Pd-catalyzed Asymmetric Allylic Alkylation Reaction Research Articles

Enantioselective Rh(I)-Catalyzed C-H Arylation of Ferroceneformaldehydes.

As an important class of platform molecules, planar chiral ferrocene carbonyl compounds could be transformed into various functional groups offering facile synthesis of chiral ligands and catalysts. However, developing efficient and straightforward methods for accessing enantiopure planar chiral ferrocene carbonyl compounds, especially ferroceneformaldehydes, remains highly challenging. Herein, we report a rhodium(I)/phosphoramidite-catalyzed enantioselective C-H bond arylation of ferroceneformaldehydes. Readily available aryl halides such as aryl iodides, aryl bromides, and even aryl chlorides are suitable coupling partners in this transformation, leading to a series of planar chiral ferroceneformaldehydes in good yields and excellent enantioselectivity (up to 83% yield and >99% ee). The aldehyde group could be transformed into diverse functional groups smoothly, and enantiopure Ugi's amine and PPFA analogues could be synthesized efficiently. The latter was found to be a highly efficient ligand in Pd-catalyzed asymmetric allylic alkylation reactions. Mechanistic experiments supported the formation of imine intermediates as the key step during the reaction.

Simple selenide-phosphoramidite as chiral ligand for Pd-catalyzed asymmetric allylic alkylation reactions

Simple selenide-phosphoramidite as chiral ligand for Pd-catalyzed asymmetric allylic alkylation reactions

Desymmetrization of Phosphinic Acids via Pd-Catalyzed Asymmetric Allylic Alkylation: Rapid Access to P-Chiral Phosphinates.

The synthesis of P-chiral compounds is challenging, especially since useful catalytic methods for preparing such molecules are scarce. Herein we disclose a desymmetrization that employs phosphinic acids as prochiral nucleophiles in a Pd-catalyzed asymmetric allylic alkylation reaction, furnishing phosphinates with high enantio- and diastereoselectivity. This new method has broad scope and is applied to the synthesis of an enantioenriched tertiary phosphine oxide.

Chemo-, Regio-, Diastereo-, and Enantioselective Palladium Allylic Alkylation of 1,3-Dioxaboroles as Synthetic Equivalents of α-Hydroxyketones

We describe the development of a Pd-catalyzed asymmetric allylic alkylation (Pd-AAA) of acyclic α-hydroxyketones using boronic acids as traceless templates. Condensation of boronic acids with hydroxyketones generates 1,3-dioxaboroles, which can be used directly as pronucleophiles in Pd-AAA reactions. This strategy enables control of the enolate geometry, while removing the issue of O-alkylation. Allylic alcohols can be directly ionized in the presence of Pd(0) and chiral ligands to afford alkylation products with regio- and enantioselectivity. Additionally, a dynamic kinetic asymmetric transformation of allenyl electrophiles affords C-alkylation products in high regio-, diastereo-, and enantioselectivity. To the best of our knowledge, this method represents the first example in Pd-AAA for setting point chirality on a nucleophile simultaneous to stereoinduction on an axial chiral allene.

Enantioselective Allylic Alkylation with 4-Alkyl-1,4-dihydro-pyridines Enabled by Photoredox/Palladium Cocatalysis.

Highly regio- and enantioselective allylic alkylation has been achieved enabled by the merger of photoredox and palladium catalysis. In this dual catalytic process, alkyl radicals generated from 4-alkyl-1,4-dihydropyridines act as the coupling partners of the π-allyl palladium complexes. The generality of this method has been illustrated through the reaction of a variety of allyl esters with 4-alkyl-1,4-dihydropyridines. This mechanistically novel strategy expands the scope of the traditional Pd-catalyzed asymmetric allylic alkylation reaction and serves as its alternative and potential complement.

Synthesis and application of a new hexamethyl-1,1'-spirobiindane-based chiral bisphosphine (HMSI-PHOS) ligand in asymmetric allylic alkylation.

The emerging and versatile application of chiral bisphosphine ligands in diverse asymmetric reactions has resulted in great demand for novel bisphosphine ligands containing different innovative backbones. Herein, a new type of chiral spiro bisphosphine ligand (HMSI-PHOS) has been developed on the basis of a hexamethyl-1,1'-spirobiindane motif. A series of new HMSI-PHOS ligands were synthesized and used in Pd-catalyzed asymmetric allylic alkylation reactions, and moderate to good yields and enantioselectivities were obtained with phenyl substituted ligands.

Regioselective Direct C-4 Functionalization of Indole: Total Syntheses of (−)-Agroclavine and (−)-Elymoclavine

An efficient rhodium-catalyzed method for direct C-H functionalization at the C4 position of unprotected indoles has been developed. The utility of this method is demonstrated by the concise total syntheses of agroclavine and elymoclavine in a divergent manner. These syntheses feature a Pd-catalyzed asymmetric allylic alkylation reaction to assemble the triyclic indole moiety, and a ring-closing metathesis reaction to form the D ring.

Enantioselective synthesis of 4-substituted tetrahydroisoquinolines via palladium-catalyzed intramolecular Friedel-Crafts type allylic alkylation of phenols.

Palladium-catalyzed asymmetric intramolecular Friedel-Crafts type allylic alkylation reaction of phenols was developed under mild conditions. In the presence of Pd2(dba)3 with (1R,2R)-DACH-phenyl Trost ligand (L2) in toluene at 50 °C, the reaction provides various C4 substituted tetrahydroisoquinolines with moderate to excellent yields, regioselectivity and enantioselectivity.

ChemInform Abstract: Highly Regio and Enantioselective Synthesis of Chiral Polysubstituted 2H‐Pyrroles

AbstractReview: 3 refs.

Kinetic resolution of 4-substituted-3,4-dihydrocoumarins via Pd-catalyzed asymmetric allylic alkylation reaction: enantioselective synthesis of trans-3,4-disubstituted-3,4-dihydrocoumarins

The kinetic resolution of 4-substituted-3,4-dihydrocoumarins was realized via Pd-catalyzed allylic substitution reaction using Trost's chiral ligand L12, affording optically active mono- and trans-3,4-disubstituted dihydrocoumarin derivatives in high yields and with high enantioselectivities with an S factor up to 55.

Highly regio- and enantioselective synthesis of chiral polysubstituted 2H-pyrroles

As one of the most important five-member heterocyclic aromatic rings, pyrrole is widely distributed in numerous natural products and pharmaceutical agents. Asymmetric dearomatization of pyrroles is very attractive in organic synthesis given the fact that highly functionalized chiral pyrrolines and pyrrolidines could be easily accessed from the readily available pyrroles. However, the reported asymmetric dearomatization reactions of pyrroles are limited to transition-metal-catalyzed [4+3] cycloaddition and hydrogenation reactions. The enantioselective intermolecular alkylative dearomatization of pyrroles is rare and challenging due to multiple selectivity issues including the chemoselectivity (C2&N1), regioselectivity (C2&C4, C2&C5) and enantioselectivity (Scheme 1) [1]. During the past few years, the You group from Shanghai Institute of Organic Chemistry has focused on the transition-metal-catalyzed asymmetric allylic dearomatization reactions [2]. Recently, the researchers in this group found that highly enantioenriched poly-substituted 2H-pyrroles could be easily accessed via Pd-catalyzed intermolecular asymmetric allylic dearomatization reaction of polysubstituted pyrroles (Scheme 1). With the commercially available palladium precursor and chiral ligand, various poly-substituted 2H-pyrrole products containing a chiral quaternary carbon center were obtained with up to 97% ee under mild reaction conditions. Interestingly, they found the reaction occurred smoothly to give good to excellent regioselectivities when tri-substituted and tetra-substituted pyrrole derivatives were used. In addition, chiral pyrrolines and cyclic imines could be conveniently prepared by selective reductions of the enantioenriched 2H-pyrrole products, further demonstrating the synthetic utility of this newly developed method. Moreover, this reaction represents the first example involving the multi-substituted pyrroles as prochiral nucleophiles in Pd-catalyzed asymmetric allylic alkylation reactions.

ChemInform Abstract: Enantioselective Synthesis of Planar Chiral Ferrocenes via Pd(0)‐Catalyzed Intramolecular Direct C—H Bond Arylation.

A highly efficient synthesis of planar chiral ferrocenes by enantioselective Pd(0)-catalyzed direct C–H arylation from readily available starting materials under mild reaction conditions was developed (up to 99% yield, 99% ee). The products can be easily transformed to the highly efficient planar ferrocene ligands, which have demonstrated high efficiency in Pd-catalyzed asymmetric allylic alkylation and amination reactions.

Enantioselective Synthesis of Planar Chiral Ferrocenes via Pd(0)-Catalyzed Intramolecular Direct C–H Bond Arylation

A highly efficient synthesis of planar chiral ferrocenes by enantioselective Pd(0)-catalyzed direct C-H arylation from readily available starting materials under mild reaction conditions was developed (up to 99% yield, 99% ee). The products can be easily transformed to the highly efficient planar ferrocene ligands, which have demonstrated high efficiency in Pd-catalyzed asymmetric allylic alkylation and amination reactions.

ChemInform Abstract: The Synthesis of Phosphine Oxide‐Linked Bis(oxazoline) Ligands and Their Application in Asymmetric Allylic Alkylation.

Abstract The phosphine oxide-linked bis(oxazoline) ligands were designed and synthesized in two ways. One is the coupling of Grignard reagent derived from 2-(2-bromophenyl)oxazoline with phenylphosphonic dichloride, another route is the condensation of bis(2-formylphenyl)(phenyl)phosphine oxide with chiral amino alcohols followed by NBS oxidation. These new bis(oxazoline) ligands were applied in Pd-catalyzed asymmetric allylic alkylation reactions and good yields and enantioselectivities were obtained with diphenyl substituted ligand (up to 95% ee).

Regio- and Enantioselective Palladium-Catalyzed Allylic Alkylation of Nitromethane with Monosubstituted Allyl Substrates: Synthesis of (R)-Rolipram and (R)-Baclofen

The Pd-catalyzed asymmetric allylic alkylation (AAA) reaction of nitromethane with monosubstituted allyl substrates was realized for the first time to provide corresponding products in high yields with excellent regio- and enantioselectivities. The protocol was applied to the enantioselective synthesis of (R)-baclofen and (R)-rolipram.

ChemInform Abstract: Highly Enantioselective Synthesis of 3‐Substituted Furanones by Palladium‐Catalyzed Kinetic Resolution of Unsymmetrical Allyl Acetates.

The Pd-catalyzed asymmetric allylic alkylation (AAA) holds a prominent position among the most versatile methods for C C bond formation that are widely applied in natural product synthesis. This transformation typically features broad functional group tolerance and excellent regioand enantioselectivity. In particular, Pd-catalyzed kinetic resolutions of symmetrical allylic substrates and dynamic kinetic transformations have been developed recently, which extends their potential in synthetic chemistry. However, Pd-catalyzed kinetic resolutions of unsymmetrical acyclic allylic substrates with high yield and enantioselectivity are rare. Furthermore, the enantioselective allylic alkylation of silyl enol ethers is still a challenging reaction. Graening and Hartwig reported a highly enantioselective alkylation of monosubstituted allylic substrates with silyl enol ethers catalyzed by an Ir complex. Although excellent results of allylic alkylations have been reported with enolates that are preformed or generated in situ, to the best of our knowledge, Pd-catalyzed AAAwith a nonstabilized silyl enol ether as nucleophile remains an elusive goal (Scheme 1). Herein, we present the Pd-catalyzed kinetic resolution of 1,3-disubstituted unsymmetrical allylic substrates with nonstabilized silyl enol ethers as nucleophiles, which provides a highly regioand enantioselective synthesis of 3-substituted g-butenolides. The g-butyrolactone skeleton is present in more than 13000 natural products, which have attracted considerable attention because of the range of important biological activities associated with this class of compounds. As part of our program to develop catalytic enantioselective methods to access optically active g-butenolides and lactones, we envisioned the possibility of using 2-trimethylsilyloxyfuran (TMSOF) as nucleophile in a Pd-catalyzed AAA reaction. Initially, we examined the allylic substitution of carbonate 1a by utilizing TMSOFas nucleophile and a chiral Pd catalyst based on Trost Ligand L1 (Table 1, entry 1). The 3-substituted product 3 and 5-substituted product 4 were obtained in a 2:1 ratio and in 36% ee for product 3 (Table 1, entry 1). Using a lower temperature (0 8C), the ee value only slightly increased (49% ee, Table 1, entry 2). With tert-butyl carbonate as the leaving group, the regioselectivity shifted in favor of the formation of the 5-substituted product (3/4= 1:2, Table 1,

The synthesis of phosphine oxide-linked bis(oxazoline) ligands and their application in asymmetric allylic alkylation

The phosphine oxide-linked bis(oxazoline) ligands were designed and synthesized in two ways. One is the coupling of Grignard reagent derived from 2-(2-bromophenyl)oxazoline with phenylphosphonic dichloride, another route is the condensation of bis(2-formylphenyl)(phenyl)phosphine oxide with chiral amino alcohols followed by NBS oxidation. These new bis(oxazoline) ligands were applied in Pd-catalyzed asymmetric allylic alkylation reactions and good yields and enantioselectivities were obtained with diphenyl substituted ligand (up to 95% ee).

Highly Enantioselective Synthesis of 3‐Substituted Furanones by Palladium‐Catalyzed Kinetic Resolution of Unsymmetrical Allyl Acetates

The Pd-catalyzed asymmetric allylic alkylation (AAA) holds a prominent position among the most versatile methods for C C bond formation that are widely applied in natural product synthesis. This transformation typically features broad functional group tolerance and excellent regioand enantioselectivity. In particular, Pd-catalyzed kinetic resolutions of symmetrical allylic substrates and dynamic kinetic transformations have been developed recently, which extends their potential in synthetic chemistry. However, Pd-catalyzed kinetic resolutions of unsymmetrical acyclic allylic substrates with high yield and enantioselectivity are rare. Furthermore, the enantioselective allylic alkylation of silyl enol ethers is still a challenging reaction. Graening and Hartwig reported a highly enantioselective alkylation of monosubstituted allylic substrates with silyl enol ethers catalyzed by an Ir complex. Although excellent results of allylic alkylations have been reported with enolates that are preformed or generated in situ, to the best of our knowledge, Pd-catalyzed AAAwith a nonstabilized silyl enol ether as nucleophile remains an elusive goal (Scheme 1). Herein, we present the Pd-catalyzed kinetic resolution of 1,3-disubstituted unsymmetrical allylic substrates with nonstabilized silyl enol ethers as nucleophiles, which provides a highly regioand enantioselective synthesis of 3-substituted g-butenolides. The g-butyrolactone skeleton is present in more than 13000 natural products, which have attracted considerable attention because of the range of important biological activities associated with this class of compounds. As part of our program to develop catalytic enantioselective methods to access optically active g-butenolides and lactones, we envisioned the possibility of using 2-trimethylsilyloxyfuran (TMSOF) as nucleophile in a Pd-catalyzed AAA reaction. Initially, we examined the allylic substitution of carbonate 1a by utilizing TMSOFas nucleophile and a chiral Pd catalyst based on Trost Ligand L1 (Table 1, entry 1). The 3-substituted product 3 and 5-substituted product 4 were obtained in a 2:1 ratio and in 36% ee for product 3 (Table 1, entry 1). Using a lower temperature (0 8C), the ee value only slightly increased (49% ee, Table 1, entry 2). With tert-butyl carbonate as the leaving group, the regioselectivity shifted in favor of the formation of the 5-substituted product (3/4= 1:2, Table 1,

Palladium-Catalyzed Regio-, Diastereo-, and Enantioselective Allylic Alkylation of Acylsilanes with Monosubstituted Allyl Substrates

Acylsilanes as a new type of "hard" carbon prenucleophile reacted with monosubstituted allyl reagents under Pd-catalyzed asymmetric allylic alkylation reaction conditions to provide products with high regio-, diastereo-, and enantioselectivities. The usefulness of the protocol has been demonstrated by the ready conversion of the allylated products into the corresponding alcohols, esters, and ketones with retention of stereochemistry as well as by the enantioselective synthesis of cis-3-ethyl-4-phenylpiperidine and cinnamomumolide.

Asymmetric Allylic Alkylation with ‘Hard’ Amide Carbanions

Until the work of Trost and Schroeder (J. Am. Chem. Soc. 1999, 121, 6759), transition-metal-catalyzed asymmetric allylic alkylation (AAA) reactions were confined to the use of ‘soft’, stabilized carbanions. However, general methods to apply carboxylic acid carb­anions in AAA reactions remain undeveloped. As a large step forward, the authors report the use of acyclic amides as nucleophiles in the Pd-catalyzed AAA reaction with 1,1′-P,N ferrocene ligand L1. Alkylation of a variety of α-substituted aliphatic and aromatic amides proceeded in high yield with good to high levels of asymmetric induction.