Chiral Research Articles

Turning Enol Triflates into Axially Chiral Allenes by Palladium-Catalyzed Enantioselective β-H Elimination

Key words allenes - β-H elimination - enol triflates - palladium catalysis

Dynamic Axial-to-Helical Communication Mechanism in Poly[(allenylethynylenephenylene)acetylene]s under External Stimuli.

Helix inversion in chiral dynamic helical polymers is usually achieved by conformational changes at the pendant groups induced through external stimuli. Herein, a different mechanism of helix inversion in poly(phenylacetylene)s (PPAs) is presented, based on the activation/deactivation of supramolecular interactions. We prepared poly[(allenylethynylenephenylene)acetylene]s (PAEPAs) in which the pendant groups are conformationally locked chiral allenes. Therefore, their substituents are placed in specific spatial orientations. As a result, the screw sense of a PAEPA is fixed by the allenyl substituent with the optimal size/distance relationship to the backbone. This helical sense command can be surpassed by supramolecular interactions between another substituent on the allene and appropriate external stimuli, such as amines. So, a helix inversion occurs through a novel axial-to-helical communication mechanism, opening a new scenario for taming the helices of chiral dynamic helical polymers.

Dynamic Axial‐to‐Helical Communication Mechanism in Poly[(allenylethynylenephenylene)acetylene]s under External Stimuli

AbstractHelix inversion in chiral dynamic helical polymers is usually achieved by conformational changes at the pendant groups induced through external stimuli. Herein, a different mechanism of helix inversion in poly(phenylacetylene)s (PPAs) is presented, based on the activation/deactivation of supramolecular interactions. We prepared poly[(allenylethynylenephenylene)acetylene]s (PAEPAs) in which the pendant groups are conformationally locked chiral allenes. Therefore, their substituents are placed in specific spatial orientations. As a result, the screw sense of a PAEPA is fixed by the allenyl substituent with the optimal size/distance relationship to the backbone. This helical sense command can be surpassed by supramolecular interactions between another substituent on the allene and appropriate external stimuli, such as amines. So, a helix inversion occurs through a novel axial‐to‐helical communication mechanism, opening a new scenario for taming the helices of chiral dynamic helical polymers.

Stereospecific [3+2] Cycloaddition of Chiral Arylallenes with C,N-Cyclic Azomethine Imines

A novel α,β-regioselective [3+2] cycloaddition reaction of arylallene with C,N-cyclic azomethine imine is reported. The axial-to-central chirality transfer phenomenon has been disclosed with chiral allenes in the reaction. The wide substrate scope, including different functional groups and natural products, reveals the generality of the methodology. Both experiments and density functional theory calculations have been used to elucidate a plausible mechanism.

Pd/Xu-Phos-catalyzed asymmetric elimination of fully substituted enol triflates into axially chiral trisubstituted allenes.

The β-H elimination, as one of the most important elementary reactions in transition metal chemistry, is a key step in quenching the carbon-palladium bond for the Heck reaction. However, the β-H elimination of the alkenyl palladium species leading to allene is an energetically unfavored process, and therefore, it has been a long-standing challenge in control of this process via enantioselective manner. We developed a concise and efficient methodology to construct trisubstituted chiral allenes from stereodefined fully substituted enol triflates by the enantioselective β-H elimination of the alkenyl palladium species under mild conditions. The identified Xu-Phos play a crucial role in the chemoselectivity and enantioselectivity. Multiple linear regression analysis shows the important steric effect on enantioselectivity. DFT computation results allow us to propose an intramolecular base (-OAc)-assisted deprotonation mechanism for this progress. Distortion-interaction and energy decomposition analysis indicate that the difference in electrostatic energy (Eelec) of the two intramolecular base-assisted deprotonation transition states dominates the stereoselectivity.

Palladium-catalyzed stereoselective construction of chiral allenes bearing nonadjacent axial and two central chirality.

It is challenging to enantioselectively construct molecules bearing multiple nonadjacent stereocenters, in contrast to those bearing a single stereocenter or adjacent stereocenters. Herein, we report an enantio- and diastereoselective synthesis of substituted chiral allenes with nonadjacent axial and two central chiral centers through a combination of retro-oxa-Michael addition and palladium-catalyzed asymmetric allenylic alkylation. This methodology exhibits good functional-group compatibility, and the corresponding allenylic alkylated compounds, including flavonoid frameworks, are obtained with good yields and diastereoselectivities and excellent enantioselectivities (all >95% ee). Furthermore, the scalability of the current synthetic protocol was proven by performing a gram-scale reaction.

Nickel-catalysed asymmetric hydromonofluoromethylation of 1,3-enynes for enantioselective construction of monofluoromethyl-tethered chiral allenes.

An unprecedented nickel-catalysed enantioselective hydromonofluoromethylation of 1,3-enynes is developed, allowing the diverse access to monofluoromethyl-tethered axially chiral allenes, including the challenging deuterated monofluoromethyl (CD2F)-tethered ones that are otherwise inaccessible. It represents the first asymmetric 1,4-hydrofunctionalization of 1,3-enynes using low-cost asymmetric nickel catalysis, thus opening a new avenue for the activation of 1,3-enynes in reaction development. The utility is further verified by its broad substrate scope, good functionality tolerance, mild conditions, and diversified product elaborations toward other valuable fluorinated structures. Mechanistic experiments and DFT calculations provide insights into the reaction mechanism and the origin of the enantioselectivity.

Scope and limitations of absolute configuration determination of allenic natural products using the CCC stretching VCD signal.

The allene functional group in natural products isolated so far exists in a non-racemic form, but its axial chirality is difficult to elucidate. Allenes exhibit a characteristic antisymmetric CCC stretching mode at around 1950 cm-1, and their VCD properties have not been studied in detail. This work, for the first time, applied VCD spectroscopy to allenic natural products and allenic molecules with other asymmetric centers focusing on the antisymmetric CCC stretching mode. This vibrational mode yielded a negligibly weak VCD signal for several molecules, but in the presence of electron-withdrawing and/or conjugating substituents, it generated a stronger one. Its sign was found to be influenced by the nature of substituents. These findings should deepen the understanding of the VCD properties of the allene functional group and should be useful for future studies of chiral allenes.

Chemodivergence in Pd-catalyzed desymmetrization of allenes: enantioselective [4+3] cycloaddition, desymmetric allenylic substitution and enynylation.

A class of prochiral allenylic di-electrophiles have been introduced for the first time as three-atom synthons in cycloadditions, and a new type of [4+3] cycloaddition involving transition metal-catalyzed enantioselective sequential allenylic substitution has been successfully developed, enabling challenging seven-membered exocyclic axially chiral allenes to be accessed in good yields with good enantioselectivity. Through the addition of a catalytic amount of ortho-aminoanilines or ortho-aminophenols, the racemization of the [4+3] cycloaddition products is effectively suppressed. Mechanistic studies reveal that elusive Pd-catalyzed enantioselective intramolecular allenylic substitution rather than intermolecular allenylic substitution is the enantio-determining step in this cycloaddition. By tuning the ligands, a Pd-catalyzed enantioselective desymmetric allenylic substitution leading to linear axially chiral tri-substituted allenes or a Pd-catalyzed tandem desymmetric allenylic substitution/β-vinylic hydrogen elimination (formal enynylation) leading to multi-functionalized 1,3-enynes is achieved chemodivergently.

Organocatalytic synthesis of chiral allene catalyzed by chiral phosphoric acid via asymmetric 1,8-addition of indole imine methide: Mechanism and origin of enantioselectivity

Organocatalytic synthesis of chiral allene can be successfully achieved through the reaction between propargylic alcohol and 3-phenylindole catalyzed by chiral phosphoric acid with high yield and high enantioselectivity. The detailed reaction mechanism and origin of enantioselectivity were uncovered by quantum mechanical calculations. The results indicate that the reactions undergo the dehydration process, the C–C bonding reaction, the hydrogen abstraction and the regeneration of catalyst. Eight possible pathways were found and the most favorable reaction paths leading to the major and minor products were evaluated which were consistent with the experimental results. The distortion/interaction analyses of the transition states in enantioselectivity-determining steps confirm the most favorable pathway in leading the major product. QTAIM and IGM analyses are used to illustrate the role of intermolecular interactions. EDA analysis is also employed to understand the origin of selectivity. This work would provide insightful viewpoints on the asymmetric organocatalytic reaction by chiral phosphoric acid.

Asymmetric 1,4-functionalization of 1,3-enynes via dual photoredox and chromium catalysis

The merger of photoredox and transition-metal catalysis has evolved as a robust platform in organic synthesis over the past decade. The stereoselective 1,4-functionalization of 1,3-enynes, a prevalent synthon in synthetic chemistry, could afford valuable chiral allene derivatives. However, tremendous efforts have been focused on the ionic reaction pathway. The radical-involved asymmetric 1,4-functionalization of 1,3-enynes remains a prominent challenge. Herein, we describe the asymmetric three-component 1,4-dialkylation of 1,3-enynes via dual photoredox and chromium catalysis to provide chiral allenols. This method features readily available starting materials, broad substrate scope, good functional group compatibility, high regioselectivity, and simultaneous control of axial and central chiralities. Mechanistic studies suggest that this reaction proceeds through a radical-involved redox-neutral pathway.

Enyne diketones as substrate in asymmetric Nazarov cyclization for construction of chiral allene cyclopentenones

The Nazarov cyclization is one of the most powerful tools for the stereoselective synthesis of various cyclopentenone scaffolds. Therefore, developing the new classes substrate of Nazarov reaction is an important endeavor in synthetic chemistry. Herein, we report enyne diketones, enables diastereo- and enantioselective construction of chiral allene cyclopentenones in moderate to good yields with good enantioselectivities (up to 97% ee). Importantly, it is a typical example for asymmetric synthesis of cyclopentanones with allene moiety using Nazarov cyclisation. Mechanistic studies indicate that this metal-organo relay catalysis protocol involves a rhodium-catalyzed tandem oxonium ylide formation/[2,3]-sigmatropic rearrangement/reverse benzylic acid rearrangement, followed by organo-catalyzed asymmetric Nazarov cyclization/alkyne-to-allene isomerization to give the final chiral allene cyclopentenones.

Back Cover: Catalytic Regio‐ and Enantioselective Protonation for the Synthesis of Chiral Allenes: Synergistic Effect of the Counterion and Water (Angew. Chem. Int. Ed. 27/2022)

A chiral Lewis acid accelerated asymmetric Pudovik addition/[1,2]-phospha-Brook rearrangement is described by Shunxi Dong, Qian Peng, Xiaoming Feng, and co-workers in their Research Article (e202203650). Control experiments and theoretical calculations revealed that a synergistic effect of the counterion and water was critical for the regio- and enantioselective protonation after the [1,2]-phospha-Brook rearrangement.

Rücktitelbild: Catalytic Regio‐ and Enantioselective Protonation for the Synthesis of Chiral Allenes: Synergistic Effect of the Counterion and Water (Angew. Chem. 27/2022)

Eine chirale Lewis-Säure beschleunigt die asymmetrische Pudovik-Addition/[1,2]-Phospha-Brook-Umlagerung, wie Shunxi Dong, Qian Peng, Xiaoming Feng und Mitarbeiter in ihrem Forschungsartikel berichten (e202203650). Kontrollexperimente und theoretische Berechnungen zeigen, dass ein synergistischer Effekt des Gegenions und von Wasser für die regio- und enantioselektive Protonierung nach der [1,2]-Phospha-Brook-Umlagerung entscheidend ist.

Catalytic Regio‐ and Enantioselective Protonation for the Synthesis of Chiral Allenes: Synergistic Effect of the Counterion and Water

AbstractA highly enantioselective tandem Pudovik addition/[1,2]‐phospha‐Brook rearrangement of α‐alkynylketoamides with diarylphosphine oxides was achieved with a N,N′‐dioxide/ScIII complex as the catalyst. This protocol features broad substrate scope, high regio‐ and enantioselectivity, and good functional‐group compatibility, providing a straightforward route to various trisubstituted allenes with a diarylphosphinate functionality in good yields with high enantioselectivities (up to 97 % yield, 96 % ee). Control experiments and theoretical calculations revealed that a synergistic effect of the counterion and water was critical for the regio‐ and enantioselective protonation after [1,2]‐phospha‐Brook rearrangement. The synthetic utility of this methodology was demonstrated by the conversion of products into complex bridged polycyclic architectures through intramolecular dearomatizing arene/allene cycloaddition.

Catalytic Regio- and Enantioselective Protonation for the Synthesis of Chiral Allenes: Synergistic Effect of the Counterion and Water.

A highly enantioselective tandem Pudovik addition/[1,2]-phospha-Brook rearrangement of α-alkynylketoamides with diarylphosphine oxides was achieved with a N,N'-dioxide/ScIII complex as the catalyst. This protocol features broad substrate scope, high regio- and enantioselectivity, and good functional-group compatibility, providing a straightforward route to various trisubstituted allenes with a diarylphosphinate functionality in good yields with high enantioselectivities (up to 97 % yield, 96 % ee). Control experiments and theoretical calculations revealed that a synergistic effect of the counterion and water was critical for the regio- and enantioselective protonation after [1,2]-phospha-Brook rearrangement. The synthetic utility of this methodology was demonstrated by the conversion of products into complex bridged polycyclic architectures through intramolecular dearomatizing arene/allene cycloaddition.

Recent Advances in Organocatalytic Enantioselective Synthesis of Axially Chiral Allenes

AbstractAxially chiral allenes occur on a wide range of natural products and synthetic molecules with significant biological activity. Furthermore, they are versatile building blocks in organic synthesis because of their inherent chemical properties. Accordingly, catalytic enantioselective synthesis of axially chiral allenes has been paid much attention. Benefited from the development of asymmetric organocatalysis, many simple and efficient methods in terms of different catalytic systems as well as reaction partners have been developed. This review will focus on the recent progress in the field of organocatalytic enantioselective synthesis of allenes (2000–2022), which is organized according to types of allenes and the catalyst system used.magnified image

Ni-Catalyzed Decarboxylative Silylation of Alkynyl Carbonates: Access to Chiral Allenes via Enantiospecific Conversions.

A Ni-mediated decarboxylative silylation of alkynyl cyclic carbonates used as versatile propargylic surrogates is reported affording a wide range of highly substituted 2,3- and 3,4-allenol products in good yields. The formal cross-coupling between a tentative intermediate Ni(allenyl) and the silyl reagent was further extended to enantiospecific conversions providing access to chiral allene synthons. This protocol marks the first Ni-catalyzed propargylic silylation proceeding through an SN2' manifold.

Recent advances in the metal-catalyzed asymmetric synthesis of chiral allenes

Recent advances in the metal-catalyzed asymmetric synthesis of chiral allenes are summarized. This review is categorized based on the starting material, including alkynes, racemic allenes, and conjugated dienes.

Recent Advances in Polyallenes: Preparation, Self-Assembly, and Stimuli-Responsiveness.

Polyallenes, as a typical type of reactive polymers, are of great significance and have aroused widespread interest because they contain double bonds that can be post-modified into other functionalities to afford varieties of functional materials. This Minireview firstly highlights the recent advances in the preparation of polyallenes, including preparation of helical polyallenes through directly polymerization of chiral allene monomers or helix-sense-selective polymerization (HSSP) of achiral allene monomers, synthesis of 1,2-regulated polyallenes and 2,3-regulated polyallenes via selective polymerization of allene monomers, polymerization of allene monomers catalyzed by Ni(II)-terminated poly(3-hexylthiophene) (P3HT), and so on. Then, latest progress on the self-assembly and stimuli-responses of polyallene-based diblock, ABA and ABC triblock copolymers is summarized. We hope this Minireview will inspire more interest in developing polyallenes and encourage further advances in functional materials.