Chiral Quaternary Center Research Articles

Gold(I)‐Catalyzed Desymmetrization of Homopropargylic Alcohols via Cycloisomerization: Enantioselective Synthesis of Cyclopentenes Featuring a Quaternary Chiral Center

AbstractCyclopentene rings possessing a chiral quaternary center are important structural motifs found in various natural products. In this work, we disclose expedient and efficient access to this class of synthetically valuable structures via highly enantioselective desymmetrization of prochiral propargylic alcohols. The efficient chirality induction in this asymmetric gold catalysis is achieved via two‐point bindings between a gold catalyst featuring a bifunctional phosphine ligand and the substrate homopropargylic alcohol moiety—an H‐bonding interaction between the substrate HO group and a ligand phosphine oxide moiety and the gold‐alkyne complexation. The propargylic alcohol substrates can be prepared readily via propargylation of enoate and ketone precursors. In addition to monocyclic cyclopentenes, spirocyclic and bicyclic ones are formed with additional neighboring chiral centers of flexible stereochemistry in addition to the quaternary center. This work represents rare gold‐catalyzed highly enantioselective cycloisomerization of 1,5‐enynes. Density functional theory (DFT) calculations support the chirality induction model and suggest that the rate acceleration enabled by the bifunctional ligand can be attributed to a facilitated protodeauration step at the end of the catalysis.

Gold(I)-Catalyzed Desymmetrization of Homopropargylic Alcohols via Cycloisomerization: Enantioselective Synthesis of Cyclopentenes Featuring a Quaternary Chiral Center.

Cyclopentene rings possessing a chiral quaternary center are important structural motifs found in various natural products. In this work, we disclose expedient and efficient access to this class of synthetically valuable structures via highly enantioselective desymmetrization of prochiral propargylic alcohols. The efficient chirality induction in this asymmetric gold catalysis is achieved via two-point bindings between a gold catalyst featuring a bifunctional phosphine ligand and the substrate homopropargylic alcohol moiety-an H-bonding interaction between the substrate HO group and a ligand phosphine oxide moiety and the gold-alkyne complexation. The propargylic alcohol substrates can be prepared readily via propargylation of enoate and ketone precursors. In addition to monocyclic cyclopentenes, spirocyclic and bicyclic ones are formed with additional neighboring chiral centers of flexible stereochemistry in addition to the quaternary center. This work represents rare gold-catalyzed highly enantioselective cycloisomerization of 1,5-enynes. Density functional theory (DFT) calculations support the chirality induction model and suggest that the rate acceleration enabled by the bifunctional ligand can be attributed to a facilitated protodeauration step at the end of the catalysis.

Catalytic Asymmetric [4+2] Cyclization of Hydroxyphenyl Indolinone with Azlactone to Construct Spirooxindole δ‐Lactone

Comprehensive SummaryAn efficient asymmetric [4+2] cyclization of hydroxyphenyl indolinone with azlactone for the synthesis of spirooxindole δ‐lactone has been developed, which realized the first asymmetric reaction of hydroxyphenyl indolinone. A series of intricate structures with congested vicinal quaternary chiral centers were provided in good yields with excellent enantioselectivities via the in situ generated o‐QM from hydroxyphenyl indolinone.

Catalytic enantioselective nitrone cycloadditions enabling collective syntheses of indole alkaloids

Tetrahydro-β-carboline skeletons are prominent and ubiquitous in an extraordinary range of indole alkaloid natural products and pharmaceutical compounds. Powerful synthetic approaches for stereoselective synthesis of tetrahydro-β-carboline skeletons have immense impacts and have attracted enormous attention. Here, we outline a general chiral phosphoric acid catalyzed asymmetric 1,3-dipolar cycloaddition of 3,4-dihydro-β-carboline-2-oxide type nitrone that enables access to three types of chiral tetrahydro-β-carbolines bearing continuous multi-chiral centers and quaternary chiral centers. The method displays different endo/exo selectivity from traditional nitrone chemistry. The distinct power of this strategy has been illustrated by application to collective and enantiodivergent total syntheses of 40 tetrahydro-β-carboline-type indole alkaloid natural products with divergent stereochemistry and varied architectures.

Creation of a Chiral All-Carbon Quaternary Center Induced by CF3 and CH3 Substituents via Cu-Catalyzed Asymmetric Conjugate Addition.

Cu-catalyzed asymmetric construction of a chiral quaternary center bearing CH3 and CF3 groups was achieved with high to excellent enantioselectivity using our originally developed ligands. The asymmetric conjugate addition of Me3Al to β-CF3-substituted enones and unsaturated ketoesters proceeded efficiently. The use of unsaturated ketoesters gives optically active furanones in high yields with high enantioselectivities. The perfluoroalkyl-substituted enone does not seem to be favorable in the present reaction.

Advances and Strategies towards Synthesis of Aspidosperma Indole Alkaloids Goniomitine.

Goniomitine is of the aspidosperma alkaloid family, with an angularly fused tetracyclic skeleton housing an all-carbon quaternary carbon chiral center alongside an aminal functional group. This natural product has garnered attention as a synthetic target due to its intriguing molecular architecture and anti-proliferative activity in recent years. Following the first synthesis of (-)-goniomitine by Takano in 1991, synthetic chemists have developed various methods. This review provides an overview of the methodologies used in the synthesis of goniomitine in racemic and enantiopure forms via divergent construction indole framework, indole functionalization, and the integrated oxidation/reduction/cyclization (iORC) sequence from 1991 to 2023.

Organocatalyzed Enantio- and Diastereoselective Formal Domino 1,3-Dipolar Cycloaddition/Rearrangement: Synthesis of Chiral Pyrrolo-thiazine-2-carbaldehydes.

An efficient approach for the synthesis of chiral pyrrolo[1,2-d][1,4]thiazine-2-carbaldehydes is achieved via formal 1,3-dipolar cycloaddition/rearrangement reactions of benzothiazolium salt and α,β-unsaturated aldehydes, utilizing an asymmetric organocatalyst. This process results in the formation of fluorescent, highly enantioenriched chiral molecules with three contiguous stereogenic centers, one of which is a chiral quaternary center, with excellent yields and enantio- and diastereoselectivity. A computational study demonstrated the understanding of the reaction mechanism. The synthetic utility of this protocol was successfully employed for gram scale synthesis. Fluorescent and in silico studies showed the application of the present methodology.

Asymmetric Synthesis of 3,4‐Dihydroquinolin‐2‐ones via Organocatalytic [4+2]‐Cyclization of 2‐Amino‐β‐nitrostyrenes with Azlactones

AbstractDihydroquinolin‐2‐ones, recognized for their bioactive properties, feature a six‐membered structure with nitrogen‐containing heterocycles. A method has been developed for synthesizing enantioenriched 3,4‐dihydroquinoline‐2‐one derivatives. This approach utilizes an asymmetric [4+2]‐cyclization process, combining 2‐amino‐β‐nitrostyrenes with azlactones, and is facilitated by a bifunctional squaramide‐based organocatalyst. This process has enabled the creation of chiral 3,4‐dihydroquinoline‐2‐ones with complex structures, including chiral tetrasubstituted carbon stereocenters, delivering corresponding products in 26–95% yield with a diastereomeric ratio of 1.2:1–19:1 and 52–97 ee.

Desymmetric homologating annulation to access chiral pentafulvenes and their application in bioimaging

The architectural design of polycyclic/multisubstituted pentafulvenes has demonstrated great potential for the development of electrochromic materials and biologically active motifs. Unfortunately, the enantioselective construction of such distinctive cores with all carbon quaternary chiral centers has remained untouched to date. Herein, we disclose an enantioselective homologating annulation of cyclopent-4-ene-dione with 3-cyano-4-methylcoumarins through L-tert-leucine derived thiourea catalysis, affording a wide range of enantioenriched polycyclic multisubstituted embedded aminopentafulvenes with excellent stereocontrol (up to 99:1 er) and chemical yields up to 87%. A detailed photophysical and cytotoxicity analysis of racemic and chiral homologated adducts unveils the exceptional behavior of chiral adducts over their racemic analogs, highlighting the importance of stereoselectivity of the developed scaffolds. A cellular uptake experiment in a mammalian fibroblast cell line confirmed the potential of developed polycyclic aminopentafulvene cores as a highly promising labeling dye that can be utilized for bioimaging without any adverse effects.

Bispidine‐Based S,N‐Chiral Ligands for Palladium‐Catalyzed Asymmetric Arylation of Cyclic N‐Sulfonyl Ketimines

AbstractDevelopment of new chiral ligands is essentially important in the field of asymmetric metal catalysis. Bispidines, steming from natural alkaloids, represent an intriguing yet underexplored class of chiral ligands. In this article, we developed a series of bispidine‐based chiral ligands with chirality locked in the side chain, and explore their properties by applying in the palladium‐catalyzed asymmetric addition of arylboric acids to cyclic N‐sulfonyl ketimines. A S,N‐bispidine ligand was found especially efficient, affording a series of chiral benzosultams with a quaternary chiral center in excellent yields with excellent ee values. Density functional theory (DFT) calculations and crystal structure of catalyst helped to propose a reasonable mechanism including a possible transition state model to explain the origin of stereoselectivity.

Organocatalytic Enantioselective Synthesis of Polycyclic Benzosultams from 2-Amino-β-nitrostyrenes with Cyclic N-Sulfonyl Ketimines.

A highly efficient enantioselective [4 + 2] cycloaddition of 2-amino-β-nitrostyrenes with cyclic N-sulfonyl ketimines has been developed. This reaction utilizes an organocatalytic approach, employing a multiple-hydrogen-bonding bifunctional squaramide-based catalyst. The process allows for the precise synthesis of chiral polycyclic benzosultams, showcasing intricate structures that incorporate chiral quaternary centers. Noteworthy outcomes of this method include high yields with excellent enantioselectivities and diastereoselectivities (up to 97% yield, 96% ee, and >20:1 dr).

Asymmetric Cyanation of α-Ketimino Ester Derivatives with Chiral Ru-Li Combined Catalysts.

Asymmetric cyanation of α-ketimino esters catalyzed by combined systems of amino acid/BINAP derivative/Ru(II) complexes and lithium compounds was examined. The use of an appropriate combination of amino acid and BINAP ligands achieved high enantioselectivity for a variety of α-alkynyl (Val/XylBINAP/Ru), α-alkenyl (Val/TolBINAP/Ru), and α-aryl imino esters (Val/XylBINAP/Ru) as well as an isatin-derived cyclic imino amide (t-Leu/BINAP/Ru) to afford the α-cyano-α-amino esters and the amide with an α-nitrogen-substituted quaternary chiral center with up to 98% ee.

Recent advances in stereoselective construction of fluorinated quaternary carbon centers from fluorinated compounds.

There are many fluorinated quaternary carbon structural units in pharmaceuticals and bioactive compounds. Organic chemists are interested in the stereoselective synthesis of fluorinated quaternary carbon structural units. Constructing a fluorinated quaternary carbon stereocenter can be achieved directly and efficiently by the asymmetric catalytic reaction of fluorinated compounds as substrates. This approach aims to construct fluorinated quaternary carbon stereocenters while diversifying the types of fluorinated compounds. This review introduces a series of reactions for synthesizing fluorinated quaternary carbon chiral centers through asymmetric organic catalysis and transition metal catalysis, including alkylation, arylation, Mannich, Michael addition, and allylation reactions. This work will contribute to the development of the synthesis of fluorinated quaternary carbon chiral center-containing compounds in the future.

Organocatalytic formal [4 + 2] cycloaddition of o-quinone-methyl derivatives and 2-isocyanatomalonate diesters for the construction of chroman derivatives with adjacent quaternary chiral centers

An asymmetric organocatalytic formal [4 + 2] cycloaddition/annulation cascade of ortho-quinone methides with 2-isocyanatomalonate diesters has been reported.

Catalytic enantioselective [3+2] and [4+2]-annulation of cyclic N-sulfonyl ketimines with γ- or δ-hydroxy-α,β-unsaturated ketones.

A highly efficient asymmetric [3+2] and [4+2]-annulation of cyclic N-sulfonyl ketimines with γ- or δ-hydroxy-α,β-unsaturated ketones has been developed. This innovative reaction employs an organocatalytic approach, utilizing a hydrogen-bonding bifunctional squaramide-based catalyst. The process enables precise synthesis of chiral polyheterotricyclic oxazolidines and 1,3-oxazinane derivatives, revealing intricate structures with incorporated chiral quaternary centers. Remarkably, this method delivers high yields and exceptional enantioselectivities and diastereoselectivities, achieving up to 99% yield, >20 : 1 dr, and >99% ee.

Organocatalytic Asymmetric [4 + 2]-Cycloadditions of 2-Aminophenyl Enones with Isatin-Derived Ketimines: Diastereo- and Enantioselective Synthesis of Spirooxindole-Tetrahydroquinazolines.

A novel method for the enantioselective synthesis of spiro N,N-heterocyclic oxindoles has been developed, employing asymmetric [4 + 2]-cycloadditions of 2-aminophenyl enones with isatin-derived ketimines. This method employs an organocatalytic approach, utilizing a bifunctional squaramide-based catalyst. It enables the precise synthesis of chiral spirooxindole-tetrahydroquinazolines with intricate structures, featuring chiral quaternary centers. This process achieves remarkable results, including high yields and exceptional levels of enantioselectivity and diastereoselectivity (up to 96% yield, 95% ee, and >20:1 dr).

Desymmetrization and Parallel Kinetic Resolution of 1-Ethynylcyclobutanols via Asymmetric Cooperative Gold Catalysis.

Enantioselective gold catalysis remains a challenging area of research. By harnessing gold-ligand cooperation in the presence of a chiral bifunctional phosphine ligand featuring a novel 3'-phosphine oxide moiety, highly enantioselective desymmetrization of 1-ethynylcyclobutanols is achieved, permitting access to chiral α-methylenecyclopentanones featuring a diverse array of chiral quaternary and tertiary centers. This cooperative gold catalysis also enables parallel kinetic resolution in gold catalysis, delivering cyclopentanone regioisomers with excellent enantiomeric excesses. DFT calculations of the transition states support the distinct mechanism of asymmetric induction via controlling the conformation of the bound substrate and hence dictating the ring bond undergoing migration.

Highly enantio-stereoselective Ni-catalyzed reductive cyclization to cyclopentanes with chiral quaternary centres of trisubstituted allylic siloxanes

The construction of chiral quaternary carbon stereocenters is a significant challenge in asymmetric synthesis. Catalytic synthesis of these structures with trisubstituted allylic alcohols is highly important. However, most of the reported methodologies required noble transition-metals. Herein we reported the first highly asymmetric stereoselective synthesis of cyclopentanes bearing chiral quaternary carbon stereocenters of trisubstituted allylic siloxanes by reductive cyclization of all carbon 1,6-alkynones with the non-noble nickel catalysis of Ni(cod)2 with P-chiral monophosphine ligand (S)-BIDIME. Various multi-substituted functionalized cyclopentanes were obtained in high yields (up to 96%), excellent enantioselectivities (up to >99% ee) and perfect stereoselectivities (>99:1 ​E/Z). Thirty-two examples were successfully established for this method. Clarified mechanism studies were investigated first time by React-IR and DFT calculations to understand and explain the ligand-control of excellent enantio-stereoselectivity. Gram-scale reaction and control experiments were carried out. A new reaction design was proposed for further application of this type of catalysis.

Enantioselective Synthesis of Isoindolones via Palladium – Catalyzed Intramolecular Heck‐Mizoroki Reactions of Endocyclic Enamides Using N,N‐Ligands

AbstractThe enantioselective synthesis of isoindolones via Heck‐Mizoroki reactions of endocyclic enamides using a palladium‐bis(oxazoline) catalyst system is described. The N,N‐ligands, which are under‐represented in palladium‐catalyzed reactions involving aryl halides, proved to be an effective and low‐cost alternative to their phosphine‐based chiral ligand counterparts. The intramolecular Heck reaction of aryl iodides and endocyclic enamides enabled the construction of tricyclic isoindolones containing tertiary and quaternary chiral centers under mild conditions in yields up to 73 % and enantiomeric ratios up to 97 : 3. Vibrational circular dichroism (VCD) was instrumental in determining the absolute configuration of the enantioenriched isoindolones.

Enantioselective Photochemical Carbene Insertion into C–C and C–H Bonds of 1,3-Diketones by a Guanidine-Amide Organocatalyst

A visible-light-induced enantioselective free carbene transfer reaction of α-diazoesters with 1,3-diketones is established by utilizing a chiral bifunctional guanidine-amide organocatalyst. Selective insertion of free carbene into the C–C or C–H bonds of 1,3-diketone could be achieved with α-diazoesters bearing different steric hindrances. The transformations enable the preparation of a series of 1,4-diketones with a quaternary carbon chiral center or chiral 2-substituted-1,3-diketones in good enantioselectivities. On the basis of the control experiments and DFT calculation, a stepwise triplet free carbene coupling pathway is suggested. A possible reaction mechanism is proposed to explain the origin of high enantioselectivities via hydrogen-bonds and electrostatic interactions of the catalyst.