All-carbon Quaternary Stereogenic Center Research Articles

Concise Synthesis of Norzoanthamine Enabled by a Set of Photochemical Transformations.

Norzoanthamine is a structurally complex polycyclic natural product that expresses a broad range of biological activities, rendering facile access to it and its analogs of considerable importance in drug discovery and development. However, strategies for efficient access to this class of marine alkaloids remain lacking. Here, we report a strategy, characterized by three key photochemical reactions, that we used to synthesize norzoanthamine in 16 steps. A photoinduced dearomative-6π-desymmetrization was developed for facile access to the ABC-tricyclic core of the alkaloid. This was supplemented by a [2 + 2]-photocycloaddition, a visible-light-induced decarboxylative borylation, and a retro-aldol process, constituting an effective solution to the challenging problem of establishing the C9-C22 vicinal all-carbon quaternary stereogenic centers. Finally, a one-pot cascade transformation, involving global deprotection, cyclization, and epimerization reaction, was designed for efficient and stereocontrolled assembly of the core framework of norzoanthamine.

Enantioselective Synthesis of P-Chiral Phosphine Oxides Bearing an All-Carbon Quaternary Stereogenic Center via Palladium-Catalyzed Domino Heck–Suzuki Reaction

Enantioselective Synthesis of <i>P</i>-Chiral Phosphine Oxides Bearing an All-Carbon Quaternary Stereogenic Center via Palladium-Catalyzed Domino Heck–Suzuki Reaction

Chiral Phosphine Ligands of COAP and SKP Switched Regiodivergent Asymmetric Allylic Alkylation of MBH Adducts.

The palladium-catalyzed highly regioselective asymmetric allylic alkylation of 3'-indolyl-3-oxindole derivatives with Morita-Baylis-Hillman (MBH) carbonates was developed to facilely construct chiral 3,3'-bisindole derivatives under mild reaction conditions. The regioselectivity (α/γ) of MBH carbonates was efficiently switched in the presence of chiral oxalamide phosphine or spiroketal-based diphosphine/Pd(0) complexes as a chiral catalyst. A series of multifunctional 3,3'-bisindole derivatives with all-carbon quaternary stereogenic centers were obtained in high yields with good to excellent enantio-, diastereo-, and regioselectivity. The present process is endowed with some salient features such as broad substrate scope, N-protecting group-free, excellent stereoselectivity, as well as adjustable regioselectivity.

Catalytic Enantioselective Primary C-H Borylation for Acyclic All-Carbon Quaternary Stereocenters.

Creating a perfect catalyst to operate enzyme-like chiral recognition has been a long-sought aim. A challenging example in this context is constructing acyclic all-carbon quaternary stereogenic centers by transition metal-catalyzed enantioselective C-H activation. We now report highly enantioselective iridium-catalyzed primary C-H borylation of α-all-carbon substituted 2,2-dimethyl amides enabled by a tailor-made chiral bidentate boryl ligand (CBL). The success of the current transformation is attributed to the CBL/iridium catalyst, which has a confined chiral pocket. This protocol provides a diverse array of acyclic all-carbon quaternary stereocenters with excellent enantiocontrol and distinct structural features. Computational study reveals that steric hindrance of CBL could regulate the type of dominant orbital interaction between the catalyst and substrate, which is crucial to conferring high chiral induction.

Total synthesis of atropodiastereomers of heterodimeric Amaryllidaceae alkaloids: narcipavline and narcikachnine.

We report the first asymmetric total synthesis of recently isolated heterodimeric Amaryllidaceae alkaloids, narcipavlines A (1a) and B (1b), and narcikachnines A (2a) and B (2b), thereby confirming their absolute stereochemistry. These alkaloids showcase a unique heterodimeric structure, amalgamating two distinct types of Amaryllidaceae alkaloids: the cis-hydrodibenzofuran containing tetracyclic galantamine core (6a) and the galanthindole core (7) featuring a biaryl axis. The presence of this biaryl axis, coupled with the substantial galantamine core (6a) at the ortho substituents, imposes constraints on free rotation around the C-C axis, resulting in atropisomerism, an exceedingly rare phenomenon in nature. Key steps in the synthesis encompass the utilization of a one-pot double reductive amination approach for the establishment of C-N-C bonds to merge both the galantamine (6a) and galanthindole (7) cores. Additionally, the Mitsunobu reaction and intramolecular Heck cyclization have emerged as pivotal techniques for crafting the tricyclic hydrodibenzofuran core [(-)-13], incorporating an all-carbon quaternary stereogenic center.

Catalytic asymmetric intramolecular propargylation of cyclopropanols to access the cuparane core.

The catalytic asymmetric propargylation of enol(ate) intermediates is a well-established method for the synthesis of α-propargyl-substituted carbonyl compounds. However, the propargylation of homo-enol(ate) or its equivalents for the synthesis of β-propargyl-substituted carbonyl compounds remains underdeveloped. A catalytic enantioselective decarboxylative intramolecular propargylation of cyclopropanols has been developed using a PyBox-complexed copper catalyst. This reaction offers an effective approach to assemble a cyclopentanone skeleton bearing an all-carbon quaternary stereogenic center and an adjacent quaternary gem-dimethyl carbon center, which is the core scaffold of the naturally occurring cuparenoids. Key to the success of this protocol is the use of a new structurally optimized PyBox ligand. This study represents the first example of catalytic asymmetric intramolecular propargylation of cyclopropanols.

Organocatalytic Tandem Synthesis of Chiral Hexacyclic Bisindoles from Propargylic 3-Methyleneindoles with 2-Indolylmethanols.

A novel chiral phosphoric acid-catalyzed tandem regioselective 1,6-addition/double intramolecular nucleophilic addition annulation of the propargylic 3-methyleneindoles in situ generated from α-indolyl propargylic alcohols with 2-indolylmethanols has been developed. The methodology afforded the new chiral trifluoromethyl pentalenobisindoles bearing an all-carbon quaternary stereogenic center in generally good yields with excellent enantioselectivities.

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.

A Homo-Mannich Reaction Strategy Enables Collective Access to Ibophyllidine, Aspidosperma, Kopsia, and Melodinus Alkaloids.

We report here a homo-Mannich reaction of cyclopropanol with iminium ion generated by an asymmetric allylic dearomatization of indole to construct a tricyclic hydrocarbazole core, which is shared by a variety of monoterpenoid indole alkaloids across families. Through this skeleton-constructing process, an all-carbon quaternary stereogenic center as well as an allyl and a ketone groups were installed. Using this functionalized hydrocarbazole as the structural platform, D ring and E rings of different sizes (i.e., five-, six-, and seven-membered) were successively or simultaneously assembled, leading to a collective asymmetric synthesis of seven alkaloids belonging to the ibophyllidine, Aspidosperma, Kopsia, and Melodinus alkaloid families.

Total Synthesis of (+)-Haperforin G.

(+)-Haperforin G was synthesized in 20 steps from commercially available starting materials. A Co-catalyzed intramolecular Pauson-Khand reaction was used for stereoselective construction of cyclopentanone bearing an all-carbon quaternary stereogenic center at the bridge-head position. Light-initiated photocatalysis was used for convergent and asymmetric cross-coupling of the unstabilized C(sp3) radical with an enone. The developed chemistry paves the way to the synthesis of structurally diverse analogs of haperforin G (6).

Diastereodivergent Desymmetric Annulation to Access Spirooxindoles: Chemical Probes for Mitosis.

Spirooxindoles have emerged as promising architectures for engineering biologically active compounds. The diastereodivergent construction of unique scaffolds of this type with full control of continuous chiral centers including an all-carbon quaternary stereogenic center is yet to be developed. Here, we report an unprecedented diastereodivergent desymmetric [3 + 3] annulation of oxabicyclic alkenes with enals enabled by N-heterocyclic carbene (NHC)/Rh cooperative catalysis, leading to a series of enantiomerically enriched spirooxindole lactones with excellent enantioselectivities (up to >99% ee) and diastereoselectivities (up to >95:5 dr). The combined catalyst system comprises a rhodium complex that controls the configuration at the electrophilic carbon and an NHC catalyst that controls the configuration at the nucleophilic oxindole-containing carbon; thus, four stereoisomers of the spirooxindole products can be readily obtained simply by switching the configurations of the two chiral catalysts. Transformations of the chiral spirooxindoles delivered synthetically useful compounds. Importantly, those chiral spirooxindoles arrested mammalian cells in mitosis and exhibited potent antiproliferative activities against HeLa cells. Significantly, both absolute and relative configurations exert prominent effects on the bioactivities, underscoring great importance of catalytic asymmetric diastereodivergent synthesis beyond creating useful tools for the exploration of structure-activity relationships.

Enantioselective Oxidative Enolate Coupling of Oxindoles Catalyzed by Chiral Guanidinium Hypoiodite

Hypoiodite is an environmentally friendly oxidant that has been developed to drive a variety of bond-forming reactions. Recently, asymmetric oxidative bond-forming reactions using hypoiodite in the presence of chiral onium organocatalysts have been used to synthesize carbon–heteroatom bonds, but asymmetric carbon–carbon bond-forming reactions have not been reported. Herein, we present an oxidative enolate coupling reaction of oxindoles to provide optically active oxindole dimers bearing consecutive all-carbon quaternary stereogenic centers, using a chiral guanidinium hypoiodite catalyst. This reaction affords the corresponding homocoupling products with high enantioselectivity. We also describe oxidative enolate cross-coupling reactions of two oxindoles bearing electronically distinct substituents.

The Use of Aryl-Substituted Homophthalic Anhydrides in the Castagnoli–Cushman Reaction Provides Access to Novel Tetrahydroisoquinolone Carboxylic Acid Bearing an All-Carbon Quaternary Stereogenic Center

Novel aryl-substituted homophthalic acids were cyclodehydrated to the respective homophthalic anhydrides for use in the Castagnoli-Cushman reaction. With a range of imines, this reaction proceeded smoothly and delivered hitherto undescribed 4-aryl-substituted tetrahydroisoquinolonic acids with remarkable diastereoselectivity, good yields and no need for chromatographic purification. These findings significantly extend the range of cyclic anhydrides employable in the Castagnoli-Cushman reaction and signify access to a novel substitution pattern around the medicinally relevant tetrahydroisoquinolonic acid scaffold.

Construction of Successive Stereogenic Centers of ent-Kauranoid through an Oxidative Dearomatization/1,2-Shift Cascade

AbstractThe construction of the successive stereogenic centers, including an all-carbon quaternary stereogenic center, of ent-kauranoid through an oxidative dearomatization/1,2-shift cascade is described. The developed cascade reaction of a substrate bearing a trans-2-(p-methoxyphenyl)vinyl group as the migrating group afforded the desired product in 83% yield. The 1,2-shift in the cascade is strongly affected by a stereoelectronic effect. The X-ray crystal structure of a compound bearing four successive stereogenic centers in the fused-ring moiety of ent-kauranoid diterpene, which was prepared by the oxidative dearomatization/1,2-shift cascade and subsequent stereoselective transformations, is also reported.

Electrooxidative palladium- and enantioselective rhodium-catalyzed [3 + 2] spiroannulations.

Despite indisputable progress in the development of electrochemical transformations, electrocatalytic annulations for the synthesis of biologically relevant three-dimensional spirocyclic compounds has as of yet not been accomplished. In sharp contrast, herein, we describe the palladaelectro-catalyzed C–H activation/[3 + 2] spiroannulation of alkynes by 1-aryl-2-naphthols. Likewise, a cationic rhodium(iii) catalyst was shown to enable electrooxidative [3 + 2] spiroannulations via formal C(sp3)–H activations. The versatile spiroannulations featured a broad substrate scope, employing electricity as a green oxidant in lieu of stoichiometric chemical oxidants under mild conditions. An array of spirocyclic enones and diverse spiropyrazolones, bearing all-carbon quaternary stereogenic centers were thereby accessed in a user-friendly undivided cell setup, with molecular hydrogen as the sole byproduct.

Radical differentiation of two ester groups in unsymmetrical diazomalonates for highly asymmetric olefin cyclopropanation

Diazomalonates have been demonstrated as effective metalloradicophiles for asymmetric radical olefin cyclopropanation via Co(II)-metalloradical catalysis (MRC). Supported by D 2-symmetric chiral amidoporphyrin ligand, Co(II)-based metalloradical system can efficiently activate unsymmetrical methyl phenyl diazomalonate (MPDM) with effective differentiation of the two ester groups for asymmetric cyclopropanation, enabling stereoselective construction of 1,1-cyclopropanediesters bearing two contiguous chiral centers, including all-carbon quaternary stereogenic center. The Co(II)-catalyzed asymmetric cyclopropanation, which operates at room temperature without slow addition of the diazo compound, is generally applicable to broad-ranging olefins and tolerates various functionalities, providing a streamlined synthesis of chiral 1,1-cyclopropanediesters in high yields with both high diastereoselectivity and enantioselectivity. Combined computational and experimental studies support the underlying stepwise radical mechanism for Co(II)-catalyzed cyclopropanation. In addition to functioning as 1,3-dipoles for forming five-membered structures, enantioenriched (E)-1,1-cyclopropanediesters serve as useful building blocks for stereoselective synthesis of different cyclopropane derivatives. In addition, the enantioenriched (E)-1,1-cyclopropanediesters can be stereoselectively converted to (Z)-diastereomers.

Nickel-Catalyzed Arylcarbamoylation of Alkenes of N-(o-Iodoaryl)acrylamides with Nitroarenes via Reductive Aminocarbonylation: Facile Synthesis of Carbamoyl-Substituted Oxindoles.

Nickel-catalyzed arylcarbamoylation reactions of alkenes of N-(o-haloaryl)acrylamides with CO and nitroarenes via reductive aminocarbonylation to produce carbamoyl-substituted oxindoles with an all-carbon quaternary stereogenic center are presented. Starting with N-(o-haloaryl)acrylamides, simple CO, and inexpensive nitroarenes and using a Ni catalyst, a dinitrogen-based ligand, a Zn reductant, a TMSCl additive, and a base system, this protocol enables the synthesis of various carbamoyl-substituted oxindoles and allows the efficient late-stage derivatization of valuable molecules.

Enantioselective Total Synthesis of Cepharatines via Bioinspired Ring Reconstruction.

We describe enantioselective total syntheses of cepharatines A-D, members of the hasubanan alkaloid family, which feature an unusual tetracyclic skeleton including an azabicyclo[3.3.1]nonane motif. A key reaction is a regio-divergent oxidative phenolic coupling reaction that affords the tricyclic core structure of hasubanan with different substitution patterns on the A-ring, including the all-carbon quaternary stereogenic center at C13, in a single step. The characteristic tetracyclic azabicyclo[3.3.1]nonane motif was constructed by means of a bioinspired cascade reaction involving the retro-aza-Michael reaction/hemiaminal formation.

Synthesis of Novel Crown Ether-Squaramides and Their Application as Phase-Transfer Catalysts.

This work presents the synthesis of six new phase-transfer organocatalysts in which the squaramide unit is directly linked to the nitrogen atom of an aza-crown ether. Four chiral skeletons, namely hydroquinine, quinine, cinchonine (cinchonas), and α-d-glucopyranoside were responsible for the asymmetric construction of an all-carbon quaternary stereogenic center in α-alkylation and Michael addition reactions of malonic esters. We investigated the effects of these different chiral units and that of crown ethers with different sizes on catalytic activity and enantioselectivity. During extensive parameter investigations, both conventional and emerging green solvents were screened, providing valuable α,α-disubstituted malonic ester derivatives with excellent yields (up to 98%).

Palladium-Catalyzed Asymmetric Intramolecular Dearomative Heck Annulation of Aryl Halides to Furnish Indolines.

An unprecedented Pd-catalyzed asymmetric intramolecular cascade cyclization of aryl halides with readily available arylboronic acids proceeds through a Heck-type dearomative cyclization terminated with arylation in the presence of Pd2(dba)3 (10 mol %), Cu2O (5 mol %), and Cs2CO3 (2.0 equiv) in 1,2-dichloroethane (1.0 mL) at 100 °C for 15 h in air using BINOL-based phosphoramidite as the chiral ligand. This dearomative Heck protocol, which tolerates a broad variety of functional groups, is amenable to the generation of optically active indoline derivatives bearing all-carbon quaternary stereogenic centers in one step in moderate to excellent yields, with excellent diastereoselectivities (>20:1) and enantioselectivities (up to >99% ee). It is worth mentioning that no decrease in the enantiopurity of the indoline derivatives was observed during the synthetic transformations of the products.