Teresa Martínez del Campo

Organocatalyzed Enantioselective Fluorocyclizations

Enantioenriched fluorinated heterocycles can be prepared through fluorocyclizations of prochiral indoles (see scheme; Ts=tosyl, Bn=benzyl, Boc=tert-butoxycarbonyl). More than twenty examples for this cascade fluorination-cyclization, which is catalyzed by cinchona alkaloids and employs N-fluorobenzenesulfonimide as the electrophilic fluorine source have been explored, and an unprecedented catalytic asymmetric difluorocyclization has also been identified.

Cross-Coupling/Cyclization Reactions of Two Different Allenic Moieties

The allene moiety represents an excellent building block for allene cross-coupling cyclization reactions, affording heterocyclic skeletons in a single step. This strategy is of particular interest when two different allene derivatives are involved in a series of metal-catalyzed cross-coupling heterocyclization processes. This Concept article is focused on the Pd-catalyzed union of two different allenic moieties, with cyclization of at least one of them by intramolecular cyclometalation. These new, versatile, and highly effective transformations are complex multistep processes leading to potential privileged structures that could find wide applications in related medicinal chemistry.

Regioselectivity Control in the Metal‐Catalyzed OC Functionalization of γ‐Allenols, Part 1: Experimental Study

We describe versatile regiocontrolled metal-catalyzed heterocyclization reactions of gamma-allenol derivatives leading to a variety of fused enantiopure tetrahydrofurans, dihydropyrans, and tetrahydrooxepines. Regioselectivity control in the O-C functionalization of gamma-allenols can be achieved through the choice of catalyst: use of AuCl(3) exclusively affords tetrahydrofurans, use of La[N(SiMe(3))(2)](3) usually favors the formation of dihydropyrans, whereas use of PdCl(2) solely gives tetrahydrooxepines. In addition, it has been observed that for the Au-catalyzed cycloisomerization, the presence of a methoxymethyl protecting group not only masks a hydroxy functionality, but also exerts directing effects as a controlling unit in a regioselectivity reversal (7-endo versus 5-exo cyclization). In addition, the regioselectivity of the La-catalyzed cycloetherification can be tuned (5-exo versus 7-endo) simply through a subtle variation in the substitution pattern of the allene component (Ph versus Me). Thus, for the first time the regiocontrolled heterocyclization of gamma-allenol derivatives is both catalyst- and substrate-directable. These metal-catalyzed heterocyclization reactions have been developed experimentally (Part 1, this paper), and their mechanisms have additionally been investigated by a theoretical study (Part 2, accompanying paper).

Metal‐Catalyzed Cycloetherification Reactions of β,γ‐ and γ,δ‐Allendiols: Chemo‐, Regio‐, and Stereocontrol in the Synthesis of Oxacycles

Versatile routes that lead to a variety of functionalized enantiopure tetrahydrofurans, dihydropyrans, and tetrahydrooxepines are based on chemo-, regio-, and stereocontrolled metal-catalyzed oxycyclization reactions of β,γ- and γ,δ-allendiols, which were readily prepared from (R)-2,3-O-isopropylideneglyceraldehyde. The application of Pd(II), Pt(II), Au(III), or La(III) salts as the catalysts gives controlled access to differently sized oxacycles in enantiopure form. Usually, chemoselective cyclization reactions occurred exclusively by attack of the secondary hydroxy group (except for the oxybromination of phenyl β,γ-allenic diols 3b and 3d) to an allenic carbon atom. Regio- and stereocontrol issues are mainly influenced by the nature of the metal catalysts and substituents.

Fascinating reactivity in gold catalysis: synthesis of oxetenes through rare 4-exo-dig allene cyclization and infrequent β-hydride elimination

A novel reactivity in gold catalysis, namely the unusual preference for the 4-exo-dig cyclization in allene chemistry as well as the rare β-hydride elimination reaction, was uncovered starting from readily available allenols.

Synthesis of Spiroheterocycles by Palladium-Catalyzed Domino Cycloisomerization/Cross-Coupling of α-Allenols and Baylis-Hillman Acetates

First insights into the reaction between a Baylis-Hillman adduct and an allene moiety have been obtained from the novel domino heterocyclization/cross-coupling reaction of alpha-allenols and Baylis-Hillman acetates, which furnishes [(2,5-dihydrofuran-3-yl)methyl]acrylate derivatives in moderate to good yields.

Metal‐Catalyzed Cyclization of β‐ and γ‐Allenols Derived from D‐Glyceraldehyde—Synthesis of Enantiopure Dihydropyrans and Tetrahydrooxepines: An Experimental and Theoretical Study

Regiocontrolled metal-catalyzed preparations of enantiopure dihydropyrans and tetrahydrooxepines have been synthesized starting from beta- and gamma-allenols derived from D-glyceraldehyde. The Pd(II)-catalyzed cyclizative coupling reactions of beta-allenols 1 a and 1 b with allyl bromide effectively afforded enantiopure tetrafunctionalized dihydropyrans through a 6-endo oxycyclization protocol, whereas the gold-, platinum-, and palladium-mediated heterocyclization of gamma-allenol 2 furnished tetrahydrooxepines 13-16 through regioselective 7-endo-trig oxycyclization reactions. Moreover, density functional calculations were performed to predict the regioselectivity of the gamma-allenol cycloetherification to tetrahydrooxepines on the basis of both the tether nature and characteristics of the metals, and to gain an insight into the mechanism of the oxycyclization reactions.

Gold-catalysed tuning of reactivity in allenes: 9-endo hydroarylation versus formal 5-exo hydroalkylation

The divergent gold-catalysed reactivity (C(sp(2))-H versus C(sp(3))-H) of aryloxy-tethered allenes has been uncovered.

Chemo- and regioselective palladium-catalyzed oxycyclization reactions of allendiols: preparation of five-, six-, and eight-membered cycles.

Positive discrimination: Chemo- and regioselective palladium-catalyzed cycloetherification of allendiols, namely beta,gamma- and gamma,delta-allendiols, may occur by judicious choice of palladium-catalyzed conditions owing to their potential ability to discriminate between both nucleophilic sites (see scheme).

Regioselectivity Control in the Metal-Catalyzed Functionalization of γ-Allenols, Part 2: Theoretical Study†

The gold-, palladium- and lanthanum-catalyzed oxycyclization reactions of azetidin-2-one-tethered gamma-allenol derivatives to a variety of fused enantiopure tetrahydrofurans, dihydropyrans, and tetrahydrooxepines have been developed experimentally (Part 1, accompanying paper). The mechanisms of these regiocontrolled metal-catalyzed heterocyclization reactions have now been computationally explored at the DFT level (Part 2). The energies of the reaction intermediates and transition states for different possible pathways have been calculated in various model systems very close to the real system. Additionally, we selected the La[N(SiH(3))(2)](3) complex to simulate the lanthanide amide precatalyst species. The agreement of theoretically predicted and experimentally observed selectivities is very good in all cases.