Palladium-catalyzed Asymmetric Allylic Alkylation Research Articles

Synthesis of Chiral L2/Z-Type Ligands Featuring a Bisoxazoline Framework and Their Application to Palladium-Catalyzed Asymmetric Allylic Alkylation

AbstractChiral L2/Z*-type ligands featuring a bisoxazoline framework have been successfully synthesized and applied in asymmetric allylic alkylation. These ligands, designed based on an oxazoline skeleton and derived from chiral amino acid derivatives, incorporate antimony and bismuth as Z-type ligands. Ligands with bulky, electron-withdrawing groups on antimony and bismuth showed enhanced catalytic performance. This research highlights the potential of these novel chiral L2/Z*-type ligands to improve asymmetric catalysis.

Relay PHOS: Ligands with Fluxional Chirality in Asymmetric Palladium-Catalyzed Allylic Alkylation.

A modular route toward the synthesis of P,N ligands containing a fluxional group along the pyrazoline ring core is described. The racemic ligands were accessed in three steps from commercially available fluoroacetophenone in overall yields ranging from 18 to 76%. The enantiopure ligands were obtained using semi-preparative chiral high-performance liquid chromatography and chiral enantioselective phase-transfer catalysis. The effectiveness of the new ligands was assessed in palladium-catalyzed allylic alkylation with diphenylpropenyl acetate and dimethylpropenyl acetate. Under optimized conditions, diphenylpropenyl acetate underwent alkylation with dimethyl malonate in 98% yield and 94% ee. In general, the enantioselectivity for the product correlates with the size of the ligand fluxional group; the larger the fluxional group, the higher the selectivity.

Palladium-Catalyzed Asymmetric Allylic Alkylation of Azlactones: An Efficient Access to Unsaturated Trifluoromethylated α-Amino Acid Derivatives Possessing α-Quaternary Stereogenic Centers

AbstractA new strategy for the asymmetric allylic alkylation of azlactones with α-(trifluoromethyl)allyl acetates catalyzed by Pd(OAc)2/(R)-BINAP is designed and developed, providing access to unsaturated α-quaternary α-amino acid derivatives bearing a trifluoromethyl group and contiguous quaternary and tertiary stereogenic centers. The products are obtained in good yields with exclusive regioselectivity and excellent stereoselective control under relatively mild reaction conditions. A scale-up experiment shows no loss of reactivity or stereoselectivity. The synthetic utility of the current strategy is demonstrated through transformations of a representative product to afford several potentially bioactive species.

Application of sSPhos as a Chiral Ligand for Palladium-Catalyzed Asymmetric Allylic Alkylation.

Palladium-catalyzed asymmetric allylic alkylation is a versatile method for C-C bond formation. Many established classes of chiral ligands can perform allylic alkylation reactions enantioselectively, but identification of new ligand classes remains important for future development of the field. We demonstrate that enantiopure sSPhos, a bifunctional chiral monophosphine ligand, when used as its tetrabutyl ammonium salt, is a highly effective ligand for a benchmark Pd-catalyzed allylic alkylation reaction. We explore the scope and limitations and perform experiments to probe the origin of selectivity. In contrast with reactions previously explored using enantiopure sSPhos, it appears that steric bulk around the sulfonate group is responsible for the high enantioselectivity in this case, rather than attractive noncovalent interactions.

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.

Tandem Dearomatization/Enantioselective Allylic Alkylation of Pyridines.

Herein, we report a multistep one-pot reaction of substituted pyridines leading to N-protected tetrahydropyridines with outstanding enantioselectivity (up to 97% ee). An iridium(I)-catalyzed dearomative 1,2-hydrosilylation of pyridines enables the use of N-silyl enamines as a new type of nucleophile in a subsequent palladium-catalyzed asymmetric allylic alkylation. This telescoped process overcomes the intrinsic nucleophilic selectivity of pyridines to synthesize enantioenriched, C-3-substituted tetrahydropyridine products that have been otherwise challenging to access.

Palladium-Catalyzed Asymmetric Hydrogenolysis of Aryl Triflates for Construction of Axially Chiral Biaryls.

Here we report the first palladium-catalyzed asymmetric hydrogenolysis of readily available aryl triflates via desymmetrization and kinetic resolution for facile construction of axially chiral biaryl scaffolds with excellent enantioselectivities and s selectivity factors. The axially chiral monophosphine ligands could be prepared from these chiral biaryl compounds and were further applied to palladium-catalyzed asymmetric allylic alkylation with excellent ee values and high branched and linear ratio, which demonstrated the potential utility of this methodology.

Atroposelective desymmetrization of 2-arylresorcinols via Tsuji-Trost allylation

Palladium-catalyzed asymmetric allylic alkylation has proven to be a powerful method for the preparation of a wide variety of chiral molecules. However, the catalytic and atroposelective allylic alkylation is still rare and challenging, especially for biaryl substrates. Herein, we report the palladium-catalyzed desymmetric and atroposelective allylation, in which the palladium complex with a chiral phosphoramidite ligand enables desymmetrization of nucleophilic 2-arylresorcinols in a highly enantioselective manner. With the aid of the secondary kinetic resolution effect, a wide variety of substrates containing a hydroxymethyl group at the bottom aromatic ring are able to provide O-allylated products up to 98:2 er. Computational studies show an accessible quadrant of the allylpalladium complex and provide three plausible transition states with intra- or intermolecular hydrogen bonding. The energetically favorable transition state is in good agreement with the observed enantioselectivity and suggests that the catalytic reaction would proceed with an intramolecular hydrogen bond.

Regio- and Enantioselective Synthesis of Dihydropyrido[1,2-a]indoles via Catalytic Asymmetric Annulative Allylic Alkylation.

A palladium-catalyzed asymmetric annulative allylic alkylation reaction of 2-[(1H-indol-2-yl)methyl]malonates with (E)-but-2-ene-1,4-diyl dicarbonates is described, leading to the regio- and enantioselective synthesis of dihydropyrido[1,2-a]indoles with a chiral cyclic allyl stereocenter adjacent to the ring-junction nitrogen atom in moderate to good yields. The salient features of this protocol include mild conditions, a broad substrate scope, and good compatibility with substituents as well as high regio- and stereoselectivities, providing a catalytic asymmetric entry for fabricating chiral pyridoindole scaffolds.

Influence of Achiral Phosphine Ligands on a Synergistic Organo- and Palladium-Catalyzed Asymmetric Allylic Alkylation.

An unusual diastereodivergent stereoselective allylation reaction is presented. It consists of a palladium-catalyzed allylation reaction of an organocatalytically generated amino isobenzofulvene, where the diastereoselectivity is controlled by the electronic properties of a monodentate, achiral ligand on palladium. One major diastereoisomer is formed using triarylphosphines substituted with neutral or electron-donating substituents of the aryl group, while those with electron-withdrawing substituents favor the other diastereoisomer. The diastereoselectivity correlates with the Taft inductive parameter of substituents on the triarylphosphine ligand on palladium. The synergistic reaction involves both a catalytic secondary amine catalyst for the indene-aldehyde activation and the monodentate phosphine ligands on palladium, affording a highly enantioselective reaction with up to 98 % enantiomeric excess. Based on computational investigations, the role of the monodentate phosphine ligand on the diastereoselectivity is discussed.

Diastereo- and Enantioselective Metathesis Dimerization/Kinetic Resolution of Racemic Planar-Chiral Vinylferrocenes.

Diastereo- and enantioselective kinetic resolution of racemic planar-chiral 1-R-2-vinylferrocenes (rac-1) was attained by the molybdenum-catalyzed asymmetric metathesis dimerization (AMD). Two sequential AMD reactions of rac-1a (R = Br) provided (E)-(S,S)-1,2-di(2-bromoferrocenyl)ethylene in >99% ee, which was converted to (S,S)-1,2-bis[(2-diphenylphosphino)ferrocenyl]ethane (S,S)-5. Planar-chiral bisphosphine (S,S)-5 coordinated to a dichloropalladium(II) fragment in a trans-chelating fashion, which was applied as a chiral ligand in the palladium-catalyzed asymmetric allylic alkylation showing enantioselectivity of up to 90% ee.

Introducing C2 asymmetry in chromans—a brief story

The Trost group made notable attempts in the 1990s to synthesize several natural products such as vitamin E and its analogs, clusifoliol, rhododaurichromanic acid A, siccanin, and calanolide A and B through the palladium-catalyzed asymmetric allylic alkylation (AAA) reaction.

Dynamic Kinetic Resolution of Flavonoids via Asymmetric Allylic Alkylation: Construction of Two Contiguous Stereogenic Centers on Nucleophiles

The extension of racemization strategies of dynamic kinetic resolution in organic synthesis is a longstanding challenge, especially racemizing two or more stereogenic centers simultaneously. Through the combination of a palladium-catalyzed asymmetric allylic alkylation and a base-promoted retro-oxa-Michael addition, a dynamic kinetic resolution of 2,3-disubstituted flavonoids was achieved with up to 99% enantioselectivities, and two contiguous stereocenters (including a quaternary stereogenic center) were constructed simultaneously on the nucleophile flavonoids. The key feature of the reaction was a base-promoted retro-oxa-Michael addition for fast racemization of two stereogenic centers on the nucleophiles, which can pave the way to developing asymmetric reactions of flavonoids through dynamic kinetic resolution.

Palladium-Catalyzed Asymmetric Trifluoromethylated Allylic Alkylation of Pyrazolones Enabled by α-(Trifluoromethyl)alkenyl Acetates

The first asymmetric trifluoromethylated allylic alkylation of pyrazolones using α-(trifluoromethyl)alkenyl acetates as a novel trifluoromethylated allylation reagent is described, affording various functionalized chiral pyrazolones containing a trifluoromethylated allyl substituent in high yields with excellent regio-/enantio-/diastereoselectivities. Mechanistically, the double-bond migration of α-(trifluoromethyl)alkenyl acetates in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene is initial and interesting step. More importantly, this study is of significance in providing a novel and widely applicable trifluoromethyl-containing allylation reagent.

The Enantioselective Synthesis of Eburnamonine, Eucophylline, and 16'-epi-Leucophyllidine.

A synthetic approach to the heterodimeric bisindole alkaloid leucophyllidine is disclosed herein. An enantioenriched lactam building block, synthesized through palladium-catalyzed asymmetric allylic alkylation, served as the precursor to both hemispheres. The eburnamonine-derived fragment was synthesized through a Bischler-Napieralski/hydrogenation approach, while the eucophylline-derived fragment was synthesized by Friedländer quinoline synthesis and two sequential C-H functionalization steps. A convergent Stille coupling and phenol-directed hydrogenation united the two monomeric fragments to afford 16'-epi-leucophyllidine in 21 steps from commercial material.

Palladium-catalyzed enantioselective linear allylic alkylation of vinyl benzoxazinanones: An inner-sphere mechanism

Palladium-catalyzed asymmetric allylic alkylation (AAA) of vinyl benzoxazinanones has become an important strategy for the synthesis of chiral nitrogen-containing heterocycle compounds. However, the asymmetric synthesis of linear-selective products has rarely been reported. The simultaneous control of regio-, E/Z- and enantioselectivities constitutes a major challenge and inhibits the advancement of this chemistry. Herein, we present a palladium-catalyzed AAA of vinyl benzoxazinanones with α-thiocyanato ketones, affording various chiral thiocyanates characterized with high linear-, E- and stereoselectivities. The reaction has a broad substrate scope and the chiral thiocyanates can be transformed to useful heterocycles. Experimental and computational studies suggest an inner-sphere mechanism for AAA process, which results from the acidic and coordination effect of the nucleophilic substrates with palladium catalyst.

Palladium-catalyzed asymmetric allylic alkylation (AAA) with alkyl sulfones as nucleophiles.

An efficient palladium-catalyzed AAA reaction with a simple α-sulfonyl carbon anion as nucleophiles is presented for the first time. Allyl fluorides are used as superior precursors for the generation of π-allyl complexes that upon ionization liberate fluoride anions for activation of silylated nucleophiles. With the unique bidentate diamidophosphite ligand ligated palladium as catalyst, the in situ generated α-sulfonyl carbon anion was quickly captured by the allylic intermediates, affording a series of chiral homo-allylic sulfones with high efficiency and selectivity. This work provides a mild in situ desilylation strategy to reveal nucleophilic carbon centers that could be used to overcome the pKa limitation of “hard” nucleophiles in enantioselective transformations.

Palladium-catalyzed asymmetric allylic alkylation of 3-aminooxindoles to access chiral homoallylic aminooxindoles.

An organometal catalytic conversion of 3-aminooxindoles for the diastereo- and enantioselective synthesis of homoallylic aminooxindoles has been described. The asymmetric allylic alkylation of 3-aminooxindoles with allyl carboxylates proceeded smoothly to afford a series of chiral 3-allyl-3-aminooxindoles. This work offers an alternative route to build these scaffolds. The application of this protocol is also highlighted by a significant conversion of products to the potential applicable spiro[indoline-3,2'-pyrrolidin]-2-one derivatives.

Effective synthesis of bicyclodienes via palladium-catalyzed asymmetric allylic alkylation and ruthenium-catalyzed cycloisomerization.

[n.3.0]Bicycles (n = 3–6) can be synthesized using palladium-catalyzed asymmetric allylic alkylation followed by ruthenium-catalyzed cycloisomerization. New types of triarylphosphino-1,2-diaminooxazoline ligands show the same high levels of enantioselectivity observed with Trost ligand when employed in Pd-catalyzed allylic alkylation reactions. The enyne products of these allylic alkylation reactions were further elaborated using a Ru-catalyzed redox isomerization process, for which a mechanism is proposed.

Design of P-Chirogenic Aminophosphine-Phosphinite Ligands at Both Phosphorus Centers: Origin of Enantioselectivities in Pd-Catalyzed Allylic Reactions.

We have recently patented an unprecedented stereospecific N → O phosphinyl migration process which transforms P-chirogenic aminophosphines into phosphinites. A fine design of aminophosphine phosphinite ligands (AMPP*) derived from ephedrine and bearing a P-chirogenic center either at the aminophosphine or phosphinite moiety was performed. The synthesis of AMPP* ligands with a P-chirogenic aminophosphine moiety was based on the well-established stereospecific reaction of oxazaphospholidine borane with organolithium reagents, followed by trapping with a chlorophosphine and borane decomplexation. Concurrently, the preparation of AMPP* ligands with a P-chirogenic phosphinite moiety was performed by N → O phosphinyl migration of aminophosphines borane by heating at 50 °C with DABCO and then reaction with chlorophosphines. AMPP* ligands were studied in palladium-catalyzed asymmetric allylic alkylations, leading to enantioselectivities from 91% (R) to 95% ee (S). X-ray crystallographic data for relevant Pd-AMPP* complexes and computer modeling explained the origin of the enantioselectivities based on MO interactions of most stable conformers with nucleophiles.