P‐Chiral Organophosphorus Compounds: Synthesis, Mechanism, and Applications

ABSTRACT

The enantioselective synthesis of P‐stereogenic compounds has emerged as a central focus in modern asymmetric catalysis, driven by their pivotal roles as ligands (Ls), organocatalysts, and bioactive molecules. Over the past decade, significant advances have been made in developing catalytic strategies that enable precise control over phosphorus stereochemistry, expanding both the structural diversity and synthetic utility of these scaffolds. This review highlights recent progress in two key areas: direct P–C bond formation and desymmetrization. P–C bond‐forming approaches include cross‐coupling reactions of secondary phosphines or their oxides with aryl, alkyl, or benzyl halides, as well as hydrophosphination of alkenes and alkynes. Desymmetrization strategies encompass nucleophilic substitution at P(V) centers, cyclization, C–H activation (CHA), phenolic –OH activation, and P–O alkylation/arylation. Mechanistic insights into these transformations have been discussed, along with the derivatization of P‐chiral products and their applications in catalysis, L design, and bioactive molecule synthesis. This comprehensive overview shall serve as a valuable resource for researchers working in asymmetric organophosphorus chemistry.

This review highlights recent advances in the enantioselective synthesis of P‐chiral organophosphorus compounds, with an emphasis on catalytic strategies, such as P–C bond formation and desymmetrization reactions. Key methodologies, including desymmetrization of prochiral phosphorus substrates and catalytic enantioselective P–C bond‐forming reactions, are discussed, along with mechanistic insights, product transformations, and applications in asymmetric catalysis. Together, these approaches provide a comprehensive overview of modern synthetic strategies shaping the field of P‐chiral phosphorus chemistry.

Abbreviations

ARCM

asymmetric ring‐closing metathesis

BDPP

2,2′‐bis(diphenylphosphino)‐1,1′‐binaphthyl

BIMP

bifunctional iminophosphorane

CPA

chiral phosphoric acid

CuAAC

copper‐catalyzed azide‐alkyne cycloaddition

DKR

dynamic kinetic resolution

dr

diastereomeric ratio

DYKAT

dynamic kinetic asymmetric transformation

ee

enantiomeric excess

Et‐DuPHOS

1,2‐bis(2,5‐diethylphospholano)benzene

HG‐II

Hoveyda–Grubbs second‐generation catalyst

KR

kinetic resolution

L

ligand

MBH

Morita–Baylis–Hillman

Me‐DuPHOS

1,2‐bis(2,5‐dimethylphospholano)benzene

NHC

N‐heterocyclic carbene

PAMP

1,2‐bis[(2‐methoxyphenyl)(phenyl)phosphino]ethane

PPO

primary phosphine oxide

rr

regioisomeric ratio

SPO

secondary phosphine oxide

TPO

tertiary phosphine oxide

1. Introduction

Organophosphorus compounds occupy a central position in modern chemistry due to their diverse roles in catalysis, materials science, agrochemicals, and medicinal chemistry [1, 2, 3, 4]. Among them, chiral phosphorus compounds have emerged as indispensable structural motifs, particularly in the field of asymmetric catalysis, where they often serve as ligands (Ls), organocatalysts, or intermediates for the construction of enantioenriched molecules [5, 6, 7, 8]. Their ability to modulate both the steric and electronic environment of a catalytic center enables remarkable levels of selectivity in numerous transformations [9]. Over the past decades, the development of structurally and stereochemically defined phosphorus‐containing molecules has attracted sustained research interest, driven by the expanding scope of catalytic reactions and the increasing demand for enantioselective synthesis in the pharmaceutical and fine chemical industries.

Chirality in organophosphorus chemistry can arise from different structural features, and it is broadly classified into three main types by the location of their chirality. C‐chirality, the most familiar form, results from a sp³‐hybridized carbon center bearing four distinct substituents; for example, DIOP by Kagan and Dang [10]. Axial chirality (backbone) arises when restricted rotation about a bond creates nonsuperimposable stereoisomers; in organophosphorus chemistry, this is exemplified by the backbone‐chiral L BINAP, developed by Noyori and Takaya [11], in which the rigid binaphthyl framework imposes a well‐defined chiral axis. In addition to these, chiral phosphoramidite Ls derived from BINOL or amino alcohol scaffolds, represent an important class of C‐chiral phosphorus‐containing Ls. In these systems, the chirality resides in the organic backbone and play a crucial role in asymmetric catalysis due to their tunable electronic and steric environments [12]. P‐chirality, in contrast, originates from a stereogenic phosphorus center itself, typically in trivalent or pentavalent states, such as in tert‐butylmethylphenylphosphine or menthylphenylphosphinate. The introduction of P‐chiral (1S,2S)‐bis[(2‐methoxyphenyl)phenylphosphino]ethane (DIPAMP) by Knowles [13] exemplify such advancements. The configurational stability of the phosphorus stereocenter depends on its coordination state, substituent bulk, and electronic properties, making the control of P‐stereogenicity a uniquely challenging but rewarding endeavor in synthesis. In particular, P‐chiral compounds and their derivatives have emerged as indispensable chiral Ls, organocatalysts, and functional building blocks in asymmetric synthesis (Figure 1).

FIGURE 1.

Representative modes of chirality in phosphorus Ls.

P‐chiral phosphorus compounds have a profound impact across multiple branches of chemistry [14, 15, 16, 17, 18]. In asymmetric catalysis, P‐stereogenic phosphines, phosphoramidites, and phosphinites function as highly tunable Ls for transition metals, enabling outstanding stereocontrol in hydrogenations [19, 20, 21], cross‐couplings, cycloadditions, and other key transformations. Beyond catalysis, these compounds find utility in drug design, as chiral phosphorus‐containing motifs are present in bioactive molecules [22]. Extending to pharmaceuticals such as Remdesivir and Sofosbuvir, both of which are nucleoside analogues with potent antiviral activity [23]. Additionally, Phostine, a drug with antiproliferative properties [24], Cyclophostin, an acetylcholinesterase inhibitor [25], and (Rp)‐cAMPS, a potent competitive inhibitor of cAMP‐dependent protein kinase [26, 27, 28, 29, 30], all demonstrate diverse medicinal uses. Moreover, Salition [31, 32, 33], Cytoxan [34, 35, 36, 37], and Salinipostin [38] are utilized in pesticides, antitumor drugs, and antimalarial treatments, respectively (Figure 2). In materials science, P‐chiral frameworks contribute to optoelectronic properties, supramolecular assemblies, and chiroptical devices. The unique combination of stereoelectronic effects imparted by a P‐stereogenic center allows for fine adjustment of catalyst reactivity and selectivity, often outperforming C‐chiral or backbone‐chiral Ls in specific transformations.

FIGURE 2.

Applications of P‐chiral phosphorus compounds.

The synthesis of P‐chiral compounds can be approached through three principal strategies: resolution, chiral auxiliary‐mediated synthesis, and enantioselective (asymmetric) synthesis.

Early strategies developed in the 1960s–1980s primarily relied on classical resolution techniques, including diastereomeric salt formation [39], enzymatic kinetic resolution (KR) [40], and chiral chromatography [41], to separate enantiomers from racemic mixtures of phosphines or phosphine oxides [42]. While these methods laid the groundwork for the field, they suffered from fundamental limitations: low efficiency, poor scalability, the need for stoichiometric amounts of resolving agents, and the inevitable loss of one enantiomer and often requires multiple steps for racemate preparation.

Subsequent approaches attempted to circumvent these limitations through the use of chiral auxiliaries, stoichiometric chiral reagents, or asymmetric synthesis under substrate control. Chiral auxiliaries enable stereocontrol through temporary covalent attachment of a chiral moiety to the phosphorus precursor, but they necessitate additional steps for auxiliary installation and removal, reducing atom economy. Importantly, recent developments by Gilheany et al. [43, 44], Vantourout et al. [45], and Feringa et al. [46, 47] have demonstrated that auxiliary‐controlled strategies can provide broad substrate scope and modular access to structurally diverse P‐stereogenic frameworks, and in many cases the auxiliary can be efficiently recovered. Nevertheless, despite these advances, the broader implementation of P‐chiral compounds in synthesis expanded significantly only after the emergence of catalytic asymmetric methodologies and improved stereochemical analysis techniques [48, 49, 50, 51].

Enantioselective synthesis employs chiral catalysts (either metal complexes or organocatalysts) to directly induce P‐stereogenicity from prochiral precursors. In the past decade, the field has undergone a transformative shift driven by the emergence of catalytic enantioselective methodologies that enable direct and efficient construction of P‐stereogenic centers under mild condition. It has emerged as the most attractive approach due to its efficiency, scalability, and atom‐economical conditions. Notably, the development of transition metal‐catalyzed cross coupling reactions with aryl and alkyl halides, hydrophosphination reactions [52] with alkenes and alkynes, dynamic kinetic resolutions (DKRs), nucleophilic addition to unsaturated acceptors, asymmetric substitution reactions, and oxidative desymmetrization has vastly expanded the toolbox for accessing P‐chiral compounds with high enantioselectivity. Research in the past years has focused on the catalytic synthesis of phosphines [53, 54]. Recent reviews from Su and coworkers, as well as Long, Gu, and coworkers, have summarized selected aspects of asymmetric synthesis of P‐stereogenic compounds through organizing methods by catalyst class or substrate type [55, 56, 57]. In parallel, notable progress has also been achieved in N‐heterocyclic carbene (NHC) catalysis for the enantioselective construction of heteroatom‐centered stereogenic frameworks, including those bearing phosphorus chirality [58]. The asymmetric catalytic synthesis of chiral phosphines has only recently emerged and is under full development. The design of chiral Ls and catalyst architectures, particularly those capable of stabilizing key reactive intermediates and enforcing stereocontrol, has been pivotal in overcoming prior limitations and achieving generalizable solutions. Despite progress in catalytic methods, asymmetric synthesis of chiral phosphines remains challenging, largely due to limited synthetic approaches and the difficulty of producing optically pure chiral phosphines [59, 60].

This review aims to provide a comprehensive and structured overview of the modern asymmetric synthetic strategies of P‐chiral compounds, with a particular emphasis on developments from the past decade (2015–2025). The discussion is organized around a key synthetic approach; we examine the underlying mechanistic insights, scope, the potential for product derivatization, and their demonstrated applications in asymmetric catalysis. Special attention will be paid to enantioselective catalysis strategies in the stereoselective synthesis of phosphorus‐chiral frameworks. Through this integrative perspective, we aim to highlight the conceptual evolution of the field, identify emerging trends, and provide a framework for future exploration in phosphorus stereochemistry and its exploitation in asymmetric synthesis.

2. P–C Cross‐Coupling Reactions

2.1. Arylation of Secondary Phosphines or Phosphine‐Oxides With Aryl Halides

Transition metal‐catalyzed asymmetric P–C bond formation between secondary phosphines or secondary phosphine oxides (SPOs) and aryl halides has emerged as a highly efficient strategy for the synthesis of P‐stereogenic phosphines. The first notable advance came from Glueck and coworkers (2002), who pioneered a Pd‐catalyzed enantioselective C–P cross coupling of racemic secondary phosphines, such as PH(Me)(2,4,6‐ ⁱ Pr₃C₆H₂), with aryl iodides using a chiral 1,2‐bis(2,5‐dimethylphospholano)benzene (Me‐DuPHOS) L to obtain P‐chiral phosphines [61, 62]. In the presence of the chiral Pd‐phosphido complex, one enantiomeric Pd‐phosphido intermediate undergoes reductive elimination more rapidly than the other, while the slower‐reacting enantiomer re‐equilibrates back through inversion, effectively funneling both enantiomers into the same stereochemical pathway. This constitutes a DKR in which epimerization at phosphorus and enantioselective C–P bond formation operate cooperatively to deliver a single P‐chiral product (Scheme 1a). This strategy furnished tertiary phosphines with up to 78% enantiomeric excess (ee).

SCHEME 1.

Pd‐catalysed asymmetric phosphination.

Building on this concept, Helmchen and coworkers (2004) developed an improved Pd‐catalyzed enantioselective arylation of diarylphosphines with ortho‐substituted aryl iodides. Using an in situ generated catalyst from [Pd₂(dba)₃], (R,R)‐Et,Et‐FerroTANE, and LiBr [63], achieved triarylphosphines with >90% ee. Both the presence of ortho‐substituents on the aryl iodide and the choice of base (e.g., NEt₃ or N‐Me‐piperidine) were critical for high stereoselectivity, while LiBr further enhanced yield and enantiocontrol. Compared to Glueck's protocol, Helmchen's method provided a broader substrate scope and improved practicality for L synthesis (Scheme 1b).

A further advancement was reported by Zhang and coworkers (2016), who achieved a Pd‐catalyzed kinetic arylation of diarylphosphine oxides. Using ortho‐substituted aryl iodides in combination with chiral phosphine Ls such as L1, the authors optimized conditions with N‐methyl morpholine as the base and acetonitrile as the preferred solvent (Scheme 2). This method produced triarylphosphine oxides in up to 95% yield and 83% ee, with enantiopurity enhanced to >99% ee by recrystallization [64]. The work highlighted phosphine oxides as air‐stable and versatile intermediates, enabling straightforward access to chiral phosphines.

SCHEME 2.

Arylation of diarylphosphine oxides.

To address the challenges posed by the high nucleophilicity and strong metal‐binding ability of SPOs, factors that can hinder stereoselective catalysis by competing with chiral Ls, Zhang and coworkers (2019) introduced a new generation of hemilabile Ls, (S, R_S )‐Xiao‐Phos (Scheme 3). Based on a sulfinamide–phosphine scaffold, Xiao‐Phos displayed dynamic coordination to the Pd‐center, thereby maintaining high stereocontrol. This system enabled the synthesis of a wide variety of P‐chiral phosphine oxides in up to 97% ee and 96% yield, and facilitated the modular preparation of DiPAMP analogues, underscoring its versatility in L design [65].

SCHEME 3.

Palladium/Xiao‐Phos‐catalyzed asymmetric P–C cross‐coupling.

Most recently, Zhang and coworkers (2023) developed a Ni(II)‐catalyzed asymmetric C–P cross‐coupling of SPOs with heteroaryl chlorides under mild conditions. Using [Ni(DME)Br₂]/(S,S)‐CHIRAPHOS, the method delivered heterocyclic tertiary phosphine oxides (TPOs) with high efficiency and up to 98% ee [66]. The reaction proceeds without an external reductant; it involves formal changes in the oxidation state of Ni. The steric and electronic properties of the P‐substituents were found to be key determinants of selectivity, and electron‐deficient heterocycles such as pyrazines, quinoxalines, and pyridines were particularly well tolerated.

The approach also enabled double C–P bond formation to access bidentate Ls with excellent stereocontrol. The resulting P‐chiral phosphine oxides were readily reduced or derivatized into P(III) Ls, which readily coordinated to metal centers to form well‐defined complexes. Furthermore, Suzuki coupling of selected products enabled the preparation of chiral photoluminescent materials with circularly polarized luminescence (CPL), underscoring their potential in optoelectronic and chiroptical applications (Scheme 4).

SCHEME 4.

Ni‐catalyzed asymmetric C−P cross‐coupling reaction.

Wang, Duan, and coworkers developed a Ni–PHOX‐catalyzed asymmetric arylation of SPOs and aryl and heteroaryl halides, affording P‐chiral phosphine oxides (Scheme 5) with good functional group tolerance and excellent enantioselectivity (up to 99% ee) [67]. Aryl bromides reacted more efficiently than aryl chlorides, reflecting faster oxidative addition.

SCHEME 5.

Ni‐catalyzed asymmetric arylation.

To overcome the inherent limitations of classical KR, copper catalysis has been leveraged to perform dynamic kinetic asymmetric transformations (DYKATs). In 2023, Su and coworkers reported a Cu‐catalyzed DYKAT of SPOs with aryl iodides, employing a tailored 1,2‐diamine L (Scheme 6) [68]. This reaction delivered a broad range of P‐stereogenic TPOs in high yields and excellent enantioselectivities (average ee = 89%). Rapid interconversion between trivalent intermediates (phosphinous acids, (S_P )‐PA and (R_P )‐PA) occurs through tautomerization of the (rac)‐SPO, under the reaction conditions. The (S_P )‐PA enantiomer undergoes faster oxidative coupling with Ar–I in the presence of Cu and base, likely via a trivalent Cu–P intermediate, to afford (S_P )‐TPO in a stereoretentive manner. In contrast, the coupling of (R_P )‐PA is considerably slower, allowing it to re‐equilibrate to (S_P )‐PA. This DYKAT thus selectively channels the faster‐reacting enantiomer into the product, leading to the enantioenriched TPO. The resulting chiral P(V) could be readily reduced to P(III) Ls for subsequent catalytic applications. Other various transformations were also carried out to broaden the structural diversity of the resulting chiral TPOs.

SCHEME 6.

Cu‐catalyzed dynamic kinetic asymmetric P−C coupling.

Zhang and coworkers (2024) reported a Cu‐catalyzed asymmetric P–C coupling to construct pyrimidinyl phosphines bearing both axial and P‐central chirality. The strategy involved in situ generation of secondary phosphines followed by coupling with heteroaryl chlorides, facilitated by a chiral NHC‐1 L in combination with an achiral diphosphine [69]. This cooperative L system effectively suppressed background reactions and L poisoning by the P(III) species, delivering P‐chiral phosphines with up to 96% ee and diastereomeric ratios (drs) as high as 14:1. Moreover, the resulting dual‐chirality scaffolds readily undergo S_NAr reactions with diverse nucleophiles, enabling rapid synthesis (Scheme 7).

SCHEME 7.

Cu/NHC‐catalyzed asymmetric synthesis of pyrimidinyl phosphine.

Building on this concept, Liu and coworkers (2025) reported a Pd‐catalyzed C–P coupling that achieves the simultaneous construction of axial and P‐centered chirality in heterobiaryl phosphine oxides. Using racemic heterobiaryl triflates and racemic SPOs under [Pd₂(dba)₃]/(S)‐tol‐BINAP catalysis, a range of P‐ and axially chiral phosphine oxides were obtained in good yields and with excellent diastereo‐ and enantioselectivities (up to 98% ee) [70]. Mechanistically, the reaction operates through a DyKAT of the heterobiaryl electrophile, combined with KR of the SPO partner. Synthetic value was demonstrated through the oxidation of the products with m‐CPBA resulted in the corresponding N‐oxides and P‐oxides (R, S_P )‐L3 and (R)‐L4 with >99% ee, which were further applied as chiral Lewis‐base catalysts in enantioselective reactions (Scheme 8).

SCHEME 8.

Pd‐catalyzed C–P coupling of heterobiaryl triflates and SPOs.

In 2007, Glueck and coworkers reported an enantioselective intramolecular Pd‐catalyzed C–P cyclization strategy to access P‐stereogenic benzophospholanes. Using chiral diphosphine Ls, secondary phosphines or their borane‐protected analogs were cyclized to yield enantioenriched cyclic phosphines with up to 70% ee [71], and substrate scope was limited (Scheme 9). The work represented an important early proof‐of‐concept but highlighted the challenge of achieving high enantioselectivity and generality in asymmetric intramolecular phosphination.

SCHEME 9.

Pd‐catalyzed intramolecular phosphination.

Building upon this foundation, Yang and coworkers made a series of significant advances in Cu‐catalyzed DYKATs and DKRs to overcome the limitations of the earlier Pd systems [72, 73, 74, 75]. In 2022, they developed a Cu‐catalyzed dynamic kinetic intramolecular C–P cross‐coupling of H‐phosphinates using a chiral ethylenediamine L (L5), enabling concise and highly enantioselective synthesis of six‐ to eight‐membered P‐stereogenic heterocycles under mild conditions, with yields and ee up to 99%. Later, this strategy was extended to SPOs, DKR delivered cyclic P(V)‐stereogenic phosphine oxides that could be reduced to useful P(III)‐chiral phosphines without erosion of enantiopurity. Further, they expanded the scope to five‐ to eight‐membered benzo‐fused P‐heterocycles via DKR of racemic H–P(O) compounds (ee up to 94%). Most recently, in 2025, they reported an unprecedented DKR of secondary phosphine‐boranes, a class of air‐stable yet previously underutilized substrates. This method furnished medium‐sized P(III)‐stereogenic benzophosphine‐boranes (7–10‐membered cycles) in excellent enantioselectivities up to 97% ee (Scheme 10), with the added advantage that the BH₃ adducts could be readily deprotected under mild conditions to yield free chiral phosphines.

SCHEME 10.

Cu‐catalyzed intramolecular cyclization.

The Chikkali group has made pioneering contributions toward the development of P‐chiral supramolecular phosphines through catalytic enantioselective C–P cross‐coupling reactions. In 2015, they disclosed the first highly enantioselective synthesis of P‐chiral supramolecular Ls via Pd‐catalyzed phosphination of racemic secondary phosphines with aryl iodides containing urea motifs. A preformed Pd(II)‐Me‐DuPHOS [Pd‐3] complex efficiently catalyzed the transformation, delivering urea‐functionalized P‐chiral phosphines with an unprecedented ee of 97% [76]. Importantly, the installed urea unit enabled subsequent supramolecular self‐assembly [Rh‐1] on transition metal templates, allowing these monodentate Ls to mimic bidentate coordination. When evaluated in Rh‐catalyzed asymmetric hydrogenation, the self‐assembled supramolecular L provided hydrogenated products in up to 99% ee, highlighting the potential of these newly designed Ls in asymmetric catalysis.

Building upon this initial success, further efforts were directed toward improving the sluggish kinetics observed in the DuPHOS‐based system. In 2018, the group reported an accelerated protocol by employing a newly designed Pd‐FerroLANE [Pd‐2] complex as catalyst [77]. The electron‐rich ferrocene backbone and wider bite angle of FerroLANE were shown to facilitate oxidative addition and reductive elimination steps, thereby dramatically reducing the reaction time from several days to less than 24 h (Scheme 11). This improvement enabled the preparation of a library of 18 P‐chiral urea phosphines with excellent conversions and ees ranging from 15% to 62%. The study also revealed structure‐selectivity relationships, where the position of the urea group and steric environment around phosphorus critically influenced the stereochemical outcome. Although the enantioselectivities were moderate compared to the earlier system, the accelerated access to a diverse set of Ls significantly expanded the chemical space of supramolecular P‐chiral phosphines.

SCHEME 11.

P‐chiral supramolecular phosphine synthesis.

In parallel, mechanistic investigations were undertaken to understand the origin of enantioselectivity in supramolecular catalysis. Using NMR spectroscopy, IR, and isotopic labeling experiments, the group provided direct experimental evidence for hydrogen‐bonding interactions between the P‐chiral supramolecular Ls and substrates during catalysis. The studies revealed that free Ls engage in intermolecular hydrogen bonding, whereas their self‐assembled Rh complexes such as [Rh‐1] exhibit intramolecular H‐bonding, a key factor stabilizing the catalytic assembly. Furthermore, stoichiometric experiments with dehydrophenylalanine substrates showed downfield shifts of the L's NH/NH₂ resonances upon complexation, unambiguously confirming catalyst‐substrate H‐bonding. These interactions were directly correlated with the observed high enantioselectivities in Rh‐catalyzed asymmetric hydrogenation of amino acid precursors, in contrast to modest ee values obtained for benchmark substrates lacking hydrogen‐bond acceptor groups [78].

Most recently, the group advanced this strategy by addressing the configurational lability of P‐stereogenic centers. In 2024, same group reported the synthesis of thermally robust P‐chiral supramolecular phosphines by employing cyclic secondary phosphines such as phosphindolines in asymmetric Pd‐catalyzed P–C coupling. The use of a chiral QuinoxP*‐based Pd catalyst [Pd‐5] enabled highly enantioselective synthesis of cyclic supramolecular phosphines (up to 99% ee). Remarkably, these Ls retained their stereochemical integrity even after heating at 150°C in air, a feature unprecedented in P‐chiral systems. The Ls readily self‐assembled with Pt, Pd, and Rh templates to generate catalytically competent complexes. Application of the Rh‐supramolecular assembly in asymmetric hydrogenation of functionalized alkenes delivered a broad range of products in nearly quantitative yields and >99% ee across 16 different substrates [79]. This work not only addressed the issue of configurational stability at phosphorus but also established a versatile platform for robust and high‐performing P‐chiral supramolecular Ls in asymmetric catalysis (Scheme 12).

SCHEME 12.

Thermally stable P‐chiral supramolecular phosphine synthesis.

Overall, the evolution from Pd‐catalyzed KR to Cu‐catalyzed dynamic kinetic transformations and dual‐chirality scaffold construction has significantly broadened the synthetic toolkit for accessing enantioenriched P‐stereogenic phosphorus compounds. Additionally, these studies demonstrate a clear progression in the design and utility of supramolecular P‐chiral phosphines, from the first catalytic enantioselective access, to accelerated L synthesis, mechanistic elucidation of H‐bonding interactions, and finally to thermally stable, high‐performing systems with broad catalytic scope. Together, they establish P‐chiral supramolecular phosphines as a powerful class of Ls that combine synthetic accessibility, self‐assembly, and high stereocontrol in asymmetric catalysis.

2.2. Alkylation of Secondary Phosphines or Oxides With Benzyl or Alkyl Halides

In recent years, catalytic asymmetric alkylation of secondary phosphines or their oxides with benzyl or alkyl halides has emerged as a powerful and direct approach for accessing structurally diverse P‐chiral scaffolds. Advances in this field have relied on a range of transition metals, including platinum, ruthenium, palladium, nickel, copper, manganese, and cobalt to address the dual challenges of stereochemical control and chemoselectivity.

One of the earliest breakthroughs was reported by Glueck and coworkers in 2006, who developed a Pt‐catalyzed asymmetric alkylation of secondary phosphines with benzyl halides using the chiral complex [Pt‐1] and NaOSiMe₃ as base. Benzyl bromide emerged as the optimal electrophile, delivering P‐chiral products in up to 93% ee [80]. Mechanistic studies revealed the intermediacy of a Pt‐phosphido species undergoing rapid inversion at phosphorus, establishing a dynamic equilibrium between diastereomers. The high enantioselectivity was attributed to differential alkylation rates of these interconverting species under low‐temperature conditions (Scheme 13).

SCHEME 13.

Asymmetric benzylation of secondary phosphines.

Building on this concept, Toste and Bergman employed Ru(II)‐phosphido complexes to achieve enantioselective alkylation via DYKAT. In their 2006 report, a [((R)‐ ⁱ Pr‐PHOX)₂RuH] catalyst mediated the alkylation of secondary phosphines with benzyl chlorides, delivering P‐chiral phosphine boranes. The method showed broad substrate scope, tolerating para‐, ortho‐, and heteroaryl substituents, and even enabled the synthesis of chiral bisphosphines and pincer Ls in high enantioselectivity up to 95% ee (Scheme 14a) [81].

SCHEME 14.

Ru(II)‐catalyzed enantioselective alkylation via DYKAT.

Their 2009 follow‐up expanded the scope and clarified the mechanism: Nucleophilic attack by the Ru‐phosphido was identified as the stereochemistry‐determining step, controlled by the chiral L environment. Chiral mixed‐L Ru(II)‐hydride complexes such as (R)‐MeO‐BiPHEP/dmpe and (R)‐DIFLUORPHOS/dmpe enabled the alkylation of racemic secondary phosphines with both benzylic and less activated alkyl halides in high enantioselectivity (Scheme 14b). The high nucleophilicity of Ru‐phosphido intermediates, generated upon deprotonation of coordinated phosphines, facilitated rapid inversion at phosphorus, allowing selective trapping of one enantiomer through alkylation [82]. This work systematically explored L effects, inversion barriers at phosphorus, and electronic influences of the electrophiles, thereby providing a general mechanistic platform for asymmetric P–C bond construction via alkylation.

A distinct strategy was introduced by Zhang and coworkers in 2021, who reported a Pd‐catalyzed KR of SPOs via P‐benzylation using the Xiao‐Phos L. Benzyl diethyl phosphate was identified as the optimal electrophile, affording tertiary P‐chiral phosphine oxides and recovering unreacted SPOs with high selectivity factors (up to s = 226.1) [83]. Mechanistic studies suggested stereocontrol arose from catalyst‐substrate complexation via phosphinous acid tautomers. The resulting P‐chiral products were readily derivatized into bidentate Ls and metal complexes, demonstrating immediate applicability in asymmetric catalysis (Scheme 15).

SCHEME 15.

Pd‐catalyzed KR of SPOs via P‐benzylation.

Cai and Zhang (2022) extended this transformation to a Ni(II)‐catalyzed enantioselective benzylation of SPOs using (S,S)‐Me‐Duphos as L and K₂HPO₄ or K₂CO₃ as base in mesitylene. This operationally simple protocol afforded P‐chiral TPOs in up to 98% ee and high yield (Scheme 16) [84]. The mechanism was proposed to involve a Ni‐η³‐benzyl intermediate, analogous to known allylation pathways.

SCHEME 16.

Ni(II)‐catalyzed benzylation of SPOs.

From a sustainability perspective, Yin and coworkers developed a Cu(I)‐catalyzed alkylation of unsymmetrical diaryl secondary phosphines (HPAr¹Ar²) with a broad range of alkyl halides, including allyl, propargyl, benzyl, and alkyl iodides. Employing Cu(I‐R,R_P )‐TANIAPHOS complexes, the protocol delivered mono‐, di‐, and tri‐alkylated P‐chiral phosphines in high yields and ee values [85]. Mechanistic investigations via ³¹P NMR confirmed the formation of Cu‐PAr¹Ar² species as the active nucleophile. Then, in the presence of RBr, a fast asymmetric S_N2 substitution takes place, delivering the desired chiral RPAr¹Ar² product while simultaneously regenerating the Cu‐catalyst (Scheme 17). The products were readily transformed into chiral mono‐ and bisphosphine Ls, which were further used to prepare Cu(I) complexes.

SCHEME 17.

Cu(I)‐catalyzed alkylation and benzylation of diaryl secondary phosphines.

In a rare example of base‐metal‐mediated enantioselective alkylation, Harutyunyan and coworkers (2025) reported a Mn(I)‐catalyzed alkylation of secondary phosphines such as HPPhMes with benzyl chlorides, achieving up to 90% ee at room temperature using a chiral Clarke‐type Mn(I) complex and Cs₂CO₃ as a base in acetonitrile [86]. Furthermore, up to 94% ee was achieved with different secondary phosphines and alkyl or benzyl halides. Mechanistic studies identified Mn‐phosphido intermediates, confirming an S_N2‐type pathway. The newly synthesized chiral PNP‐Mn‐1 complex was applied in the asymmetric transfer hydrogenation of an aryl ketone, affording the corresponding product with 98% ee (Scheme 18). This study is significant not only due to its use of an earth‐abundant metal but also because it effectively activates less reactive alkyl chlorides.

SCHEME 18.

Mn(I)‐catalyzed synthesis of P‐chiral phosphines and their application.

Finally, Duan and Zhang (2021) showcased a cobalt‐catalyzed asymmetric alkylation of SPOs containing pyridinyl substituents as directing groups. These substituents enhanced coordination to the Co center and improved aryl group differentiation, enabling up to 99.5% ee [87]. To showcase the utility of the resulting chiral product, the pyridinyl unit could be removed either via nucleophilic attack by MeMgBr or MeLi in the presence of additives, or through a Ni‐catalyzed cross‐coupling reaction (Scheme 19). These transformations provided the corresponding products in moderate yields, accompanied by a partial erosion of enantioselectivity.

SCHEME 19.

Co‐catalyzed asymmetric synthesis of TPOs and transformations.

Collectively, these diverse catalytic systems ranging from noble metal complexes (Pt, Ru, Pd) to base metals (Cu, Ni, Mn, Co) highlight the growing versatility and sophistication in designing enantioselective alkylation methodologies for accessing P‐stereogenic phosphines. These advances not only offer improved sustainability but also open new avenues for constructing chiral Ls and organophosphorus frameworks central to asymmetric catalysis.

2.3. Cross‐Coupling Reactions With Other Electrophiles and Allylation Strategies

Recent advances highlight the strategic use of secondary phosphines or their oxides as nucleophiles, enabling their coupling with a range of electrophiles under transition metal catalysis to forge P‐stereogenic centers. An early landmark was provided by Gaunt and coworkers, who reported the first example of Cu‐catalyzed dynamic kinetic enantioselective arylation of SPOs with diaryliodonium salts. The reaction employed a chiral pyridinebisoxazoline(PyBOX)/Cu‐complex (Cu‐1) to achieve enantioselective reductive elimination, furnishing P‐stereogenic diarylphosphine oxides in high yields and ees (Scheme 20) [88]. High enantioselectivity (up to 98% ee) was achieved under mild conditions, making this a foundational example of DKR‐based C–P bond formation. The resulting chiral phosphine oxides were transformed under Suzuki cross‐coupling to form a chiral P(V) L analogue.

SCHEME 20.

Enantioselective arylation of SPOs with diaryliodonium salts.

Expanding the structural diversity further, Wang, Duan, and coworkers developed a Ni‐PHOX‐catalyzed asymmetric alkenylation of racemic SPOs and alkenyl bromides (Scheme 21), providing P‐stereogenic phosphine oxides in high enantioselectivity (up to 97% ee) [67]. The transformation proceeds through oxidative addition, followed by L exchange with the SPO and enantiodetermining reductive elimination step.

SCHEME 21.

Ni‐catalyzed asymmetric alkenylation.

Su and coworkers introduced the dynamic kinetic asymmetric P–C coupling between SPOs and alkenyl iodides. This Cu‐catalyzed transformation, facilitated by a novel chiral 1,2‐diamine L (L6), delivers a wide variety of P‐chiral TPOs in good yields and with excellent enantioselectivity (up to 93% ee) [89]. Additionally, the enantioenriched P‐chiral products underwent further transformations, showcasing their synthetic versatility and enhancing structural diversity (Scheme 22).

SCHEME 22.

Dynamic kinetic asymmetric P–C coupling of SPOs with alkenyl iodides.

A major advance came in 2023 when Zhang's group developed a Ni‐catalyzed enantioselective C(sp)–P cross‐coupling between secondary phosphines and bromoalkynes, providing access to P‐chiral alkynylphosphines [90]. Utilizing [Ni(cod)₂] and (S,S)‐Et‐DuPHOS, the reaction proceeded under mild conditions and exhibited excellent enantioselectivity (up to 97% ee). The alkynyl group, with its rigid linear geometry and strong 𝜋‐character, offered orthogonal steric and electronic contrast to the bulky alkyl substituents on phosphorus, which favored high enantiodiscrimination (Scheme 23a). The resulting P‐chiral alkynylphosphines were successfully elaborated into β‐ketophosphines, phosphole oxides, and even phosphepines, some of these materials showed strong chiroptical responses, including CPL, indicating their potential in photonic applications.

SCHEME 23.

Ni‐catalyzed enantioselective C(sp)–P cross‐coupling.

In a related advancement, Zhao and coworkers [91] demonstrated a Ni‐catalyzed enantioselective cross‐coupling of SPOs with alkyl bromides. Using (S,S)‐Ph‐BPE as the chiral L, the reaction delivered P‐stereogenic alkynylphosphorus compounds in high yields and excellent ees (up to 97%) (Scheme 23b). Mechanistically, the enantioselective substitution at one of the enantiotopic P–H bonds allows KR of the racemic SPOs. The direct use of SPOs simplified the process and expanded substrate compatibility, while maintaining excellent stereocontrol. The obtained alkynylphosphines were readily derivatized to phosphine Ls, making the method highly practical.

Expanding the electrophiles, Zhang and coworkers devised a purely organocatalytic approach using the chiral bifunctional phosphine Le‐Phos to enable the asymmetric allylation of SPOs with Morita–Baylis–Hillman (MBH) carbonates [92]. This transformation effectively functioned as a KR, providing access to both enantioenriched SPOs and TPOs. The ureidopeptide motif of Le‐Phos played a dual role in activating the SPO nucleophile and the MBH electrophile through hydrogen‐bonding and nucleophilic catalysis, thereby achieving high levels of enantioselectivity. Importantly, the P‐chiral products were further elaborated into privileged L scaffolds, demonstrating the synthetic utility of this resolution‐type strategy (Scheme 24).

SCHEME 24.

Le‐Phos catalyzed asymmetric allylation of SPOs with MBH carbonates.

Huang, Li, and coworkers reported the first example of asymmetric carbene insertion into P–H bonds, enabling the direct synthesis of P‐chiral triarylphosphine oxides [93]. Using a Rh(I)‐catalyzed system designed with an optimized L (L7), substrate and additive combination, the reaction couples SPOs with diazonaphthoquinones under mild conditions to deliver products with excellent enantioselectivity (Scheme 25). Mechanistic studies reveal that the process follows a KR pathway, accompanied by a slow dynamic kinetic transformation. The enantioenriched P‐chiral triarylphosphine oxides were readily diversified via Mitsunobu reactions, esterifications, halogenation, silylation, and Pd‐catalyzed cross‐couplings, as well as nucleophilic substitutions with S–H, P–H, N–H, and CN sources. These modifications proceeded without loss of enantiopurity, enabling access to amides, acids, and oxazolines, thus showcasing broad synthetic utility. The products served as precursors to organocatalysts and chiral Ls. A thiourea derivative catalyzed enantioselective α‐amination of β‐ketoesters, while reduced phosphines acted as Ls in Ru‐ and Pd‐catalyzed asymmetric transformations, affirming their potential in catalysis.

SCHEME 25.

Asymmetric carbene insertion into P–H bonds.

In another key contribution, Zhang and coworkers introduced the first Ni‐catalyzed DYKAT for the allylation of SPOs, providing an efficient route to P‐stereogenic TPOs (Scheme 26). The reaction proceeds with high enantioselectivity through a P‐stereo retention process, confirmed by absolute configuration analysis of both substrates and products [94]. Mechanistic studies revealed that Ni(II)‐catalyzed racemization of SPOs, facilitated by KOAc as an additive, underpins the DYKAT process. This method significantly broadens the synthetic utility of SPOs and establishes allylation as a powerful strategy for constructing P‐chiral phosphine frameworks.

SCHEME 26.

Ni‐catalyzed allylation of SPOs.

In 2021, the same group developed allylic alkylation of H‐phosphinates, offering an efficient route to P‐stereogenic allylic phosphinates. Using H‐phosphinates and allylic acetates as substrates, the method delivers products in high yields with excellent enantioselectivities of up to 92% ee [95]. The protocol is practical, as demonstrated by successful scale‐up, and the facile conversion of the phosphinates into TPO was also achieved by MeLi under mild conditions (Scheme 27).

SCHEME 27.

Ni‐catalyzed enantioselective allylic alkylation of H‐phosphinates.

Together, these contributions underscore the growing power and versatility of transition metal catalysis in constructing P‐stereogenic frameworks via asymmetric C–P bond formation. The methods leverage different electrophile classes, alkynyl, allyl, and alkenyl, and enable product derivatization toward functional Ls and chiral materials, highlighting the synthetic potential of this rapidly evolving area.

2.4. Catalytic Enantioselective Hydrophosphination of Alkenes

The enantioselective hydrophosphination of alkenes is a direct and atom‐economic method to forge P–C bonds with control over the stereochemistry at the phosphorus center. This transformation entails the direct addition of primary or secondary phosphines or phosphine oxides across unsaturated carbon–carbon bonds, often catalyzed by transition metals.

One of the earliest demonstrations came from Glueck and coworkers in 1997 [96], who employed a chiral [Pt(Me‐Duphos)(stilbene)] [Pt‐2] catalyst for the asymmetric addition of Ph₂PH to acrylonitrile (Scheme 28). Although the enantioselectivities were modest (up to 25% ee), their mechanistic investigation offered a detailed view of the catalytic cycle involving oxidative addition of P–H, diastereoselective alkene insertion into the Pt–P bond, and subsequent reductive elimination pioneered the concept of transition‐metal‐mediated asymmetric hydrophosphination for the synthesis of P‐chiral phosphines from activated olefins.

SCHEME 28.

Pt‐catalyzed asymmetric hydrophosphination of alkenes.

Subsequent advances leveraged both catalyst design and substrate tuning to achieve high levels of stereocontrol. In 2014, Duan and coworkers reported a Pd‐catalyzed enantioselective 1,4‐addition of secondary alkylphenylphosphines to α,β‐unsaturated carbonyl compounds, employing PCP‐ and NCN‐type pincer [Pd‐6] and [Pd‐7] complexes (Scheme 29). Operating under mild conditions, this method provided chiral phosphorus compounds bearing both P‐ and C‐stereogenic centers with excellent enantioselectivities (up to 99% ee) [97]. This work established a versatile route for constructing dual stereogenic architectures in a single step.

SCHEME 29.

Pd‐catalyzed asymmetric hydrophosphination of α,β‐unsaturated carbonyl compounds.

Further progress came in 2021, when Duan's group developed a pincer–nickel complex that catalyzed the asymmetric hydrophosphination of enones to generate P‐stereogenic secondary phosphine‐boranes. This strategy delivered high yields and excellent enantioselectivities (up to 99% ee), even on a gram scale, demonstrating robustness and scalability. Mechanistically, transphosphination between the P–H precursor and the nickel complex formed a phosphido‐nickel species, which then underwent enantioselective addition to the β‐position of enones (Scheme 30) [98]. The resulting chiral phosphines could be derivatized into tertiary phosphines and bisphosphines, and one such product was converted into a pincer‐NiBr complex that was catalytically active in asymmetric conjugate hydrophosphination.

SCHEME 30.

Asymmetric hydrophosphination of enones.

In 2022, Yin's group further advanced the field with a Ni/Brønsted acid dual‐catalyzed hydrophosphinylation of 1,3‐dienes using SPOs. The reaction proceeded regio‐ and enantioselectively to afford chiral allylic phosphine oxides with broad scope and high atom economy [99]. Mechanistic studies suggested that the regioselective 1,3‐diene insertion into a chiral Ni–H species is the irreversible (formation of C–P bond) and enantio‐determining step (Scheme 31). These allylic phosphine oxides represent valuable intermediates for further elaboration in L synthesis and medicinal chemistry.

SCHEME 31.

Ni/Brønsted acid‐catalyzed hydrophosphinylation of 1,3‐dienes.

Yin and coworkers (2020) reported a Cu(I)‐catalyzed asymmetric 1,4‐conjugate hydrophosphination of α,β‐unsaturated amides using secondary phosphines [100]. With (R,R)‐BDPP as the chiral L, a variety of substrates were converted into enantioenriched phosphines with high yields and enantioselectivities (up to >99% ee). ¹H and ³¹P NMR studies supported the involvement of a nucleophilic Cu(I)‐phosphide intermediate stabilized by L coordination, enabling a DKR of unsymmetrical diarylphosphines. The same group later extended the method to α,β‐unsaturated phosphine sulfides, achieving the synthesis of 1,2‐bisphosphine derivatives with diverse steric and electronic properties in excellent yields and ee values up to 94% (Scheme 32) [101]. This hydrophosphination/protonation cascade proved particularly powerful for α‐substituted substrates, and several of the resulting Ls were successfully applied in Rh‐catalyzed asymmetric hydrogenation of α‐amino esters, affording valuable amino acid derivatives with high enantioselectivity.

SCHEME 32.

Cu(I)‐catalyzed hydrophosphination of α,β‐unsaturated amides and phosphine sulfides.

A particularly elegant strategy was disclosed in 2021 by Duan and coworkers, who developed a cobalt‐catalyzed asymmetric nucleophilic addition of SPOs, using a pyridinyl group as a directing element. This method delivered a wide array of TPOs in up to 99% yield and 99.5% ee with broad functional group tolerance (Scheme 33) [87]. Mechanistic insights reveal a preferential interaction between (R)‐SPOs and the cobalt catalyst [Co‐1], guiding the enantioselective outcome. This strategy offers a powerful and general approach for accessing P‐chiral scaffolds useful in L and catalyst design.

SCHEME 33.

Co‐catalyzed asymmetric nucleophilic addition.

Wang et al. (2023) developed a chiral Brønsted acid‐catalyzed asymmetric hydrophosphinylation of 2‐vinylazaarenes with SPOs, delivering P‐chiral 2‐azaaryl‐ethylphosphine oxides in high yields and enantioselectivities (92% yield and 94% ee) [102]. This method features broad substrate scope, effective KR of racemic SPOs, and modular control over phosphine and azaarene substituents (Scheme 34). Mechanistic insights from DFT studies revealed that the enantioselectivity is governed by hydrogen‐bonding and chiral interactions during the nucleophilic addition step. The resulting P‐chiral phosphines serve as efficient hybrid P,N‐Ls demonstrating promise in asymmetric catalysis.

SCHEME 34.

Brønsted acid‐catalysed asymmetric hydrophosphinylation of 2‐vinylazaarenes.

2.5. Catalytic Enantioselective Hydrophosphination of Alkynes

This strategy offers direct access to enantioenriched secondary or tertiary phosphines or their oxidized/protected derivatives through the direct formation of C–P bonds. This transformation involves the addition of a P─H bond across a C≡C bond, typically using secondary phosphine, primary phosphine, or their oxides (SPOs or PPOs), under the influence of chiral transition metal catalysis.

The first catalytic asymmetric alkyne hydrophosphination was reported in 2006 by Gaumont and coworkers, who reacted methylphenylphosphine‐borane with 1‐ethynylcyclohexene in the presence of various chiral palladium complexes to afford P‐stereogenic vinylphosphine‐boranes [103]. Operating under KR conditions with racemic secondary phosphine–borane, the reaction reached moderate conversions (up to 30%) and modest ees (10%–30% ee) with ferrocenyl and phosphine–oxazoline Ls with Pd(OAc)₂ in toluene at 35 °C. Notably, electron‐rich, sterically demanding Ls such as (R,R)‐Me‐DuPHOS afforded the highest enantioselectivity 42% ee at 50 °C, indicating that both steric bulk and electronic effects at the L's phosphorus center contributed to enantioinduction (Scheme 35). Despite the moderate selectivity, this work laid the foundation for P‐chiral phosphine synthesis via asymmetric alkyne hydrophosphination and showcased the feasibility of chirality transfer from a chiral metal complex to a P‐centered stereogenic center.

SCHEME 35.

Catalytic asymmetric alkyne hydrophosphination.

Zhang and coworkers developed a Pd‐catalyzed hydrophosphinylation of alkynes using SPOs to directly access P‐chiral alkenylphosphine oxides with anti‐Markovnikov selectivity [104]. Employing a Pd/Xiao‐Phos catalytic system in the presence of a hydrogen source (silane or water), the reaction delivered P‐chiral alkenylphosphine oxides with excellent chemo‐, regio‐, and enantioselectivity (up to > 99% ee, rr > 20:1). Mechanistic studies supported a hydropalladation pathway, with in situ generated Pd–H species playing a decisive role in enantioinduction step (Scheme 36a). The use of hydrogen sources like silane or water promoted the generation of active Pd–H intermediates. The process also enabled KR, allowing recovery of unreacted SPOs in enantioenriched form. A more L‐focused approach was described by the same group in 2022. Following the asymmetric addition step, the intermediate alkenylphosphine oxides were subjected to a base‐promoted intramolecular cyclization to generate benzophospholane derivatives. The products were obtained in good yields and high enantioselectivities (up to 99% ee) [105]. These Ls were competent in enantioselective α‐arylation of amides and domino Heck/Suzuki couplings, illustrating how hydrophosphinylation products can be leveraged in asymmetric catalysis (Scheme 36b).

SCHEME 36.

Pd‐catalyzed asymmetric hydrophosphinylation of alkynes.

Parallel developments came from Wang and coworkers, who applied a palladium‐catalyzed approach to the asymmetric hydrophosphorylation of alkynes using racemic phosphinates [106]. The reaction furnished P‐chiral alkenylphosphinates in moderate to high yields and up to 86% ee (Scheme 37). Through a detailed L screen, the authors demonstrated that both electronic and steric effects of the L framework played crucial roles in controlling enantioselectivity. The reaction was compatible with a broad range of aryl and alkyl phosphinates. The system evaluates the potential and generality by synthetic transformations of the hydrophosphorylation products.

SCHEME 37.

Pd‐catalyzed asymmetric hydrophosphorylation.

Jian Li, Xinyao Li, Tianjiao Hu, and coworkers reported a Ni‐catalyzed asymmetric hydrophosphorylation of unactivated alkynes using H‐phosphinates, providing direct access to P‐stereogenic alkenyl phosphinates with high regioselectivity (>20:1) and enantioselectivity (up to 94% ee). Kinetic studies indicated that the reaction proceeds under KR of the H‐phosphinate reagent, while DFT calculations identified the reductive elimination as the enantiodetermining step. Deuterium‐labeling experiments further supported a vinyl‐Ni intermediate formed via protonation of a Ni‐alkynyl species, followed by stereocontrolled C–P bond formation [107]. The reaction was performed on a gram scale without loss of stereoselectivity, and the resulting alkenyl phosphinates were readily derivatized through selective reduction of the C═C bond, demonstrating the synthetic versatility of this method for accessing functionalized P‐chiral phosphinate scaffolds (Scheme 38).

SCHEME 38.

Ni‐catalyzed asymmetric hydrophosphorylation of alkynes.

In 2021, Zhang's group achieved a major leap in efficiency with a Ni(0)‐catalyzed Markovnikov‐selective hydrophosphination of unactivated alkynes using in situ generated secondary phosphines from bench‐stable SPOs [108]. Using Ni(cod)₂ with (S,S)‐BDPP or L10 at −30°C, the method delivered tertiary phosphines with >99% ee and high regioselectivity (>20:1 rr), with yields ranging from moderate to excellent across a wide array of alkyne and SPO substrates. A DKR mechanism was proposed, enabling concurrent racemization and resolution of SPs, leading to efficient enrichment at the P‐chiral center (Scheme 39). Mechanistic tuning also allowed the same group to reverse regioselectivity: switching from Ni(0) to Ni(II) catalysis shifted the outcome to anti‐Markovnikov products via a different mechanistic pathway. In contrast to the Ni(0) system, which proceeds through hydrometallation, L exchange, and reductive elimination, the Ni(II)‐catalyzed process involves migratory insertion of the alkyne followed by protonation of a cationic nickel–phosphine intermediate [109]. Such regiodivergence illustrates the flexibility of nickel catalysis for tailored P‐chiral synthesis.

SCHEME 39.

Ni‐catalyzed Markovnikov and anti‐Markovnikov selective hydrophosphination of unactivated alkynes.

Recently, the same group reported a Ni(0)‐catalyzed enantioselective hydrophosphinylation of alkynes using preformed primary phosphine oxides (PPOs), which provided access to structurally rich ambiphilic P‐stereogenic alkenyl SPOs [110]. The steric bulk introduced by aryl substituents on PPOs enhanced substrate stability and enabled high regio‐ and enantioselectivity (up to 97% ee) across a wide alkyne scope (Scheme 40). Notably, the resulting ambiphilic SPO products exhibited orthogonal reactivity, bearing both nucleophilic phosphorus and electrophilic olefinic functionalities, and were amenable to a wide range of derivatizations such as alkylation, acylation, and Michael additions, thereby enabling access to structurally elaborate P‐chiral scaffolds.

SCHEME 40.

Ni(0)‐catalyzed enantioselective hydrophosphinylation of alkynes with PPO.

Complementing this, a nickel‐catalyzed hydrophosphinylation of conjugated enynes was reported, featuring a mechanistic pathway distinct from the traditional Chalk–Harrod model of metal‐catalyzed P–H additions. Through a combination of kinetic experiments and DFT calculations, proposed a mechanism in which the alkene moiety of the enyne plays a directing role, coordinating to the nickel center during the transition state. This interaction proved critical for controlling both regio‐ and enantioselectivity, resulting in the formation of enantioenriched alkenyl SPOs in high yields and with excellent ee (up to 99%) [111]. Further, intramolecular olefin metathesis of chiral TPO, catalyzed by the Hoveyda–Grubbs (II) catalyst at room temperature, proceeded efficiently to yield the cyclized product without compromising the P‐chirality (Scheme 41). The mechanistic insight underscored the role of the alkene in enyne substrates in directing the reaction via transition‐state stabilization.

SCHEME 41.

Ni‐catalyzed hydrophosphinylation of conjugated enynes.

Zhang and coworkers reported Ni‐catalyzed enantioselective synthesis of P‐stereogenic allenylphosphines via propargylic substitution between racemic propargylic carbonates and secondary phosphines. The method furnished a broad scope of allenylphosphine derivatives with high enantioselectivity (Scheme 42). Notably, the strategy enabled the enantioconvergent construction of P, axial‐stereogenic 1,3‐disubstituted allenylphosphines with excellent stereocontrol (up to 97% ee, 14:1 dr) [112]. Mechanistic studies (experimental and computational) revealed an enantioconvergent pathway, wherein racemic propargylic carbonates afford enantioenriched products. The resulting chiral phosphines were further incorporated into metal complexes while retaining stereopurity, underscoring their potential as Ls in asymmetric catalysis.

SCHEME 42.

Ni‐catalyzed enantioselective synthesis of P‐stereogenic allenylphosphines.

In 2025, Su and coworkers introduced a Cu‐catalyzed DYKAT of racemic SPOs with unactivated terminal alkynes. The process furnished cis‐selective, anti‐Markovnikov P‐stereogenic products in high yield (up to 95%) and ee (up to 96%), achieving full conversion without the limitations of KR (50% maximum yield) [113]. Mechanism undergoes phosphoryl copper intermediate P(O)–[Cu] reacts with alkyne through coordination and cis‐addition to yield alkenyl‐[Cu] species (Scheme 43). This species subsequently forms the anti‐Markovnikov hydrophosphorylated product upon protonation. Moreover, the resultant phosphine oxides were converted into diverse derivatives, demonstrating broad structural flexibility for further applications.

SCHEME 43.

Cu‐catalyzed DYKAT of racemic SPOs with alkynes.

Further expanding this domain, Jiang and Cao (2025) reported a Cu‐catalyzed enantioselective hydrophosphinylation of ethynylazaarenes that yielded P‐chiral TPOs with azaarene substituents, enabling access to 1,5‐hybrid P,N‐Ls, which incorporate both soft (P) and hard (N) donor atoms and display diverse coordination modes (Scheme 44) [114]. Through transformations at the olefin moiety, additional C‐centered chirality was introduced, offering enhanced enantioselectivity in downstream catalytic applications, particularly asymmetric metal‐catalyzed reactions such as Pd‐catalyzed Tsuji–Trost allylation. This modular derivatization highlights the synthetic utility of the P‐chiral products generated by alkyne hydrophosphinylation.

SCHEME 44.

Cu‐catalyzed enantioselective hydrophosphinylation of ethynylazaarenes.

Atroposelective strategies have also been explored. A different strategic direction was adopted by Li and coworkers in 2022, who realized a palladium‐catalyzed atroposelective hydrophosphination of internal alkynes, thereby enabling simultaneous construction of axial and P‐centered chirality (Scheme 45) [115]. Using sterically hindered 1‐indolylalkynes and a chiral bidentate L (L13), the authors achieved high E‐selectivity, regioselectivity, and excellent enantioselectivity (up to 92% ee). The resulting trisubstituted vinylphosphines represented a previously underexplored class of open‐chain C–N axially chiral olefins.

SCHEME 45.

Pd‐catalyzed atroposelective hydrophosphination of internal alkynes.

In a conceptually distinct approach, Tan and Wang (2023) developed a dual Cu/CPA co‐catalyzed system for the atroposelective hydrophosphinylation of alkynes using ortho‐hydroxynaphthyl alkynes as precursors (Scheme 46). This methodology enabled the synthesis of axially chiral styrene–phosphines with excellent enantioselectivity (up to 87% ee) [116]. This protocol relied on the in situ generation of vinylidene ortho‐quinone methide (VQM) intermediates, which acted as reactive electrophiles for P‐nucleophiles.

SCHEME 46.

Cu/CPA‐catalyzed atroposelective hydrophosphinylation of alkynes.

Collectively, these developments highlight the versatility of alkyne hydrophosphination as a platform for synthesizing both P‐chiral and axially chiral phosphorus compounds. Advances in catalyst design, mechanistic understanding, and regiodivergence have progressively expanded substrate scope and selectivity, while the ease of product derivatization underlines their value as Ls and building blocks in asymmetric catalysis.

3. Desymmetrization

The catalytic desymmetrization of prochiral P(V) species has emerged as a particularly powerful strategy for constructing P‑stereogenic centers. This approach leverages the inherent symmetry of the substrate and introduces asymmetry via a catalytic transformation that discriminates between two identical or enantiotopic groups.

3.1. Nucleophilic Substitution at P(V)

Jacobsen and Forbes (2022) introduced a catalytic hydrogen‐bond‐donor strategy to access chlorophosphonamidates, which served as versatile chiral P(V) building blocks. Their approach relied on dual H‑bond donor sulfinamido urea (Cat‐1) catalysis to selectively activate one of the two enantiotopic chlorides in phosphonic dichlorides, thereby achieving enantioselective desymmetrization (Scheme 47). A particular strength of this methodology was the orthogonal reactivity of the chloride and amino substituents, which allowed for sequential and stereospecific displacement to furnish a diverse array of stereogenic P(V) scaffolds. Importantly, these intermediates could be diversified into numerous biologically relevant derivatives while maintaining stereochemical integrity [117].

SCHEME 47.

Desymmetrization of phenyl phosphonic dichlorides.

Building upon this foundation, Dixon and coworkers (2023) reported a superbasic bifunctional iminophosphorane BIMP‐1 catalyzed nucleophilic desymmetrization of phosphonate esters. This strategy achieved highly enantioselective discrimination between enantiotopic leaving groups, delivering configurationally stable P‐stereogenic intermediates that could be further diversified in a second substitution step to furnish a broad library of O‐, N‐, and S‐linked chiral phosphonates, including nucleoside and drug derivatives (Scheme 48a) [118]. The enantioinduction relied on key hydrogen‐bonding interactions from the ureidopeptide motif of the catalyst. In a subsequent study, the group expanded this platform using modified BIMP‐2 catalysts in 2024, which broadened the scope of nucleophiles and P‐substituents with excellent selectivity and demonstrated downstream derivatizations [119]. This platform was remarkable in its modularity, enabling divergent access to structurally diverse P(V) compounds from a single prochiral precursor (Scheme 48b). While Jacobsen's dual H‑bond donor catalysis was limited to amine nucleophiles, Dixon's BIMP system expanded the horizon by accommodating a broad spectrum of nucleophiles and offering exceptional downstream flexibility.

SCHEME 48.

BIMP‐catalyzed nucleophilic desymmetrization of phosphonate esters.

Shortly thereafter, Dong and coworkers (2025) developed a yttrium‐Feng‐L (Y‐Feng)‐catalyzed desymmetrization of oxazolidinyl phosphorodichloridates. This transformation proceeded at ambient temperature with phenolic nucleophiles, followed by stereospecific amination in a one‐pot process [120]. The oxazolidinone auxiliary played a dual role: facilitating bidentate coordination to the yttrium catalyst and acting as a removable leaving group (Scheme 49). The resulting P‑stereogenic phosphoramidates acted as trifunctional building blocks, enabling stereodivergent synthesis of ProTide analogues and, notably, the first stereoselective total synthesis of the natural product phosmidosine.

SCHEME 49.

Yttrium catalyzed desymmetrization of oxazolidinyl phosphorodichloridates.

In parallel, Li and coworkers (2025) introduced a three‐phase catalytic desymmetrization strategy employing electrophilic phosphorus reagents bearing three leaving groups. This design allowed for stepwise nucleophilic attack by alcohols and amines, thereby generating a wide array of stereogenic phosphorus motifs (Scheme 50). The modularity of this system significantly accelerated the synthesis and screening of biologically active phosphoramidates [121].

SCHEME 50.

Three‐phase strategy for modular preparation of phosphoramidates.

Lovinger and Jacobsen reported a metal‐free enantioselective desymmetrization of prochiral phosphonites P(III) through a chiral bis(amidine) hydrogen‐bond‐donor catalyst, enabling S_N2(P) substitution with inversion at phosphorus to furnish P(V)‐chiral phosphinates in high enantioselectivity [122]. The stereochemical outcome arises from transition‐state ion‐pairing between the phosphonite and the chiral proton donor, which selectively stabilizes one enantiomeric substitution pathway. This strategy constitutes a complementary desymmetrization approach to P‐chiral compounds.

The complementary nature of these strategies often enables broader scope and faster reaction rates. These findings highlight a future where the integration of diverse catalytic platforms may offer the most comprehensive solutions for stereoselective P(V) chemistry.

3.2. Cyclization

In a pioneering report by Gouverneur and Hoveyda, Mo‐catalyzed asymmetric ring‐closing metathesis (ARCM) was employed for the enantioselective desymmetrization of phosphinates and phosphine oxides. Using a set of chiral molybdenum complexes [Mo‐1], [Mo‐2], and [Mo‐3], prochiral P‐containing trienes underwent ring‐closing metathesis to yield five‐, six‐, and seven‐membered P‐heterocycles with enantioselectivities up to 98% ee (Scheme 51) [123]. Mechanistically, the desymmetrization proceeds via coordination of the substrate to the molybdenum alkylidene complex, followed by cyclization. However, catalyst deactivation was observed in certain substrates due to chelation of the Lewis‐basic phosphorus group. Subsequent mechanistic studies supported the formation of alkylidyne species that sequestered the catalyst. This insight led to substrate redesign, including modifications to increase the distance between the phosphorus atom and the alkene moieties, thus restoring catalytic activity.

SCHEME 51.

Synthesis of P‐chiral compounds by ARCM.

Extending this concept, Gouverneur's group later applied diastereoselective enyne ring‐closing metathesis (DSRCM) to P‐containing enyne. In this study, the Hoveyda–Grubbs second‐generation catalyst (HG‐II) enabled the diastereoselective formation of P‐stereogenic heterocycles bearing an exocyclic alkynyl group (Scheme 52). Stereoinduction originated from a secondary alkoxy substituent proximal to the phosphorus center [124]. Although this transformation was not enantioselective, it demonstrated how diastereoselective desymmetrization can be applied to construct functionally rich P‐stereogenic compounds.

SCHEME 52.

Enyne ring‐closing metathesis.

Recent advances in Pd‐catalyzed desymmetrization of bisallyl phosphine oxides have enabled simultaneous construction of P‐ and quaternary C‐stereogenic centers in a single transformation. Maruoka, Liu, and Wang (2024) developed a domino Heck–Suzuki process, achieving cyclic P‐chiral phosphine oxides in excellent yields (91%) and enantioselectivities (up to >20:1 dr and 99% ee) [125]. DFT calculations revealed that the intramolecular migratory insertion was both rate‐ and enantioselectivity‐determining step, with the steric environment of a TADDOL‐derived phosphoramidite L (L15) steering selectivity (Scheme 53). In contrast, Lin and Yao reported a tandem Heck‐carbonylation under CO atmosphere, affording benzoheterocycles with comparable stereocontrol (up to 92% ee, 12:1 dr) [126]. The method tolerated various alkene substituents, nucleophiles (phenols, alcohols, amines), and aromatic substituents. Both methods demonstrated versatile product derivatization (e.g., reduction to P(III)‐chiral phosphines, borylation, hydrolysis, Curtius rearrangement, amidation, hydrogenation, and conversion to phosphine‐borane adducts), showcasing their potential as L precursors for asymmetric catalysis.

SCHEME 53.

Pd‐catalyzed asymmetric tandem Heck/carbonylation of bisallyl‐phosphine oxides.

In another notable example, Tanaka and coworkers reported the desymmetrization of symmetrical dialkynylphosphine oxides via Rh(I)‐catalyzed [2+2+2] cycloaddition with 1,6‐diynes. The selective mono‐cycloaddition afforded P‐stereogenic alkynylphosphine oxides with yields >99% and ee up to 95% using (R)‐DTBM‐segPHOS [127]. This strategy capitalized on the steric and electronic differentiation at phosphorus to achieve regio‐ and stereoselective cyclization (Scheme 54). Mechanistically, the process involves coordination of the diyne and phosphine oxide to the cationic Rh(I) complex, followed by sequential insertion of alkyne units and reductive elimination. The steric interactions between the alkyne and the L determine the enantiotopic face selectivity. Importantly, the resulting P‐stereogenic alkynylphosphine oxides served as versatile intermediates, enabling access to C₂‐symmetric P‐chiral bisphosphine oxides and other privileged Ls for transition metal catalysis.

SCHEME 54.

Rh(I)‐catalyzed [2+2+2] cycloaddition.

Finally, Zhou group (2020) developed a highly enantioselective method to synthesize P‐chiral TPOs with an ethynyl group via copper(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC). Using chiral PYBOX Ls L17‐L20 with bulky C4 shielding groups, they achieved excellent suppression of bis‐triazole side products and high enantioselectivity, even when the P‐chiral center was remotely located four bonds away (Scheme 55) [128]. Moreover, the reaction merged desymmetrization and KR mechanisms for improved selectivity. The resulting P‐chiral phosphine oxides are versatile synthons, enabling diverse modifications such as Sonogashira couplings and reductions. Additionally, phosphole oxide derivatives formed by remote desymmetrization showed potential for optoelectronic applications.

SCHEME 55.

Cu(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC).

3.3. C–H Activation

In 2015, two complementary Pd‐catalyzed strategies were reported for constructing P‐stereogenic heterocycles via intramolecular C–H activation (CHA)/arylation. Duan and coworkers developed the first enantioselective C–H arylation of N‐(o‐bromoaryl)‐diarylphosphinic amides, using a chiral TADDOL‐based N‐Me‐phosphoramidite L (L21) to achieve high enantioselectivities (up to 93% ee) in forming P‐stereogenic compounds [129]. To demonstrate the utility of the current protocol, the P–N bond cleavage was examined using RLi to synthesize P‐chiral biphenyl monophosphine Ls. Independently, Liu and Ma established a similar C–H arylation with TADDOL‐derived N‐Et‐phosphoramidite L (L22), affording cyclic P‐chiral phosphinic amides in excellent yields (61%–99%) and ee values (88%–97%) [130]. The substrate scope was broad, tolerating aryl bromides and iodides, though aryl chlorides were inert under the same conditions. Mechanistically, the process proceeds through oxidative addition of the prochiral P(V) compound (a) to Pd(0). The adduct (A) converts into (B) in the presence of base, followed by a remote CHA to give Pd(II)‐complex (C) (Scheme 56). Finally, a reductive elimination occurs, forming (b), the final product, and regenerates the Pd catalyst.

SCHEME 56.

Pd(0)‐catalyzed desymmetrization via enantioselective intramolecular C–H arylation.

In the same year, the Han group reported a pioneering approach to synthesize P‐stereogenic phosphinamides via Pd‐catalyzed desymmetric ortho C–H arylation of diarylphosphinamides using boronic esters (Scheme 57a). Marking the first application of desymmetric C–H functionalization for generating P‐stereogenic compounds, the method offers broad substrate scope and delivers products in up to 74% yield and 98% ee [131, 132]. The strategy is scalable and allows further transformation of the resulting chiral phosphinamides into diverse P‐stereogenic derivatives. Expanding beyond arylation, the same group later developed a Ce(IV)‐mediated radical oxidative C–N coupling for the efficient synthesis of cyclic P‐stereogenic phosphinamides from acyclic precursors. This Ce(NH₄)₂(NO₃)₆ (CAN)‐promoted approach overcame limitations of earlier methods, which struggled with electron‐deficient N‐protecting groups, and provided a robust platform for constructing P‐chiral frameworks (Scheme 57b) [133]. The method not only complements previously reported Pd‐catalyzed C–H functionalizations but also broadens the scope of accessible N,P‐containing P‐stereogenic compounds. Similarly, the Zhang group established an intramolecular electrochemical C–H phosphinamidation strategy to construct six‐membered cyclic phosphinamides, notably without the use of oxidants or transition metals [134].

SCHEME 57.

Desymmetrizing C–H arylation for the synthesis of phosphinamides.

A significant advance was reported by Yu and coworkers in 2021, who developed an Ir‐catalyzed enantioselective C–H borylation of diarylphosphinates (c). Using a phosphinate directing group, the reaction proceeded with good step‐ and atom‐economy, broad functional group tolerance, and high enantioselectivities (up to 92% ee) [135]. This approach successfully introduced P‐chirality through enantioselective CHA on one of the two enantiotopic aryl rings (Scheme 58). The catalytic cycle begins with Ir(III)‐tris(boryl) formation, followed by P═O coordination and ortho‐CHA to give an Ir(V) intermediate. Reductive elimination furnishes the ortho‐borylated product (d), while reaction with B₂pin₂ regenerates the active Ir(III) species. The method is scalable to gram quantities and allows further functional transformations through the reactive C–B and P–O bonds.

SCHEME 58.

Ir‐catalyzed enantioselective C–H borylation of diarylphosphinates.

In 2023, Shi and coworkers reported a Pd(II)‐catalyzed enantioselective C–H alkynylation strategy for synthesizing P‐stereogenic phosphinamides, key motifs in organocatalysis and medicinal chemistry. Employing L‐pyroglutamic acid as a chiral L and a newly designed sterically demanding directing group, the method achieved high yields and enantioselectivities (up to 97% ee) through a combination of desymmetrization and KR (Scheme 59). The resulting chiral phosphinamides can be further transformed into a variety of valuable P‐stereogenic structures, enhancing their synthetic and functional utility [136].

SCHEME 59.

Pd(II)‐catalyzed enantioselective C–H alkynylation.

Cramer and coworkers (2017) introduced a Rh(III)‐catalyzed enantioselective CHA of diaryl phosphinamides using an atropochiral cyclopentadienyl (Cp*) L, producing P(V)‐stereogenic phosphinamides in high yield and ee [137]. The mechanistic insight suggests that K₂CO₃ reduces the reversibility of the CHA. Moreover, the NH group of diaryl phosphinamide should be kept free, which will direct the CHA with this catalyst system (Scheme 60). Importantly, the products could be reduced enantiospecifically to P(III)‐chiral phosphines, offering a valuable route to enantiopure Ls for transition‐metal and organocatalysis.

SCHEME 60.

Rh‐catalyzed enantiotopic CHA of phosphinamides.

Later, the same group reported an Ir(III)‐catalyzed enantioselective C–H amidation of arylphosphine oxides using a dual‐chiral system atropochiral Cpx L and phthaloyl tert‐leucine (S)‐A1, achieving up to 99:1 er and high yields, with enantiospecific reduction to P(III)‐chiral phosphines (Scheme 61a). The cooperative effect between these two chiral components proved critical for achieving high efficiency and selectivity [138]. The same catalyst system utilized in asymmetric C–H arylation of phosphine oxides with o‐quinone diazides, delivering both P‐chiral and atropisomeric biaryl phosphine oxides with outstanding diastereo‐ and enantioselectivity [139]. The method features enantiodetermining P‐chirality desymmetrization followed by formation of stable atropisomers via arylation and aromatization (Scheme 61b). Notably, atropo‐enantioselective cyclization creates sterically demanding biaryl backbones, which, combined with enantiospecific reductions, afford chiral monodentate P(III) Ls crucial for asymmetric catalysis.

SCHEME 61.

Enantioselective Ir‐Catalyzed C−H Amidation of Phosphine Oxides.

In 2021, Hu et al. described a desymmetrizing twofold C–H arylation of phosphinamides with diarylacetylenes catalyzed by chiral Rh(III) complex (R)‐[Rh‐3], to afford axially and P‐centrally chiral biaryl phosphines with excellent stereoselectivity (Scheme 62). The stereochemical outcome stems from two catalyst‐controlled CHA events: an enantio‐determining first activation and a diastereo‐determining second CHA [140]. The concerted metalation‐deprotonation mechanisms and the involvement of cis‐trans isomerization of rhodium vinyl intermediates allow access to thermodynamically stable rhodacycles that preserve chiral integrity. Product derivatization through reduction and Pd‐catalyzed arylation enabled access to chiral phosphine Ls, effectively applied in asymmetric allylic alkylation (AAA).

SCHEME 62.

Rh‐catalyzed twofold C–H arylation of phosphinamides with diarylacetylenes.

Duan and coworkers (2022) introduced a method combining an achiral CpIr catalyst with chiral carboxylic amides to achieve asymmetric CHA for synthesizing P‐ and axially chiral biaryl phosphine oxides, circumventing the need for custom chiral Cp Ls (Scheme 63). The N‐alkoxy substituted amide L24 enabled high enantioselectivity (up to 96% ee) by controlling stereochemistry during a concerted metalation‐deprotonation CHA step, forming P‐chiral iridacycles [141]. Subsequent alkyne insertion and a second CHA installed axial chirality, yielding biaryl phosphine oxides with both chiral elements. Products were readily convertible to trivalent phosphines, highlighting the method's practical relevance.

SCHEME 63.

Asymmetric CHA for the synthesis of P‐and axially chiral biaryl phosphine oxides.

Shi and coworkers (2022) reported an unprecedented enantioselective C–H annulation of arylphosphinamides with alkynes and allenes using a cobalt‐salicyloxazoline (Salox) catalytic system that operates via easily accessible Co(II) salts under mild conditions. The in situ formation of chiral octahedral Co(III) complexes, stabilized by novel Salox Ls with 𝜋‐stacking interactions, allowed efficient and selective enantiodetermining CHA (Scheme 64a) [142]. This method enabled broad substrate scope, including challenging heterocycles and functional groups, and could be scaled up with low catalyst loadings. Mechanistic studies, including isolation of cobaltacycle intermediates, provide a foundational understanding of earth‐abundant metal catalysis for P‐chiral synthesis. Late‐stage annulations of allenes and alkynes further demonstrate synthetic utility. The same catalytic system innovatively applied for base‐promoted, electrochemical enantioselective C–H alkoxylation to phosphinamides, affording diverse alkoxylated P‐chiral products with excellent yields and enantioselectivities (up to 98% yield and 99% ee) [143]. This approach uniquely avoids stoichiometric chemical oxidants in favor of electricity, generating hydrogen gas as the only byproduct, thereby enhancing sustainability (Scheme 64b). Mechanistic elucidation through isolation of cobalt(III)‐alcohol intermediates and cyclic voltammetry highlighted the redox cycling between Co(III) and Co(IV) as key to catalysis and stereocontrol. This study sets a new benchmark in environmentally friendly, asymmetric C–H functionalization toward P‐chirality.

SCHEME 64.

Co‐Salox‐catalyzed enantioselective C–H annulation and alkoxylation.

Finally, the group advanced the field by developing Pd(II)‐catalyzed enantioselective arylation of C(sp³)–H bonds in dialkylphosphinamides, overcoming the long‐standing limitation to C(sp²)–H activation. Utilizing 3,3′‐CN₂‐H₈‐BINOL as a chiral L and PIP as the directing group, the method enabled desymmetrization of gem‐diethyl groups to generate a variety of P‐stereogenic dialkylphosphinamides in moderate to good yields and excellent enantioselectivities (96‐>99% ee) [144]. The reaction's robustness is evidenced by successful gram‐scale synthesis and downstream derivatization to P‐chiral trialkylphosphines, showcasing its synthetic utility in accessing complex, multifunctional P‐chiral frameworks (Scheme 65a). Building on this, the group later constructed phosphinamides with contiguous P,C‐stereocenters using a 2‐pyridinylisopropyl (PIP) auxiliary and (S)‐6,6′‐(CN)₂‐SPINOL L, delivering high chemo‐, diastereo‐, and enantioselectivity (up to >99% ee) [145]. This work represents a significant step forward in accessing densely functionalized P‐chiral frameworks and offers valuable synthetic access to scaffolds relevant for chiral L development in asymmetric catalysis (Scheme 65b).

SCHEME 65.

Pd(II)‐catalyzed enantioselective arylation of C(sp³)–H bonds.

3.4. Phenolic ─OH Activation

Phenolic ─OH activation has become a valuable approach in the stereoselective synthesis of P‑chiral compounds. Compared with aliphatic alcohols, phenols offer higher acidity and nucleophilicity, allowing efficient C–O bond formation under mild conditions. Their aryl substituents also serve as handles for subsequent functionalization, making this approach highly attractive for generating P‑chiral scaffolds relevant to catalysis and drug discovery.

One of the earliest breakthroughs came from Song and Chi (2016), who developed an (NHC)‐catalyzed desymmetrization of bis(2‑hydroxyphenyl)phosphinates. This elegant approach exploited acylation of one phenolic group in the presence of aldehydes and quinone oxidants. Despite the remote position of the enantiotopic phenolic groups from the P‑stereogenic center, the NHC‐2 and NHC‐3 catalysts induced high enantioselectivity (up to 97:3 e.r.) through precise control of the acyl transfer process (Scheme 66). Mechanistic studies revealed that a KR of the initially formed monoester could occur via a second acylation, but the main enantiodifferentiation arose from the first desymmetrization step [146]. Notably, the monoacylated products could undergo methylation, Grignard addition, or conversion into a bidentate Lewis base (L25) without loss of stereochemical integrity. P‐stereogenic phosphinate L25 efficiently catalyzed tandem conjugate reduction/aldol reactions of enones with aldehydes using trichlorosilane, affording β‐hydroxy ketones in good yields.

SCHEME 66.

NHC‐catalyzed desymmetrization of bis(2‑hydroxyphenyl)phosphinates.

Building upon the concept of bisphenol activation, Li, and coworkers (2019) introduced a biscinchona alkaloid‐catalyzed enantioselective allylic alkylation of bisphenol phosphine oxides using MBH carbonates as allylating agents (Scheme 67). This organocatalytic desymmetrization delivered a broad array of optically active P‑chiral phosphine oxides in excellent yields (up to 99%) and enantioselectivities (up to 98.5:1.5 e.r.). Linear free energy relationship (LFER) analyses revealed that steric hindrance around the phosphorus substituents strongly influenced enantioselectivity, with bulkier groups favoring higher e.r. values [147]. Mechanistic insights supported the idea that the catalyst created a chiral pocket capable of differentiating remote enantiotopic phenolic groups. The method tolerated both electron‐rich and electron‐poor substrates, underscoring its robustness.

SCHEME 67.

Biscinchona alkaloid‐catalyzed enantioselective allylic alkylation of bisphenol phosphine oxides.

Around the same period, Zi and coworkers (2018) reported a Au(I)‐catalyzed enantioselective hydroetherification of alkynes via intramolecular desymmetrization of bisphenols containing P‑stereogenic centers. Using a [(AuCl)₂] /(S)‐DTBM‐SegPHOS system, they achieved cyclic P‑chiral phosphine oxides in excellent yields and enantioselectivities (up to 99% ee) [148]. Mechanistic investigations indicated that the 6‑endo‑dig cyclization pathway brought the prochiral phosphorus center in the close proximity of the chiral L environment, maximizing enantioinduction. Furthermore, the products underwent valuable downstream transformations, including reduction to borane adducts, selective bromination for cross‐coupling potential, and hydrogenolysis to acyclic phosphine oxides while preserving stereopurity (Scheme 68). This study was notable for extending phenolic desymmetrization into the domain of gold catalysis, a relatively unexplored area for enantioselective hydrofunctionalization of alkynes.

SCHEME 68.

Au(I)‐catalyzed enantioselective intramolecular desymmetrization of bisphenols.

Most recently, Wang, Xu, and coworkers (2025) developed a peptide‐phosphonium salt (PPS)‐catalyzed enantioselective S_NAr desymmetrization of prochiral bisphenol phosphine oxides. This organocatalytic strategy provided access to densely aryl‐substituted P‑stereogenic centers with remarkable enantioselectivities (up to 98% ee) and yields approaching 93% (Scheme 69) [149]. The PPS catalysts, inspired by peptide scaffolds, created a semi‐enclosed chiral pocket where deprotonated bisphenols engaged in dual hydrogen bonding and ion‐pairing with electron‐deficient aryl fluorides, stabilizing the Meisenheimer intermediate. Mechanistic experiments and DFT calculations confirmed the key role of noncovalent interactions in asymmetric induction, with the preferred transition state (TS‑R) favored by 3.7 kcal/mol over its enantiomeric counterpart. Beyond high selectivity, the method demonstrated scalability (gram‐scale synthesis) and synthetic utility, with functionalized products undergoing bromination or further diversification. This work stands out as one of the first successful organocatalytic S_NAr strategies for building P‑chiral frameworks, addressing limitations of metal catalysis in functional group tolerance.

SCHEME 69.

PPS‐catalyzed S_NAr desymmetrization of bisphenol phosphine oxides.

Taken together, these reports highlight the versatility of phenolic ─OH activation in accessing P‑chiral P(V) compounds. From NHC‐mediated acylations and alkylation with MBH carbonates, to gold(I)‐catalyzed hydroetherifications and peptide‐phosphonium salt catalyzed S_NAr reactions, chemists have established multiple, complementary pathways to control stereochemistry at phosphorus through phenolic activation.

3.5. Conjugate Addition to Phosphine Oxide

Conjugate addition to vinyl‐ or alkynyl‐substituted phosphine oxides has emerged as an attractive strategy for constructing P‐stereogenic scaffolds. Hayashi and coworkers reported two landmark Rh‐catalyzed desymmetrization methods. In 2017, they developed a Rh/(R)segPHOS‐catalyzed DKR of 2,5‐dihydrophosphole oxides with aryl boronate ester, in which base‐promoted isomerization interconverts reactive intermediates, enabling highly enantio‐ and diastereoselective arylation (up to 99% yield, 97:3 dr, 96% ee) (Scheme 70a) [150]. A year later, they disclosed a Rh/(R)DTBM‐segPHOS‐catalyzed enantioposition‐selective hydroarylation of divinylphosphine oxides, where one vinyl group undergoes arylation and the other hydrorhodation through intramolecular Rh‐H migration, affording monoarylated products with excellent enantioselectivity (up to 95% ee) [151]. Importantly, the latter intermediates could be further elaborated via conjugate addition to give bis(phosphine) oxides, which, upon reduction, provided chiral bisphosphines, one of which was successfully applied as a Pd‐L in asymmetric catalysis (Scheme 70b).

SCHEME 70.

Rh‐catalyzed desymmetrization of 2,5‐dihydrophosphole oxides and divinylphosphine oxides.

Feng and coworkers (2019) reported a rare‐earth‐catalyzed enantioselective conjugate addition of thiols to dialkynyl phosphine oxides using a chiral N,N′‐dioxide‐Tm(III) complex. This methodology provided P‐stereogenic alkynylphosphine oxides with excellent Z/E control and high enantioselectivities (up to 97% ee). Structural and mechanistic studies highlighted the role of the metal ionic radius and L geometry in governing stereocontrol [152]. The resulting alkynylated products were readily derivatized into diverse P‐chiral scaffolds, underscoring their potential as versatile L precursors (Scheme 71).

SCHEME 71.

Conjugate addition of thiols to dialkynyl phosphine oxides.

3.6. P–O–C Bond Formation via Alkylation and Arylation

Catalytic P–O–C bond formation has recently emerged as a powerful approach to construct P‑chiral compounds. Unlike strategies relying on phenolic ─OH activation or desymmetrization of bisphenol derivatives, these methodologies directly functionalize phosphinic acids through transition metal‐catalyzed PO‑alkylation and PO‑arylation, thereby expanding both the structural diversity and synthetic utility of P‑chiral scaffolds.

In 2019, Trost and coworkers introduced a Pd‐catalyzed AAA of phosphinic acids. This method differentiated enantiotopic oxygen atoms on the phosphinic acid, achieving desymmetrization with high enantio‐ and diastereoselectivity (up to 99% ee, 26:1 d.r.). Optimization of Ls revealed that an anthracenyl Trost L (S,S)‐L26 provided the best stereoinduction (Scheme 72) [153]. Mechanistically, the Pd(0)‐𝜋‑allyl intermediate underwent nucleophilic attack by the phosphinate anion, with L control guiding stereodifferentiation. Notably, this approach tolerated diverse aryl and alkyl substituents on phosphorus, and sterically demanding ortho‐substituents further enhanced diastereoselectivity. Importantly, the method was scalable, and the resulting phosphinates could be stereospecifically converted into TPOs, including (R)‐PAMPO, a key precursor to the DiPAMP L family. This work therefore not only broadened desymmetrization chemistry but also established a general route to valuable P‐chiral Ls.

SCHEME 72.

Pd‐catalyzed AAA of phosphinic acids.

More recently, Li and coworkers (2025) reported a Cu‐catalyzed enantioselective O‑arylation of phosphinic acids with unsymmetric diaryliodonium salts. Under optimized conditions (CuI with C₂‐symmetric bisoxazoline L, L27), the reaction furnished a wide variety of enantioenriched P‑chiral phosphinates in up to 99% ee. The proposed mechanism involves formation of a Cu(III)–aryl intermediate, enabling the selective transfer of the aryl fragment to phosphorus [154]. Structural scope was broad: both electron‐rich and electron‐deficient DAIS reagents were effective, though ortho‐substitution reduced enantioselectivity. The O‐arylated products proved highly versatile electrophile, undergoing stereospecific derivatization with O‐, N‐, and C‐nucleophiles to yield phosphinamides and TPOs without erosion of stereochemistry (Scheme 73). Notably, the method allowed enantiodivergent synthesis simply by switching to the enantiomeric L. Applications extended to late‐stage modification of natural products (e.g., estrone and tocopherol derivatives), showcasing its potential in medicinal chemistry.

SCHEME 73.

Cu‐catalyzed enantioselective O‑arylation of phosphinic acids.

These methods underline how judicious choice of metal catalysis and electrophiles can convert phosphinic acids into highly versatile building blocks for asymmetric catalysis and pharmaceutical development.

4. Summary and Outlook

The past decade has seen remarkable progress in the enantioselective synthesis of P‐chiral organophosphorus compounds, with the development of both P–C bond formation and desymmetrization strategies providing powerful and complementary approaches to this long‐standing synthetic challenge. P–C bond construction, through cross‐coupling of secondary phosphines or their oxides with aryl, alkyl, and benzyl halides, and catalytic hydrophosphination of alkenes and alkynes, has enabled direct access to structurally diverse P‐stereogenic frameworks under increasingly mild and selective conditions. Desymmetrization strategies, including nucleophilic substitution at P(V) centers, cyclization, CHA, phenolic –OH activation, and P–O alkylation and arylation, have further expanded the synthetic repertoire, offering efficient routes to highly functionalized scaffolds with exceptional levels of stereocontrol.

Beyond methodological advances, significant attention has been directed toward the derivatization of chiral phosphorus products and the translation of these frameworks into asymmetric catalysis, medicinal chemistry, and materials science, underscoring their practical value. However, key challenges remain. The scope of many catalytic systems is still limited with respect to unactivated or sterically encumbered substrates, and the precise control of stereochemistry at densely substituted phosphorus centers remains nontrivial. Additionally, operational simplicity and scalability continue to pose bottlenecks, especially for transformations involving sensitive P(III) intermediates. A further emerging frontier is the iterative construction of molecules bearing multiple P‐stereocenters, which currently lacks general, predictable, and catalyst‐controlled strategies.

Looking forward, addressing these challenges will require advances in L and catalyst design, deeper mechanistic understanding of P‐centered stereochemical relay strategies that provide access to broad substrate scope. The integration of computational design, mechanistic elucidation, and high‐throughput experimentation is expected to accelerate the discovery of next‐generation catalytic platforms. As these innovations continue to emerge, the precise and efficient synthesis of P‐chiral compounds will undoubtedly play an increasingly pivotal role in shaping the future of organophosphorus chemistry.

Conflicts of Interest

The authors declare no conflicts of interest.

Biographies

Amol C. Chandanshive was born in Maharashtra, India. He received his B.Sc. and M.Sc. (Organic Chemistry) degrees from Solapur University, Solapur, India. Subsequently, he worked for 2 years in the Lupin Pharmaceuticals, Tarapur, India. In 2017, he qualified the NET‐JRF and GATE examinations. He joined the Ph.D. program in January 2018 at the CSIR‐National Chemical Laboratory (NCL), Pune, under the supervision of Dr. Samir H. Chikkali. His doctoral research focuses on the design and applications of P‐chiral supramolecular and phosphine–phosphite ligands in asymmetric catalysis.

Samir H. Chikkali earned his Ph.D. under the supervision of Prof. Dietrich Gudat from the University of Stuttgart, Germany. Subsequently, he did postdoctoral research with Prof. Joost Reek at the University of Amsterdam, the Netherlands, and Prof. Stefan Mecking at the University of Konstanz, Germany. In 2012, he returned to India and joined CSIR‐National Chemical Laboratory (CSIR‐NCL), Pune, to start his independent research career. Currently, he leads a team of highly motivated researchers in organometallics, polyolefins, renewable/degradable polymers, and depolymerization.