Nickel-catalyzed asymmetric reductive arylation of α-chlorosulfones with aryl halides

We report an asymmetric Ni-catalyzed reductive cross-coupling of aryl/heteroaryl halides with racemic α-chlorosulfones to afford enantioenriched sulfones. The reaction tolerates a variety of functional groups under mild reaction conditions, which complements the current methods. The utility of this work was demonstrated by facile late-stage functionalization of commercial drugs.

In this work Ni-Catalyzed reductive cross-coupling between (hetero)aryl halides and racemic α-chlorosulfones to prepare enantioenriched α,α-disubstituted sulfones was demonstrated, allowing facile structural derivatization of drug precursors.     

Introduction of a 7-aza-6-MeO-indoline auxiliary in Lewis-acid/photoredox cooperative catalysis: highly enantioselective aminomethylation of α,β-unsaturated amides

An efficient cooperative chiral Lewis acid/photoredox catalytic system for engaging highly reactive radicals in highly enantioselective conjugate addition to α,β-unsaturated carbonyls is highly desirable. Direct photoexcitation of unbound substrates typically induces undesired background pathways for racemic products and remains a formidable challenge to be addressed in the area of enantioselective photocatalysis. Herein, we report a cooperative catalytic system comprising a chiral Cu(i) complex and an Ir(iii) photocatalyst fueled by visible-light irradiation that allows for seamless integration of the catalytic formation of α-amino alkyl radicals and subsequent enantioselective addition to α,β-unsaturated amides. A 7-aza-6-MeO-indoline attachment on the amide substrates plays a pivotal role in suppressing the undesired pathways, resulting in excellent enantioselectivity and enabling expedited access to valuable γ-aminobutyramides. The indoline amide was readily diversified with full recovery of the azaindoline attachment, highlighting the synthetic utility of this cooperative catalytic system.

An efficient cooperative chiral Lewis acid and photoredox catalytic system towards the highly enantioselective radical conjugate addition of α-amino radicals to α,β-unsaturated amides is developed with the implementation of unique auxiliaries.     

Asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters to functionalized chiral allylic alcohols via dynamic kinetic resolution

An iridium catalyzed asymmetric hydrogenation of racemic exocyclic γ,δ-unsaturated β-ketoesters via dynamic kinetic resolution to functionalized chiral allylic alcohols was developed. With the chiral spiro iridium catalysts Ir-SpiroPAP, a series of racemic exocyclic γ,δ-unsaturated β-ketoesters bearing a five-, six-, or seven-membered ring were hydrogenated to the corresponding functionalized chiral allylic alcohols in high yields with good to excellent enantioselectivities (87 to >99% ee) and cis-selectivities (93 : 7 to >99 : 1). The origin of the excellent stereoselectivity was also rationalized by density functional theory calculations. Furthermore, this protocol could be performed on gram scale and at a lower catalyst loading (0.002 mol%) without the loss of reactivity and enantioselectivity, and has been successfully applied in the enantioselective synthesis of chiral carbocyclic δ-amino esters and the β-galactosidase inhibitor isogalactofagomine.

An iridium catalyzed asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters via dynamic kinetic resolution was developed, providing efficient protocol for enantioselective synthesis of functionalized chiral allylic alcohols.     

Restoration of catalytic activity by the preservation of ligand structure: Cu-catalysed asymmetric conjugate addition with 1,1-diborylmethane

Reported herein is a novel reaction engineering protocol to enhance the efficiency of a transition metal-catalysed process by strategically preventing ligand degradation. Based on spectroscopic investigations, a decomposition pathway of a chiral phosphoramidite ligand during a Cu-catalysed reaction was identified. The involvement of the destructive process could be minimized under the modified reaction conditions that control the amount of nucleophilic alkoxide base, which is the origin of ligand decomposition. Overall, the strategy has been successfully applied to a new class of asymmetric conjugate addition reactions with bis[(pinacolato)boryl]methane, in which α,β-unsaturated enones are utilised as substrates.

A novel Cu-catalysed asymmetric conjugate addition reaction with bis[(pinacolato)boryl]methane using α,β-unsaturated enones as substrates has been developed on the basis of strategic preservation of the supporting ligand.     

Preparation of α-amino acids via Ni-catalyzed reductive vinylation and arylation of α-pivaloyloxy glycine

This work emphasizes easy access to α-vinyl and aryl amino acids via Ni-catalyzed cross-electrophile coupling of bench-stable N-carbonyl-protected α-pivaloyloxy glycine with vinyl/aryl halides and triflates. The protocol permits the synthesis of α-amino acids bearing hindered branched vinyl groups, which remains a challenge using the current methods. On the basis of experimental and DFT studies, simultaneous addition of glycine α-carbon (Gly) radicals to Ni(0) and Ar–Ni(ii) may occur, with the former being more favored where oxidative addition of a C(sp²) electrophile to the resultant Gly–Ni(i) intermediate gives a key Gly–Ni(iii)–Ar intermediate. The auxiliary chelation of the N-carbonyl oxygen to the Ni center appears to be crucial to stabilize the Gly–Ni(i) intermediate.

We have developed Ni-catalyzed reductive coupling of N-carbonyl protected α-pivaloyloxy glycine with Csp²-electrophiles that enabled facile preparation of α-amino acids, including those bearing hindered branched vinyl groups.     

Catalytic asymmetric synthesis of quaternary trifluoromethyl α- to ε-amino acid derivatives via umpolung allylation/2-aza-Cope rearrangement

In this study, we developed an efficient Ir-catalyzed cascade umpolung allylation/2-aza-Cope rearrangement of tertiary α-trifluoromethyl α-amino acid derivatives for the preparation of a variety of quaternary α-trifluoromethyl α-amino acids in high yields with excellent enantioselectivities. The umpolung reactivity empowered by the activation of the key isatin-ketoimine moiety obviates the intractable enantioselectivity control in Pd-catalyzed asymmetric linear α-allylation. In combination with quasi parallel kinetic resolution or kinetic resolution, the generality of this method is further demonstrated by the first preparation of enantioenriched quaternary trifluoromethyl β-, γ-, δ- and ε-amino acid derivatives.

In this study, we developed an efficient Ir-catalyzed cascade umpolung allylation/2-aza-Cope rearrangement for the preparation of a variety of quaternary trifluoromethyl α-ε-amino acids in high yields with excellent enantioselectivities.     

Oxidative additions of alkynyl/vinyl iodides to gold and gold-catalyzed vinylation reactions triggered by the MeDalphos ligand

The hemilabile Ad₂P(o-C₆H₄)NMe₂ ligand promotes fast, quantitative and irreversible oxidative addition of alkynyl and vinyl iodides to gold. The reaction is general. It works with a broad range of substrates of various electronic bias and steric demand, and proceeds with complete retention of stereochemistry from Z and E vinyl iodides. Both alkynyl and vinyl iodides react faster than aryl iodides. The elementary step is amenable to catalysis. Oxidative addition of vinyl iodides to gold and π-activation of alkenols (and N-alkenyl amines) at gold have been combined to achieve hetero-vinylation reactions. A number of functionalized heterocycles, i.e. tetrahydrofuranes, tetrahydropyranes, oxepanes and pyrrolidines were obtained thereby (24 examples, 87% average yield). Taking advantage of the chemoselectivity for vinyl iodides over aryl iodides, sequential transformations involving first a hetero-vinylation step and then a C–N coupling, a C–C coupling or an heteroarylation were achieved from a vinyl/aryl bis-iodide substrate.

The hemilabile Ad₂P(o-C₆H₄)NMe₂ ligand promotes fast, quantitative and irreversible oxidative addition of alkynyl and vinyl iodides to gold.     

A bifunctional iminophosphorane squaramide catalyzed enantioselective synthesis of hydroquinazolines via intramolecular aza-Michael reaction to α,β-unsaturated esters

An efficient synthesis of enantioenriched hydroquinazoline cores via a novel bifunctional iminophosphorane squaramide catalyzed intramolecular aza-Michael reaction of urea-linked α,β-unsaturated esters is described. The methodology exhibits a high degree of functional group tolerance around the forming hydroquinazoline aryl core and wide structural variance on the nucleophilic N atom of the urea moiety. Excellent yields (up to 99%) and high enantioselectivities (up to 97 : 3 er) using both aromatic and less acidic aliphatic ureas were realized. The potential industrial applicability of the transformation was demonstrated in a 20 mmol scale-up experiment using an adjusted catalyst loading of 2 mol%. The origin of enantioselectivity and reactivity enhancement provided by the squaramide motif has been uncovered computationally using density functional theory (DFT) calculations, combined with the activation strain model (ASM) and energy decomposition analysis (EDA).

The activation of both aromatic and aliphatic ureas as N-centered nucleophiles in intramolecular Michael addition reactions to α,β-unsaturated esters was achieved under bifunctional iminophosphorane squaramide superbase catalysis.     

Direct catalytic asymmetric and anti-selective vinylogous addition of butenolides to chromones

An anti-selective catalytic asymmetric Michael-type vinylogous addition of β,γ-butenolides to chromones was developed. The catalyst system developed herein is characterized by tuning of the steric and electronic effects using a proper Biphep-type chiral ligand to invert the diastereoselection, and improvement of the catalyst turnover by a coordinative phenolic additive. The catalytic protocol renders potentially biologically active natural product analogs accessible in good yield with moderate diastereoselectivity and high enantiomeric purity, mostly greater than 99% ee.

An anti-selective catalytic asymmetric Michael-type vinylogous addition of β,γ-butenolides to chromones was developed.     

Construction of chiral α-tert-amine scaffolds via amine-catalyzed asymmetric Mannich reactions of alkyl-substituted ketimines

Stereoselective Mannich reactions of aldehydes with ketimines provide chiral β-amino aldehydes that bear an α-tert-amine moiety. However, the structural variation of the ketimines is limited due to the formation of inseparable E/Z isomers, low reactivity, and other synthetic difficulties. In this study, a highly diastereodivergent synthesis of hitherto difficult-to-access β-amino aldehydes that bear a chiral α-tert-amine moiety was achieved using the amine-catalyzed Mannich reactions of aldehydes with less-activated Z-ketimines that bear both alkyl and alkynyl groups.

Stereoselective Mannich reactions of aldehydes with ketimines provide chiral β-amino aldehydes that bear an α-tert-amine moiety.     

Catalytic asymmetric addition of thiols to silyl glyoxylates for synthesis of multi-hetero-atom substituted carbon stereocenters

A chiral Lewis acid-catalyzed enantioselective addition of thiols to silyl glyoxylates was developed. The reaction proceeds well with a broad range of thiols and acylsilanes, affording the target tertiary chiral α-silyl–α-sulfydryl alcohols with multi-hetero-atom carbon stereocenters in excellent yields (up to 99%) and enantioselectivities (up to 98% ee). A series of control experiments were conducted to elucidate the reaction mechanism.

Enantioselective addition of thiols to silyl glyoxylates for construction of a multi-hetero-atom substituted carbon stereocenter was described.     

Asymmetric synthesis of dihydro-1,3-dioxepines by Rh(ii)/Sm(iii) relay catalytic three-component tandem [4 + 3]-cycloaddition

Heterocycles have been widely used in organic synthesis, agrochemical, pharmaceutical and materials science industries. Catalytic three-component ylide formation/cycloaddition enables the assembly of complex heterocycles from simple starting materials in a highly efficient manner. However, asymmetric versions remain a yet-unsolved task. Here, we present a new bimetallic catalytic system for tackling this challenge. A combined system of Rh(ii) salt and chiral N,N′-dioxide–Sm(iii) complex was established for promoting the unprecedented tandem carbonyl ylide formation/asymmetric [4 + 3]-cycloaddition of aldehydes and α-diazoacetates with β,γ-unsaturated α-ketoesters smoothly, affording various chiral 4,5-dihydro-1,3-dioxepines in up to 97% yield, with 99% ee. The utility of the current method was demonstrated by conversion of products to optically active multi-substituted tetrahydrofuran derivatives. A possible reaction mechanism was provided to elucidate the origin of chiral induction based on experimental studies and X-ray structures of catalysts and products.

Catalytic asymmetric tandem carbonyl ylide formation/[4 + 3]-cycloaddition of β,γ-unsaturated α-ketoesters, aldehydes and α-diazoacetates was achieved by using a bimetallic rhodium(ii)/chiral N,N′-dioxide–Sm(iii) complex catalyst.     

Inhibition of (dppf)nickel-catalysed Suzuki–Miyaura cross-coupling reactions by α-halo-N-heterocycles

A nickel/dppf catalyst system was found to successfully achieve the Suzuki–Miyaura cross-coupling reactions of 3- and 4-chloropyridine and of 6-chloroquinoline but not of 2-chloropyridine or of other α-halo-N-heterocycles. Further investigations revealed that chloropyridines undergo rapid oxidative addition to [Ni(COD)(dppf)] but that α-halo-N-heterocycles lead to the formation of stable dimeric nickel species that are catalytically inactive in Suzuki–Miyaura cross-coupling reactions. However, the corresponding Kumada–Tamao–Corriu reactions all proceed readily, which is attributed to more rapid transmetalation of Grignard reagents.

Nickel complexes with a dppf ligand can form inactive dinickel(ii) complexes during Suzuki–Miyaura cross-coupling reactions. However, these complexes can react with Grignard reagents in Kumada–Tamao–Corriu cross-coupling reactions.     

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 pK_a limitation of “hard” nucleophiles in enantioselective transformations.

A variety of “hard” α-sulfonyl carbanions of aryl, heteroaryl and alkyl sulfones were successfully employed as nucleophiles in palladium-catalyzed asymmetric allylic alkylation with excellent enantioselectivities.     

A step-economic and one-pot access to chiral Cα-tetrasubstituted α-amino acid derivatives via a bicyclic imidazole-catalyzed direct enantioselective C-acylation

C^α-Tetrasubstituted α-amino acids are ubiquitous and unique structural units in bioactive natural products and pharmaceutical compounds. The asymmetric synthesis of these molecules has attracted a lot of attention, but a more efficient method is still greatly desired. Here we describe the first sequential four-step acylation reaction for the efficient synthesis of chiral C^α-tetrasubstituted α-amino acid derivatives from simple N-acylated amino acids via an auto-tandem catalysis using a single nucleophilic catalyst. The synthetic efficiency is improved via a direct enantioselective C-acylation; the methodology affords the corresponding C^α-tetrasubstituted α-amino acid derivatives with excellent enantioselectivities (up to 99% ee). This step-economic, one-pot, and auto-tandem strategy provides facile access to important chiral building blocks, such as peptides, serines, and oxazolines, which are often used in medicinal and synthetic chemistry.

The first four-step sequential reaction for the synthesis of C^α-tetrasubstituted chiral α-amino acid derivatives via auto-tandem catalysis has been developed.     

Nickel-catalyzed three-component olefin reductive dicarbofunctionalization to access alkylborates

We report a three-component olefin reductive dicarbofunctionalization for constructing alkylborates, specifically, nickel-catalyzed reductive dialkylation and alkylarylation of vinyl boronates with a variety of alkyl bromides and aryl iodides. This reaction exhibits good coupling efficiency and excellent functional group compatibility, providing convenient access to the late-stage modification of complex natural products and drug molecules. Combined with alkylborate transformations, this reaction could also find applications in the modular and convergent synthesis of complex compounds.

Nickel-catalyzed three-component olefin reductive dicarbofunctionalization for constructing alkylborates was achieved.     

An umpolung-enabled copper-catalysed regioselective hydroamination approach to α-amino acids

A copper-catalysed regio- and stereoselective hydroamination of acrylates with hydrosilanes and hydroxylamines has been developed to afford the corresponding α-amino acids in good yields. The key to regioselectivity control is the use of hydroxylamine as an umpolung, electrophilic amination reagent. Additionally, a judicious choice of conditions involving the CsOPiv base and DTBM-dppbz ligand of remote steric hindrance enables the otherwise challenging C–N bond formation at the α position to the carbonyl. The point chirality at the β-position is successfully controlled by the Xyl-BINAP or DTBM-SEGPHOS chiral ligand with similarly remote steric bulkiness. The combination with the chiral auxiliary, (−)-8-phenylmenthol, also induces stereoselectivity at the α-position to form the optically active unnatural α-amino acids with two adjacent stereocentres.

A copper-catalysed regio- and enantioselective hydroamination of acrylates has been developed to afford the corresponding optically active unnatural α-amino acids.     

Photoredox-enabled 1,2-dialkylation of α-substituted acrylates via Ireland–Claisen rearrangement

Herein, we report the 1,2-dialkylation of simple feedstock acrylates for the synthesis of valuable tertiary carboxylic acids by merging Giese-type radical addition with an Ireland–Claisen rearrangement. Key to success is the utilization of the reductive radical-polar crossover concept under photocatalytic reaction conditions to force the [3,3]-sigmatropic rearrangement after alkyl radical addition to allyl acrylates. Using readily available alkyl boronic acids as radical progenitors, this redox-neutral, transition-metal-free protocol allows the mild formation of two C(sp³)–C(sp³) bonds, thus providing rapid access to complex tertiary carboxylic acids in a single step. Moreover, this strategy enables the efficient synthesis of highly attractive α,α-dialkylated γ-amino butyric acids (GABAs) when α-silyl amines are used as radical precursors – a structural motif that was still inaccessible in related transformations. Depending on the nature of the radical precursors and their inherent oxidation potentials, either a photoredox-induced radical chain or a solely photoredox mechanism is proposed to be operative.

A photocatalytic 1,2-dialkylation of α-substituted acrylates is enabled by a reaction cascade combining reductive radical-polar crossover with the established Ireland–Claisen rearrangement for the synthesis of valuable tertiary carboxylic acids.     

Carbene-catalyzed enantioselective annulation of dinucleophilic hydrazones and bromoenals for access to aryl-dihydropyridazinones and related drugs

4,5-Dihydropyridazinones bearing an aryl substituent at the C6-position are important motifs in drug molecules. Herein, we developed an efficient protocol to access aryl-dihydropyridazinone molecules via carbene-catalyzed asymmetric annulation between dinucleophilic arylidene hydrazones and bromoenals. Key steps in this reaction include polarity-inversion of aryl aldehyde-derived hydrazones followed by chemo-selective reaction with enal-derived α,β-unsaturated acyl azolium intermediates. The aryl-dihydropyridazinone products accessed by our protocol can be readily transformed into drugs and bioactive molecules.

Polarity inversion of arylidene hydrazones to react with bromoenals via carbene organic catalysis is disclosed. The reaction enantioselectively affords 6-aryl-4,5-dihydropyridazinones and related drugs with proven commercial applications.     

Palladium/Xu-Phos-catalyzed asymmetric carboamination towards isoxazolidines and pyrrolidines

An efficient palladium-catalyzed enantioselective carboamination reaction of N-Boc-O-homoallyl-hydroxylamines and N-Boc-pent-4-enylamines with aryl or alkenyl bromides was developed, delivering various substituted isoxazolidines and pyrrolidines in good yields with up to 97% ee. The reaction features mild conditions, general substrate scope and scalability. The obtained products can be transformed into chiral 1,3-aminoalcohol derivatives without erosion of chirality. The newly identified Xu-Phos ligand bearing an ortho-OⁱPr group is responsible for the good yield and high enantioselectivity.

The new chiral ligand (S,Rs)-Xu4 with ortho-OⁱPr showed good performance in the asymmetric carboamination reaction of N-Boc-O-homoallyl-hydroxylamines and N-Boc-pent-4-enylamines with aryl or alkenyl bromides.