All-carbon Quaternary Stereocenter Research Articles

Formation of Chiral All-Carbon Quaternary Stereocenters by Photoinduced Cobalt-Catalyzed Enantioselective Radical Coupling

Formation of Chiral All-Carbon Quaternary Stereocenters by Photoinduced Cobalt-Catalyzed Enantioselective Radical Coupling

Biocatalytic Synthesis of Nitrile-Bearing All-Carbon Quaternary Stereocenters.

The synthesis of all-carbon quaternary stereocenters containing nitriles is a very important and challenging subject in organic chemistry. We used a biocatalytic approach under mild conditions to obtain new derivatives of these scaffolds by oxidation of catechols by Myceliophthora thermophila laccase (Novozym 51003) to afford o-quinones and 1,4-addition of a series of carbon nucleophiles containing tertiary alkyle nitriles to these intermediates. Using this approach, α-cyano carbonyls bearing a quaternary stereocenter were also prepared. Finally, the yields for the prepared compounds were 72-94%.

Ni/Cu Dual-Catalyzed Propargylation for the Stereodivergent Synthesis of Methohexital.

The development of efficient methodologies for the controlled manufacture of specific stereoisomers bearing quaternary stereocenters has prompted advances in a variety of scientific disciplines including pharmaceutical chemistry, materials science, and chemical biology. However, complete control of the absolute and relative stereochemical configurations of alkyne derivatives remains an unmet synthetic challenge. Herein, a Ni/Cu dual-catalyzed asymmetric propargylic substitution reaction is presented to produce propargylated products with all-carbon quaternary stereocenters in high yields with significant diastereo- and enantioselectivities (up to >20:1 dr, >99% ee). The synthesis of all stereochemical variants of methohexital, a widely used sedative-hypnotic drug, exemplifies the efficacy of dual-catalyzed stereodivergent propargylation.

Synthesis of Unsymmetrical 3,3'-Dialkyloxindole Boronic Esters from 3-Alkylidene-2-oxindoles Enabled by Copper Catalysis.

We describe a 1,2-alkylboration of 3-alkylidene-2-oxindoles with a diboron reagent and alkyl bromides and iodides enabled by copper/bisphosphine catalysis. This scalable alkylboration method provides facile access to 3,3'-dialkyloxindole boronic esters featuring an all-carbon quaternary stereocenter and an increased F(sp3) fraction. In addition to good functional group tolerance and prolific utilization of drug/pesticide-derived alkyl iodides, the conversion of the C-B bond to a C-C/C-X bond offers further opportunities for structural variation of 3,3'-dialkyloxindoles.

Enantioselective Construction of Quaternary Stereocenters via A Chiral Spiro Phosphoric Acid-Assisted Formal Gold Carbene gem-Dialkylation Reaction.

Enantioselective construction of all-carbon quaternary stereocenters has attracted much attention over the past few decades. A variety of catalytic asymmetric methods have been disclosed based on the use of presynthesized complex reagents that impart congested steric hindrance to the reaction center, which generally produce the chiral molecules through forming one C-C bond. The use of readily available reagents that could build two C-C bonds on the same carbonic center with the concomitant assembly of quaternary stereocenters remains challenging. Herein, we disclose a catalytic asymmetric alkyne multifunctionalization reaction using a gold complex and a chiral spiro phosphoric acid (SPA) for synergistic catalysis. In this method, the readily accessible internal alkynes served as the key gold carbene precursors, followed by carbene gem-dialkylation through Mannich-type addition of enolate species or stepwise formal cycloaddition with methylenimines that are derived from 1,3,5-triazinanes in the presence of SPA. The reaction provides practical access to poly-functionalized chiral linear and cyclic ketones that bear two adjacent quaternary stereocenters in generally good yields and excellent enantioselectivities, leading to an essential complement to the asymmetric construction of quaternary stereocenters using readily available materials with high bond formation efficiency.

Total Synthesis of (+)-Eburnamonine Using Asymmetric Alkene Cyanoamidation through C-CN Bond Activation.

We report the total synthesis of (+)-eburnamonine using enantioselective alkene cyanoamidation to form the all-carbon quaternary stereocenter. Palladium, phosphoramidite ligand, and a Lewis acid combine to form a co-catalyst that promotes C-CN activation of a cyanoformamide, followed by intramolecular alkene cyanoamidation. Overall, the synthesis of (+)-eburnamonine is accomplished in 8 steps from 4-methylene hexanoic acid and tryptamine, providing an example of asymmetric aliphatic-tethered alkene cyanoamidation and its use in total synthesis.

Phosphine-Catalyzed Asymmetric Allylic Alkylation of Isoxazol-5(4H)-ones with Morita-Baylis-Hillman Carbonates

Aims: Phosphine-catalyzed asymmetric allylic alkylation of isoxazol-5(4H)-ones with achiral Morita-Baylis-Hillman (MBH) carbonates has been developed. A series of isoxazol-5(4H)- ones bearing all-carbon quaternary stereocenters were obtained in 55-96% yield with 75-90% ee. Gram-scale reaction and further transformation of allylation products were conducted to demonstrate the synthetic practicability. Methods: Under Ar atmosphere, the mixture of isoxazol-5-one 1 (0.1 mmol), MBH carbonate 2 (0.12 mmol, 1.2 equiv), catalyst P5 (10 mol%), and 4Å MS (10 mg) in toluene (1 mL) was stirred at 0 oC for 24 h. The solvent was removed under vacuum, and the residue was purified by flash chromatography (petroleum ether/ethyl acetate = 3/1) to provide product 3. Result and Conclusion: We developed an efficient and enantioselective allylic alkylation of isoxazol- 5(4H)-ones with achiral MBH carbonates in the presence of chiral phosphine catalyst. A broad range of isoxazol-5(4H)-ones bearing all-carbon quaternary stereocenters were prepared with high efficiency and enantioselectivity. Importantly, the organocatalytic δ-stereocontrol of MBH carbonates was achieved via the synthetic strategy.

Pd(II)/N,N'-Disulfonyl Bisimidazoline-Catalyzed Enantioselective Synthesis of Cyclic Quaternary Centers and Mechanistic Investigations.

A Pd(II)/N,N'-disulfonyl bisimidazoline-catalyzed asymmetric 1,4-conjugate addition reaction of low-cost arylboronic acids with readily available β-substituted cyclic enones is described, providing a straightforward way of constructing cyclic all-carbon quaternary stereocenters with high enantioselectivity, in which ≥96% ee was obtained in most cases. The reaction proceeded without the protection of inert gas, making the operation process simple. Theoretical calculations have been applied to understand the origins of enantioselectivity.

Catalytic asymmetric [4 + 2] dearomative photocycloadditions of anthracene and its derivatives with alkenylazaarenes

Photocatalysis through energy transfer has been investigated for the facilitation of [4 + 2] cycloaddition reactions. However, the high reactivity of radical species poses a challenging obstacle to achieving enantiocontrol with chiral catalysts, as no enantioselective examples have been reported thus far. Here, we present the development of catalytic asymmetric [4 + 2] dearomative photocycloaddition involving anthracene and its derivatives with alkenylazaarenes. This accomplishment is achieved by utilizing a cooperative photosensitizer and chiral Brønsted acid catalysis platform. Importantly, this process enables the activation of anthracene substrates through energy transfer from triplet DPZ, thereby initiating a precise and stereoselective sequential transformation. The significance of our work is highlighted by the synthesis of a diverse range of pharmaceutical valuable cycloadducts incorporating attractive azaarenes, all obtained with high yields, ees, and drs. The broad substrate scope is further underscored by successful construction of all-carbon quaternary stereocenters and diverse adjacent stereocenters.

Enantioselective nickel-catalyzed anodic oxidative dienylation and allylation reactions

Precision control of stereochemistry in radical reactions remains a formidable challenge due to the prevalence of incidental racemic background reactions resulting from undirected substrate oxidation in the absence of chiral induction. In this study, we devised an thoughtful approach—electricity-driven asymmetric Lewis acid catalysis—to circumvent this impediment. This methodology facilitates both asymmetric dienylation and allylation reactions, resulting in the formation of all-carbon quaternary stereocenters and demonstrating significant potential in the modular synthesis of functional and chiral benzoxazole-oxazoline (Boox) ligands. Notably, the involvement of chiral Lewis acids in both the electrochemical activation and stereoselectivity-defining radical stages offers innovative departures for designing single electron transfer-based reactions, significantly underscoring the relevance of this approach as a multifaceted and universally applicable strategy for various fields of study, including electrosynthesis, organic chemistry, and drug discovery.

Catalytic Asymmetric Desymmetrization of Cyclic 1,3-Diketones Using Chiral Boro-phosphates.

Herein, we report a chiral boro-phosphate-catalyzed reductive amination for the desymmetrization of 2,2-disubstituted 1,3-cyclopentadiones with pinacolborane as the reducing agent, delivering chiral β-amino ketones with an all-carbon quaternary stereocenter in good yields (≤94%), high enantioselectivities (≤97% ee), and excellent diastereoselectivities (>20:1 dr). This reaction has a broad substrate scope and high functional group tolerance. The importance of the chiral products was also demonstrated through the preparation of multifunctional building blocks and heterocycles.

Rh-Catalyzed Enantioselective Hydroalkenylative Cyclization of 1,6-Enynes Constructing All-Carbon Quaternary Stereocenters

Rh-Catalyzed Enantioselective Hydroalkenylative Cyclization of 1,6-Enynes Constructing All-Carbon Quaternary Stereocenters

Enantioselective [2π + 2σ] Cycloadditions of Bicyclo[1.1.0]butanes with Vinylazaarenes through Asymmetric Photoredox Catalysis.

Here we present a highly enantioselective [2π + 2σ] photocycloaddition of bicyclo[1.1.0]butanes (BCBs). The reaction uses a variety of vinylazaarenes as partners and is catalyzed by a polycyclic aromatic hydrocarbon (PAH)-containing chiral phosphoric acid as a bifunctional chiral photosensitizer. A wide array of pharmaceutically important bicyclo[2.1.1]hexane (BCH) derivatives have been synthesized with high yields, enantioselectivity, and diastereoselectivity. In addition to the diverse 1-ketocarbonyl-3-substituted BCBs, α/β-substituted vinylazaarenes are compatible with such an unprecedented photoredox catalytic pathway, resulting in the successful assembly of an all-carbon quaternary stereocenter or two adjacent tertiary stereocenters on the product.

Copper/Chiral Phosphoric-Acid-Catalyzed Intramolecular Reductive Isocyanide-Alkene (1 + 2) Cycloaddition: Enantioselective Construction of 2-Azabicyclo[3.1.0]hexanes.

Enantioenriched 2-azabicyclo[3.1.0]hexanes are accessed from readily available allyl substituted α-isocyanoesters by intramolecular (1 + 2) cycloaddition with the olefinic moiety and isocyano carbon as the respective C2 and C1 units. Cyclopropanation is initiated by 1,1-hydrocupration of isocyanide followed by formimidoylcopper to copper α-aminocarbenoid equilibration and subsequent (1 + 2) cycloaddition. The unprecedented copper/chiral phosphoric acid (CPA) catalytic system can be operated in the presence of water under air, delivering a variety of 2-azabicyclo[3.1.0]hexanes containing an angular all-carbon quaternary stereocenter in good to excellent yields and enantioselectivity.

Stereocontrolled Construction of Spirooxindole-Containing 5,6,7,8-Tetrahydropyrrolo[1,2-a]pyridine via Michael/Friedel-Crafts Domino Reaction Promoted by Secondary Amine-Squaramide.

An asymmetric Michael/Friedel-Crafts cascade reaction with Morita-Baylis-Hillman (MBH) nitroallylic esters and 3-pyrrolyloxindoles has been developed for the stereoselective construction of spirooxindole-containing tetrahydroindolizines. A range of tetracyclic scaffolds possessing three consecutive chiral centers, including an all-carbon quaternary stereocenter, were generated in 53-85% isolated yields with high diastereoselectivities and enantiopurities (≥3:1 dr, 50-98% ee). A newly synthesized bifunctional secondary amine/squaramide organocatalyst was demonstrated to exhibit better stereochemical control than their tertiary analogues.

Silver-Catalyzed Asymmetric Double Desymmetrization via Vinylogous Michael Addition of Prochiral α,α-Dicyanoalkenes to Cyclopentendiones.

An asymmetric double desymmetrization methodology has been developed for synthesizing densely functionalized chiral cyclopentylcyclohexane scaffolds. We have constructed four chiral centers, including an all-carbon quaternary stereocenter in a single C-C bond formation event. The methodology has high functional-group tolerance and delivers a broad range of enantioenriched products. This vinylogous Michael addition reaction of prochiral α,α-dicyanocyclohexane to 2,2-disubstituted cyclopentene-1,3-dione is catalyzed by a chiral Ag-(R)-DTBM-SEGPHOS catalyst.

Enantioselective Ir-Catalyzed Allyl Alkylation/Semipinacol Rearrangement.

The semipinacol rearrangement is a powerful and versatile method for constructing all-carbon quaternary stereocenters. The development of catalytic asymmetric semipinacol rearrangements using multifunctionalizable electrophiles remains highly sought-after in organic synthesis. In this study, a catalytic enantioselective allylic cation-induced semipinacol rearrangement reaction was presented that enables the simultaneous construction of two skipped chiral carbon centers. Chiral Ir(I)-(P,olefin) and Sc(OTf)3 catalysts cooperatively initiate the asymmetric allylic alkylation of alkenyl cyclobutanols with allylic alcohols, triggering ring expansion of the cyclobutanol moiety through a stereoselective 1,2-alkyl migration. The reaction afforded a range of cyclopentanones bearing an α-quaternary carbon that is adjacent to a chiral allyl scaffold. The products were applied to synthesize enantioenriched fused tricyclopentanoids bearing four stereogenic carbon centers.

Catalytic enantioselective reductive Eschenmoser-Claisen rearrangements.

An important challenge in enantioselective catalysis is developing strategies for the precise synthesis of neighboring congested all-carbon quaternary stereocenters. The well-defined transition states of [3,3]-sigmatropic rearrangements and their underlying stereospecificity render them powerful tools for the synthesis of such arrays. However, this type of pericyclic reaction remains notoriously difficult to catalyze, especially in an enantioselective fashion. Herein, we describe an enantioselective reductive Eschenmoser-Claisen rearrangement catalyzed by chiral 1,3,2-diazaphospholene-hydrides. This developed transformation enables full control of the two newly formed acyclic stereogenic centers, leading to amides with vicinal all-carbon quaternary-tertiary or quaternary-quaternary carbon atoms.

Chromium(III)-Catalyzed Desymmetrization of meso-Epoxides via Remote Stereocontrol: Synthesis of Chiral Fluorenes Bearing All-Carbon Quaternary Stereocenters.

An asymmetric desymmetrization of fluorene-derived meso-epoxides is disclosed for the construction of chiral fluorenes bearing an all-carbon quaternary stereocenter at C9. This desymmetrization is catalyzed by a chiral (salen)CrIII complex via remote stereocontrol, producing diverse chiral fluorenes with excellent yields and stereoselectivity. The practicality of this protocol was demonstrated through the transformation of the obtained products to some intriguing enantioenriched polymerizable monomers.

Rhodium-catalyzed enantioselective in situ C(sp3)−H heteroarylation by a desymmetrization approach

A rhodium-catalyzed desymmetrization reaction for enantioselective methyl C−H arylation is achieved by utilizing an in situ arylating reagent via nucleophilic cyclization of o-aminoaryl alkyne. The reaction results in chiral indoles containing all-carbon quaternary stereocenters under atmospheric conditions, with a wide range of substrates exhibiting good enantioselectivity (44 examples). Mechnism and DFT studies show that the stereocontrol is reasonably achieved through the collaborative control of a large silicon substituted chiral ligand and C−H···π, LP···π interactions between aryl rings of the carboxylate group and the substrate. Control experiments demonstrate that Rh-aryl bond formation via in situ nucleophilic cyclization is more critical for reaction efficiency than via C−H activation of the nucleophilic cyclization byproduct.