Chiral Phosphate Research Articles

Enantioselective Amination of β-Keto Esters Catalyzed by Chiral Calcium Phosphates.

A catalytic enantioselective amination of β-keto esters using (S)-BINOL chiral calcium phosphate has been developed. The reaction produces chiral α-amino-β-keto ester derivatives in most cases with moderate to excellent enantioselectivities (up to 99 %) and good yields (up to 99 %). This mild synthetic method highlights a low catalyst loading and high catalytic efficiency. When the substrate backbone was changed to 1-tetralone-derived β-keto esters, unexpectedly high yields of selective redox products were obtained. The practicality of the reaction was realized by a scale-up without any significant loss in the enantioselectivity and yield. Chiral calcium phosphate was successfully recovered and reused for four runs, indicating its stability and high catalytic activity.

Cover Picture: Non‐Covalent Interactions between Chiral Phosphate and Lanthanide Ion by Chiroptical Spectroscopy (Chem. Methods 3/2022)

The Front Cover shows the lanthanide circularly polarized luminescence (CPL) used for analyzing intermolecular interactions between chiral phosphate and europium(III) aqua ion measured by Raman optical activity spectrometer. By adjusting the solvent components, the induced CPL spectra of europium(III) are alternated and pattern of preferred 5D0→7F1 transition can be linked to similar Eu-phosphate binding mode in water solution. More information can be found in the Full Paper by Tao Wu.

Modular and Facile Access to Chiral α-Aryl Phosphates via Dual Nickel- and Photoredox-Catalyzed Reductive Cross-Coupling.

Chiral phosphine-containing skeletons are important motifs in bioactive natural products, pharmaceuticals, chiral catalysts, and ligands. Herein, we report a general and modular platform to access chiral α-aryl phosphorus compounds via a Ni/photoredox-catalyzed enantioconvergent reductive cross-coupling between α-bromophosphates and aryl iodides. This dual catalytic regime exhibited high efficiency and good functional group compacity. A wide variety of substrates bearing a diverse set of functional groups could be converted into chiral phosphates in good to excellent yields and enantioselectivities. The utility of the method was also demonstrated by the development of a new phosphine ligand and the synthesis of enzyme inhibitor derivatives. The detailed mechanistic studies supported a radical chain process and revealed a unique distinction compared with traditional reductive cross-coupling.

Enantioselective Peroxidation of C-alkynyl imines enabled by chiral BINOL calcium phosphate.

Herein, we report a catalytic enantioselective addition of C-alkynyl imines with hydroperoxides catalyzed by chiral BINOL calcium phosphate, affording a broad range of enantioenriched α-peroxy propargylamines in good yields (80-99%) with high enantioselectivities (up to 94% ee). The protocol is characterized by mild conditions, easy accessibility and good practicability.

Interrogating the thionium hydrogen bond as a noncovalent stereocontrolling interaction in chiral phosphate catalysis.

CH⋯O bonds are a privileged noncovalent interaction determining the energies and geometries of a large number of structures. In catalytic settings, these are invoked as a decisive feature controlling many asymmetric transformations involving aldehydes. However, little is known about their stereochemical role when the interaction involves other substrate types. We report the results of computations that show for the first time thionium hydrogen bonds to be an important noncovalent interaction in asymmetric catalysis. As a validating case study, we explored an asymmetric Pummerer rearrangement involving thionium intermediates to yield enantioenriched N,S-acetals under BINOL-derived chiral phosphate catalysis. DFT and QM/MM hybrid calculations showed that the lowest energy pathway corresponded to a transition state involving two hydrogen bonding interactions from the thionium intermediate to the catalyst. However, the enantiomer resulting from this process differed from the originally published absolute configuration. Experimental determination of the absolute configuration resolved this conflict in favor of our calculations. The reaction features required for enantioselectivity were further interrogated by statistical modeling analysis that utilized bespoke featurization techniques to enable the translation of enantioselectivity trends from intermolecular reactions to those proceeding intramolecularly. Through this suite of computational modeling techniques, a new model is revealed that provides a different explanation for the product outcome and enabled reassignment of the absolute product configuration.

Turning Renewable Feedstocks into a Valuable and Efficient Chiral Phosphate Salt Catalyst

AbstractSolketal, the chiral acetonide of glycerol, has been employed as the starting material in the design of a novel punctually chiral phosphate sodium salt for catalytic applications in organic and asymmetric synthesis. The racemate and the two enantiomers of the substrate are economic and commercially available, straightforwardly prepared in high yields from naturally occurring feedstocks. Therefore, remarkably, both enantiomers of the final catalyst can be synthesized by simple procedures in high yield and in compliance with several principles of green chemistry. To further demonstrate the usefulness of the novel catalyst, its application in a solventless protocol for cyanohydrin synthesis from a series of aldehydes has been presented.

Non‐Covalent Interactions between Chiral Phosphate and Lanthanide Ion by Chiroptical Spectroscopy

AbstractChiroptical spectroscopy is instrumental in chiral recognition studies. Induced circularly polarized luminescence (CPL) of europium(III) aqua ion in optically active phosphate solution was observed on a standard Raman optical activity (ROA) spectrometer. The ROA‐CPL method displays characteristic CPL couplet of Eu‐phosphate interactions avoiding the participation of costly antenna chromophore. Similar CPL patterns pertaining 5D0→7F1 transition was also observed in other europium(III) complexes able to bind with phosphate. Titration data and simulations revealed the presence of hydrogen bond between the phosphate group and water molecules surrounding the metal core.

Chiral Dirhodium Tetraphosphate-Catalyzed Enantioselective Si-H Bond Insertion of α-Aryldiazoacetates.

A highly enantioselective Si-H bond insertion reaction of α-aryldiazoacetates catalyzed by chiral spiro dirhodium tetraphosphate was developed. Various chiral α-silyl esters were prepared with high yield (up to 92%) and excellent enantioselectivity (up to >99% ee) through this protocol. It is noteworthy that the 2-substituted aryl diazoacetates, which are challenging substrates for other chiral dirhodium catalysts, also exhibited good results in this reaction. This work represents one of the few successful applications of chiral dirhodium phosphates in asymmetric catalysis.

Computational Insights into Privileged Stereocontrolling Interactions Involving Chiral Phosphates and Iminium Intermediates.

The precise design of a catalyst for a given reaction is extremely difficult, often requiring a significant empirical screening campaign to afford products in high yields and enantiomeric excess. Design becomes even more challenging if one requires a catalyst that performs well for a diverse range of substrates. Such "privileged" catalysts exist, but little is known why they operate so generally. We report the results of computations which show that when substrate and catalyst features are conserved between significantly different mechanistic regimes, similar modes of activation can be invoked. As a validating case study, we explored a Hantzsch ester hydrogenation of α,β-unsaturated iminiums involving BINOL-derived chiral phosphates and find they impart asymmetric induction in an analogous fashion to their acid counterpart. Specifically, DFT calculations at the IEFPCM(1,4-dioxane)-B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level predicted enantioselectivity to be close to the experimental value (82% ee calculated, 96% ee experimental) and showed that the reaction proceeds via a transition state involving two hydrogen-bonding interactions from the iminium intermediate and nucleophile to the catalyst. These interactions lower the energy of the transition structure and provide extra rigidity to the system. This new model invokes "privileged" noncovalent interactions and leads to a new explanation for the enantioselectivity outcome, ultimately providing the basis for the development of general catalyst design principles and the translation of mechanistically disparate reaction profiles for the prediction of enantioselectivity outcomes using statistical models.

Enantioselective Insertion of Alkynyl Carbenes into Si-H Bonds: An Efficient Access to Chiral Propargylsilanes and Allenylsilanes.

Chiral propargylsilanes and chiral allenylsilanes have emerged as versatile building blocks for organic synthesis. However, efficient methods for preparing these organosilicon compounds are lacking. We herein report a highly enantioselective method for synthesis of chiral propargylsilanes and chiral allenylsilanes from readily available alkynyl sulfonylhydrazones. Specifically, chiral spiro phosphate dirhodium complexes were used to catalyze asymmetric insertion of alkynyl carbenes into the Si-H bonds of silanes to afford a variety of chiral propargylsilanes with excellent enantioselectivity. Subsequently, a platinum catalyst was used for stereospecific isomerization of the chiral propargylsilanes to the corresponding chiral allenylsilanes.

Synthesis and structure determination of diastereomeric carbapenems in the AdNE-reaction of (±)-4,4-dimethyl-3-mercaptodihydrofuran-2(3H)-one with chiral carbapenem enol phosphate

Synthesis and structure determination of diastereomeric carbapenems in the AdNE-reaction of (±)-4,4-dimethyl-3-mercaptodihydrofuran-2(3H)-one with chiral carbapenem enol phosphate

Enantioselective Au(I)-catalyzed dearomatization of 1-naphthols with allenamides through Tethered Counterion-Directed Catalysis.

The Tethered Counterion-Directed Catalysis (TCDC) approach has been applied to the enantioselective Au(I) catalyzed dearomatizations of 1-naphthols with allenamides. Stereocontrol is ensured by the intramolecular ion-pairing between the chiral gold-tethered phosphate and an iminium unit, that provides a rigid, well-defined chiral environment to the key electrophilic intermediate.

The helical supramolecular assembly of oligopyridylamide foldamers in aqueous media can be guided by adenosine diphosphates.

A metal-free and achiral tri-pyridylamide foldamer, DM 11, containing a critical naphthalimide side chain self-assembles in a left-handed helical manner in the presence of chiral adenosine phosphates, under physiological conditions. Surprisingly, a very high degree of helicity in the foldamer assemblies was observed with ADP compared to other nucleoside phosphates, including ATP.

Dynamic parallel kinetic resolution of α-ferrocenyl cation initiated by chiral Brønsted acid catalyst.

The dynamic parallel kinetic resolution (DPKR) of an α-ferrocenyl cation intermediate under the influence of a chiral conjugate base of a chiral phosphoric acid catalyst has been demonstrated in an SN1 type substitution reaction of a racemic ferrocenyl derivative with a nitrogen nucleophile. The present method provides efficient access to a ferrocenylethylamine derivative in a highly enantioselective manner, which is potentially useful as a key precursor of chiral ligands for metal catalysis. The mechanism of the present intriguing resolution system was elucidated by control experiments using the enantio-pure precursor of relevant α-ferrocenyl cation intermediates and the hydroamination of vinylferrocene. Further theoretical studies enabled the elucidation of the origin of the stereochemical outcome as well as the efficient DPKR. The present DPKR, which opens a new frontier for kinetic resolution, involves the racemization process through the formation of vinylferrocene and the chemo-divergent parallel kinetic resolution of the enantiomeric α-ferrocenyl cations generated by the protonation/deprotonation sequence of vinylferrocene.

A Computational and Experimental Investigation of the Origin of Selectivity in the Chiral Phosphoric Acid Catalyzed Enantioselective Minisci Reaction.

The Minisci reaction is one of the most valuable methods for directly functionalizing basic heteroarenes to form carbon–carbon bonds. Use of prochiral, heteroatom-substituted radicals results in stereocenters being formed adjacent to the heteroaromatic system, generating motifs which are valuable in medicinal chemistry and chiral ligand design. Recently a highly enantioselective and regioselective protocol for the Minisci reaction was developed, using chiral phosphoric acid catalysis. However, the precise mechanism by which this process operated and the origin of selectivity remained unclear, making it challenging to develop the reaction more generally. Herein we report further experimental mechanistic studies which feed into detailed DFT calculations that probe the precise nature of the stereochemistry-determining step. Computational and experimental evidence together support Curtin–Hammett control in this reaction, with initial radical addition being quick and reversible, and enantioselectivity being achieved in the subsequent slower, irreversible deprotonation. A detailed survey via DFT calculations assessed a number of different possibilities for selectivity-determining deprotonation of the radical cation intermediate. Computations point to a clear preference for an initially unexpected mode of internal deprotonation enacted by the amide group, which is a crucial structural feature of the radical precursor, with the assistance of the associated chiral phosphate. This unconventional stereodetermining step underpins the high enantioselectivities and regioselectivities observed. The mechanistic model was further validated by applying it to a test set of substrates possessing varied structural features.

Atropselective Hydrolysis of Chiral Binol-Phosphate Esters Catalyzed by the Phosphotriesterase from Sphingobium sp. TCM1.

The phosphotriesterase from Sphingobium sp. TCM1 (Sb-PTE) is notable for its ability to hydrolyze a broad spectrum of organophosphate triesters, including organophosphorus flame retardants and plasticizers such as triphenyl phosphate and tris(2-chloroethyl) phosphate that are not substrates for other enzymes. This enzyme is also capable of hydrolyzing any one of the three ester groups attached to the central phosphorus core. The enantiomeric isomers of 1,1'-bi-2-naphthol (BINOL) have become among the most widely used chiral auxiliaries for the chemical synthesis of chiral carbon centers. PTE was tested for its ability to hydrolyze a series of biaryl phosphate esters, including mono- and bis-phosphorylated BINOL derivatives and cyclic phosphate triesters. Sb-PTE was shown to be able to catalyze the hydrolysis of the chiral phosphate triesters with significant stereoselectivity. The catalytic efficiency, kcat/Km, of Sb-PTE toward the test phosphate triesters ranged from ∼10 to 105 M-1 s-1. The product ratios and stereoselectivities were determined for four pairs of phosphorylated BINOL derivatives.

Chiral Calcium Phosphate Catalyzed Enantioselective Amination of 3-Aryl-2-benzofuranones.

A 4-tert-butyl-phenyl substituted (R)-[H8]-BINOL chiral calcium phosphate catalyzed enantioselective amination of 3-aryl-2-benzofuranones with dibenzyl azodicarboxylate is described. The catalyst loading of the reaction is 1 mol %. This transformation is facile and has a high degree atom economy, which gave products with good yields and high enantioselectivities (79% to 99%). This reaction has excellent ee and a broad substrate scope with mild reaction conditions.

Asymmetric Spirocyclization Enabled by Iridium and Brønsted Acid-Catalyzed Formal Reductive Cycloaddition

A catalytic, enantioselective spirocyclization of formanilides or formylindolines and enamides has been developed herein. The reaction proceeds through a sequential iridium-catalyzed hydrosilylatio...

Catalytic Asymmetric Three-Component Reaction of 2-Alkynylbenzaldehydes, Amines, and Dimethylphosphonate.

An efficient enantioselective synthesis of cyclic α-aminophosphonates via multicomponent reactions of 2-alkynylbenzaldehydes, amines, and dimethylphosphonate has been developed with the use of a chiral silver spirocyclic phosphate as the catalyst. This protocol provides straightforward access to a series of chiral C1-phosphonylated 1,2-dihydroisoquinoline derivatives with high yields (up to 99%) and high enantioselectivities (up to 94% ee) for a broad substrate scope. The products could be further transformed into densely functionalized compounds and corresponding α-aminophosphonic acids.

Imine Amidation Catalyzed by a Chiral VAPOL Calcium Phosphate.

Over the last 16 years, chiral phosphoric acids (CPAs) have been shown to be excellent asymmetric catalysts, very effectively used in constructing chiral molecules with high enantiocontrol. In 2010, Ishihara et al. discovered that chiral metal phosphate complexes (or salts) could be found in substantial quantities, as contaminates, in some reported CPA-catalyzed reactions (Hatano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Angew. Chem., Int. Ed. 2010, 49, 3823-3826). These metal phosphates were shown to actually catalyze the reactions in addition to CPAs. In this work, we have investigated in depth a reaction first reported to be catalyzed by CPAs based on a vaulted bis-phenanthrol (VAPOL) backbone. We have found that VAPOL metal phosphates were, in fact, superior catalysts for this reaction. Upon optimization, a wide substrate scope, low catalyst loading, and mild conditions could provide intermolecular imine amidation reactions producing chiral N,N'-aminal products in high yields and with excellent ee values (up to >99% yield, >99% ee).