Catalytic Asymmetric Dearomatization Research Articles

A metalloenzyme platform for catalytic asymmetric radical dearomatization.

Catalytic asymmetric dearomatization represents a powerful means to convert flat aromatic compounds into stereochemically well-defined three-dimensional molecular scaffolds. Using new-to-nature metalloredox biocatalysis, we describe an enzymatic strategy for catalytic asymmetric dearomatization via a challenging radical mechanism that has eluded small-molecule catalysts. Enabled by directed evolution, new-to-nature radical dearomatases P450rad1-P450rad5 facilitated asymmetric dearomatization of a broad spectrum of aromatic substrates, including indoles, pyrroles and phenols, allowing both enantioconvergent and enantiodivergent radical dearomatization reactions to be accomplished with excellent enzymatic control. Computational studies revealed the importance of additional hydrogen bonding interactions between the engineered metalloenzyme and the reactive intermediate in enhancing enzymatic activity and enantiocontrol. Furthermore, designer non-ionic surfactants were found to significantly accelerate this biotransformation, providing an alternative means to promote otherwise sluggish new-to-nature biotransformations. Together, this evolvable metalloenzyme platform opens up new avenues to advance challenging catalytic asymmetric dearomatization processes involving free radical intermediates.

Catalytic Asymmetric Dearomative [2 + 2] Photocycloaddition/Ring-Expansion Sequence of Indoles with Diversified Alkenes.

Developing novel strategies for catalytic asymmetric dearomatization (CADA) reactions is highly valuable. Visible light-mediated photocatalysis is demonstrated to be a powerful tool to activate aromatic compounds for further synthetic transformations. Herein, a catalytic asymmetric dearomative [2 + 2] photocycloaddition/ring-expansion sequence of indoles with simple alkenes was reported, providing a facile access to enantioenriched cyclopenta[b]indoles with good to high yields and enantioselectivities by means of chiral lanthanide photocatalysis. This protocol exhibited a broad substrate scope and good functional group tolerance, as well as potential applications in the synthesis of bioactive molecules. Mechanistic studies, including control experiments, UV-vis absorption spectroscopy, emission spectroscopy, and DFT calculations, were carried out, shedding insights into the reaction mechanism and the origin of enantioselectivity.

Gd(III)-Catalyzed Regio-, Diastereo-, and Enantioselective [4 + 2] Photocycloaddition of Naphthalene Derivatives.

Catalytic asymmetric dearomatization (CADA) reactions have evolved into an efficient strategy for accessing chiral polycyclic and spirocyclic scaffolds from readily available planar aromatics. Despite the significant developments, the CADA reaction of naphthalenes remains underdeveloped. Herein, we report a Gd(III)-catalyzed asymmetric dearomatization reaction of naphthalene with a chiral PyBox ligand via visible-light-enabled [4 + 2] cycloaddition. This reaction features application of a chiral Gd/PyBox complex, which regulates the reactivity and selectivity simultaneously, in excited-state catalysis. A wide range of functional groups is compatible with this protocol, giving the highly enantioenriched bridged polycycles in excellent yields (up to 96%) and selectivity (up to >20:1 chemoselectivity, >20:1 dr, >99% ee). The synthetic utility is demonstrated by a 2 mmol scale reaction, removal of directing group, and diversifications of products. Preliminary mechanistic experiments are performed to elucidate the reaction mechanism.

Switchable divergent synthesis of chiral indole derivatives via catalytic asymmetric dearomatization of 2,3-disubstituted indoles.

A strategy allowing the switchable divergent synthesis of chiral indole derivatives was established via chiral phosphoric acid-catalyzed asymmetric dearomatization of 2,3-disubstituted indoles using naphthoquinone monoimines as electrophiles. The products were switched between chiral indolenines and fused indolines according to the post-processing conditions. Both two types of products were obtained in good to high yields with generally excellent enantioselectivities. NaBH4 was found to work as a promoter as well as a reductant in the cyclization process leading to fused indolines.

Catalytic Asymmetric Dearomatization of 2,3-Disubstituted Indoles by a [4 + 2] Cycloaddition Reaction with In Situ Generated Vinylidene ortho-Quinone Methides: Access to Polycyclic Fused Indolines.

A protocol of enantioselective dearomatization of 2,3-disubstituted indoles by an organocatalytic intermolecular (4 + 2) cycloaddition reaction with in situ generated vinylidene ortho-quinone methide has been documented. A wide range of polycyclic 2,3-fused indolines containing vicinal quaternary carbon stereocenters was readily prepared in high yields and with excellent diastereo- and enantioselectivities.

Catalytic asymmetric functionalization and dearomatization of thiophenes.

The asymmetric synthesis of thiophene-derived compounds, including catalytic asymmetric dearomatization of thiophene and atroposelective synthesis of benzothiophene derivatives, has rarely been reported. In this work, the asymmetric transformation of the thiophene motif is investigated. Through the rational design of substrates with a thiophene structure, by using the vinylidene ortho-quinone methide (VQM) intermediate as a versatile tool, axially chiral naphthyl-benzothiophene derivatives and thiophene-dearomatized chiral spiranes were obtained in high yields with excellent enantioselectivities.

Asymmetric dearomatization of benzyl 1-naphthyl ethers via [1,3] O-to-C rearrangement.

A catalytic asymmetric dearomatization reaction of benzyl 1-naphthyl ethers accelerated by a chiral N,N'-dioxide/Co(II) complex is disclosed. The reaction proceeds via an enantioselective [1,3] O-to-C rearrangement through a tight ion-pair pathway, providing a wide array of α-naphthalenone derivatives bearing an all-carbon quaternary center in high yields with excellent ee values.

Dearomative Access to (-)-Thebaine and Derivatives.

A synthesis of the natural product thebaine is reported in eight steps from commercially available starting materials, hinging on the dearomatization and coupling of simple aromatic starting materials. This provides divergent access to two unnatural opioid derivatives and is aimed at the long-term development of synthetic opioid analogs of the "wonderdrug" Naloxone. Additionally, a formal enantioselective synthesis of all reported targets is disclosed that leverages a catalytic asymmetric dearomatization via anion-pairing catalysis.

Diversity-Oriented Catalytic Asymmetric Dearomatization of Indoles with o-Quinone Diimides.

Herein, the first diversity-oriented catalytic asymmetric dearomatization of indoles with o-quinone diimides (o-QDIs) is reported. The catalytic asymmetric dearomatization (CADA) of indoles is one of the research focuses in terms of the structural and biological importance of dearomatized indole derivatives. Although great achievements have been made in target-oriented CADA reactions, diversity-oriented CADA reactions are regarded as more challenging and remain elusive due to the lack of synthons featuring multiple reaction sites and the difficulty in precise control of chemo-, regio-, and enantio-selectivity. In this work, o-QDIs are employed as a versatile building block, enabling the chemo-divergent dearomative arylation and [4+2] cycloaddition reactions of indoles. Under the catalysis of chiral phosphoric acid and mild conditions, various indolenines, furoindolines/pyrroloindolines, and six-membered-ring fused indolines are collectively prepared in good yields with excellent enantioselectivities. This diversity-oriented synthesis protocol enriches the o-quinone chemistry and offers new opportunities for CADA reactions.

Catalytic asymmetric dearomatization of phenols via divergent intermolecular (3 + 2) and alkylation reactions.

The catalytic asymmetric dearomatization (CADA) reaction has proved to be a powerful protocol for rapid assembly of valuable three-dimensional cyclic compounds from readily available planar aromatics. In contrast to the well-studied indoles and naphthols, phenols have been considered challenging substrates for intermolecular CADA reactions due to the combination of strong aromaticity and potential regioselectivity issue over the multiple nucleophilic sites (O, C2 as well as C4). Reported herein are the chiral phosphoric acid-catalyzed divergent intermolecular CADA reactions of common phenols with azoalkenes, which deliver the tetrahydroindolone and cyclohexadienone products bearing an all-carbon quaternary stereogenic center in good yields with excellent ee values. Notably, simply adjusting the reaction temperature leads to the chemo-divergent intermolecular (3 + 2) and alkylation dearomatization reactions. Moreover, the stereo-divergent synthesis of four possible stereoisomers in a kind has been achieved via changing the sequence of catalyst enantiomers.

Catalytic Asymmetric Synthesis of Aza-Quaternary Carbon Cyclohexadieneones Enabled by Aminative Dearomatization of Phenols.

Reported herein is the catalytic asymmetric aminative dearomatization reaction of common phenols. As opposed to the well-studied indoles and naphthols, phenols are supposed to be challenging substrates for catalytic asymmetric dearomatization reactions in terms of their strong aromaticity and regioselectivity issues. Under the catalysis of a chiral phosphoric acid, the C4-regiospecific aminative dearomatization of phenols with azodicarboxylates readily occurred at ambient temperature, delivering an array of biologically and synthetically important aza-quaternary carbon cyclohexadieneones in good yields and with excellent enantioselectivities (29 examples, up to 98% yield, and >99% ee).

Organocatalytic Asymmetric Dearomatization Reaction for the Construction of Axially Chiral Urazole Embedded Naphthalenones

AbstractHerein we disclose a catalytic asymmetric dearomatization reaction of β‐naphthols with 4‐aryl‐1,2,4‐triazole‐3,5‐diones. A chiral phosphoric acid with spiro motif was found to be effective for this reaction. The chiral urazole embedded naphthalenones having both axial and central chirality were obtained in good to high yields (70–85%) with high diastereo‐ and enantioselectivities (>20:1, 8–96% ees), having C−N rotational energy barrier 31.54 K.Cal.mol−1 and t1/225 °C=589.8 years. The scope of the reaction was broad and few applications including a bromo‐amination reaction have been demonstrated.magnified image

Catalyst-Substrate Helical Character Matching Determines the Enantioselectivity in the Ishihara-Type Iodoarenes Catalyzed Asymmetric Kita-Dearomative Spirolactonization.

Catalyst design has traditionally focused on rigid structural elements to prevent conformational flexibility. Ishihara's elegant design of conformationally flexible C2-symmetric iodoarenes, a new class of privileged organocatalysts, for the catalytic asymmetric dearomatization (CADA) of naphthols is a notable exception. Despite the widespread use of the Ishihara catalysts for CADAs, the reaction mechanism remains the subject of debate, and the mode of asymmetric induction has not been well established. Here, we report an in-depth computational investigation of three possible mechanisms in the literature. Our results, however, reveal that this reaction is best rationalized by a fourth mechanism called "proton-transfer-coupled-dearomatization (PTCD)", which is predicted to be strongly favored over other competing pathways. The PTCD mechanism is consistent with a control experiment and further validated by applying it to rationalize the enantioselectivities. Oxidation of the flexible I(I) catalyst to catalytic active I(III) species induces a defined C2-symmetric helical chiral environment with a delicate balance between flexibility and rigidity. A match/mismatch effect between the active catalyst and the substrate's helical shape in the dearomatization transition states was observed. The helical shape match allows the active catalyst to adapt its conformation to maximize attractive noncovalent interactions, including I(III)···O halogen bond, N-H···O hydrogen bond, and π···π stacking, to stabilize the favored transition state. A stereochemical model capable of rationalizing the effect of catalyst structural variation on the enantioselectivities is developed. The present study enriches our understanding of how flexible catalysts achieve high stereoinduction and may serve as an inspiration for the future exploration of conformational flexibility for new catalyst designs.

3,3]‐Sigmatropic Rearrangements of Naphthyl 1‐Propargyl Ethers: para‐Propargylation and Catalytic Asymmetric Dearomatization

AbstractThe para‐Claisen rearrangement of aryl 1‐propargyl ethers involves two‐step [3,3]‐sigmatropic rearrangements and dearomatization process, which has high activation barriers and is of challenge. Here we discovered thermal para‐Claisen rearrangement of naphthyl 1‐propargyl ethers, and it enabled the formation of formal para‐C−H propargylation products upon rearomatization. Chirality transfer occurred if optically active propargyl ethers were employed, leading to the construction of aryl/propargyl‐containing stereogenic centers. Moreover, catalytic asymmetric dearomatization of naphthyl 1‐propargyl ethers with different substitution at para‐position gave access to benzocyclohexenones bearing all‐carbon quaternary stereocenters. The reaction was accelerated by a chiral N,N′‐dioxide/Co(OTf)2 complex catalyst to achieve high yields (up to 98 %) and high enantioselectivities (up to 93 % ee). The DFT calculations and experimental results provided important clues to clarify the para‐Claisen rearrangement process as well as the chiral induction and remote delivery.

3,3]-Sigmatropic Rearrangements of Naphthyl 1-Propargyl Ethers: para-Propargylation and Catalytic Asymmetric Dearomatization.

The para-Claisen rearrangement of aryl 1-propargyl ethers involves two-step [3,3]-sigmatropic rearrangements and dearomatization process, which has high activation barriers and is of challenge. Here we discovered thermal para-Claisen rearrangement of naphthyl 1-propargyl ethers, and it enabled the formation of formal para-C-H propargylation products upon rearomatization. Chirality transfer occurred if optically active propargyl ethers were employed, leading to the construction of aryl/propargyl-containing stereogenic centers. Moreover, catalytic asymmetric dearomatization of naphthyl 1-propargyl ethers with different substitution at para-position gave access to benzocyclohexenones bearing all-carbon quaternary stereocenters. The reaction was accelerated by a chiral N,N'-dioxide/Co(OTf)2 complex catalyst to achieve high yields (up to 98 %) and high enantioselectivities (up to 93 % ee). The DFT calculations and experimental results provided important clues to clarify the para-Claisen rearrangement process as well as the chiral induction and remote delivery.

Brønsted acid-catalyzed asymmetric dearomatization of indolyl ynamides: Practical and enantioselective synthesis of polycyclic indolines

Catalytic asymmetric dearomatization of indoles and alkynes has received much attention in the past decade because this strategy offers an attractive and alternative way for the efficient synthesis of valuable chiral polycyclic indolines. However, these reactions have been mostly limited to transition-metal catalysts, and the related chiral Brønsted acid catalysis has been scarcely reported. Herein, we disclose a chiral phosphoric acid-catalyzed asymmetric dearomatization of indolyl ynamides by direct activation of alkynes. This metal-free method enables the practical and atom-economical construction of an array of valuable chiral polycyclic indolines in moderate to good yields with high enantioselectivities

Organocatalytic Asymmetric Dearomatizing Hetero-Diels-Alder Reaction of Nonactivated Arenes.

Nonactivated arenes, such as benzene derivatives, are chemically inert due to their intrinsic aromaticity and low polarity. The catalytic asymmetric dearomatization (CADA, coined by You and co-workers) of the nonactivated arenes represents a formidable challenge. We herein demonstrated an organocatalytic asymmetric dearomatizing hetero-Diels-Alder reaction of benzene derivatives. The tunable regioselectivity of this strategy allowed delivery of a diversity of stereochemically complex polycyclic compounds and oxahelicenes with excellent stereoselectivity. The high complexity and three-dimensionality of the products are crucial for their potential applications in materials science and drug discovery. Mechanistic studies suggested that this reaction proceeds through a chiral tetra-substituted vinylidene ortho-quinone methide (VQM) intermediate, which is extremely active to overcome the loss of aromaticity of benzene derivatives with concomitant chirality transfer.

Chemo-, regio- and enantioselective dearomative (3+2) reaction of non-functionalized 1-naphthols

The catalytic asymmetric dearomatization reaction of non-functionalized arenes poses a long-standing synthetic challenge to organic chemists because of the relative ease of rearomatization via the departure of a proton. In this work, the direct dearomatization of non-functionalized 1-naphthols was achieved through a phosphoric acid-catalyzed asymmetric (3+2) annulation reaction with azoalkenes. The reported convergent method allows the use of readily available simple 1-naphthols without pre-functionalization under mild conditions, furnishing a variety of tricyclic hexahydrobenz[e]indole derivatives in good yields and excellent enantioselectivities (75%–96% yields and 92%–99% ee). Density functional theory (DFT) calculations were performed to gain insights into the origins of the observed chemo-, regio-, and enantioselectivities. It is noteworthy that using azoalkenes as 1,3-dipole surrogates, in combination with powerful chiral phosphoric acid (CPA) catalysis, was key to the success of current reaction.

A tandem asymmetric oxidation-oxa-Michael sequence for dearomatization of β-naphthols

A catalytic asymmetric hydroxylative dearomatization reaction has been disclosed, and the products can smoothly transform into spiroannulation adducts by simply treated with a base under mild conditions. Novel in-situ generated magnesium catalytic methods are developed by application of combinational ligands. Related concise transformaitons of the spiroannulation adducts have been carried out.

Catalytic Asymmetric Dearomatization (CADA) through Activation of Ynamide by Chiral Brønsted Acids

Catalytic Asymmetric Dearomatization (CADA) through Activation of Ynamide by Chiral Brønsted Acids