Chiral Research Articles

Asymmetric Construction of Chiral 2‐Azetines and Axially Chiral Tetrasubstituted Allenes via Phosphine Catalysis

Chiral 2‐azetines and allenes are highly valuable structural units in natural products and useful chemicals. However, enantioselective synthesis of both 2‐azetines and allenes has been extremely challenging. Herein, we present asymmetric construction of chiral 2‐azetines (70–98% yields and up to 96% ee) through chiral phosphine‐catalyzed [2+2] annulation of yne‐enones with sulfamate‐derived cyclic imines. These 2‐azetines were easily transformed into chiral allenes upon treatment with Et3SiH, BF3•Et2O and water at rt for 2 minutes. Based on the above transformations, a concise one‐pot synthetic procedure combining [2+2] annulation of yne‐enones and sulfamate‐derived cyclic imines under phosphine catalysis and sequential reduction/isomerization/ring‐opening reaction through Et3SiH, BF3•Et2O and water was thus set up, providing axially chiral tetrasubstituted allenes in satisfactory yields and enantioselectivities (56–90% yields and up to 91% ee).

Asymmetric Construction of Chiral 2-Azetines and Axially Chiral Tetrasubstituted Allenes via Phosphine Catalysis.

Chiral 2-azetines and allenes are highly valuable structural units in natural products and useful chemicals. However, enantioselective synthesis of both 2-azetines and allenes has been extremely challenging. Herein, we present asymmetric construction of chiral 2-azetines (70-98% yields and up to 96% ee) through chiral phosphine-catalyzed [2+2] annulation of yne-enones with sulfamate-derived cyclic imines. These 2-azetines were easily transformed into chiral allenes upon treatment with Et3SiH, BF3•Et2O and water at rt for 2 minutes. Based on the above transformations, a concise one-pot synthetic procedure combining [2+2] annulation of yne-enones and sulfamate-derived cyclic imines under phosphine catalysis and sequential reduction/isomerization/ring-opening reaction through Et3SiH, BF3•Et2O and water was thus set up, providing axially chiral tetrasubstituted allenes in satisfactory yields and enantioselectivities (56-90% yields and up to 91% ee).

Axially chiral α-boryl-homoallenyl boronic esters as versatile toolbox for accessing centrally and axially chiral molecules

Axially chiral allenes bearing organoboron groups are highly sought-after building blocks in organic synthesis due to their potential for generating a wide range of axially and centrally chiral molecules. However, the existing methods for preparing axially chiral allenes containing boron group are primarily limited to the synthesis of allenyl boronic esters, and strategies for accessing axially chiral homoallenyl boronic esters are still scarce. Here, we report the general method for synthesizing axially chiral α-boryl-homoallenyl boronic esters through a highly regio- and stereoselective copper-mediated SN2’-addition of newly prepared (diborylalkyl)copper species to chiral propargyl electrophiles. The reaction conditions were optimized to achieve high yields and excellent stereospecificity. The obtained products were successfully transformed into various axially chiral allenes and other chiral molecules by transforming diboron units. The potential for axial-to-central chirality transfer of axially chiral α-boryl-homoallenyl boronic esters is also demonstrated through the stereospecific addition to aldehydes and N-H aldimines, yielding enantioenriched 1,2-oxaborinin-3,5-dienes and 2-aminomethyl-1,3-dienes.

Photoexcited Palladium-Catalyzed Synthesis of Chiral Allenes from Alkynes via Isomerization and Deracemization Sequence

Photoexcited Palladium-Catalyzed Synthesis of Chiral Allenes from Alkynes via Isomerization and Deracemization Sequence

Recent Advances in the Synthesis of Chiral Allenes via Asymmetric 1,4‐Difunctionalization of 1,3‐Enynes

AbstractAllenes represent a distinctive class of organic molecules characterized by their unique physical and chemical properties. Among them, chiral allenes play a significant role in modern chemistry. They not only serve as pivotal frameworks for natural products and drug molecules but also are essential building blocks in organic synthesis. Over the years, numerous remarkable and efficient methods have been developed for the synthesis of chiral allenes. Notably, the catalytic synthesis of chiral allenes using transition metals in conjunction with chiral ligands has garnered considerable attention. This review paper aims to provide an overview of recent advancements in the synthesis of chiral allenes through asymmetric 1,4‐difunctionalization of 1,3‐enynes, in which two distinct strategies including non‐radical and radical processes are highlighted.

Stereoselective Synthesis of Axially Chiral Allenes and Styrenes via Chiral Phosphoric Acid Catalysis: An Overview.

Chiral allenes and styrenes are essential components in fields like medicinal chemistry, materials science, and organic synthesis. They serve a crucial role as chiral ligands and catalysts in asymmetric synthesis. Over the past decade, there has been a significant advancement in the development of practical methods utilizing organocatalytic strategies for the synthesis of chiral allenes and styrenes. It is noteworthy that despite extensive studies on the formation of allenes and styrenes, existing reviews on their construction confined to a specific organocatalysis, called chiral phosphoric acid catalysis, are less documented. This review aims to explore different conceptual approaches based on the electrophilic species involved in the reaction to produce stereoselective chiral allenes and styrenes, providing insights into recent advancements in the field. Emphasis is placed on works published since 2017, with detailed discussions on reaction mechanisms and examples from recent literature.

Photoexcited Palladium-Catalyzed Deracemization of Allenes.

The different enantiomers of specific chiral molecules frequently exhibit disparate biological, physiological, or pharmacological properties. Therefore, the efficient synthesis of single enantiomers is of particular importance not only to the pharmaceutical sector but also to other industrial sectors, such as agrochemical and fine chemical industries. Deracemization, a process during which a racemic mixture is converted into a nonracemic product with 100% atom economy and theoretical yield, is the most straightforward method to access enantioenriched molecules but a challenging task due to a decrease in entropy and microscopic reversibility. Axially chiral allenes bear a distinctive structure of two orthogonal cumulative π-systems and are acknowledged as synthetically versatile synthons in organic synthesis. The selective creation of axially chiral allenes with high optical purity under mild reaction conditions has always been a very popular and hot topic in organic synthesis but remains challenging. Herein, a photoexcited palladium-catalyzed deracemization of nonprefunctionalized disubstituted allenes is disclosed. This method provides an efficient and economical strategy to accommodate a broad scope of allenes with good enantioselectivities and yields (53 examples, up to 96% yield and 95% ee). The use of a suitable chiral palladium complex with visible light irradiation is an essential factor in achieving this transformation. A metal-to-ligand charge transfer mechanism was proposed based on control experiments and density functional theory calculations. Quantum mechanical studies implicate dual modes of asymmetric induction behind our new protocol: (1) sterically controlled stereoselective binding of one allene enantiomer under the ground-state and (2) facile, noncovalent interaction-driven excited-state isomerization toward the opposite enantiomer. The success of this newly established photochemical deracemization strategy should provide inspiration for expansion to other multisubstituted allenes and will open up a new mode for enantioselective excited-state palladium catalysis.

Organocatalytic Enantioselective 1,12-Addition of Alkynyl Biphenyl Quinone Methides Formed In Situ.

The chemistry of quinone methides formed in situ has been flourishing in recent years. In sharp contrast, the development and utilization of biphenyl quinone methides are rare. In this study, we achieved a remote stereocontrolled 1,12-conjugate addition of biphenyl quinone methides formed in situ for the first time. In the presence of a suitable chiral phosphoric acid, alkynyl biphenyl quinone methides were generated from α-[4-(4-hydroxyphenyl)phenyl]propargyl alcohols, followed by enantioselective 1,12-conjugate addition with indole-2-carboxylates. The strategy enabled the alcohols to serve as efficient allenylation reagents, providing practical access to a broad range of axially chiral allenes bearing a (1,1'-biphenyl)-4-ol unit, which were previously less accessible. Combined with control experiments, density functional theory calculations shed light on the reaction mechanism, indicating that enantioselectivity originates from the nucleophilic addition of alkynyl biphenyl quinone methides. Notably, not only the presence of biphenyl quinone methides as versatile intermediates was confirmed but also organocatalytic enantioselective 1,12-addition was established.

Organocatalytic Enantioselective 1,12‐Addition of Alkynyl Biphenyl Quinone Methides Formed In Situ

AbstractThe chemistry of quinone methides formed in situ has been flourishing in recent years. In sharp contrast, the development and utilization of biphenyl quinone methides are rare. In this study, we achieved a remote stereocontrolled 1,12‐conjugate addition of biphenyl quinone methides formed in situ for the first time. In the presence of a suitable chiral phosphoric acid, alkynyl biphenyl quinone methides were generated from α‐[4‐(4‐hydroxyphenyl)phenyl]propargyl alcohols, followed by enantioselective 1,12‐conjugate addition with indole‐2‐carboxylates. The strategy enabled the alcohols to serve as efficient allenylation reagents, providing practical access to a broad range of axially chiral allenes bearing a (1,1′‐biphenyl)‐4‐ol unit, which were previously less accessible. Combined with control experiments, density functional theory calculations shed light on the reaction mechanism, indicating that enantioselectivity originates from the nucleophilic addition of alkynyl biphenyl quinone methides. Notably, not only the presence of biphenyl quinone methides as versatile intermediates was confirmed but also organocatalytic enantioselective 1,12‐addition was established.

Novel Stereo‐Induction Pattern in Pudovik Addition/Phospha‐Brook Rearrangement Towards Chiral Trisubstituted Allenes

AbstractDespite the significance of chiral allene skeletons in catalysis, organic synthesis and medicinal chemistry et al., there is a scarcity of reports on axially chiral allenyl phosphorus compounds. Here, we disclosed an efficient and straightforward cascade reaction between ethynyl ketones and phosphine oxides, resulting in a broad array of trisubstituted allenes incorporating a phosphorus moiety in high yields with excellent stereoselectivities facilitated by peptide‐mimic phosphonium salt (PPS) catalysis, Additionally, comprehensive series of mechanistic experiments have been conducted to elucidate that this cascade reaction proceeds via an asymmetric Pudovik addition reaction followed by a subsequent phospha‐Brook rearrangement that occurs concomitantly with kinetic resolution, representing a stereospecific rearrangement and protonation process facilitating central‐to‐axial chirality transfer in a cascade manner. We anticipate that our research will pave the way for a promising exploration of novel stereo‐induction pattern in the Pudovik addition/phospha‐Brook rearrangement cascade reaction.

Novel Stereo-Induction Pattern in Pudovik Addition/Phospha-Brook Rearrangement Towards Chiral Trisubstituted Allenes.

Despite the significance of chiral allene skeletons in catalysis, organic synthesis and medicinal chemistry et al., there is a scarcity of reports on axially chiral allenyl phosphorus compounds. Here, we disclosed an efficient and straightforward cascade reaction between ethynyl ketones and phosphine oxides, resulting in a broad array of trisubstituted allenes incorporating a phosphorus moiety in high yields with excellent stereoselectivities facilitated by peptide-mimic phosphonium salt (PPS) catalysis, Additionally, comprehensive series of mechanistic experiments have been conducted to elucidate that this cascade reaction proceeds via an asymmetric Pudovik addition reaction followed by a subsequent phospha-Brook rearrangement that occurs concomitantly with kinetic resolution, representing a stereospecific rearrangement and protonation process facilitating central-to-axial chirality transfer in a cascade manner. We anticipate that our research will pave the way for a promising exploration of novel stereo-induction pattern in the Pudovik addition/phospha-Brook rearrangement cascade reaction.

One stone three birds: Ni-catalyzed asymmetric allenylic substitution of allenic ethers, hydroalkylation of 1,3-enynes and double alkylation of enynyl ethers

The development of low-cost, earth-abundant and environmentally benign transition metal catalysts, which can catalyze multiple different types of asymmetric reactions, is an important objective in modern asymmetric catalysis. Herein we demonstrate that a chiral Ni/P-Phos catalyst achieves three types of asymmetric reactions: allenylic substitution of racemic allenic ethers, 1,4-hydroalkylation of prochiral 1,3-enynes and double alkylation of newly designed enynyl ether reagents. Three methods complement each other and produce various axially chiral allene derivatives bearing a pyrazolidine-3,5‑dione unit, which is widely present in drugs and biologically active molecules with versatile pharmacological activities.

Palladium-catalyzed asymmetric [4 + 3] cycloaddition of methylene-trimethylenemethane: access to seven-membered exocyclic axially chiral allenes

A palladium-catalyzed asymmetric [4 + 3] cycloaddition of the methylene-trimethylenemethane donor with an azadiene has been developed, affording benzofuro[3,2-b]azepine-derived exocyclic chiral allene with control of axial and point chirality.

P/M Macromolecular Switch Based on Conformational Control Exerted by an Achiral Side Chain within an Axially Chiral Locked Pendant.

Molecular switches, supramolecular chemistry, and polymers can be combined to create stimuli-responsive multichiral materials. Therefore, by acting on the extended/bent conformational composition of an achiral arm, it is possible to create a macromolecular gear, where different supramolecular interactions can be activated/deactivated to control the helical sense of a polymer containing up to five different chiral axial motifs. For this, a chiral allene with a flexible achiral arm was introduced as a pendant in poly(phenylacetylene). Through flexible arm control between extended and bent conformations, it is possible to selectively induce either a P or M helical sense in the polymer, while the relative spatial distribution of the substituents in the allene remains unaltered in two perpendicular planes (configurationally locked). These results show that complex dynamic multichiral materials can be obtained by the polymerization of appropriate monomers that combine chirality, switching properties, and the ability to generate chiral supramolecular assemblies.

Stereoselectivity control in Rh-catalyzed β-OH elimination for chiral allene formation

Stereoselectivity control and understanding in the metal-catalyzed reactions are fundamental issues in catalysis. Here we report sterically controlled rhodium-catalyzed SN2’-type substitution reactions of optically active tertiary propargylic alcohols with arylmetallic species affording the non-readily available enantioenriched tetrasubstituted allenes via either exclusive syn- or anti-β-OH elimination, respectively, under two sets of different reaction parameters. Detailed mechanistic experiments and density functional theory (DFT) studies reveal that the exclusive anti-Rh(I)-OH elimination is dictated by the simultaneous aid of in situ generated boric acid and ambient water, which act as the shuttle in the hydroxy relay to facilitate the Rh(I)-OH elimination process via a unique ten-membered cyclic transition state (anti-TS2_u). By contrast, the syn-Rh(III)-OH elimination in C–H bond activation-based allenylation reaction is controlled by a four-membered cyclic transition state (syn-TS3) due to the steric surroundings around the Rh(III) center preventing the approach of the other assisting molecules. Under the guidance of these mechanistic understandings, a stereodivergent protocol to construct the enantiomer of optically active tetrasubstituted allenes from the same starting materials is successfully developed.

Heterogeneous Copper-Catalyzed Cross-Coupling for Sustainable Synthesis of Chiral Allenes: Application to the Synthesis of Allenic Natural Products.

Classical Crabbé type SN 2' substitutions of propargylic substrates has served as one of the standard methods for the synthesis of allenes. However, the stereospecific version of this transformation often requires either stoichiometric amounts of organocopper reagents or special functional groups on the substrates, and the chirality transfer efficiency is also capricious. Herein, we report a sustainable methodology for the synthesis of diverse 1,3-di and tri-substituted allenes by using a simple and cheap cellulose supported heterogeneous nanocopper catalyst (MCC-Amp-Cu(I/II)). This approach represents the first example of heterogeneous catalysis for the synthesis of chiral allenes. High yields and excellent enantiospecificity (up to 97 % yield, 99 % ee) were achieved for a wide range of di- and tri-substituted allenes bearing various functional groups. It is worth noting that the applied heterogeneous catalyst could be recycled at least 5 times without any reduced reactivity. To demonstrate the synthetic utility of the developed protocol, we have applied it to the total synthesis of several chiral allenic natural products.

Heterogeneous Copper‐Catalyzed Cross‐Coupling for Sustainable Synthesis of Chiral Allenes: Application to the Synthesis of Allenic Natural Products

AbstractClassical Crabbé type SN2' substitutions of propargylic substrates has served as one of the standard methods for the synthesis of allenes. However, the stereospecific version of this transformation often requires either stoichiometric amounts of organocopper reagents or special functional groups on the substrates, and the chirality transfer efficiency is also capricious. Herein, we report a sustainable methodology for the synthesis of diverse 1,3‐di and tri‐substituted allenes by using a simple and cheap cellulose supported heterogeneous nanocopper catalyst (MCC‐Amp‐Cu(I/II)). This approach represents the first example of heterogeneous catalysis for the synthesis of chiral allenes. High yields and excellent enantiospecificity (up to 97 % yield, 99 % ee) were achieved for a wide range of di‐ and tri‐substituted allenes bearing various functional groups. It is worth noting that the applied heterogeneous catalyst could be recycled at least 5 times without any reduced reactivity. To demonstrate the synthetic utility of the developed protocol, we have applied it to the total synthesis of several chiral allenic natural products.

Progress on the Enantioselective Synthesis of Axially Chiral Cycloalkylidenes

AbstractThe discovery of new asymmetric synthetic methodologies and the asymmetric synthesis of new chiral compounds have been a major focus of synthetic organic chemists for decades. Axially chiral compounds have gained considerable attention in recent years because of their widespread utility in asymmetric catalysis and synthesis. Methods for the asymmetric synthesis of axially chiral cycloalkylidenes, a subset of axially chiral molecules, are far fewer compared to those developed for the preparation of chiral allenes and chiral biaryl compounds. In this review, different approaches for the synthesis of axially chiral cycloalkylidenes are summarized.1 Introduction2 Methods for the Enantioselective Synthesis of Axially Chiral Cycloalkylidenes2.1 Asymmetric Synthesis of Axially Chiral Cycloalkylidenes2.1.1 Asymmetric Horner–Wadsworth–Emmons (HWE) Reactions2.1.2 Asymmetric Wittig Reactions2.1.3 Asymmetric Dehydrohalogenation Reactions2.1.4 Asymmetric Elimination Reactions of Chiral Sulfoxides/Selenoxides2.1.5 Kinetic Resolution of Prochiral Compounds2.1.6 Other Miscellaneous Methods2.2 Catalytic Asymmetric Synthesis of Axially Chiral Cycloalkylidenes3 Conclusion

Development of robust chiroptical systems through spirobifluorenes.

Chiroptical responses are valuable for the structural determination of dissymmetric molecules. However, the development of everyday applications based on chiroptical systems is yet to come. We have been earlier using axially chiral allenes for the construction of linear, cyclic, and cage-shaped molecules that present remarkable chiroptical responses. Additionally, we have developed chiral surfaces through upstanding chiral architectures. Since the goal is to obtain robust chiroptical materials, more recently we have been studying spirobifluorenes (SBFs), a well-established building block in optoelectronic applications. After theoretical and experimental demonstration, the suitability of chiral SBFs for the development of robust chiroptical systems was certified by the construction all-carbon double helices, flexible shape-persistent macrocycles, chiral frameworks for surface functionalization, and structures featuring helical or spiroconjugated molecular orbitals. Here, we give an overview of our contribution to these matters.

Copper‐Catalyzed Asymmetric 1,4‐Aryl/Alkynylation of 1,3‐Enynes to Access Axially Chiral Tetrasubstituted Allenes

AbstractThe asymmetric 1,4‐difunctionalization of 1,3‐enynes represents a concise and highly efficient strategy for the preparation of chiral allenes. Herein, we developed a copper‐catalyzed three‐component asymmetric radical 1,4‐aryl/alkynylation of 1,3‐enynes by employing inexpensive, readily available, and highly reactive diaryliodonium salts as precursors to generate aryl radicals. The success of this reaction relied on the use of iminophenyl oxazolinylphenylamines (IPOPA) as chiral ligands. The reaction exhibited good compatibility with various alkynes, 1,3‐enynes, and diaryliodonium salts, providing an effective method for constructing highly enantioselective tetrasubstituted axially chiral allene compounds.