Asymmetric Allylic Substitution Reactions Research Articles

Asymmetric Allylic Substitution Reactions Based on Relay Catalysis

AbstractTransition-metal-catalyzed asymmetric allylic substitution reactions represent a hot research topic in the field of asymmetric synthesis, with significant progress having been made. Among diverse catalysis systems, relay catalysis enables sequential activation of multiple steps in one pot and the rapid construction of multiple chiral centers, providing a simple and powerful platform for organic synthesis. Recently, relay catalysis has been successfully applied to asymmetric allylic substitution reactions, and a variety of challenging transformations have been realized. This Short Review summarizes the related progress on asymmetric allylic substitution reactions based on relay catalysis over the last decade.1 Introduction2 The General Transformation Model3 Allylation Relays Further Reaction4 Initial Reaction Relays Allylation5 Conclusion and Outlook

Z-Retentive Asymmetric Allylic Substitution Reactions of Aldimine Esters under Ru/Cu Dual Catalysis.

Ru/Cu dual catalysis has been applied for Z-retentive asymmetric allylic substitution reactions of aldimine esters. This reaction provides an enantioselective synthesis of chiral Z-olefins in high yields (up to 91% yield) with excellent enantioselectivity (up to 98% ee) under mild conditions. The previously unreacted trisubstituted allylic electrophiles under Ir catalytic system are found to be compatible, affording the stereoretentive products in either Z- or E-form. Both linear and branched allylic electrophiles are suitable substrates with excellent reaction outcomes. Notably, Ru and Cu complexes are added in one-pot and simplifies the manipulation of this protocol and self-sorting phenomena could be observed in this Ru/Cu dual catalytic system.

Application of mixed phosphorus/sulfur ligands based on terpenoids in Pd-catalyzed asymmetric allylic substitution and Rh-catalyzed hydrogenation.

A small library of easily prepared diamidophosphite-sulfides based on 1,3-thioether alcohols, primarily of terpenoid nature, was developed. Upon complexation with Pd(II) ions, these hemilabile ligands showed the ability to form both P,S-chelates and complexes with two ligands P-monodentately bonded to the metal. The structures of the ligands and their complexes were determined by 2D NMR spectroscopy and X-ray diffraction. The use of these stereoselectors provided up to 95% ee in the classic Pd-catalyzed asymmetric allylic substitution reactions of (E)-1,3-diphenylallyl acetate with C- and N-nucleophiles and up to 80% ee in the Pd-mediated allylic alkylation of cinnamyl acetate with β-ketoesters. In addition, ee values of up to 90% with quantitative conversion were achieved in the Rh-catalyzed asymmetric hydrogenation of methyl esters of unsaturated acids. The effects of the structural parameters, reaction conditions and ligand-to-metal ratio on the catalytic results are discussed.

Stereodivergent Construction of 1,3‐Chiral Centers via Tandem Asymmetric Conjugate Addition and Allylic Substitution Reaction

AbstractHerein, we report a synthesis of cyclohexanones bearing multi‐continuous stereocenters by combining copper‐catalyzed asymmetric conjugate addition of dialkylzinc reagents to cyclic enones with iridium‐catalyzed asymmetric allylic substitution reaction. Good to excellent yields, diastereoselectivity and enantioselectivity can be obtained. Unlike the stereodivergent construction of adjacent stereocenters (1,2‐position) reported in the literature, the current reaction can achieve the stereodivergent construction of nonadjacent stereocenters (1,3‐position) by a proper combination of two chiral catalysts with different enantiomers.

Stereodivergent Construction of 1,3-Chiral Centers via Tandem Asymmetric Conjugate Addition and Allylic Substitution Reaction.

Herein, we report a synthesis of cyclohexanones bearing multi-continuous stereocenters by combining copper-catalyzed asymmetric conjugate addition of dialkylzinc reagents to cyclic enones with iridium-catalyzed asymmetric allylic substitution reaction. Good to excellent yields, diastereoselectivity and enantioselectivity can be obtained. Unlike the stereodivergent construction of adjacent stereocenters (1,2-position) reported in the literature, the current reaction can achieve the stereodivergent construction of nonadjacent stereocenters (1,3-position) by a proper combination of two chiral catalysts with different enantiomers.

New P,Nsp3 ligands for palladium-catalyzed asymmetric allylic substitutions.

New P,Nsp3 bidentate ligands containing two chiral carbon centers were developed and applied to palladium-catalyzed asymmetric allylic substitution reactions. Good generalities with various nucleophiles, including carbon, nitrogen and oxygen containing nucleophiles, were achieved with up to 96% ee and 98% yield. This reaction provides an efficient method for the asymmetric formation of C-C, C-N and C-O bonds.

Axially chiral N-alkyl-N-cinnamoyl amide type P,olefin ligands for Pd-catalyzed reactions.

We synthesized N-alkyl-N-cinnamoyl amide type phosphine-olefin compounds 1 and found axial chirality in a C(aryl)-N(amide) bond in compounds 1 by HPLC analysis using a chiral stationary phase column. We successfully obtained enantiomeric isomers of 1 and demonstrated the use of (-)-1 for chiral ligands in Pd-catalyzed asymmetric allylic substitution reactions of allylic esters with indoles (up to 97% ee).

Asymmetric Rhodium-Catalyzed Allylic Substitution Reactions with Nitrile-Stabilized Carbanions

AbstractThis Account summarizes our recent work on rhodium-catalyzed allylic alkylation reactions with nitrile-stabilized carbanions. Despite the challenges associated with employing nitrile-stabilized nucleophiles in transition-metal-catalyzed reactions, we have developed enantiospecific and enantioselective allylic alkylation reactions. Notably, these novel reactions permit expedient and selective access to an array of acyclic ternary and quaternary stereogenic centers present in important biologically active and functional molecules.1 Introduction2 Enantiospecific Allylic Alkylation Reactions with Nitrile-Stabilized Anions3 Enantioselective Allylic Alkylation Reactions with Nitrile-Stabilized Anions4 Conclusion

Iridium-Catalyzed Asymmetric Allylic Substitution of Methyl Azaarenes.

Herein, an Ir-catalyzed asymmetric allylic substitution reaction of methyl azaarenes is described. Azaarenes such as (benzo)thiazole, oxazole, benzoimidazole, pyridine, and (iso)quinoline are all tolerated. The corresponding chiral azaarene derivatives are obtained in good yields with high enantioselectivity (up to 96 % yield and 99 % ee). The utilization of the Knochel reagent TMPZnBr⋅LiBr warrants the in situ formation of benzylic nucleophiles without additional activating reagents. 1 H NMR studies suggested a two-fold function of the Knochel reagent in this reaction. The synthetic utility of this method has been showcased by a concise enantioselective synthesis of an allosteric protein kinase modulator.

Iridium‐Catalyzed Asymmetric Allylic Substitution of Methyl Azaarenes

AbstractHerein, an Ir‐catalyzed asymmetric allylic substitution reaction of methyl azaarenes is described. Azaarenes such as (benzo)thiazole, oxazole, benzoimidazole, pyridine, and (iso)quinoline are all tolerated. The corresponding chiral azaarene derivatives are obtained in good yields with high enantioselectivity (up to 96 % yield and 99 % ee). The utilization of the Knochel reagent TMPZnBr⋅LiBr warrants the in situ formation of benzylic nucleophiles without additional activating reagents. 1H NMR studies suggested a two‐fold function of the Knochel reagent in this reaction. The synthetic utility of this method has been showcased by a concise enantioselective synthesis of an allosteric protein kinase modulator.

Enantioselective Synthesis of Medium-Sized-Ring Lactones via Iridium-Catalyzed Z-Retentive Asymmetric Allylic Substitution Reaction

Medium-sized rings are important structural units, but their synthesis, especially in a highly enantioselective manner, has been a great challenge. Herein we report an enantioselective synthesis of medium-sized-ring lactones by an iridium-catalyzed Z-retentive asymmetric allylic substitution reaction. The reaction features mild conditions and a broad substrate scope. Various eight- to 11-membered-ring lactones can be afforded in moderate to excellent yields (up to 88%) and excellent enantioselectivity (up to 99% ee). The utilization of both Z-allyl precursors and an Ir catalyst is critical for the medium-sized-ring formation.

Synthesis of Morita–Baylis–Hillman-fluorides using 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine

Morita–Baylis–Hillman (MBH)-fluorides are valuable platforms for asymmetric allylic substitution reactions. However, the preparation of MBH-fluorides requires the use of an explosive fluorinating reagent, namely (diethylamino)sulfur trifluoride (DAST). Thus, we herein report a safe, alternative method for the preparation of MBH-fluorides via the deoxyfluorination of MBH-alcohols using 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine (TFEDMA). Accordingly, a variety of MBH-alcohols were smoothly converted to their corresponding MBH-fluorides in moderate to good yields without the requirement for an activator. This fluorination reaction was found to proceed via an SN1 process involving a stable allylic cation intermediate.

Iridium Catalysed Asymmetric Allylic Substitution Reaction of Indolizine Derivatives

AbstractA highly efficient direct asymmetric allylic substitution (AAS) reaction of indolizine derivatives with allylic alcohols for accessing enantioenriched indolizine derivatives was realized by combining a chiral iridium complex catalyst with Lewis acid under mild reaction conditions, delivering various chiral allylation products in remarkably high yields and excellent enantioselectivities. This protocol distinguishes itself by availability of the starting materials, mild reaction conditions, broad substrate scope, high yields, excellent selectivity and easy scale‐up in a stereoselective manner, which provides a highly efficient protocol for chiral indolizines.

Synthesis of C5-Allylindoles through an Iridium-Catalyzed Asymmetric Allylic Substitution/Oxidation Reaction Sequence of N-Alkyl Indolines.

Iridium/Brønsted acid cooperative catalyzed asymmetric allylic substitution reactions at the C5 position of indolines have been reported for the first time. The highly efficient protocol allows rapid access to various C5-allylated products in good to high yields (48-97%) and enantioselectivities (82% to >99% ee) with wide functional group tolerance. The transformations allow not only the formation of C5-allylindoline derivatives but also the synthesis of C5-allylindole analogues in good yields and excellent stereoselectivities via an allylation/oxidation reaction sequence.

Iridium-Catalyzed Asymmetric Allylic Alkylation of Deconjugated Butyrolactams.

Compared with the ever-growing list of nonprochiral nucleophiles in Ir-catalyzed asymmetric allylic substitution reactions, prochiral nucleophiles are less studied. We present a new prochiral nucleophile, namely, deconjugated butyrolactam, for Ir-catalyzed asymmetric allylic alkylation (AAA). This reaction provides access to α-allyl deconjugated butyrolactams with a moderate to good dr and an excellent er. This is the first AAA reaction of deconjugated butyrolactams. Allyl transposition through Cope rearrangement appears to proceed stereospecifically to form γ-allyl conjugated butyrolactams.

Synthesis of P‐Chirogenic Diphosphinotriazoles and Their Use in Asymmetric Catalysis

AbstractThe stereoselective synthesis of P‐chirogenic diphosphinotriazoles using ephedrine methodology was described. The coordination behavior of these compounds as P,P‐ligands has been demonstrated by the preparation as well as the spectroscopic and X‐ray crystallographic analyses of a palladium complex. The efficiency of these new P‐chirogenic diphosphines in the palladium‐catalyzed asymmetric allylic substitution reaction was also evaluated.

Iridium-catalyzed Z-retentive asymmetric allylic substitution reactions.

Z-Olefins are challenging synthetic targets owing to their relative thermodynamic instability. Transition metal-catalyzed asymmetric allylic substitution reactions are well known for installing stereocenters adjacent to branched or E-linear olefins. However, analogous reactions for the synthesis of optically active Z-olefin products are rare. Here we report iridium-catalyzed asymmetric allylic substitution reactions that retain Z-olefin geometries while establishing an adjacent quaternary stereocenter. The formation of transient anti-π-allyl-iridium intermediates and their capture by external nucleophiles before isomerization to the thermodynamically more stable syn-π-allyl-iridium counterparts have been observed. These results provide a promising method for preparing chiral Z-olefinic compounds.

Cinnamoyl amide type chiral P,olefin ligands for Pd-catalyzed reactions.

We synthesized cinnamoyl amide type chiral P,olefin ligand (S)-4. We successfully obtained separable diastereomers of 4d and demonstrated Pd-catalyzed asymmetric allylic substitution reactions of indoles using (S,aS)-4d as a chiral ligand with high enantioselectivities (up to 98% ee).

Applications of Transition-Metal-Catalyzed Asymmetric Allylic Substitution in Total Synthesis of Natural Products: An Update.

Metal-catalyzed asymmetric allylic substitution (AAS) reaction is one of the most synthetically useful reactions catalyzed by metal complexes for the formation of carbon-carbon and carbon-heteroatom bonds. It comprises the substitution of allylic substrates with a wide range of nucleophiles or SN 2'-type allylic substitution, which results in the formation of the above-mentioned bonds with high levels of enantioselective induction. AAS reaction tolerates a broad range of functional groups, thus has been successfully applied in the asymmetric synthesis of a wide range of optically pure compounds. This reaction has been extensively used in the total synthesis of several complex molecules, especially natural products. In this review, we try to highlight the applications of metal (Pd, Ir, Mo, or Cu)-catalyzed AAS reaction in the total synthesis of the biologically active natural products, as a key step, updating the subject from 2003 till date.

Enantioselective α-Functionalization of 1,3-Dithianes by Iridium-Catalyzed Allylic Substitution.

An iridium-catalyzed asymmetric allylic substitution reaction with 2-alkoxy carbonyl-1,3-dithianes has been achieved with high regio- and enantioselectivities. The transformation provides a new method for the enantioselective α-functionalization of dithianes. The corresponding dithiane-containing products are easily converted into many other derivatives with high yields and enantioselectivities.