Figure - available from: Chemical Science
This content is subject to copyright. Terms and conditions apply.
Source publication
A novel biscinchona alkaloid-catalyzed highly enantioselective desymmetrization reaction of bisphenol compounds by using achiral Morita–Baylis–Hillman carbonate agents was developed. Through the asymmetric allylic alkylation strategy, a broad range of optically active P-stereogenic phosphine oxides were generated with good yields (up to 99%) and hi...
Citations
... Notwithstanding sophisticated, contemporary enantioselective arylation 23,24 and allylation 25 protocols of secondary phosphine oxides (limited to all carbon substituents on phosphorus), a few notable reports have also been seen where a P-stereogenic centre is generated indirectly through the functionalization of enantiotopic P-bound groups. However, this approach inherently limits the scope and application of these protocols (Fig. 1a) [26][27][28][29][30][31][32][33][34][35][36] LG2; 34% yield 67% e.e. ...
... All four DNA nucleosides (26)(27)(28)(29), hepatitis C treatment sofosbuvir (30) as well as acetal-protected uridine (31) and adenosine (32) were successfully phosphorylated at the 5′-OH with moderate to good yields and >95:5 d.r. Acetal-protected d-glucose (33) and deoxythymidine (34) were both phosphorylated at the more hindered secondary 3′-OH in excellent yields and diastereoselectivity. Having established reactivity with alcohol nucleophiles we proceeded to investigate the stereocontrolled formation of alternative P-heteroatom linkages. However, when using n-propanethiol as the nucleophile, no desired product was obtained when using t BuMgCl to promote the reaction. ...
Molecules that contain a stereogenic phosphorus atom are crucial to medicine, agrochemistry and catalysis. While methods are available for the selective construction of various chiral organophosphorus compounds, catalytic enantioselective approaches for their synthesis are far less common. Given the vastness of possible substituent combinations around a phosphorus atom, protocols for their preparation should also be divergent, providing facile access not only to one but to many classes of phosphorus compounds. Here we introduce a catalytic and enantioselective strategy for the preparation of an enantioenriched phosphorus(V) centre that can be diversified enantiospecifically to a wide range of biologically relevant phosphorus(V) compounds. The process, which involves an enantioselective nucleophilic substitution catalysed by a superbasic bifunctional iminophosphorane catalyst, can accommodate a wide range of carbon substituents at phosphorus. The resulting stable, yet versatile, synthetic intermediates can be combined with a multitude of medicinally relevant O-, N- and S-based nucleophiles.
... Based on the bis(2-hydroxyphenyl) phosphine oxides, the Li group demonstrated a biscinchona alkaloid-catalyzed desymmetric allylation reaction with the Morita-Baylis-Hillman carbonate to produce P-stereogenic phosphine oxides ( Figure 2D; Supplementary Scheme S4) (Yang et al., 2019). Multiple functional groups were tolerated under mild reaction conditions, with a wide range of chiral P-stereogenic phosphine oxides prepared with good yields (up to 99%) and high enantioselectivities (up to 98.5:1.5 er). ...
P-chirality broadly appears in natural and synthetic functional molecules. The catalytic synthesis of organophosphorus compounds bearing P-stereogenic centers is still challenging, due to the lack of efficient catalytic systems. This review summarizes the key achievements in organocatalytic methodologies for the synthesis of P-stereogenic molecules. Different catalytic systems are emphasized for each strategy class (desymmetrization, kinetic resolution, and dynamic kinetic resolution) with examples cited to illustrate the potential applications of the accessed P-stereogenic organophosphorus compounds.
... 3,4 Traditionally, the construction of P-stereogenic centers has been considered to be challenging, and classical methods toward these compounds mainly rely on resolutions with stoichiometric chiral reagents or using chiral auxiliaries attached to the starting materials. [5][6][7] Over the past 2 decades, many powerful strategies have been developed for the catalytic enantioselective synthesis of P-stereogenic compounds, 8 including the desymmetrization of prochiral phosphorus substrates, [9][10][11][12][13][14][15][16][17] the hydrophosphination of alkenes or alkynes, 9,[18][19][20][21][22][23][24][25][26] the C-P coupling reactions, 27,28 and other miscellaneous reactions. 4,[29][30][31][32][33][34][35] Most of these existing methods have relied on asymmetric transition metal catalysis, while a relatively small yet significant portion of them are metalfree strategies. ...
... 4,[29][30][31][32][33][34][35] Most of these existing methods have relied on asymmetric transition metal catalysis, while a relatively small yet significant portion of them are metalfree strategies. 13,14,17,24,30,31,[33][34][35] In this context, transition metal-catalyzed enantioselective C-P coupling reactions represent straightforward methods for the expedient construction of P-stereogenic centers, and significant progress has been made in the recent few years. This perspective aims to provide a concise overview and the major advances in the aspect with particular emphasis on mechanistic insights concerning stereochemical control. ...
The transition metal-catalyzed C–P coupling reaction represents an effective strategy for the construction of P-stereogenic centers. These reactions involve different stereochemical mechanistic details depending on the phosphorus starting materials employed. The stereospecific transition metal-catalyzed C–P coupling of enantioenriched P-stereogenic compounds was mainly investigated in the early days. With the development of asymmetric catalysis, corresponding efficient kinetic resolution and dynamic kinetic asymmetric C–P coupling of racemic P-stereogenic starting compounds have recently been disclosed. This perspective discusses the impressive advances and provides an outlook on the directions of further developments.
... Notwithstanding sophisticated, contemporary enantioselective arylation 20,21 and allylation 22 protocols of secondary phosphine oxides (limited to all carbon substituents on phosphorous), a few notable reports have also been disclosed generating a P-stereogenic centre indirectly through the functionalisation of enantiotopic Pbound groups. This approach however, inherently limits the scope and application of these protocols (Figure 1, A). 3,[23][24][25][26][27][28][29][30][31][32][33] Despite these impressive advances, to date, no catalytic enantioselective desymmetrisation protocols have been established with reactivity occurring directly at the phosphorous atom. 34 We envisioned a novel, two-stage desymmetrisation-derivatisation strategy by which enantiotopic phenolic leaving groups on a pro-chiral phosphonate ester are enantiodiscriminated by a suitable nucleophile under the control of a chiral Brønsted base catalyst, 35 To explore the proposed reaction design, we began our investigations by identifying a suitable model system containing a phosphonyl dichloride mimic, utilising 2,4-dimethyl phenol as the 4 nucleophile and a BIMP superbase catalyst. ...
... All four DNA nucleosides (24)(25)(26)(27) as well as acetal protected uridine (28) and adenosine (29) were successfully phosphorylated at the 5'-OH with moderate to good yields and >95:5 dr. Acetal protected D-glucose (30) and deoxythymidine (31) were both phosphorylated at the more hindered secondary 3'-OH in excellent yields and diastereoselectivity. Having established reactivity with alcohol nucleophiles we proceeded to investigate the stereocontrolled formation of alternative P-heteroatom linkages. When using npropane thiol as the nucleophile, however, no desired product was obtained when using t-BuMgCl to promote the reaction, with the main by-product observed being (2-methyl-6nitrophenyl)(propyl)thioether obtained via SNAr . ...
Compounds containing one or more stereogenic phosphorous atoms in the P(V) oxidation state are important to chemistry, biology and medicine. These include marketed antiviral drugs such as Tenofovir alafenamide and Remdesivir, an effective treatment for Ebola which has also recently been approved for use against SARS-CoV-2 in the US. Existing approaches for the stereoselective synthesis of P-stereogenic centers, while elegant, remain mostly diastereoselective, with catalytic enantioselective approaches remaining limited in application. Accordingly, conceptually novel, broad-scope, catalytic strategies for the efficient stereoselective synthesis of diverse stereogenic P(V) containing compounds remain essential. To this end, we describe a novel enantioselective two-stage strategy, exploiting the first catalytic and highly enantioselective desymmetrisation of phosphonate esters. Pivoting on the stereocontrolled, sequential nucleophilic substitution of enantiotopic leaving groups from readily accessible pro-chiral P(V) precursors, a bifunctional iminophosphorane (BIMP) superbase catalyst was found to be essential in delivering reactive desymmetrised intermediates capable of downstream enantiospecific substitution. This uniquely modular, catalytic platform allows broad-scope, stereoselective access to a diverse library of chiral P(V) compounds including those with O, N and S-linkages.
... Notwithstanding sophisticated, contemporary enantioselective arylation 20,21 and allylation 22 protocols of secondary phosphine oxides (limited to all carbon substituents on phosphorous), a few notable reports have also been disclosed generating a P-stereogenic centre indirectly through the functionalisation of enantiotopic Pbound groups. This approach however, inherently limits the scope and application of these protocols (Figure 1, A). 3,[23][24][25][26][27][28][29][30][31][32][33] Despite these impressive advances, to date, no catalytic enantioselective desymmetrisation protocols have been established with reactivity occurring directly at the phosphorous atom. 34 We envisioned a novel, two-stage desymmetrisation-derivatisation strategy by which enantiotopic phenolic leaving groups on a pro-chiral phosphonate ester are enantiodiscriminated by a suitable nucleophile under the control of a chiral Brønsted base catalyst, 35 To explore the proposed reaction design, we began our investigations by identifying a suitable model system containing a phosphonyl dichloride mimic, utilising 2,4-dimethyl phenol as the 4 nucleophile and a BIMP superbase catalyst. ...
... All four DNA nucleosides (24)(25)(26)(27) as well as acetal protected uridine (28) and adenosine (29) were successfully phosphorylated at the 5'-OH with moderate to good yields and >95:5 dr. Acetal protected D-glucose (30) and deoxythymidine (31) were both phosphorylated at the more hindered secondary 3'-OH in excellent yields and diastereoselectivity. Having established reactivity with alcohol nucleophiles we proceeded to investigate the stereocontrolled formation of alternative P-heteroatom linkages. When using npropane thiol as the nucleophile, however, no desired product was obtained when using t-BuMgCl to promote the reaction, with the main by-product observed being (2-methyl-6nitrophenyl)(propyl)thioether obtained via SNAr . ...
Compounds containing one or more stereogenic phosphorous atoms in the P(V) oxidation state are important to chemistry, biology and medicine. These include marketed antiviral drugs such as Tenofovir alafenamide and Remdesivir, an effective treatment for Ebola which has also recently been approved for use against SARS-CoV-2 in the US. Existing approaches for the stereoselective synthesis of P-stereogenic centers, while elegant, remain mostly diastereoselective, with catalytic enantioselective approaches being limited in application. Accordingly, conceptually novel, broad-scope, catalytic strategies for the efficient stereoselective synthesis of diverse stereogenic P(V) containing compounds remain essential. To this end, we describe a novel enantioselective two-stage strategy, exploiting a catalytic and highly enantioselective desymmetrisation of phosphonate esters. Pivoting on the first stereocontrolled, sequential nucleophilic substitution of enantiotopic leaving groups from readily accessible pro-chiral P(V) precursors, a bifunctional iminophosphorane (BIMP) superbase catalyst was found to be essential in delivering reactive desymmetrised intermediates capable of downstream enantiospecific substitution. This uniquely modular, catalytic platform allows broad-scope, stereoselective access to a diverse library of chiral P(V) compounds including those with O, N and S-linkages.
... Notwithstanding sophisticated, contemporary enantioselective arylation 20,21 and allylation 22 protocols of secondary phosphine oxides (limited to all carbon substituents on phosphorous), a few notable reports have also been disclosed generating a P-stereogenic centre indirectly through the functionalisation of enantiotopic Pbound groups. This approach however, inherently limits the scope and application of these protocols (Figure 1, A). 3,[23][24][25][26][27][28][29][30][31][32][33] Despite these impressive advances, to date, no catalytic enantioselective desymmetrisation protocols have been established with reactivity occurring directly at the phosphorous atom. 34 We envisioned a novel, two-stage desymmetrisation-derivatisation strategy by which enantiotopic phenolic leaving groups on a pro-chiral phosphonate ester are enantiodiscriminated by a suitable nucleophile under the control of a chiral Brønsted base catalyst, 35 To explore the proposed reaction design, we began our investigations by identifying a suitable model system containing a phosphonyl dichloride mimic, utilising 2,4-dimethyl phenol as the 4 nucleophile and a BIMP superbase catalyst. ...
... All four DNA nucleosides (24)(25)(26)(27) as well as acetal protected uridine (28) and adenosine (29) were successfully phosphorylated at the 5'-OH with moderate to good yields and >95:5 dr. Acetal protected D-glucose (30) and deoxythymidine (31) were both phosphorylated at the more hindered secondary 3'-OH in excellent yields and diastereoselectivity. Having established reactivity with alcohol nucleophiles we proceeded to investigate the stereocontrolled formation of alternative P-heteroatom linkages. When using npropane thiol as the nucleophile, however, no desired product was obtained when using t-BuMgCl to promote the reaction, with the main by-product observed being (2-methyl-6nitrophenyl)(propyl)thioether obtained via SNAr . ...
Compounds containing one or more stereogenic phosphorous atoms in the P(V) oxidation state are important to chemistry, biology and medicine. These include marketed antiviral drugs such as Tenofovir alafenamide and Remdesivir, an effective treatment for Ebola which has also recently been approved for use against SARS-CoV-2 in the US. Existing approaches for the stereoselective synthesis of P-stereogenic centers, while elegant, remain mostly diastereoselective, with catalytic enantioselective approaches being limited in application. Accordingly, conceptually novel, broad-scope, catalytic strategies for the efficient stereoselective synthesis of diverse stereogenic P(V) containing compounds remain essential. To this end, we describe a novel enantioselective two-stage strategy, exploiting a catalytic and highly enantioselective desymmetrisation of phosphonate esters. Pivoting on the first stereocontrolled, sequential nucleophilic substitution of enantiotopic leaving groups from readily accessible pro-chiral P(V) precursors, a bifunctional iminophosphorane (BIMP) superbase catalyst was found to be essential in delivering reactive desymmetrised intermediates capable of downstream enantiospecific substitution. This uniquely modular, catalytic platform allows broad-scope, stereoselective access to a diverse library of chiral P(V) compounds including those with O, N and S-linkages.
... Notwithstanding sophisticated, contemporary enantioselective arylation 20,21 and allylation 22 protocols of secondary phosphine oxides (limited to all carbon substituents on phosphorous), a few notable reports have also been disclosed generating a P-stereogenic centre indirectly through the functionalisation of enantiotopic Pbound groups. This approach however, inherently limits the scope and application of these protocols (Figure 1, A). 3,[23][24][25][26][27][28][29][30][31][32][33] Despite these impressive advances, to date, no catalytic enantioselective desymmetrisation protocols have been established with reactivity occurring directly at the phosphorous atom. 34 We envisioned a novel, two-stage desymmetrisation-derivatisation strategy by which enantiotopic phenolic leaving groups on a pro-chiral phosphonate ester are enantiodiscriminated by a suitable nucleophile under the control of a chiral Brønsted base catalyst, 35 To explore the proposed reaction design, we began our investigations by identifying a suitable model system containing a phosphonyl dichloride mimic, utilising 2,4-dimethyl phenol as the 4 nucleophile and a BIMP superbase catalyst. ...
... All four DNA nucleosides (24)(25)(26)(27) as well as acetal protected uridine (28) and adenosine (29) were successfully phosphorylated at the 5'-OH with moderate to good yields and >95:5 dr. Acetal protected D-glucose (30) and deoxythymidine (31) were both phosphorylated at the more hindered secondary 3'-OH in excellent yields and diastereoselectivity. Having established reactivity with alcohol nucleophiles we proceeded to investigate the stereocontrolled formation of alternative P-heteroatom linkages. When using npropane thiol as the nucleophile, however, no desired product was obtained when using t-BuMgCl to promote the reaction, with the main by-product observed being (2-methyl-6nitrophenyl)(propyl)thioether obtained via SNAr . ...
Compounds containing one or more stereogenic phosphorous atoms in the P(V) oxidation state are important to chemistry, biology and medicine. These include marketed antiviral drugs such as Tenofovir alafenamide and Remdesivir, an effective treatment for Ebola which has also recently been approved for use against SARS-CoV-2 in the US. Existing approaches for the stereoselective synthesis of P-stereogenic centers, while elegant, remain mostly diastereoselective, with catalytic enantioselective approaches remaining limited in application. Accordingly, conceptually novel, broad-scope, catalytic strategies for the efficient stereoselective synthesis of diverse stereogenic P(V) containing compounds remain essential. To this end, we describe a novel enantioselective two-stage strategy, exploiting the first catalytic and highly enantioselective desymmetrisation of phosphonate esters. Pivoting on the stereocontrolled, sequential nucleophilic substitution of enantiotopic leaving groups from readily accessible pro-chiral P(V) precursors, a bifunctional iminophosphorane (BIMP) superbase catalyst was found to be essential in delivering reactive desymmetrised intermediates capable of downstream enantiospecific substitution. This uniquely modular, catalytic platform allows broad-scope, stereoselective access to a diverse library of chiral P(V) compounds including those with O, N and S-linkages.
... Li and co-workers reported a novel bis-cinchona alkaloid-catalyzed desymmetrization reaction of bisphenol compounds 40 with achiral Morita-Baylis-Hillman (MBH) carbonates 41. Through this Lewis base 42 catalyzed asymmetric allylic alkylation strategy, a series of functionalized phosphine oxides 43 were constructed with high enantioselectivity (Scheme 6c) [21]. However, the slow rate of reaction resulted in long reaction times (six days) to reach completion. ...
The construction of chiral phosphorus molecules with asymmetric center on the phosphorus atom has always been considered to be challenging in synthetic chemistry. Such P-stereogenic compounds possess many unique properties allowing many potential applications in natural products synthesis, pharmaceuticals as well as ligands in asymmetric organometallic catalysis. This increase in importance P-stereogenic compounds has driven chemists to develop sophisticated strategies over the years to construct chiral phosphorus compounds. In this review, we aim to discuss the methodologies for the construction of P-stereogenic centers that were developed from 2005 to 2020. The review has been organized into seven sections according to their respective reaction principles beginning with desymmetrization, followed by phosphonoalkylation and phosphonoarylation, asymmetric addition, deprotonation, ring-closing metathesis, the use of organolithiums and Grignard reagents together with chiral auxiliaries and ending with kinetic resolution.
... To avoid the consumption of stoichiometric amounts of chiral reagents, catalytic asymmetric methods such as metalcatalyzed asymmetric couplings [12][13][14][15][16][17][18][19][20] and desymmetrization of prochiral phosphorus molecules have been developed. [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] Particularly, the desymmetrization methods have been paid more attention recently. Typical examples include transition metal-catalyzed intra-and intermolecular C-H functionalization, [22][23][24][25][26][27][28] Mo-and Rucatalyzed ring-closing metathesis, 29,30 Rh-catalyzed cycloaddition and hydroarylation, 31,32 Au-catalyzed intramolecular hydroetherification, 33 NHC-catalyzed esterification, 34 Tm-catalyzed intermolecular sulfenylation 35 and cinchona alkaloid-catalyzed allylic alkylation reaction. ...
... Typical examples include transition metal-catalyzed intra-and intermolecular C-H functionalization, [22][23][24][25][26][27][28] Mo-and Rucatalyzed ring-closing metathesis, 29,30 Rh-catalyzed cycloaddition and hydroarylation, 31,32 Au-catalyzed intramolecular hydroetherification, 33 NHC-catalyzed esterification, 34 Tm-catalyzed intermolecular sulfenylation 35 and cinchona alkaloid-catalyzed allylic alkylation reaction. 36 However, these methods often suffered from the limitations of substrate scope. Some types of P-chiral compounds with practical potential such as triaryl phosphine oxides could not be achieved. ...
Intermolecular pnictogen bonding (PnB) catalysis has received increased interest in non‐covalent organocatalysis. It has been demonstrated that organic electron‐deficient pnictogen atoms can act as prospective Lewis acids. Here, we present a catalytic approach for the asymmetric synthesis of chiral PIII compounds by combining intramolecular PnB interactions and carbene catalysis. Our design features a pre‐chiral phosphorus molecules bearing two electron‐withdrawing benzoyl groups, resulting in the formation of a σ‐hole at the P atom. X‐ray and non‐covalent interaction (NCI) analysis indicate that these phosphorus substrates exhibit intrinsic PnB interactions between the oxygen atom of the formyl group and the phosphorus atom. This induces a conformational locking effect, leading to the crystallization of the phosphorus substrates in a preferred conformation (P212121 chiral group). Under the catalysis of N–heterocyclic carbene, the aldehyde moiety activated by the pnictogen bond selectively reacts with an alcohol to yield the corresponding chiral monoester/phosphorus products with excellent enantioselectivity. This Lewis acidic phosphorus center, aroused by the non‐polarized intramolecular pnictogen bond interaction, assists in conformational and selective regulations, providing unique opportunities for catalysis and beyond.
