Enantioselective Allylation Research Articles

Copper‐Catalyzed Simultaneous Dehydrogenation and Enantioselective Allylic Oxidation of Alkanes Using Chiral Heterogeneous Ligands to Produce Allylic Esters and Theoretical Investigation of the Mechanism

ABSTRACTA new asymmetric method for preparing chiral allylic esters from various unactivated alkanes through simultaneous dehydrogenation and enantioselective allylic oxidation in the presence of chiral heterogeneous oxazoline–based ligands is reported for the first time. For this purpose, chiral amino oxazoline ligands, synthesized from chiral amino alcohols and cyanogen bromide, were immobilized on modified MCM‐41 mesoporous silica. These chiral heterogeneous ligands were then characterized using Fourier‐transform infrared spectroscopy, thermogravimetric analysis, X‐ray diffraction, scanning electron microscopy, energy‐dispersive X‐ray spectroscopy, and Brunauer–Emmett–Teller and Barrett–Joyner–Halenda techniques. Finally, copper complexes of these ligands were employed in the synthesis of chiral allylic esters, achieving the best result with a 90% yield and 77% enantiomeric excess. Evaluation of the recyclability of the chiral heterogeneous catalysts revealed that they can be reused three times without a noticeable reduction in the results. In addition, the mechanism of formation of the chiral allylic esters was investigated using a density functional theory method.

Unified Enantioselective Allylations and Vinylogous Reactions Enabled by Visible Light-Driven Chiral Lewis Acid Catalysis

Unified Enantioselective Allylations and Vinylogous Reactions Enabled by Visible Light-Driven Chiral Lewis Acid Catalysis

Rh(I)/Sulfoxide-Imine-Olefin Complex Catalyzed Enantioselective Allylic Alkylation of 2-Fluoromalonate: Synthesis of Chiral α-Fluorolactone Bearing Vicinal Stereogenic Centers.

Highly enantioselective Rh-catalyzed allylic substitution of the racemic branched allylic substrates with 2-fluoromalonate was realized enabled by a novel chiral sulfoxide-imine-olefin ligand under mild reaction conditions. The utilization of CuSO4 is beneficial for improving the enantioselectivity. Notably, the chiral fluoro-containing allyl products can be employed in a selective cyclic esterification to form chiral α-fluorolactone bearing vicinal stereogenic centers.

Regioconvergent Nucleophilic Substitutions with Morita-Baylis-Hillman Fluorides.

Lithium iodide enables regioconvergent C-F bond functionalization of isomeric Morita-Baylis-Hillman fluorides with carbon, sulfur, and nitrogen nucleophiles. The defluorinative carbon-carbon and carbon-heteroatom bond formations give multifunctional compounds in excellent yields and with good to high diastereoselectivities at room temperature. The possibility of catalytic enantioselective allylation is also discussed.

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.

Asymmetric Synthesis of Trisubstituted Vicinal Diols through Copper(I)‐Catalyzed Diastereoselective and Enantioselective Allylation of Ketones with Siloxypropadienes

AbstractChiral trisubstituted vicinal diols are a type of important organic compounds, serving as both common structure units in bioactive natural products and chiral auxiliaries in asymmetric synthesis. Herein, by using siloxypropadienes as the precursors of allyl copper(I) species, a copper(I)‐catalyzed diastereoselective and enantioselective reductive allylation of ketones was achieved, providing both syn‐diols and anti‐diols in good to excellent enantioselectivity. DFT calculations show that cis‐γ‐siloxy‐allyl copper species are generated favorably with either 1‐TBSO‐propadiene or 1‐TIPSO‐propadiene. Moreover, the steric difference of TBS group and TIPS group distinguishes the face selectivity of acetophenone, leading to syn‐selectivity for 1‐TBSO‐propadiene and anti‐selectivity for 1‐TIPSO‐propadiene. Easy transformations of the products were performed, demonstrating the synthetic utility of the present method. Moreover, one chiral diol prepared in the above transformations was used as a suitable organocatalyst for the catalytic asymmetric reductive self‐coupling of aldimines generated in situ with B2(neo)2.

Asymmetric Synthesis of Trisubstituted Vicinal Diols through Copper(I)-Catalyzed Diastereoselective and Enantioselective Allylation of Ketones with Siloxypropadienes.

Chiral trisubstituted vicinal diols are a type of important organic compounds, serving as both common structure units in bioactive natural products and chiral auxiliaries in asymmetric synthesis. Herein, by using siloxypropadienes as the precursors of allyl copper(I) species, a copper(I)-catalyzed diastereoselective and enantioselective reductive allylation of ketones was achieved, providing both syn-diols and anti-diols in good to excellent enantioselectivity. DFT calculations show that cis-γ-siloxy-allyl copper species are generated favorably with either 1-TBSO-propadiene or 1-TIPSO-propadiene. Moreover, the steric difference of TBS group and TIPS group distinguishes the face selectivity of acetophenone, leading to syn-selectivity for 1-TBSO-propadiene and anti-selectivity for 1-TIPSO-propadiene. Easy transformations of the products were performed, demonstrating the synthetic utility of the present method. Moreover, one chiral diol prepared in the above transformations was used as a suitable organocatalyst for the catalytic asymmetric reductive self-coupling of aldimines generated in situ with B2(neo)2.

Asymmetric Allylation of Aldoxime Derivatives with β‐Amidoallylboronate in Water and Its Application to Divergent Synthesis of N‐Hydroxy‐γ‐Lactam and 1,2‐Oxazinan‐6‐one

AbstractA new application involving a water–stable amido–functionalized allylboronate has been developed for 1,2‐addition to carbon–nitrogen double bonds. The process achieves highly enantioselective allylation of aldoxime derivatives in water, by employing O‐Boc oximes as substrates under Zn(OH)2–chiral aminophenol catalysis. This process affords the corresponding homoallylic amines with 91–96 % ee. The products could be transformed into N‐hydroxy‐γ‐lactam or 1,2‐oxazinan‐6‐one, through an acidic or a protection‐acidic treatment sequence, respectively, almost without enantiopurity loss.

Rhodium-Catalyzed Enantio- and Regioselective Allylation of Indoles with gem-Difluorinated Cyclopropanes.

The use of gem-difluorinated cyclopropanes (gem-DFCPs) as fluoroallyl surrogates under transition-metal catalysis has drawn considerable attention recently but such reactions are restricted to producing achiral or racemic mono-fluoroalkenes. Herein, we report the first enantioselective allylation of indoles under rhodium catalysis with gem-DFCPs. This reaction shows exceptional branched regioselectivity towards rhodium catalysis with gem-DFCPs, which provides an efficient route to enantioenriched fluoroallylated indoles with wide substrate scope and good functional group tolerance.

Rhodium‐Catalyzed Enantio‐ and Regioselective Allylation of Indoles with gem‐Difluorinated Cyclopropanes

AbstractThe use of gem‐difluorinated cyclopropanes (gem‐DFCPs) as fluoroallyl surrogates under transition‐metal catalysis has drawn considerable attention recently but such reactions are restricted to producing achiral or racemic mono‐fluoroalkenes. Herein, we report the first enantioselective allylation of indoles under rhodium catalysis with gem‐DFCPs. This reaction shows exceptional branched regioselectivity towards rhodium catalysis with gem‐DFCPs, which provides an efficient route to enantioenriched fluoroallylated indoles with wide substrate scope and good functional group tolerance.

Dual-Catalysis-Enabled Construction of Vicinal Stereogenic Centers through Diastereo- and Enantioselective Allylic Substitution

AbstractVicinal stereogenic centers represent prevalent structural motifs in organic synthetic chemistry, and their construction poses a longstanding challenge. Transition-metal-catalyzed asymmetric allylic substitution has become a well-established enantioselective C–C bond-forming reaction. When these reactions involve a prochiral nucleophile and an allylic electrophile with a terminal substituent, the creation of vicinal stereogenic centers becomes feasible. However, despite remarkable achievements having been accomplished, realizing this transformation with precise control over both the enantio- and diastereoselectivity remains a significant challenge. To address the stereoselective challenges, the introduction of a second catalyst to the transition-metal-catalyzed asymmetric allylic alkylation to control the diastereoselectivity during C–C bond formation has proven particularly fruitful. In this short review, we aim to highlight recent advances in dual catalysis that enable diastereo- and enantioselective allylic substitutions.1 Introduction2 Construction of Vicinal Stereogenic Centers by Organo and Metal Dual Catalysis2.1 Chiral Phase-Transfer Catalysis and Transition-Metal Dual Catalysis2.2 Chiral Amine and Transition-Metal Dual Catalysis2.3 NHC and Transition-Metal Dual Catalysis2.4 Chiral Aldehyde and Transition-Metal Dual Catalysis2.5 Chiral Lewis Base and Transition-Metal Dual Catalysis3 Construction of Vicinal Stereogenic Centers by Metal and Metal Dual Catalysis3.1 Lewis Acidic Metal and Iridium Dual Catalysis3.2 Lewis Acidic Metal and Palladium Dual Catalysis3.3 Palladium and Ruthenium Dual Catalysis3.4 Other Advancements in the Construction of Vicinal Stereogenic Centers through Synergistic Bimetallic Catalysis Enabling Asymmetric Allylic Alkylation4 Conclusions and Future Outlook

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.

Palladium-catalyzed enantioselective umpolung allylation of amido-tethered allylic carbonates with isatin-derived ketimines.

A palladium-catalyzed enantioselective umpolung allylation reaction of amido-tethered allyl carbonates with N-2,2,2-trifluoroethylisatin ketimines has been realized herein. The reaction worked well under mild reaction conditions to give various chiral oxindole derivatives in moderate to excellent yields with high enantioselectivities. Notably, this work represents the first Pd-catalyzed asymmetric umpolung allylation reaction of N-2,2,2-trifluoroethylisatin ketimines.

Asymmetric synthesis of enantioenriched α-allyl esters through Pd(BINAPHANE)-catalysed allylation of disubstituted ketenes.

Pd2dba3·CHCl3 (2.5 mol%)-BINAPHANE (5 mol%) was used to promote the first catalytic enantioselective allylation of disubstituted ketenes to give α-allyl esters. The ester products were formed in good to excellent yields (61-93% yield for 13 examples, 16 examples in all), with moderate to good enantioselectivity (68-80% ee for 7 examples).

Lewis-Base-Catalyzed N-Allylation of Silyl Carbamate Latent Pronucleophiles with Allylic Fluorides.

Silyl carbamates, latent pronucleophile surrogates of carbamates, undergo allylation using allylic fluorides in the presence of common Lewis base catalysts. The reactions are rendered enantioselective in the presence of chiral Lewis base catalysts and produce suitably protected derivatives of enantioenriched chiral β-amino acids. The design of the latent pronucleophile featuring both a silyl group and an electron-deficient carbamate is instrumental in lowering the nucleophilicity of nitrogen and enabling enantioselective allylation in the presence of chiral cinchona alkaloid-based catalysts.

Copper-Catalyzed Asymmetric Allylation of N-Aryl Aldimines.

The copper-catalyzed enantioselective allylation reaction of N-aryl aldimines has been developed using a combination of Cu(OAc)2 and SPINOL-based phosphonamidite. This protocol significantly broadens the substrate scope, such that imines bearing various ortho-substituents on the N-aryl were converted smoothly into homoallylic amines in up to 99% yield and 98% ee. Taking advantage of the diversity of the N-aryl motif, three kinds of N-heterocyclic compounds were constructed, respectively, from the corresponding homoallylic amines in merely one step.

Chiral, air stable, and reliable Pd(0) precatalysts applicable to asymmetric allylic alkylation chemistry

Stereoselective carbon-carbon bond formation via palladium-catalyzed asymmetric allylic alkylation is a crucial strategy to access chiral natural products and active pharmaceutical ingredients. However, catalysts based on the privileged Trost and Pfaltz-Helmchen-Williams PHOX ligands often require high loadings, specific preactivation protocols, and excess chiral ligand. This makes these reactions uneconomical, often unreproducible, and thus unsustainable. Here we report several chiral single-component Pd(0) precatalysts that are active and practically-applicable in a variety of asymmetric allylic alkylation reactions. Despite the decades-long history and widespread use of Trost-type ligands, the precatalysts in this work are the only reported examples of stable, isolable Pd(0) complexes with these ligands. Evaluating these precatalysts across nine asymmetric allylic alkylation reactions reveals high reactivity and selectivity at low Pd loading. Importantly, we also report an unprecedented Pd-catalyzed enantioselective allylation of a hydantoin, achieved on gram scale in high yield and enantioselectivity with only 0.2 mol% catalyst.

Structure Confirmation of Dechlorotrichotoxin A through Stereoselective Total Synthesis.

The stereoselective total synthesis of dechlorotrichotoxin A, alongside the synthesis of a 1:1 10E/Z mixture of trichotoxin A, was successfully achieved, commencing from the natural monoterpenoid (-)-citronellal. Key steps in the synthesis involved introducing three alkenes and establishing a stereogenic secondary alcohol center. These transformations were accomplished through olefin cross-metathesis, Tebbe olefination, and enantioselective allylation using a chiral phosphoric acid. A comparison of the spectroscopic data between the synthetic dechlorotrichotoxin A and the reported spectra confirmed that the polyketide isolated from a Smenospongia species corresponds to trichotoxin A rather than dechlorotrichotoxin A.

Copper-Catalyzed Enantioselective and Regiodivergent Allylation of Ketones with Allenylsilanes.

We report herein a regiodivergent and enantioselective allyl addition to ketones with allenylsilanes through copper catalysis. With the combination of CuOAc, a Josiphos-type bidentate phosphine ligand and PhSiH3 , allyl addition to a variety of ketones furnishes branched products in excellent enantioselectivities. The regioselectivity is completely reversed by employing the P-stereogenic ligand BenzP*, affording the linear products with excellent enantioselectivities and good Z-selectivities. The linear Z-product could be converted to E-product via a catalytic geometric isomerization of the Z-alkene group. The silyl group in the products could provide a handle for downstream elaboration.

Quaternary Stereocenters via Catalytic Enantioconvergent Allylation of Epoxides.

The development of catalytic and enantioselective transformations for the synthesis of all-carbon quaternary stereocenters has long been recognized as a significant challenge in organic synthesis. While considerable progress has been made in asymmetric allylations, their potential to functionalize the commonly used synthon, epoxide, remains largely underexplored. Here we demonstrate the first highly regio- and enantioselective allylation of epoxides that delivers a range of quaternary stereocenters in the face of potentially problematic elimination and protonation reactions. The reaction proceeds via a radical approach under mild conditions and benefits from the use of earth-abundant titanium with a highly sophisticated salen ligand, which facilitates remarkable enantiocontrol and suppresses undesired side reactions. The resulting allylation products are multifunctional building blocks that can be elaborated chemo- and stereoselectively to a broad array of stereodefined structural motifs.