Chiral Phosphate Research Articles

Improving stereoselectivity of phosphotriesterase (PTE) for kinetic resolution of chiral phosphates.

Specific stereoisomer is paramount as it is vital for optimizing drug efficacy and safety. The quest for the isolation of desired stereoisomer of active pharmaceutical ingredients or key intermediates drives innovation in drug synthetic and biocatalytic methods. Chiral phosphoramidate is an important building block for the synthesis of antiviral drugs such as remdesivir and sofosbuvir. Given the clinical potency of the (Sp)-diastereomer of the drugs, an enzyme capable of completely hydrolyzing the (Rp)-diastereomer is needed to achieve the purified diastereomers via biocatalytic reaction. In this study, protein engineering of phosphotriesterase (PTE) was aimed to improve the specificity. Employing rational design and site-directed mutagenesis, we generated a small library comprising 24 variants for activity screening. Notably, W131M and I106A/W131M variants demonstrated successful preparation of pure (Sp)-diastereomer of remdesivir and sofosbuvir precursors within a remarkably short hydrolysis time (<20min). Our work unveils a promising methodology for producing pure stereoisomeric compounds, utilizing novel biocatalysts to enable the chemoenzymatic synthesis of phosphoramidate nucleoside prodrugs.

Rh-Catalyzed Enantioselective Single-Carbon Insertion of Alkenes.

The interest in the discovery and development of skeletal editing processes that selectively insert, exchange, or delete an atom in organic molecules has significantly increased over the last few years. However, processes of this class that proceed through the creation of a chiral center with high asymmetric induction have been largely unexplored. Herein, we report an enantioselective single-carbon insertion in aryl- and alkyl-substituted alkenes mediated by a catalytically generated chiral Rh-carbynoid and phosphate nucleophiles that produce enantioenriched allylic phosphates (enantiomeric ratio (e.r.) = 89.5:10.5-99.5:0.5). The key to the process was a diastereo- and enantioselective cyclopropanation of the alkene with a chiral Rh-carbynoid and the formation of a transient cyclopropyl-I(III) intermediate. The addition of the phosphate nucleophile provided a cyclopropyl-I(III)-phosphate intermediate that undergoes disrotatory ring opening following the Woodward-Hoffmann-DePuy rules. This process led to a chiral intimate allyl cation-phosphate pair that evolved with excellent enantioretention. The evidence of an SN1-like SNi mechanism is provided by linear free-energy relationship studies, kinetic isotope effects, X-ray crystallography, and control experiments. We demonstrated the utility of the enantioenriched allylic phosphates in late-stage N-H allylations of natural products and drug molecules and in cross-coupling reactions that occurred with excellent enantiospecificity.

Construction of Ge-Stereogenic Center by Desymmetric Carbene Insertion of Dihydrogermanes.

We developed a method for the enantioselective synthesis of germanium-stereogenic compounds by the desymmetric carbene insertion of dihydrogermanes. A chiral rhodium phosphate catalyst decomposes diaryldiazo-methanes to generate rhodium carbenes that insert enantioselectively into one of the two Ge-H bonds of dihydrogermanes to form germanium-stereogenic compounds under mild reaction conditions. By this method, a variety of chiral germanes with germanium-stereogenic centers were synthesized in high yields and excellent enantioselectivities. Kinetic studies of the reaction showed that the diazo decomposition process was the rate-determining step. The remaining Ge-H bond of the chiral germane products provides a possibility for preparing chiral tetra-substituted germanium-stereogenic compounds.

Domino dehydration/intermolecular (enantioselective) ketone-ene reactions catalysed by a simple solid in batch and in flow.

The intermolecular carbonyl-ene reaction of ketones is still considered a challenge in organic chemistry, particularly with reusable solid catalysts, and implemented in a domino reaction. Herein, we show that the extremely cheap and non-toxic solid salt MgCl2 catalyzes the reaction of trifluoromethyl pyruvates not only during the conventional carbonyl-ene reaction with various aromatic and alkyl alkenes (in very high yields, up to >99%) but also in a domino reaction with the corresponding alcohols (precursors to the alkenes) in similar good yields. The solid can be reused in both cases without any erosion of the catalytic activity and can be employed in an in-flow process to maximize the reaction throughput. Besides, the reaction can be performed under solventless reaction conditions. Addition of a catalytic amount of chiral binaphthyl hydrogen phosphate allows carrying out the reaction with a reasonable enantiomeric excess (up to >70%) and in flow, in a rare example of enantioselective solid-catalyzed domino carbonyl-ene reaction using a cheap, simple, readily available and physically mixed catalytic solid. The MgCl2-catalytic system is also active in the industrially relevant citronellal-to-isopulegol carbonyl-ene reaction. These results pave the way to design sustainable domino carbonyl-ene reactions with extremely cheap solid catalysts.

Enantioselective copper-catalyzed B-H bond insertion reaction of α-diazo phosphonates to access chiral α-boryl phosphonates.

Chiral phosphorus-containing compounds find applications across various fields, including asymmetric catalysis, medicinal chemistry, and materials science. Despite the abundance of reported highly enantioselective methods for synthesizing various chiral phosphorus compounds, the enantioselective synthesis of α-boryl phosphorus compounds still remains an unknown territory. Here, we report a method for the construction of chiral α-boryl phosphates by asymmetric B-H insertion reaction using α-diazo phosphates as carbene precursors, cheap and readily available copper salt as the catalyst and chiral oxazoline as the ligand. This method can directly afford a series of stable α-boryl phosphates with a yield up to 97% and an enantioselectivity up to 98% ee. The operating procedure of this method is straightforward, offering a broad substrate applicability, remarkable tolerance towards various functional groups, and gentle reaction conditions.

Kinetic resolution of 1,1'-binaphthyl-2,2'-diamine derivatives by chiral calcium phosphate-catalyzed acylation.

1,1'-Binaphthyl-2,2'-diamine (BINAM) is a useful axially chiral compound. The kinetic resolution of BINAM is one of the most crucial methods for synthesizing chiral BINAM. We have developed a chiral calcium phosphate-catalyzed kinetic resolution of BINAM by utilizing an acylation reaction to produce a mono-amide. The kinetic resolution of BINAM derivatives was achieved by using isobutyric anhydride in the presence of chiral calcium phosphate and 4-morpholinopyridine with up to s = 127. 6,6'-Substituted BINAM derivatives were also applicable for this reaction. The resulting mono-acylated BINAM could be transformed into BINAM by hydrolysis under acidic conditions.

Organocatalytic enantio- and diastereoselective assembly of cyclopropane-incorporated polycyclic molecules via isobenzopyrylium ions.

A highly enantio- and diastereoselective organocatalytic formation of cyclopropanes embedded in a complex bridged polycyclic architecture is disclosed. In the presence of a chiral phosphoric acid catalyst, this reaction generates four new stereogenic centers and three new C-C bonds efficiently from isochromene acetals and vinylboronic acids under mild conditions. Different from conventional asymmetric cyclopropanation strategies, this process does not involve carbenes or carbenoids. The complex products can serve as precursors to useful homoenolate equivalents. Mechanistically, DFT studies provided insights into the key transition states of the enantiodetermining [4 + 2] cycloaddition, in which the enantioselectivity is induced by the chiral phosphate counter anion of the isobenzopyrylium intermediate.

Chiral Phosphoric Acid-Palladium(II) Complex Catalyzed Asymmetric Desymmetrization of Biaryl Compounds by C(sp3)-H Activation.

Desymmetrization is an essential method for the synthesis of chiral compounds, particularly chiral biaryls. We have developed an enantioselective synthesis of axially chiral biaryls by desymmetrization using C(sp3)-H activation catalyzed by chiral palladium phosphate. Mechanistic studies show that C-H activation is the rate- and enantiomer-determining step. To the best of our knowledge, this is the first report of asymmetric desymmetrization of axially chiral compounds by C(sp3)-H activation.

Discovery and Development of the Enantioselective Minisci Reaction.

ConspectusThe class of reactions now known as Minisci reactions is broadly defined as the addition of nucleophilic carbon-based radicals to basic heteroarenes with subsequent rearomatization to form a new carbon-carbon bond. Since the pioneering work of Minisci in the 1960s and 1970s, these reactions are now widely used in medicinal chemistry due to the ubiquity of basic heterocycles in druglike molecules. One of the long-standing challenges of Minisci chemistry has been that of regioselectivity due to the mixtures of positional isomers commonly obtained on many substrates if there is a choice between similarly activated sites. At the outset of the work described herein, we hypothesized that it may be possible to tackle this using a catalytic strategy whereby a bifunctional Brønsted acid catalyst simultaneously activates the heteroarene and engages attractive non-covalent interactions with the incoming nucleophile, resulting in a proximal attack. Using chiral BINOL-derived phosphoric acids, we not only were able to achieve this goal of regiocontrol but also discovered that we could control the absolute stereochemistry at the new stereocenter formed when prochiral α-amino radicals were employed. At the time, this discovery was unprecedented in the context of Minisci reactions.This Account details the discovery of this protocol and the further development, expansion, and investigations into the mechanism that we have carried out since then, several in collaboration with other research groups. Collaborative efforts have involved an expansion of the scope to diazines guided by multivariate statistical analysis through the development of a predictive model (collaboration with Sigman). Also, a mechanistic study involving detailed DFT analysis (collaboration with Goodman and Ermanis) unveiled the selectivity-determining step as being the deprotonation of a key cationic radical intermediate by the associated chiral phosphate anion. We have additionally carried out a number of synthetic developments of the protocol such as removing the need to prefunctionalize the radical nucleophile; hydrogen-atom transfer can be used to enable a formal coupling of two C-H bonds to form a C-C bond while retaining high enantio- and regioselectivity. Most recently, we have been able to expand the protocol so that α-hydroxy radicals can be used: until this point, all examples had concerned α-amino radicals. Again, HAT was used to generate the α-hydroxy radicals, and DFT studies carried out in collaboration (Ermanis) provided mechanistic insights.Since our original report, there have appeared a number of exciting developments from other research groups whereby the protocol has been applied to new substrates or using different precursors to generate the requisite α-amino radical. There have also been several examples in which alternative photocatalyst systems have been used to reduce the redox-active esters in the original enantioselective Minisci protocol. While primarily an Account, these contributions from other research groups will be covered briefly for context toward the end of the article.

New Trends in Asymmetric Phase Transfer Catalysis

AbstractPhase Transfer Catalysis (PTC) is a powerful tool to perform reactions in a practical fashion, both in laboratory and industrial scale. Significant cost savings and major process improvements can be achieved in reactions performed under PTC conditions. In the last few years remarkable results in stereoselective reactions were achieved using chiral, non‐racemic quaternary ammonium salts. Moreover, the use of bulky, chiral phosphate anions paired with achiral cations to generate lipophilic ion pairs allowed to design new avenues for the stereoselective construction of important building blocks. Hydrogen bond interactions were also shown to provide new pathways for asymmetric nucleophilic substitutions using insoluble reagents under PTC conditions. This Review will focus on recent advances in developing practical synthetic routes to construct molecules in a stereoselective fashion under PTC conditions.

Cross-assembly confined bifunctional catalysis via non-covalent interactions for asymmetric halogenation

•Assembling bifunctional catalysts via non-covalent interactions •Enantioselectivity is largely optimized by changing the achiral catalytic species •Asymmetric halogenation to give various valuable building blocks •Access to the advanced intermediates of drugs and natural products Bifunctional catalysis plays a key role in the synthesis of useful compounds. By offering a sterically confined environment, chiral bifunctional catalysts can achieve highly enantioselective reactions. However, introducing suitable substituents to create a confined microenvironment for asymmetric catalysis on many occasions involves tedious procedures, leading to inefficient reaction optimization. Herein, we report a proof-of-concept study on formulating confined bifunctional catalysts by linking catalytic species via non-covalent interactions (NCIs). Chiral phosphate and achiral cyclopropenium cations cross-assembled to give a confined bifunctional system for asymmetric bromo-semipinacol rearrangement. By changing the achiral catalyst to aminopyridine, the system can be applied to asymmetric bromocycloetherification. These reactions are largely optimized by simply changing the achiral catalyst. A computational study revealed that the strength of the NCI donor is crucial in creating tighter catalytic pockets to amplify the effect of enantiofacial discrimination of substrates. Bifunctional catalysis plays a key role in the synthesis of useful compounds. By offering a sterically confined environment, chiral bifunctional catalysts can achieve highly enantioselective reactions. However, introducing suitable substituents to create a confined microenvironment for asymmetric catalysis on many occasions involves tedious procedures, leading to inefficient reaction optimization. Herein, we report a proof-of-concept study on formulating confined bifunctional catalysts by linking catalytic species via non-covalent interactions (NCIs). Chiral phosphate and achiral cyclopropenium cations cross-assembled to give a confined bifunctional system for asymmetric bromo-semipinacol rearrangement. By changing the achiral catalyst to aminopyridine, the system can be applied to asymmetric bromocycloetherification. These reactions are largely optimized by simply changing the achiral catalyst. A computational study revealed that the strength of the NCI donor is crucial in creating tighter catalytic pockets to amplify the effect of enantiofacial discrimination of substrates.

Asymmetric Rubottom‐Type Oxidation Catalyzed by Chiral Calcium Phosphates

Invited for the cover of this issue is the group of Jon C. Antilla at Zhejiang Sci-Tech University. The image depicts asymmetric Rubottom-type oxidation catalyzed by chiral calcium phosphates. Read the full text of the article at 10.1002/chem.202203720.

Enantioselective Mukaiyama-Michael Reaction of β,γ-Unsaturated α-Keto Esters with Silyl Ketene Acetals Catalyzed by a Chiral Magnesium Phosphate.

We would like to describe an efficient and highly enantioselective Mukaiyama-Michael reaction of silyl ketene acetals with β,γ-unsaturated α-keto esters catalyzed by a chiral magnesium BINOL-derived phosphate. The resulting functionalized 1,5-dicarbonyl adducts are obtained in high yields (up to 96%) and with excellent enantioselectivities (up to 98%) under mild conditions. Two plausible mechanistic pathways were proposed, including a 1,4-addition and a hetero Diels-Alder [4 + 2] cycloaddition.

Electricity-driven asymmetric bromocyclization enabled by chiral phosphate anion phase-transfer catalysis

Electricity-driven asymmetric catalysis is an emerging powerful tool in organic synthesis. However, asymmetric induction so far has mainly relied on forming strong bonds with a chiral catalyst. Asymmetry induced by weak interactions with a chiral catalyst in an electrochemical medium remains challenging due to compatibility issues related to solvent polarity, electrolyte interference, etc. Enabled by a properly designed phase-transfer strategy, here we have achieved two efficient electricity-driven catalytic asymmetric bromocyclization processes induced by weak ion-pairing interaction. The combined use of a phase-transfer catalyst and a chiral phosphate catalyst, together with NaBr as the bromine source, constitutes the key advantages over the conventional chemical oxidation approach. Synergy over multiple events, including anodic oxidation, ion exchange, phase transfer, asymmetric bromination, and inhibition of Br2 decomposition by NaHCO3, proved critical to the success.

Asymmetric Rubottom-Type Oxidation Catalyzed by Chiral Calcium Phosphates.

A highly efficient catalytic asymmetric Rubottom-type oxidation is described. Using meta-chloroperbenzoic acid (m-CPBA) as the oxidant and chiral calcium phosphate as the catalyst, the facile transformation enables direct hydroxylation of N-Boc oxindoles and β-ketoesters in high yields (up to 99 %) and in a highly enantioenriched fashion (up to >99 % ee). The application of the established method was demonstrated by the synthesis of a pharmaceutically important 3-hydroxyoxindole with excellent enantiocontrol.

Chiral organophosphates as ligands in asymmetric metal catalysis

Chiral phosphates have successfully been used as ligands in asymmetric metal-catalysis. This Minireview discusses the most recent examples, including main-group catalysis, transition-metal catalysis and catalysis by rare-earth metals.

Anionic ligand-induced chirality in perovskite nanoplatelets.

Perovskite materials passivated by chiral ligands have recently shown unique chiroptical activity with promising optoelectronic applications. However, the ligands have been limited to chiral amines. Here, chiral phosphate molecules have been exploited to synthesize CsPbBr3 nanoplatelets. The nanoplatelets showed a distinct circular dichroism signal and maintained their chiroptical properties after purification with anti-solvent.

Enantiodivergent epoxidation of alkenes with a photoswitchable phosphate manganese-salen complex.

The development of enantiodivergent catalysts capable of preparing both enantiomeric products from one substrate in a controlled fashion is challenging. Introducing a switching function into the catalyst can address this challenge, allowing the chiral reaction environment to reversibly change during catalysis. Here we report a photoswitchable phosphate ligand, derived from 2,2'-biphenol, which axially coordinates as the counter ion to an achiral manganese(III) salen catalyst, providing the latter with the ability to switch stereoselectivity in the epoxidation of alkenes. The enantiomers of the chiral ligand exist as a pair of pseudo-enantiomers, which can be interconverted by irradiation with light of different wavelengths. The opposite axial chirality of these pseudo-enantiomers is efficiently transferred to the manganese(III) salen catalyst. With this switchable supramolecular catalyst, the enantioselectivity of the epoxidation of a variety of alkenes can be controlled, resulting in opposite enantiomeric excesses of the epoxide products. This transfer of chirality from a photoswitchable anionic ligand to a metal complex broadens the scope of supramolecular catalysts.

Inherently Chiral Cages via Hierarchical Desymmetrization.

A new type of cage inherent chirality was accessed by hierarchical desymmetrization of a D3h-symmetric prismlike cage motif. The dissymmetric C3v cage precursor C1 bearing two different phloroglucinol caps was first synthesized. The subsequent progressive substitutions on the three triazine arms by different nucleophiles furnished the desired C1-symmetric inherently chiral cages C3 and C4 with rich structural diversity. Resolution of the racemic cages was achieved by chiral chromatography, and the enantiopure cages were readily obtained on the gram scale. Convenient post-synthetic transformations of the chiral cages with retention of enantiomeric purity were also realized. The absolute configuration was determined by X-ray crystallography, and a chirality descriptor was provided to define the cage chirality. With the inherently chiral array of the electron-deficient triazine surfaces constituting three individual chiral V-shaped π cavities, regio- and enantioselective anion-π binding was probed for the first time with minimum interference of other interactions. As exemplified with chiral phosphate anions (CPAs), it was found that cage (-)-C3a preferably binds (S)-CPA- in the most electron-deficient cavity through synergistic anion-π interactions with considerable chiral selectivity.

Interrogating the Thionium Hydrogen Bond as a Noncovalent Stereocontrolling Interaction in Chiral Phosphate Catalysis

Interrogating the Thionium Hydrogen Bond as a Noncovalent Stereocontrolling Interaction in Chiral Phosphate Catalysis