Bifunctional Phosphine Research Articles

Gold(I)‐Catalyzed Desymmetrization of Homopropargylic Alcohols via Cycloisomerization: Enantioselective Synthesis of Cyclopentenes Featuring a Quaternary Chiral Center

AbstractCyclopentene rings possessing a chiral quaternary center are important structural motifs found in various natural products. In this work, we disclose expedient and efficient access to this class of synthetically valuable structures via highly enantioselective desymmetrization of prochiral propargylic alcohols. The efficient chirality induction in this asymmetric gold catalysis is achieved via two‐point bindings between a gold catalyst featuring a bifunctional phosphine ligand and the substrate homopropargylic alcohol moiety—an H‐bonding interaction between the substrate HO group and a ligand phosphine oxide moiety and the gold‐alkyne complexation. The propargylic alcohol substrates can be prepared readily via propargylation of enoate and ketone precursors. In addition to monocyclic cyclopentenes, spirocyclic and bicyclic ones are formed with additional neighboring chiral centers of flexible stereochemistry in addition to the quaternary center. This work represents rare gold‐catalyzed highly enantioselective cycloisomerization of 1,5‐enynes. Density functional theory (DFT) calculations support the chirality induction model and suggest that the rate acceleration enabled by the bifunctional ligand can be attributed to a facilitated protodeauration step at the end of the catalysis.

Gold(I)-Catalyzed Desymmetrization of Homopropargylic Alcohols via Cycloisomerization: Enantioselective Synthesis of Cyclopentenes Featuring a Quaternary Chiral Center.

Cyclopentene rings possessing a chiral quaternary center are important structural motifs found in various natural products. In this work, we disclose expedient and efficient access to this class of synthetically valuable structures via highly enantioselective desymmetrization of prochiral propargylic alcohols. The efficient chirality induction in this asymmetric gold catalysis is achieved via two-point bindings between a gold catalyst featuring a bifunctional phosphine ligand and the substrate homopropargylic alcohol moiety-an H-bonding interaction between the substrate HO group and a ligand phosphine oxide moiety and the gold-alkyne complexation. The propargylic alcohol substrates can be prepared readily via propargylation of enoate and ketone precursors. In addition to monocyclic cyclopentenes, spirocyclic and bicyclic ones are formed with additional neighboring chiral centers of flexible stereochemistry in addition to the quaternary center. This work represents rare gold-catalyzed highly enantioselective cycloisomerization of 1,5-enynes. Density functional theory (DFT) calculations support the chirality induction model and suggest that the rate acceleration enabled by the bifunctional ligand can be attributed to a facilitated protodeauration step at the end of the catalysis.

Understanding the Complexation Behavior of Carbamoylphosphine Oxide Ligands with Representative f-Block Elements.

The complexation behavior of carbamoylmethylphosphine oxide ligands (CMPO), a bifunctional phosphine oxide, and their substituted derivatives with Ce(III), Eu(III), Th(IV), U(VI), and Am(III) was probed at the density functional theory (DFT) level. The enhanced extraction of trivalent rare earth elements by the 2-diphenylphosphinylethyl derivative over the conventional CMPO ligand is identified due to the availability of an additional P═O donor group in the former. In addition, the orbital and dispersive interactions play a vital role in the preference of Th(IV) over U(VI) during extraction using CMPO ligands. The better complexing ability of ligands having long alkyl chain substituents at the P atom is justified due to the observed enhanced dispersion interactions in these systems.

Chiral Bifunctional Phosphine Ligand Enables Asymmetric Trapping of Catalytic Vinyl Gold Carbene Species.

Bifunctional ligand-enabled cooperative gold catalysis accelerates nucleophilic attacks and offers a versatile strategy to achieve asymmetric gold catalysis. Distinct from the prior studies employing alkyne/allene as the electrophilic site, this work engages an in situ-generated alkenyl/acyl gold carbene in a ligand-facilitated attack by an alcoholic nucleophile. With an amide-functionalized chiral binaphthylphosphine ligand, γ-alkoxy-α,β-unsaturated imides are formed with excellent enantiomeric excesses. The intermediacy of a carbene species is supported by its alternative access via dediazotization. The reaction tolerates a broad range of alcohols and can accommodate dienynamide substrates, in addition to arylenynamides. This work avails a versatile strategy to enrich gold chemistry and achieve challenging enantioselective gold catalysis via ligand-facilitated enantioselective trapping of reactive intermediates.

Desymmetrization and Parallel Kinetic Resolution of 1-Ethynylcyclobutanols via Asymmetric Cooperative Gold Catalysis.

Enantioselective gold catalysis remains a challenging area of research. By harnessing gold-ligand cooperation in the presence of a chiral bifunctional phosphine ligand featuring a novel 3'-phosphine oxide moiety, highly enantioselective desymmetrization of 1-ethynylcyclobutanols is achieved, permitting access to chiral α-methylenecyclopentanones featuring a diverse array of chiral quaternary and tertiary centers. This cooperative gold catalysis also enables parallel kinetic resolution in gold catalysis, delivering cyclopentanone regioisomers with excellent enantiomeric excesses. DFT calculations of the transition states support the distinct mechanism of asymmetric induction via controlling the conformation of the bound substrate and hence dictating the ring bond undergoing migration.

Phosphine‐Catalyzed (3+2) Annulation of Morita‐Baylis‐Hillman Carbonates with Pyrazolinone‐Derived Ketimines: Synthesis of Spirodihydropyrrole‐Dihydropyrazolones

AbstractA phosphine‐catalyzed (3+2) annulation of Morita‐Baylis‐Hillman carbonates with pyrazolinone‐derived ketimines has been achieved to give various spirodihydropyrrole‐dihydropyrazolones in moderate to high yields with good diastereoselectivities. The reaction tolerated diverse MBH carbonates and ketimines. Both scale‐up reaction and further transformation of the product were successfully performed. In addition, up to 98 % ee of chiral product was obtained with the use of chiral bifunctional phosphine.

Asymmetric Dearomatization of Phenols via Ligand-Enabled Cooperative Gold Catalysis.

By employing a chiral bifunctional phosphine ligand, a gold(I)-catalyzed efficient and highly enantioselective dearomatization of phenols is achieved via versatile metal-ligand cooperation. The reaction is proven to be remarkably general in scope, permitting substitutions at all four remaining benzene positions, accommodating electron-withdrawing groups including strongly deactivating nitro, and allowing carbon-based groups of varying steric bulk including tert-butyl at the alkyne terminus. Moreover, besides N-(o-hydroxyphenyl)alkynamides, the corresponding ynoates and ynones are all suitable substrates. Spirocyclohexadienone-pyrrol-2-ones, spirocyclohexadienone-butenolides, and spirocyclohexadenone-cyclopentenones are formed in yields up to 99 % and with ee up to 99 %.

Asymmetric Dearomatization of Phenols via Ligand‐Enabled Cooperative Gold Catalysis

AbstractBy employing a chiral bifunctional phosphine ligand, a gold(I)‐catalyzed efficient and highly enantioselective dearomatization of phenols is achieved via versatile metal‐ligand cooperation. The reaction is proven to be remarkably general in scope, permitting substitutions at all four remaining benzene positions, accommodating electron‐withdrawing groups including strongly deactivating nitro, and allowing carbon‐based groups of varying steric bulk including tert‐butyl at the alkyne terminus. Moreover, besides N‐(o‐hydroxyphenyl)alkynamides, the corresponding ynoates and ynones are all suitable substrates. Spirocyclohexadienone‐pyrrol‐2‐ones, spirocyclohexadienone‐butenolides, and spirocyclohexadenone‐cyclopentenones are formed in yields up to 99 % and with ee up to 99 %.

Computational Study on Ni−Al Bimetal‐Catalyzed Twofold C−H Annulation Reaction: Mechanism, Origin of Selectivity, and Role of SPO Ligand

AbstractDensity functional theory calculations have been performed to probe the reaction mechanism of the recently reported twofold C−H annulation of arylformamides with alkynes by Ni−Al bimetallic catalysis. The main pathway consisted of the formyl C−H activation, phenyl C−H activation, migratory insertion, and reductive elimination steps in succession. The desired annulation product was found to be the equilibrium‐controlled product, while the minor hydrocarbamoylation product was the kinetics‐controlled product. Calculated free‐energy profiles indicated that the annulation and hydrocarbamoylation pathways could intersect with each other and merge into a mechanism unity, in which the reaction system entered the hydrocarbamoylation pathway in early stage and switched to the annulation pathway afterwards via suitable transition states. The modified mechanism picture demonstrated the phenyl C−H activation step to be the rate‐determining step with a free‐energy barrier of 27.7 kcal/mol. However, this barrier was only 19.4 kcal/mol on the basis of a single annulation pathway, which could not satisfactorily agree with the experimental conditions and kinetic isotope effects. In addition, the crucial role of the bifunctional secondary phosphine oxide ligand in promoting the reactivity and selectivity was elucidated in detail.

"Click-to-Clear": A Strategy to Minimize Radioactivity from the Blood Pool Utilizing Staudinger Ligation.

The availability of several bioorthogonal reactions that can proceed selectively and efficiently under physiologically relevant conditions has garnered the interest of biochemists and organic chemists alike. Bioorthogonal cleavage reactions represent the latest innovation in click chemistry. Here, we employed the Staudinger ligation reaction to release radioactivity from immunoconjugates, improving target-to-background ratios. In this proof-of-concept study, model systems, including the anti-HER2 antibody trastuzumab, radioisotope I-131, and a newly synthesized bifunctional phosphine, were used. Staudinger ligation occurred when biocompatible N-glycosyl azides reacted with this radiolabeled immunoconjugate, leading to cleavage of the radioactive label from the molecule. We demonstrated this click cleavage in vitro and in vivo. Biodistribution studies in tumor models showed that radioactivity was eliminated from the bloodstream, thereby improving tumor-to-blood ratios. SPECT imaging revealed that tumors could be visualized with enhanced clarity. Our simple approach represents a novel application of bioorthogonal click chemistry in the development of antibody-based theranostics.

Bifunctional Phosphine-Enabled Regioselective Cycloisomerization of Enynyl Esters En Route to Bicyclo[2.2.1]heptenes.

Expedient access to bridged enol benzoates is realized via a tandem gold-catalyzed cycloisomerization of enynyl esters and the Diels-Alder reaction. The gold catalysis permits the use of enynyl substrates without additional propargylic substitution and achieves the highly regioselective formation of less stable cyclopentadienyl esters. The regioselectivity is enabled by a bifunctional phosphine ligand, the remote aniline group of which facilitates α-deprotonation of a gold carbene intermediate. The reaction works with different alkene substitution patterns and various dienophiles.

Creating Well-Defined monolayers of phosphine linkers incorporating ethoxysilyl groups on silica surfaces for superior immobilized catalysts

Many applications of catalysts immobilized on solid supports like silica via bifunctional phosphine linkers are still hampered by their decomposition, leaching, agglomeration, and uncontrolled nanoparticle formation, all of which change their activities and selectivities. In general, the success of an immobilized catalyst is crucially dependent on the linker and its attachment to the oxide support. In this contribution, an improved method for covalently binding phosphine linkers to silica via ethoxysilane groups is described. This method leads to well-defined sub-monolayers of linkers on silica surfaces without cross-linking of the linkers, which typically leads to clogged pores and metal agglomeration during catalysis, thus entailing less active and selective catalysts. The novel immobilization method has been supported by multinuclear classical CP/MAS solid-state NMR spectroscopy, as well as suspension NMR of slurries. It has been demonstrated by TEM that nickel complexes coordinated by immobilized phosphine linkers in a well-defined sub-monolayer coverage do not form larger aggregates or nanoparticles during the catalytic cyclotrimerization of phenylacetylene under various conditions, in contrast to analogous complexes in homogeneous catalytic runs.

Asymmetric Construction of α,γ-Disubstituted α,β-Butenolides Directly from Allylic Ynoates Using a Chiral Bifunctional Phosphine Ligand Enables Cooperative Au Catalysis

A highly efficient construction of chiral γ-substituted α-allyl-α,β-butenolides with up to >99% enantiomeric excess from readily available allylic ynoates is realized. In this asymmetric gold catalysis, the cationic gold(I) catalyst featuring a bifunctional phosphine ligand enables a four-step cascade which permits the conversion of a diverse array of allylic ynoates into valuable chiral α,γ-disubstituted α,β-butenolides.

Phosphine-catalysed intermolecular cyclopropanation reaction between benzyl bromides and activated alkenes

An intermolecular cyclopropanation reaction between benzyl bromides and activated alkenes was reported catalysed by a bifunctional phosphine.

Chiral Bifunctional Phosphine Ligand Enables Gold-Catalyzed Asymmetric Isomerization and Cyclization of Propargyl Sulfonamide into Chiral 3-Pyrroline.

This work details an asymmetric gold-ligand cooperative catalysis that transforms readily accessible chiral/achiral propargylic sulfonamides into chiral 3-pyrrolines. A bifunctional biphenyl-2-ylphosphine ligand featuring a chiral tetrahydroisoquinoline fragment is essential for the observed metal-ligand cooperation and the asymmetric induction. 2,5-cis-3-Pyrrolines are formed with excellent diastereoselectivities in a "matched" scenario. The "mismatched" scenario by using the ligand enantiomer delivers 2,5-trans-3-pyrrolines with >5/1 diastereoselectivity. The synthetic utilities of this chemistry are demonstrated.

Ni-Catalyzed Dual C-H Annulation of Benzimidazoles with Alkynes for Synthesis of π-Extended Heteroarenes.

Transition metal catalyzed dual C-H activation and annulation with alkynes was an attractive protocol to construct polycyclic π-extended structures. However, most of them were dominated by noble metal catalysts. Disclosed herein was the study of base-metal Ni-catalysis for dual C-H annulation of N-aromatic imidazole, which produced a range of desired polycyclic aza-quinolines in 48-95% yields. The use of bifunctional phosphine oxide ligand proved to be critical for success.

Photoinduced selective hydrophosphinylation of allylic compounds with diphenylphosphine oxide leading to γ-functionalized P-ligand precursors

A series of bifunctional phosphine compounds promising as γ-functionalized phosphine ligand precursors are conveniently synthesized by the radical addition of diphenylphosphine oxide (Ph2P(O)H) to allylic compounds under photoirradiation. The photoinduced addition proceeds regioselectively in an anti-Markovnikov manner, and phosphines having hydroxy, alkoxy, aryloxy, acyloxy, and thio groups at the γ-position can be prepared by simple operation. Interestingly, novel continuous addition of Ph2P(O)H to two molecules of allylic ethers and related compounds is also observed, although their yields are moderate. The substituent and steric effects of the allylic substituents on the radical addition are discussed in detail.

Phosphine-Catalyzed Asymmetric Allylic Alkylation of Achiral MBH Carbonates with 3,3'-Bisindolines: Enantioselective Construction of Quaternary Stereogenic Centers.

The asymmetric allylic alkylation (AAA) of achiral Morita-Baylis-Hillman (MBH) carbonates with 3,3'-bisindolines under the catalysis of amino-acid-derived bifunctional phosphines was accomplished. With the AAA approach introduced herein, challenging 3,3'-bisindolines bearing an all-carbon quaternary stereocenter (C3a) have been constructed in good yields with good to excellent enantioselectivties. In addition, the synthetic value of this protocol was demonstrated by the facile synthesis of the core skeleton of gliocladin C.

Gold-catalysed asymmetric net addition of unactivated propargylic C-H bonds to tethered aldehydes.

The asymmetric one-step net addition of unactivated propargylic C-H bond to aldehyde leads to an atom-economic construction of versatile chiral propargylic alcohols but has not been realized previously. Here we show its implementation in an intramolecular manner under mild reaction conditions. Via cooperative gold catalysis enabled by a chiral bifunctional phosphine ligand, this chemistry achieves asymmetric catalytic deprotonation of propargylic C-H (pKa > 30) by a tertiary amine group (pKa ~ 10) of the ligand in the presence of much more acidic aldehydic α-hydrogens (pKa ~ 17). The reaction exhibits a broad scope and readily accommodates various functional groups. The 5-/6-membered ring fused homopropargylic alcohol products are formed with excellent enantiomeric excesses and high trans-selectivities with or without a preexisting substrate chiral center. DFT studies of the reaction support the conceived reaction mechanism and the calculated energetics corroborate the observed stereoselectivity and confirm an additional metal-ligand cooperation.

Enantioselective Pd0‐Catalyzed C(sp2)–H Arylation for the Synthesis of Chiral Warped Molecules

AbstractC−H activation‐based ring‐forming methods are a powerful approach for the construction of complex molecular architectures, especially those containing a congested stereocenter. Therefore, this strategy seems perfectly suited to address the synthesis of chiral polycyclic aromatic hydrocarbons (PAHs) and bowl‐shaped molecules, which are important target molecules in the field of organic electronic materials. Herein, we describe an enantioselective Pd0‐catalyzed C(sp2)−H arylation protocol for the synthesis of chiral fluoradenes and other warped molecules, which could serve to the bottom‐up construction of chiral PAHs. The current approach relies on the use of chiral bifunctional phosphine–carboxylate ligands and delivers diverse polycyclic compounds in high yield and with good to excellent enantioselectivity. The chiroptical properties of the obtained products were investigated, and some of them were found to have a strong ellipticity and an emission band located in the visible region.