldwin oxetanes by methyl migration. For larger rings, anion-π templated autocatalysis is thought to alleviate the entropic penalty of folding to enable disfavored anti-Baldwin cyclizations into oxepanes and oxocanes.

Domino Synthesis of Benzo-Fused ß,γ-Unsaturated Ketones from Alkenylboronic Acids and N-Tosylhydrazone-Tethered Benzonitriles.

The transition-metal-free domino reaction between alkenylboronic acids and N-tosylhydrazones from o-(2-oxoalkyl)- and o-(3-oxoalkyl)benzonitriles leads to ß,γ-unsaturated indanones and tetralones featuring an α-"all-carbon" quaternary center. The employment of derivatives of α-substituted cyclopentanones and cyclohexanones led to the stereoselective preparation of ß,γ-unsaturated tetrahydrocyclopenta[ a]inden-8(1 H)-ones, hexahydrofluorenones, and hexahydroanthracenones as cis-fused single stereoisomers. A domino sequence involving diazo compound formation/reductive alkenylation/1,3-borotropic rearrangement/intramolecular bora-aza-ene reaction is proposed to justify the formation of the products as well as the stereoselectivity.

Synthesis of 1,1-Disubstituted Indenes and Dihydronaphthalenes through C-C/C-C Bond-Forming Pd-Catalyzed Autotandem Reactions.

A novel synthesis of 1,1-disubstituted 1H-indenes is described involving the Pd-catalyzed cascade reaction between o-bromophenyl-ß-bromostyrenes and N-tosylhydrazones in a process comprising the consecutive formation of two Csp3-C bonds on the same carbon atom: the cross-coupling of the N-tosylhydrazone with the alkenyl bromide and the intramolecular Heck reaction on the newly formed double bond. A similar approach has been applied to the preparation of 1,1-disubstituted naphthalenes.

Pd-Catalyzed Autotandem Reactions with N-Tosylhydrazones. Synthesis of Condensed Carbo- and Heterocycles by Formation of a C-C Single Bond and a C═C Double Bond on the Same Carbon Atom.

A new Pd-catalyzed autotandem reaction is introduced that consists of the cross-coupling of a benzyl bromide with a N-tosylhydrazone followed by an intramolecular Heck reaction with an aryl bromide. During the process, a single and a double C-C bond are formed on the same carbon atom. Two different arrangements for the reactive functional groups are possible, rendering great flexibility to the transformation. The same strategy led to 9-methylene-9H-fluorenes, 9-methylene-9H-xanthenes, 9-methylene-9,10-dihydroacridines, and also dihydropyrroloisoquinoline and dihydroindoloisoquinoline derivatives.

Pd-catalyzed cascade reactions between o-iodo-N-alkenylanilines and tosylhydrazones: novel approaches to the synthesis of polysubstituted indoles and 1,4-dihydroquinolines.

Two different Pd-catalyzed cascade reactions between o-iodo-N-alkenylanilines and tosylhydrazones are described. The outcome of the cascade processes is determined by the substitution on the N-alkenyl fragment. The reactions with N-tosyl-N-ethylene-o-iodoanilines lead to indoles through a sequence that involves the sequential migratory insertions of a carbene ligand and a C-C double bond, featuring a 5-exo-trig cyclization. The reactions with N-alkyl-N-alkenyl-o-iodoanilines provide 1,4-dihydroquinolines through a cascade reaction that includes a formal 6-endo-trig cyclization. In both cases the benzofused heterocycles are built through the formation of two C-C bonds on the hydrazonic carbon atom.

The Pd-catalyzed synthesis of benzofused carbo- and heterocycles through carbene migratory insertion/carbopalladation cascades with tosylhydrazones.

The Pd-catalyzed reaction between o-iodoallylbenzene and tosylhydrazones gives rise to indene derivatives through a process that involves a carbene migratory insertion followed by an intramolecular carbopalladation, with the formation of two C-C bonds on the same carbon atom. The same strategy has also been applied for the synthesis of 2,3-disubstituted benzofurans and indenones by selecting the appropriate o-substituted iodoarene.