Quaternary Carbon Centers Research Articles

Enantioselective Preparation of Cyclopentene-Based Amino Acids with a Quaternary Carbon Center.

Azlactone is an important starting material for synthesizing amino acids containing a quaternary α-carbon. In this study, we have developed a sequential "one-pot" procedure involving an enantioselective spirocyclization reaction followed by acidic azlactone opening, which led to amino acid derivatives. The key step of this procedure is a spirocyclization between propargylated azlactones and enals by using a cooperative catalytic approach that combines chiral secondary amine and achiral Pd(0) complexes. The final acid opening of the azlactone motif allows isolation of the corresponding amino acid derivatives as major diastereoisomers in yields ranging from 37% to 70% with enantioselectivities of 85-97% ee. These synthesized amino acid derivatives hold great potential in the pharmaceutical and bioactive compound industries. Moreover, the final amino acid products with a cyclopentene moiety can be further derivatized, opening up even more possibilities for their application.

Diastereoselective Access to Ester-Substituted cis-Phenanthridinones via Hydrogen Atom Transfer-Involved 1,7-Enyne Bicyclization.

An organophotoredox-catalyzed 1,7-enyne bicyclization for the cis-diastereoselective synthesis of ester-substituted phenanthridinones has been achieved through radical cascade cyclization involving 1,6-hydrogen atom transfer. This transition-metal- and oxidant-free one-pot protocol generates three distinct C-C bonds and two quaternary carbon centers.

Core Modifications of GSK3335103 toward Orally Bioavailable αvβ6 Inhibitors with Improved Synthetic Tractability.

The αvβ6 integrin has been identified as a target for the treatment of fibrotic diseases, based on the role it has in activating TGF-β1, a protein implicated in the pathogenesis of fibrosis. However, the development of orally bioavailable αvβ6 inhibitors has proven challenging due to the zwitterionic pharmacophore required to bind to the RGD binding site. This work describes the design and development of a novel, orally bioavailable series of αvβ6 inhibitors, developing on two previously published αvβ6 inhibitors, GSK3008348 and GSK3335103. Strategies to reduce the basicity of the central ring nitrogen present in GSK3008348 were employed, while avoiding the synthetic complexity of the chiral, fluorine-containing quaternary carbon center contained in GSK3335103. Following initial PK studies, this series was optimized, aided by analysis of the physicochemical and in vitro PK properties, to deliver lead molecules (S)-20 and 28 as potent and orally bioavailable αvβ6 inhibitors with improved synthetic tractability.

Synthesis of Dioxo-Azabicyclo[3.2.1]octanes via Hypervalent Iodine-Mediated Domino Reaction.

Bicyclo[3.2.1]octane (BCO) skeleton widely exists in natural products and biologically active molecules, whereas the development of convenient approaches to construct this structure remains a challenge. Herein, we describe a cascade reaction to synthesize 6,8-dioxa-3-azabicycle[3.2.1]octane derivatives from β-keto allylamines via an oxidation-cyclization reaction. A series of dioxo-azabicyclo[3.2.1]octanes bearing a quaternary carbon center were obtained in good yields under mild reaction conditions. Moreover, the mechanistic rationale for this novel domino reaction is supported by control experiments.

Study of Palladium-Catalyzed Site and Regioselective Reductive Heck Hydroarylation of Unactivated Alkene.

We studied the reaction pathway of our reductive Heck hydroarylation using a palladium catalyst and a hydrosilane. A key question to verify the reaction mechanism was which active species, Ar-PdII-I or Si-PdII-H, first performs migratory insertion into the alkenes. Identifying this step is crucial to elucidate the reaction mechanism. To address this, we designed a substrate containing two trisubstituted alkenes and tested its product. The results suggest that the migratory insertion of Ar-PdII-I into the alkene is the initial step of the reaction. Furthermore, this reaction can construct a quaternary carbon center and give high yields with high functional group tolerance.

New Synthetic Approaches for the Construction of Enantioenriched Molecules Bearing Quaternary Stereocenters

AbstractOptically active molecule architectures stand as an important class of organic compounds and occupy a key role in academic and industrial communities. Particularly, the molecules bearing quaternary carbon are of vital importance because of its favorable conformation and valuable three‐dimensional molecules, which frequently play a key role in a broad spectrum of functional materials, pharmaceutical relevant natural molecules, and agrochemicals. Over the past few decades, a large number of synthetic strategies for the enantioselective construction of compounds with chiral quaternary carbon centers have been the focus of a number of research initiatives. In this review, the state‐of‐the‐art toward the synthesis of enantioenriched molecules bearing quaternary stereocenters are summarized, which could be segmented into four categories: 1) Construction of optically active quaternary carbon centers by addition to prochiral sp2 carbon; 2) Construction of optically active all‐carbon quaternary stereocenters via substitution at non‐chiral tetra‐substituted carbon; 3) Construction of optically active all‐carbon quaternary stereocenters via kinetic resolution; 4) Construction of optically active all‐carbon quaternary stereocenters via desymmetrization reactions.

Visible-Light-Induced Photoredox Construction of Trifluoromethylated Quaternary All-Carbon Centers and Tertiary Alcohols via C(sp3)–Si Bond Cleavage

AbstractThe construction of trifluoromethylated quaternary carbon centers and tertiary alcohols is realized by organo-photoredox catalysis. The process proceeds via visible-light-induced C(sp3)–Si bond cleavage for the generation of α-trifluoromethylated benzyl radicals, which are readily trapped by electron-deficient alkenes with excellent regioselectivity for the construction of trifluoromethylated quaternary all-carbon centers. The α-difluoromethyl counterparts are also suitable for this radical conjugate addition. Furthermore, the in situ oxidation of these α-trifluoromethylated radicals with O2 from air affords tertiary alcohols in high yields, which extends the Fleming–Tamao reaction to tertiary carbon systems.

Enantioselective formal (3 + 3) cycloaddition of bicyclobutanes with nitrones enabled by asymmetric Lewis acid catalysis

The absence of catalytic asymmetric methods for synthesizing chiral (hetero)bicyclo[n.1.1]alkanes has hindered their application in new drug discovery. Here we demonstrate the achievability of an asymmetric polar cycloaddition of bicyclo[1.1.0]butane using a chiral Lewis acid catalyst and a bidentate chelating bicyclo[1.1.0]butane substrate, as exemplified by the current enantioselective formal (3 + 3) cycloaddition of bicyclo[1.1.0]butanes with nitrones. In addition to the diverse bicyclo[1.1.0]butanes incorporating an acyl imidazole group or an acyl pyrazole moiety, a wide array of nitrones are compatible with this Lewis acid catalysis, successfully assembling two congested quaternary carbon centers and a chiral aza-trisubstituted carbon center in the pharmaceutically important hetero-bicyclo[3.1.1]heptane product with up to 99% yield and >99% ee.

Asymmetric Rh‐Catalyzed [2+2+2] Cycloaddition: Synthesis of N‐Alkenylindoles with both Axial and Central Chirality

Axially chiral Indoline‐based scaffolds are virtually universal in biological and pharmaceutical compounds. Here we demonstrate an atroposelective Rh‐catalyzed 1,6‐enynes with steric hindered N‐alkynyl indoles, which enables simultaneous construction of both axial and central chirality, containing a quaternary carbon center, in one step. Notable features of these reactions include excellent chemo‐, regio‐, diastereo‐ and enantioselectivity, 100% atom‐economy, easily available Segphos ligand, and mild conditions.

Zinc-Catalyzed Enantioselective Formal (3+2) Cycloadditions of Bicyclobutanes with Imines: Catalytic Asymmetric Synthesis of Azabicyclo[2.1.1]hexanes.

The cycloaddition reaction involving bicyclo[1.1.0]butanes (BCBs) offers a versatile and efficient synthetic platform for producing C(sp3)-rich rigid bridged ring scaffolds, which act as phenyl bioisosteres. However, there is a scarcity of catalytic asymmetric cycloadditions of BCBs to fulfill the need for enantioenriched saturated bicycles in drug design and development. In this study, an efficient synthesis of valuable azabicyclo[2.1.1]hexanes (aza-BCHs) by an enantioselective zinc-catalyzed (3+2) cycloadditions of BCBs with imines is reported. The reaction proceeds effectively with a novel type of BCB that incorporates a 2-acyl imidazole group and a diverse array of alkynyl- and aryl-substituted imines. The target aza-BCHs, which consist of α-chiral amine fragments and two quaternary carbon centers, are efficiently synthesized with up to 94% yield and 96.5:3.5 er under mild conditions. Experimental and computational studies reveal that the reaction follows a concerted nucleophilic ring-opening mechanism of BCBs with imines. This mechanism is distinct from previous studies on Lewis acid-catalyzed cycloadditions of BCBs.

Zinc‐Catalyzed Enantioselective Formal (3+2) Cycloadditions of Bicyclobutanes with Imines: Catalytic Asymmetric Synthesis of Azabicyclo[2.1.1]hexanes

The cycloaddition reaction involving bicyclo[1.1.0]butanes (BCBs) offers a versatile and efficient synthetic platform for producing C(sp3)‐rich rigid bridged ring scaffolds, which act as phenyl bioisosteres. However, there is a scarcity of catalytic asymmetric cycloadditions of BCBs to fulfill the need for enantioenriched saturated bicycles in drug design and development. In this study, an efficient synthesis of valuable azabicyclo[2.1.1]hexanes (aza‐BCHs) by an enantioselective zinc‐catalyzed (3+2) cycloadditions of BCBs with imines is reported. The reaction proceeds effectively with a novel type of BCB that incorporates a 2‐acyl imidazole group and a diverse array of alkynyl‐ and aryl‐substituted imines. The target aza‐BCHs, which consist of α‐chiral amine fragments and two quaternary carbon centers, are efficiently synthesized with up to 94% yield and 96.5:3.5 er under mild conditions. Experimental and computational studies reveal that the reaction follows a concerted nucleophilic ring‐opening mechanism of BCBs with imines. This mechanism is distinct from previous studies on Lewis acid‐catalyzed cycloadditions of BCBs.

Concise Synthesis of Cyctetryptomycin A and B Enabled by Zr‐Catalyzed Dimerization

A concise synthetic strategy utilizing a Zr‐catalyst for the construction of cyctetryptomycin A and B is herein reported. Cyctetryptomycin A and B are recently isolated, complex tetrameric natural products for which total synthesis has not been previously reported. This study presents a practical approach for the construction of two consecutive quaternary carbon centers via a Zr‐catalyst. Furthermore, the first total synthesis of cyctetryptomycin A and B was achieved by this Zr‐catalyzed radical coupling. The radical dimerization reaction mediated by the Zr‐catalyst required dppe as an indispensable additive. Through both experimental and theoretical investigations into the mechanism of this Zr‐catalyzed reaction, the specific role of dppe was elucidated. In addition, the synthetic approach was extended to enable the practical synthesis of other dimeric natural products, including tetratryptomycin A, dibrevianamide F, and ditryptophenaline. Finally, the synthetic mechanism of cyctetryptomycin A and B, through the oxidative macrocyclization of tetratryptomycin A by CttpC, was newly elucidated by both experimental and docking simulations.

Concise Synthesis of Cyctetryptomycin A and B Enabled by Zr-Catalyzed Dimerization.

A concise synthetic strategy utilizing a Zr-catalyst for the construction of cyctetryptomycin A and B is herein reported. Cyctetryptomycin A and B are recently isolated, complex tetrameric natural products for which total synthesis has not been previously reported. This study presents a practical approach for the construction of two consecutive quaternary carbon centers via a Zr-catalyst. Furthermore, the first total synthesis of cyctetryptomycin A and B was achieved by this Zr-catalyzed radical coupling. The radical dimerization reaction mediated by the Zr-catalyst required dppe as an indispensable additive. Through both experimental and theoretical investigations into the mechanism of this Zr-catalyzed reaction, the specific role of dppe was elucidated. In addition, the synthetic approach was extended to enable the practical synthesis of other dimeric natural products, including tetratryptomycin A, dibrevianamide F, and ditryptophenaline. Finally, the synthetic mechanism of cyctetryptomycin A and B, through the oxidative macrocyclization of tetratryptomycin A by CttpC, was newly elucidated by both experimental and docking simulations.

Construction of new quaternary carbon center of fluorinated isoxazolines at C5 position via C-F bond cleavage

A substitution reaction of O-, S-, or N-nucleophiles onto fluorinated isoxazolines via carbon–fluorine (C-F) bond cleavage was achieved. The C-F bond at the C5 position of fluorinated isoxazolines was dissociated by using SnCl4 for the generation of a carbocation intermediate in this reaction. Subsequently, various nucleophiles such as alcohols, thiols, and amines were introduced, enabling the conversion to CO, C-S, or CN bonds and the formation of a new quaternary carbon center.

A magnetic nanocatalyst based on Bronsted acid and Lewis acid centers for the efficient synthesis of polycyclic melting 1,5-benzodiazepines

In this study, 3-(Triethoxysilyl)propyl chloride (CPTES) was used to modify the surface of magnetic nanoparticles Fe3O4@SiO2, and aminomethylphosphonic acid (AMPA) was further anchored on the surface. Then, Ce (III) was used as the ligand to immobilize the surface of the modified material with N/O as the donor. Magnetic nanocatalysts (Fe3O4@SiO2@CPTES@AMPA@CeCl3) were successfully prepared. The prepared catalysts were characterized by infrared spectroscopy (FT-IR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen absorption-desorption experiment (BET), vibrating sample magnetometer (VSM), energy dispersive spectroscopy (EDS) and inductively coupled plasma atomic emission spectrometry (ICP-AES). A synergetic effect of Brønsted and Lewis acid (AMPA and CeCl3) of the magnetic nanocatalyst was examined to active carbonyl, imine or enamine bonds for the synthesis of polycyclic fused 1,5-benzodiazepine with quaternary carbon centers or quinoxaline ring in a one-pot method. It was found that this catalyst exhibited excellent catalytic activities (TON up to 111368, TOF up to 110232 h−1) and high selectivities in the synthesis of fused 1,5-benzodiazepine compounds (22 examples, 85–96 % yields). The mechanism for the synthesis of polycyclic fused 1,5-benzodiazepine catalyzed by Fe3O4@SiO2@CPTES@AMPA@CeCl3 was proposed. The nanocatalyst was readily recovered by simple magnetic decantation and can be recyclable without obviously reducing catalytic activity up to seven times.

Construction of remote cyano-substituted quaternary carbon centers via nickel-catalyzed migratory hydrocyanation of unconjugated dienes

Construction of remote cyano-substituted quaternary carbon centers via nickel-catalyzed migratory hydrocyanation of unconjugated dienes

Palladium-Catalyzed Regio- and Diastereoselective Hydro(hetero)arylation for Rapid Construction of Quaternary Center Containing Cyclobutanes.

Herein we report a Pd-catalyzed regio- and diastereoselective hydro(hetero)arylation of inactivated alkylidenecyclobutanes. This protocol provides a rapid and atom-economical route to access 3-cyclobutyl (hetero)arenes with good functionalities toleration. With the assistance of the directing group, nucleophilic attack happened on the bulkier γ-position to form the quaternary carbon center. Furthermore, the selected products exhibited antitumor bioactivities.

Zinc‐Mediated Carbamoyl Amination of Alkylidenecyclopropane‐Tethered Carbamoyl Chlorides: Synthesis of Functionalized 2‐Quinolones

The transition metal catalyzed cyclization of alkene‐tethered carbamoyl chloride has now emerged as a vital tool to construct oxindoles bearing all carbon quaternary centers. However, most of these reactions proceed via carbometalation‐initiated 5‐exo‐trig cyclization followed by nucleophilic trapping of the resulting σ alkyl‐metal species to achieve diverse functionalized oxindoles. The 6‐endo‐trig type cyclization of alkene‐tethered carbamoyl chloride has been rarely reported. Herein, a zinc‐mediated carbamoyl amination of alkylidenecyclopropane‐tethered carbamoyl chlorides with anilines for the synthesis of functionalized 2‐quinolones was developed. A range of different substituted 2‐quinolones were prepared in 65‐89% yields from alkylidenecyclopropane‐tethered carbamoyl chlorides and aniline derivatives using Zn/TMSCl system.

Facile Construction of Quaternary Carbon Centers via Dinuclear Titanium(III)‐Catalyzed Reductive Coupling of Tertiary Chlorides and Activated Olefins

AbstractThe establishment of all‐carbon quaternary carbon centers represents a pivotal aspect in the synthesis of numerous natural products and pharmaceutical compounds, underscoring its paramount significance in synthetic organic chemistry. Herein, we present a novel synthetic strategy for the generation of quaternary carbon centers through the reductive coupling of tertiary halides, catalyzed by dinuclear (salen)titanium catalysts. This catalytic framework demonstrates notable reactivity towards tertiary chlorides while maintaining inertness towards secondary and primary chlorides, thereby facilitating exceptional chemoselectivity for C−C bond formation. The reaction proceeds with remarkable efficiency across a diverse range of substrates under mild reaction conditions.

Photocatalytic Reductive Azaarenylation of Cyclopropanes via Consecutive Photo‐induced Electron Transfer: A Facile Route to α‐Quaternary Azaarenes†

Comprehensive Summaryα‐Azaarene quaternary carbon centers are prevalent in drug molecules, making the development of efficient synthetic approaches of great interest. Herein, we describe an unprecedented method for constructing α‐all‐carbon quaternary carbon‐centered azaarenes by employing photocatalytic reductive coupling of various 2,2‐disubstituted cycloproarylketones with readily available cyanoazaarenes. The reaction proceeds with high efficiency, displaying excellent compatibility with various functional groups and demonstrating high chemo‐ and regioselectivity. Mechanistic investigations suggest that consecutive photo‐induced electron transfer (ConPET) plays a crucial role in the formation of photocatalyst with greater reducing capability, ultimately enabling the direct reductive conversion of unreactive π‐bonds under mild and transition‐metal‐free conditions.