Enantioselective (3+2) Annulation of Donor-Acceptor Cyclopropanes with Aldehydes and Ketones Catalyzed by Brønsted Bases.

The substituted tetrahydrofuran core is a structural motif in many biologically active and natural compounds. However, the scarcity of enantioselective methods developed towards its synthesis makes this field challenging and attractive to explore. Herein, the first Brønsted-base catalyzed enantioselective (3+2) annulation of donor-acceptor cyclopropanes with aldehydes and ketones affording enantioenriched 2,3,5-substituted tetrahydrofurans is reported. The reaction concept is based on activation of racemic ß-cyclopropyl ketones by a chiral bifunctional Brønsted base which catalyzes the (3+2) annulation for a range of aldehydes and ketones. For aldehydes, the annulation furnished tetrahydrofurans in excellent yield, good diastereoselectivity and with excellent enantioselectivity up to >99% ee. Surprisingly, aromatic aldehydes afforded the cis-2,5-substituted tetrahydrofurans as the major diastereoisomer, while for aliphatic aldehydes the trans-cycloadduct was favored. The reaction also proceeds well for ketones affording spiro tetrahydrofurans in excellent yields and enantioselectivities (up to 99% ee). Hammett studies have been conducted to elucidate the influence of the electronic nature of benzaldehydes on the stereoselectivity. Based on the diastereochemical outcome for the aldehydes, two reaction paths for aromatic and aliphatic aldehydes are proposed. Finally, two diastereoselective synthetic transformations have been conducted to demonstrate the synthetic potential of the obtained products.

Enantioselective Synthesis of α-Quaternary Isochromanes by Oxidative Aminocatalysis and Gold Catalysis.

A novel strategy that combines oxidative aminocatalysis and gold catalysis allows the preparation of chiral α-quaternary isochromanes, a motif that is prevalent in natural products and synthetic bioactive compounds. In the first step, α-branched aldehydes and propargylic alcohols are transformed into α-quaternary ethers with excellent optical purities (>90 % ee) via oxidative umpolung with DDQ and an amino acid-derived primary amine catalyst. Subsequent gold(I)-catalyzed intramolecular hydroarylation affords the isochromane products with retention of the quaternary stereocenter. A second approach explores the use of allylic alcohols as reaction partners for the oxidative coupling to furnish α-quaternary ethers with generally lower enantiopurities. Stereoretentive cyclization to isochromane products is achieved via intramolecular Friedel-Crafts type alkylation with allylic acetates as a reactive handle. A number of synthetic elaborations and a biological study on these α-quaternary isochromanes highlight the potential applicability of the presented method.

Exploring Heterotropones and Examining Their Propensity to Undergo [4 + 2] Cycloadditions.

An efficient strategy to obtain a broad array of chiral and achiral heterotropones and their corresponding [4 + 2] cycloadducts is disclosed. This strategy enables access to unique heterotropones and intricate bicyclic structures in high yields and diastereoselectivities through a simple procedure and from easily accessible starting materials.

Asymmetric [4 + 2], [6 + 2], and [6 + 4] Cycloadditions of Isomeric Formyl Cycloheptatrienes Catalyzed by a Chiral Diamine Catalyst.

Novel asymmetric aminocatalytic cycloadditions are described between formyl cycloheptatrienes and 6,6-dimethylfulvene that lead to [4 + 2], [6 + 2], and [4 + 6] cycloadducts. The unprecedented reaction course is dependent on the position of the formyl functionality in the cycloheptatriene core, and each formyl cycloheptatriene isomer displays a distinct reactivity pattern. The formyl cycloheptatriene isomers are activated by a chiral primary diamine catalyst, and the activation mode is dependent on the position of the formyl functionality relative to the cycloheptatriene core. The [4 + 2] and [6 + 2] cycloadducts are formed via rare iminocatalytic inverse electron-demand cycloadditions, while the [4 + 6] cycloadduct is formed by a normal electron-demand cycloaddition. The reactivity displayed by the different formyl cycloheptatrienes was investigated by DFT calculations. These computational studies account for the different reaction paths for the three isomeric formyl cycloheptatrienes. The aminocatalytic [4 + 2], [6 + 2], and [4 + 6] cycloadditions proceed by stepwise processes, and the interplay between conjugation, substrate distortion, and dispersive interactions between the fulvene and aminocatalyst mainly defines the outcome of each cycloaddition.

Enantioconvergent 6π Electrocyclization Enabled by Photoredox Racemization.

This study presents a novel photoredox-enabled enantioconvergent catalytic strategy used to construct chiral 2H-1,3-benzoxazines via an unprecedented oxa-6π electrocyclization utilizing racemic α-substituted glycinates as substrates. The approach leverages a cobalt-based chiral Lewis acid catalyst, which promotes the transformation under thermal or photoredox conditions. While the thermal reaction selectively converts only the (S)-configured glycinates into enantioenriched 2H-1,3-benzoxazines (up to 96:4 e.r.), the addition of 0.5 mol % of a commercially available iridium photocatalyst under visible light irradiation transforms the reaction into an enantioconvergent process. Detailed mechanistic and time course studies of optically pure α-deuterated substrates revealed the presence of an enantiospecific kinetic isotope effect, which helped to clarify the role of both the photo- and chiral Lewis acid catalyst in the reaction sequence. In this dual catalytic system, the photocatalyst promotes a dynamic interconversion between the substrate enantiomers─a process not accessible via ground-state chemistry─while the chiral Lewis acid selectively transforms only the (S)-configured substrates. Further mechanistic evidence for the proposed mechanism is provided by linear free energy relationship analysis, which suggests that the stereodetermining step involves a 6π electrocyclization under both thermal and photoredox conditions.

Atroposelective brominations to access chiral biaryl scaffolds using high-valent Pd-catalysis.

Compounds featuring atropisomerism are ubiquitous in natural products, therapeutics, advanced materials, and asymmetric synthesis. However, stereoselective preparation of these compounds presents many synthetic challenges. This article introduces streamlined access to a versatile chiral biaryl template through C-H halogenation reactions employing high-valent Pd catalysis in combination with chiral transient directing groups. This methodology is highly scalable, insensitive to moisture and air, and proceeds, in select cases, with Pd-loadings as low as 1 mol%. Chiral mono-brominated, dibrominated, and bromochloro biaryls are prepared in high yield and excellent stereoselectivity. These serve as remarkable building blocks bearing orthogonal synthetic handles for a gamut of reactions. Empirical studies elucidated regioselective C-H activation to be predicated on the oxidation state of Pd and diverging site-halogenation to result from cooperative effects of Pd and oxidant.

Asymmetric Organocatalyzed Cascade Reactions─Merging the pseudo-Halogen and Halogen Effect with Dienamine Catalysis.

The combination of asymmetric organocatalysis with the (pseudo)-halogen effect enables the formation of chiral norcarane scaffolds in high yields and selectivities (up to 92% yield, >99% ee, and >95:5 d.r.). This was achieved by reacting (pseudo)-halogenated 3-vinyl chromones with in situ generated chiral dienamines in an inverse electron demand [4 + 2] cycloaddition followed by an intramolecular SN2 reaction. These scaffolds could easily undergo photoinduced rearrangements or lactonization to form intricate chiral ring structures.

Higher-Order Cycloaddition Reactions for the Construction of Polycyclic Aromatic and Polycyclic Heteroaromatic Compounds.

Cycloadditions are an important class of reactions in materials science for the construction of polycyclic aromatic and polycyclic heteroaromatic compounds. Recently, cycloadditions have been expanded beyond the "classical" group of cycloadditions involving six π-electrons, and it is now possible to control cycloadditions for an extended number of π-electrons by applying organocatalysis. This novel field of cycloadditions-termed higher-order cycloadditions-allows new synthetic methodologies to construct polycyclic carbo- and heteroaromatic compounds in two or three dimensions. This concept presents higher-order cycloadditions as a method for accessing two- and three-dimensional azulenes and cyclazines, as well as three dimensional indenes, as polycyclic aromatic and polycyclic heteroaromatic compounds.

Organocatalytic Enantioselective Thermal [4 + 4] Cycloadditions.

Chiral eight-membered carbocycles are important motifs in organic chemistry, natural product chemistry, chemical biology, and medicinal chemistry. The lack of synthetic methods toward their construction is a challenge preventing their rational design and stereoselective synthesis. The catalytic enantioselective [4 + 4] cycloaddition is one of the most straightforward and atom-economical methods to obtain chiral cyclooctadiene derivatives. We report the first organocatalytic asymmetric [4 + 4] cycloaddition of 9H-fluorene-1-carbaldehydes with electron-deficient dienes affording cyclooctadiene derivatives in good yields and with excellent control of peri-, diastereo-, and enantioselectivities. The reaction concept is based on the aminocatalytic formation of a polarized butadiene component incorporated into a cyclic extended π-system, with restricted conformational freedom, allowing for a stereocontrolled [4 + 4] cycloaddition. FMO analysis unveiled that the HOMO and LUMO of the two reacting partners resemble those of butadiene. The methodology allows for the construction of cyclooctadiene derivatives decorated with various functionalities. The cyclooctadienes were synthetically elaborated, allowing for structural diversity demonstrating their synthetic utility for the formation of, for example, chiral cyclobutene- or cyclooctane scaffolds. DFT computational studies shed light on the reaction mechanism identifying the preference for an initial but reversible [4 + 2] cycloaddition delivering an off-cycle catalyst resting state, from which catalyst elimination is not possible. The off-cycle catalyst-bound intermediate undergoes a retro-[4 + 2] cycloaddition, followed by a [4 + 4] cycloaddition generating a cycloadduct from which catalyst elimination is possible. The reaction pathway accounts for the observed peri-, diastereo-, and enantioselectivity of the organocatalytic [4 + 4] cycloaddition.

Ambimodal Bispericyclic [6 + 4]/[4 + 6] Transition State Competes with Diradical Pathways in the Cycloheptatriene Dimerization: Dynamics and Experimental Characterization of Thermal Dimers.

The thermal dimerization of cycloheptatriene is predicted to occur by a concerted [6 + 4] cycloaddition via an ambimodal [6 + 4]/[4 + 6] transition state (TS) and a competing stepwise diradical (6 + 2) cycloaddition; both dimers subsequently undergo intramolecular [4 + 2] cycloadditions to afford thermally stable tetracyclic products. The ambimodal TS is the 10π-electron version of the prototype bispericyclic dimerization of cyclopentadiene discovered by Caramella et al. in 2002. Quantum mechanical studies using several common DFT functionals and post-HF methods, ωB97X-D, M06-2X, DLPNO-CCSD(T), NEVPT2, and PWPB95-D3(BJ), and quasiclassical molecular dynamics simulations provide details of bond timing and bifurcation pathways. By comparing the ambimodal [6 + 4]/[4 + 6] TS for cycloheptatriene dimerization with the ambimodal [4 + 2]/[2 + 4] TS of cyclopentadiene dimerization, we found that the high distortion energy in cycloheptatriene dimerization is the key to its relatively high energy barrier. The computational investigations were coupled with experimental studies of the cycloheptatriene dimerization, which resulted in the isolation of the two tetracyclic dimers. At lower temperature, the product from the predicted exo-[6 + 4]/[4 + 6] cycloaddition, followed by a subsequent intramolecular [4 + 2] cycloaddition, predominantly forms, while at higher temperature, the diradical (6 + 2) cycloadduct is the major product.

Organocatalyzed Cross-Nucleophile Couplings: Umpolung of Catalytic Enamines.

The concept of umpolung, or polarity reversal, introduced by Seebach and Corey nearly half a century ago, ushered a new paradigm into synthetic chemistry. Novel connections were able to be forged among functional groups that were typically inaccessible. Conceptually, an umpolung reaction is identified only upon retrosynthetic analysis. Stoichiometric examples have served as a platform to develop and refine elegant methodologies into catalytic processes. The advent of these unconventional arrangements of canonical synthons into new points of diversity has expanded the repertoire of the synthetic toolbox. Within this context, asymmetric organocatalyzed methodologies remain rare, and there are even fewer aminocatalyzed variants.Recent years have witnessed a renaissance in α-functionalizations of aldehydes, specifically in the context of oxidative umpolung strategies. Unlike previous open-shell approaches, application of a quinone-based oxidant in conjunction with an aminocatalyst leads to a discrete, substitutionally labile quinone adduct. These have proven to be valuable building blocks toward polar reactivity─auguring the advent of new avenues to construct tetrasubstituted tertiary stereocenters through the application of conventional nucleophiles to form C-C, C-N, C-O, and C-S bonds through an organocatalyzed cross-nucleophile coupling (organo-CNC) reaction. The resulting nonepimerizable stereocenter demonstrates high optical fidelity and provides a significant advancement in many applications that suffer from racemization, such as in vivo studies.This strategy harnesses a trifunctional aminocatalyst to promote an unusual SN2 reaction at a highly congested center. The selection of the quinone oxidant and nucleophile converges to a continuum of reactivity ranging from enantioselective oxidation to stereoselective substitution. A remarkable aspect of these developments is the identification of an asymmetric SN2 dynamic kinetic resolution (SN2-DKR) manifold. These organo-CNC reactions are highly modular and demonstrate complete stereocontrol from the catalyst with minimal influence from incoming chiral nucleophiles. Leveraging this facet, these technologies have been extended to peptidic bioconjugations bearing bio-orthogonoal linker molecules.This Account aims to highlight the progress, from an internal perspective, toward directing the initial result into established methodologies. Within this construct, the underlying principles of each reaction will be disseminated with specific content on inherent challenges and opportunity. Combined, these will serve as an instructive tool to stimulate applications in cross-disciplinary interfaces.

Enantioselective (8+3) Cycloadditions by Activation of Donor-Acceptor Cyclopropanes Employing Chiral Brønsted Base Catalysis.

A novel enantioselective (8+3) cycloaddition between donor-acceptor cyclopropanes and heptafulvenoids catalysed by a chiral bifunctional Brønsted base is described. Importantly, the reaction, which leverages an anionic activation strategy, is divergent from prototypical Lewis-acid activation protocols. A series of cyclopropylketones react with tropones affording the desired (8+3) cycloadducts in high yield and enantiomeric excess. For barbiturate substituted heptafulvenes, the (8+3) cycloaddition with cyclopropylketones proceeds in good yield, excellent diastereoselectivity and high enantiomeric excess. The experimental work is supported by DFT calculations, which indicate that the bifunctional organocatalyst activates both the donor-acceptor cyclopropane and tropone; the reaction proceeds in a step-wise manner with the ring-closure being the stereodetermining step.

Organocatalytic Enantioselective Construction of Conformationally Stable C(sp2)-C(sp3) Atropisomers.

Nonbiaryl atropisomers are molecules defined by a stereogenic axis featuring at least one nonarene moiety. Among these, scaffolds bearing a conformationally stable C(sp2)-C(sp3) stereogenic axis have been observed in natural compounds; however, their enantioselective synthesis remains almost completely unexplored. Herein we disclose a new class of chiral C(sp2)-C(sp3) atropisomers obtained with high levels of stereoselectivity (up to 99% ee) by means of an organocatalytic asymmetric methodology. Multiple molecular motifs could be embedded in this class of C(sp2)-C(sp3) atropisomers, showing a broad and general protocol. Experimental data provide strong evidence of the conformational stability of the C(sp2)-C(sp3) stereogenic axis (up to t1/225 °C >1000 y) in the obtained compounds and show kinetic control over this rare stereogenic element. This, coupled with density functional theory calculations, suggests that the observed stereoselectivity arises from a Curtin-Hammett scenario establishing an equilibrium of intermediates. Furthermore, the experimental investigation led to evidence of the operating principle of central-to-axial chirality conversions.

Metal-free, Oxidative α-Coupling of Aldehydes with Amine Nucleophiles for the Preparation of Congested C(sp3)-N Bonds.

This article discloses the direct α-amination of α-branched aldehydes applying nitrogen-based nucleophiles. Under organocatalyzed, oxidative conditions α-branched aldehydes are umpoled to their electrophilic synthons and, subsequently, displaced by a variety of nucleophilic amines to form tetrasubstituted tertiary centers. A similar strategy has been previously employed to form congested C-C, C-O, and C-S bonds; however, unsatisfactory results were received when extending the methodology to include C-N bonds. Initially, intramolecular α-amination reactions were undertaken to foster dihydroquinoxaline-type products. A solvent exchange to the polar, aprotic solvent, MeNO2, proved critical to facilitate intermolecular α-C-N bond formation with a wide range of amine coupling partners (N-heterocycles, N,N-diaryl amines, and anilines). Application of the solvent exchange to the enantioselective SN2-DKR manifold provided distinct regimes leading to refinement in yield and enantioselectivity.

Ambimodal Transition States in Diels-Alder Cycloadditions of Tropolone and Tropolonate with N-Methylmaleimide*.

The Diels-Alder reactions of tropolone and its conjugate base with N-methylmaleimide have been explored computationally and experimentally. Previous studies of the [4+2] cycloaddition under basic conditions show that both endo- and exo-products are obtained in similar, but variable amounts. Density functional theory (ωB97X-D) explorations of potential energy surfaces, and molecular dynamics trajectories show that the reaction involves an ambimodal transition state for the reaction of the ammonium tropolonate with N-methylmaleimide, and that similar amounts of endo- and exo-products are obtained. The thermal reaction, studied experimentally in detail here for the first time, is predicted to form the endo-adduct through an ambimodal transition state. The exo-adduct can be formed from the same transition state, but requires a hydrogen shift, that hinders this reaction dynamically. Longer reaction times give a small excess of the exo-product, which is thermodynamically more stable.

Enantioselective α-Etherification of Branched Aldehydes via an Oxidative Umpolung Strategy.

Saturated carbonyl compounds are, via their enolate analogues, inherently nucleophilic at the α-position. In the presence of a benzoquinone oxidant, the polarity of the α-position of racemic α-branched aldehydes is inverted, allowing for an enantioselective etherification using readily available oxygen-based nucleophiles and an amino acid-derived primary amine catalyst. A survey of benzoquinone oxidants identified p-fluoranil and DDQ as suitable reaction partners. p-Fluoranil enables the preparation of α-aryloxylated aldehydes using phenol nucleophiles in up to 91 % ee, following either a one-step or a two-step, one-pot protocol. DDQ allows for a more general etherification protocol in combination with a broader range of alcohol nucleophiles with enantioselectivities up to 95 % ee. Control experiments and isolation of a key quinol intermediate supports a mechanism proceeding via an SN 2 dynamic-kinetic resolution. These studies provide the basis for an aminocatalytic umpolung concept that allows for the asymmetric construction of tertiary ethers in the α-position of aldehydes.

Aminocatalytic [8+2] Cycloaddition Reactions toward Chiral Cyclazines.

An efficient and exceptionally stereoselective synthesis of chiral cycl[3.2.2]azines has been realized by means of the rational design and utilization of novel (E)-3-benzylidene-3H-pyrrolizines in iminium-ion-catalyzed [8+2] cycloaddition reactions. The presented protocol allows for the incorporation of diverse enals, including cinnamaldehydes, enolizable aldehydes, and substrates of extended conjugation. The obtained products contain both an electron-rich alkenyl pyrrole moiety and an electron-deficient carbaldehyde substituent, and both moieties can undergo selective transformations with retention of the stereochemical information established in the [8+2] cycloaddition.

A Direct Organocatalytic Enantioselective Route to Functionalized trans-Diels-Alder Products Having the Norcarane Scaffold.

An enantioselective methodology to construct trans-Diels-Alder scaffolds by organocatalysis with excellent selectivity, high yield and up to five contiguous stereocenters is presented. The reaction concept integrates the halogen effect and a novel discovered pseudo-halogen effect to direct an endo-selective, secondary-amine catalyzed Diels-Alder reaction allowing for the subsequent formation of trans-Diels-Alder cycloadducts featuring the norcarene scaffold. The methodology relies on the reaction between an in situ generated trienamine and an α-brominated or α-pseudo-halogenated enone to form a fleeting cis-Diels-Alder intermediate. The endo-transition state-enhanced by the (pseudo-)halogen effect-sets the stereochemistry that allows for a subsequent SN 2-like reaction at a tertiary center to obtain the trans-Diels-Alder scaffold. The mechanism was investigated and supported by experimental results as well as computational studies.

An Asymmetric SN2 Dynamic Kinetic Resolution.

The SN2 reaction exhibits the classic Walden inversion, indicative of the stereospecific backside attack of the nucleophile on the stereogenic center. Observation of the inversion of the stereocenter provides evidence for an SN2-type displacement. However, this maxim is contingent on substitution proceeding on a discrete stereocenter. Here we report an SN2 reaction that leads to enantioenrichment of product despite starting from a racemic mixture of starting material. The enantioconvergent reaction proceeds through a dynamic Walden cycle, involving an equilibrating mixture of enantiomers, initiated by a chiral aminocatalyst and terminated by a stereoselective SN2 reaction at a tertiary carbon to provide a quaternary carbon stereocenter. A combination of computational, kinetic, and empirical studies elucidates the multifaceted role of the chiral organocatalyst to provide a model example of the Curtin-Hammett principle. These examples challenge the notion of enantioenriched products exclusively arising from predefined stereocenters when operating through an SN2 mechanism. Based on these principles, examples are included to highlight the generality of the mechanism. We anticipate the asymmetric SN2 dynamic kinetic resolution to be used for a variety of future reactions.

Organocatalytic Asymmetric Multicomponent Cascade Reaction for the Synthesis of Contiguously Substituted Tetrahydronaphthols.

Isobenzopyrylium ions are unique, highly reactive, aromatic intermediates which are largely unexplored in asymmetric catalysis despite their high potential synthetic utility. In this study, an organocatalytic asymmetric multicomponent cascade via dienamine catalysis, involving a cycloaddition, a nucleophilic addition, and a ring-opening reaction, is disclosed. The reaction furnishes chiral tetrahydronaphthols containing four contiguous stereocenters in good to high yield, high diastereoselectivity (up to >20:1), and excellent enantioselectivity (93-98% ee). The obtained products are important synthetic intermediates, and it is demonstrated that they can be used for the generation of frameworks such as octahydrobenzo[h]isoquinoline and [2.2.2]octane scaffolds. Furthermore, mechanistic experiments involving oxygen-18-labeling studies and density functional theory calculations provide a vivid picture of the reaction mechanism. Finally, the bioactivity of 16 representative tetrahydronaphthol compounds has been evaluated in U-2OS cancer cells with some compounds showing a unique profile and a clear morphological change.