English

• 1. Introduction

  P-stereogenic centers play pivotal roles in various fields, particularly drug development and biological applications [1-3], where the absolute stereochemistry of phosphorus has a direct impact on the biological activity and therapeutic efficacy (Fig. 1). For example, the (S)-enantiomer of the insecticide Salithion is significantly more active than its counterpart in agrochemicals [4], and drugs such as Cytoxan are used in cancer treatment for their anti-tumour activity [5]. The modified nucleotide (Rp)-adenosyl-3′, 5′-cyclic phosphorothioate (Rp-cAMPS) can act as a protein kinase inhibitor, capable of antagonizing gene expression and DNA replication [6]. Additionally, P-stereogenic compounds play crucial roles as matrix metalloproteinase inhibitors and utrophin modulators, expanding their therapeutic utility [7]. In particular, antiviral medications such as Tenofovir, used for the treatment of HIV and Hepatitis B [8], and Remdesivir, effective against Ebola virus and SARS-CoV-2, underscore the critical role of P-stereogenic compounds in addressing global health challenges. These examples highlight the importance of P-stereogenic chemistry in drug discovery and have led to extensive research into the synthesis of P-stereogenic compounds for both medical and agricultural purposes [9, 10].

  Figure 1

  

  Figure 1.  Examples of high-value P-stereogenic compounds.

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  Beyond the traditional chiral reagent-based resolution of racemic phosphorus compounds and the diastereoselective synthesis with chiral auxiliaries (Fig. 2, left) [11-20], which typically require stoichiometric chiral reagents and multiple steps, the developed catalytic methods mainly include the desymmetrization of tertiary phosphorus (targeting distal atoms) [21-28] and the (dynamic) kinetic transformation of secondary phosphines and their derivatives for new C-P bonds (Fig. 2, right) [29, 30], typically limited to all carbon substituents on phosphorus. Recently, Jacobsen's group demonstrated that a chiral hydrogen-bond-donor catalyst enables enantioselective S_N2 dealkylation in Michaelis–Arbuzov reactions, producing highly enantioenriched H-phosphinates as versatile P-stereogenic building blocks [31]. In addition, strategies based on phosphinic acid and its derivatives [32-34], as well as phosphonium salts [35-37], have proven effective for the construction of P-chiral compounds. Most of these strategies rely on metal catalysts and are mainly applicable to the synthesis of chiral phosphine oxides, while the reported pharmaceuticals are mostly based on structures such as phosphonamidates, phosphonates, and phosphinates. To overcome these limitations, recent catalytic strategies based on nucleophilic substitution at the P-center have been developed, offering promising alternatives for the synthesis of P-stereogenic compounds with high stereoselectivity and efficiency. Despite the significant advantages of this strategy in producing high-value chiral phosphorus compounds, it is still in its infancy and faces numerous challenges. Currently, phosphorus-centered nucleophilic substitution mainly involves the desymmetrization strategies of prochiral P(Ⅴ) compounds and the (dynamic) kinetic transformation of tertiary phosphines and their derivatives (Fig. 2, bottom). This review provides an overview of advancements in the construction of P-stereogenic centers based on P-centered nucleophilic substitution, focusing on three main aspects: (1) desymmetrization strategies based on P-centered nucleophilic substitution; (2) the challenge of racemization in tertiary phosphines and their derivatives; and (3) catalytic P(Ⅴ)-centered nucleophilic substitution for high-value P-chiral compounds. We aim for our discussion to inspire further advancements and provide valuable insights for continued development in this field.

  Figure 2

  

  Figure 2.  General strategies for constructing P-stereogenic compounds.

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  2. Desymmetrization strategies based on P-centered nucleophilic substitution

  Desymmetrization via nucleophilic substitution at the P-center stands out as one of the most efficient and direct approaches to the construction of target chiral phosphorus molecules. In contrast to traditional desymmetrization strategies targeting distal atoms (Fig. 3A) [22, 38-40], such as deprotonation [41], acetylation [42, 43], metathesis [44], addition [45-50], and C—H activation [23, 24, 51-65], this approach directly targets the phosphorus atom. This enables the formation of P-chiral centers with a broader substrate scope and the potential to generate more diverse organophosphorus architectures through a two-stage nucleophilic substitution (Fig. 3B). In 2022, Jacobsen's group reported a catalytic, enantioselective nucleophilic desymmetrization of phosphoryl dichlorides with chiral urea catalysts [66], enabling the enantioselective synthesis of chlorophosphonamidates as versatile intermediates that can be further diversified through sequential nucleophilic substitutions, allowing the introduction of a wide range of functional groups at the phosphorus center with high stereocontrol (Fig. 3C). This methodology not only avoids the need for stoichiometric chiral control elements but also expands the synthetic utility of P(Ⅴ) chiral compounds beyond the limited scope offered by auxiliary-based methods [11]. However, this transformation was effective exclusively with aryl-substituted phosphoryl dichlorides, whereas alkyl-substituted phosphoryl dichlorides proved unreactive under the optimized conditions and could not be utilized for constructing non-carbon-substituted P-stereogenic compounds.

  Figure 3

  

  Figure 3.  Desymmetrization strategies for accessing stereogenic P(Ⅴ) targets.

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  In 2023, Dixon's group reported that the desymmetrization of prochiral phosphonate esters employing bifunctional iminophosphorane (BIMP) catalysts offers an efficient route to stereogenic P-centers through enantioselective substitution of enantiotopic groups (Fig. 3D) [67]. This method, however, is limited to phenol nucleophiles in the first step of nucleophilic substitution, with high enantioselectivity achieved only when phenols bearing ortho-substituents were employed, inherently narrowing the substrate scope. Furthermore, in the second step of the enantiospecific replacement, the ortho-substituted phenols introduced during the initial stage proved difficult to displace, likely due to the combined influence of steric hindrance and reduced reactivity of the phosphorus center in phosphonate esters derived from alkyl alcohols. In addition, the BIMP catalyst has been demonstrated to facilitate the enantioselective nucleophilic desymmetrization of bisthiazolidinone-derived P(Ⅴ) compounds [68]. Compared to the desymmetrization of prochiral phosphonate esters derived from 2-methyl-6-nitrophenol, this method extends to non-hindered phenols, significantly improving substrate scope, efficiency, and practicality over previous protocols. It enables the divergent synthesis of various P(Ⅴ) compounds, including those with C-, N-, O-, and S-based substituents. However, while these methods enable the synthesis of stable, versatile intermediates that can be further modified to produce a diverse array of P-chiral compounds relevant to medicinal chemistry (Fig. 3E), they remain confined to the desymmetrization of carbon-substituted prochiral phosphorus compounds.

  The development of catalytic enantioselective desymmetrization strategies based on P-centered nucleophilic substitution has significantly advanced the field of P-chiral compound synthesis. These methods not only improve the accessibility and diversity of stereogenic P(Ⅴ) compounds but also offer pathways for the efficient synthesis of medicinally relevant phosphorus molecules with high enantioselectivity, setting the stage for future innovations in organophosphorus chemistry (Fig. 3E). Despite important advances in direct nucleophilic substitution at the phosphorus atoms, challenges remain in achieving broad substrate scope and high stereoselectivity, particularly for complex, multifunctional systems. Jacobsen's strategy, for example, is limited to aryl phosphoryl dichlorides, while Dixon's desymmetrization approach with bisthiazolidinone-derived P(Ⅴ) compounds extends to alkyl-substituted phosphorus compounds. However, the desymmetrization of non-carbon-substituted prochiral phosphorus compounds remains unreported, highlighting a substantial gap in the synthesis of organophosphorus compounds. Mechanistically, all these studies rely on the use of hydrogen-bond-donor-catalyst to enable enantioselective synthesis of P-chiral compounds, facilitated by non-covalent interactions between the substrate and catalyst. These limitations highlight the need for further development in the design and screening of a broader array of catalysts to fully harness the potential of this strategy in the synthesis of diverse P-stereogenic compounds, particularly phosphorus-containing pharmaceuticals.

  3. The challenge of racemization in tertiary phosphines and their derivatives

  Significant progress has been made in the construction of P-stereogenic compounds based on the dynamic kinetic resolution (DKR) of secondary phosphines [69]. This primarily results from the low pyramidal inversion barriers in the transition metal-phosphido species generated in situ, which enable a rapid equilibrium between INT A and INT B (Fig. 4A). There are a few reports of racemization of secondary phosphine oxides (SPOs), notably with Cu and Ni catalytic systems, although the racemization pathway of SPOs remains unclear [30, 70-73]. Despite these advances, reports on the kinetic resolution of H-phosphinates for constructing P-centered phosphinate compounds remain scarce [74], and there are no reports to date on the dynamic kinetic resolution of H-phosphonates (H-P(O)(OR¹)(OR²)) or H-phosphonamidates (H-P(O)(OR¹)(NR₂²)) for this purpose. Consequently, the DKR of secondary phosphines and their derivatives has been mainly limited to the construction of all carbon-substituted tertiary phosphine oxides (TPOs), with only minimal literature available for the synthesis of P-N and P-O compounds [75-77], even though these compounds hold huge potential as drug candidates.

  Figure 4

  

  Figure 4.  The challenge of racemization in tertiary phosphines and their derivatives.

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  The stereoselective nucleophilic substitution of fully substituted phosphines and their oxides remains to be further explored as an effective strategy for the construction of P-stereogenic compounds, particularly for the high-potential nucleoside phosphate/phosphoramidate prodrugs. One of the main challenges in this strategy, whether in fully substituted phosphines (P(Ⅲ)) or their oxides (P(Ⅴ)), lies in the difficulty of achieving racemization (Fig. 4B). For example, (R)-cyclohexyl(methyl)(propyl)phosphane can racemize within a day when heated to 130 ℃ [78], whereas phosphine oxides like PAMPO are configurationally stable [14, 79]. Unlike in carbon-based systems, where chirality inversion can be manipulated more easily, the inversion of P-centered chirality is notoriously difficult due to the unique electronic and geometric properties of phosphorus. This renders classical racemization approaches ineffective for fully substituted phosphines and their oxides, which presents a fundamental obstacle to more efficient synthesis. To date, there are only a few reports on the dynamic kinetic asymmetric transformations of fully substituted phosphines or their oxides.

  In 2003, Hayakawa's group reported the first catalytic asymmetric synthesis of P-chiral trialkyl phosphates via dynamic kinetic resolution (Fig. 4C), utilizing a chiral amine promoter to achieve the stereoselective coupling of racemic phosphorochloridites with alcohols to produce optically active trialkyl phosphates after stereospecific oxidation [80]. Although only a few examples, this work represents a significant advancement in the asymmetric synthesis of organophosphorus compounds, which previously required a stoichiometric amount of the chiral source to construct the P-chiral center [81-83]. Mechanistically, the authors proposed that the INT C and INT D formed during the reaction could interconvert, with their interconversion rate being faster than their subsequent reaction with alcohol. In the same year, Humbel et al. investigated the configurational stability of chlorophosphines using DFT calculations and experimental studies and demonstrated that traces of HCl in the reaction medium could catalyze the racemization of chlorophosphines by facilitating the chiral inversion of the P-center [84]. They used dimethylchlorophosphine as a model to calculate the transition state energy barriers of several intermediates potentially involved in its racemization process (Fig. 4D). However, these results demonstrate again that the configurational inversion of tertiary phosphines requires high pyramidal inversion barriers, contradicting the proposal of Hayakawa et al. that the chiral amine-assisted intermediates INT C and INT D can rapidly interconverted.

  The high pyramidal inversion barriers of tertiary phosphines significantly constrain their potential as effective substrates for nucleophilic substitution at the P-center via dynamic kinetic processes, thereby limiting their utility in constructing valuable P-stereogenic compounds. A breakthrough in overcoming this challenge was achieved in 2021 by David K. Leahy and Scott J. Miller, who successfully realized the catalytic synthesis of P-stereogenic dinucleotides using chiral phosphoric acid (CPA) catalysis (Fig. 4E) [85]. Their approach precisely controlled the stereochemistry during phosphoramidite transfer, relying on a hypothetical mixed-valence P(Ⅲ)-P(Ⅴ) substrate-catalyst complex that undergoes rapid epimerization at P(Ⅲ). By employing distinct CPA scaffolds, such as peptide-embedded phosphothreonine-derived CPAs and C2-symmetric BINOL-derived CPAs, they achieved remarkable diastereodivergence. This method provided asymmetric catalysis with readily available phosphoramidites, marking a major breakthrough in the stereocontrolled synthesis of P-stereogenic compounds by P-centered nucleophilic substitution.

  4. Catalytic P(Ⅴ)-centered nucleophilic substitution for high-value P-chiral compounds

  Compared to P(Ⅲ) compounds, achieving (dynamic) kinetic transformation of P(Ⅴ)-stereogenic compounds is significantly more challenging. However, P(Ⅴ)-centered nucleophilic substitution holds greater potential for the synthesis of high-value P-chiral compounds due to its broader applicability and relevance in pharmaceuticals and agrochemicals [86, 87], which push the boundaries of catalytic methods for P(Ⅴ)-stereogenic compounds. A pioneering study on the catalytic asymmetric nucleophilic substitution of phosphorus(Ⅴ) compounds was reported by Zhang's group in 2011 (Fig. 5A) [88]. They developed a chiral bicyclic imidazole-catalyzed phosphorylation reaction of cyclamide, which allowed the stereoselective N-substitution of racemic phosphoryl chloride. Although only moderate enantioselectivity (34.3% ee) was achieved in the preparation of chiral phosphoramide compounds, this is the first catalytic enantioselective synthesis of P-stereogenic phosphoramides. Subsequent studies have highlighted the significant impact of the chiral bicyclic imidazole catalyst in enabling the stereoselective nucleophilic substitution of fully substituted P(Ⅴ)-compounds via a dynamic kinetic process.

  Figure 5

  

  Figure 5.  Catalytic P(Ⅴ)-centered nucleophilic substitution for high-value P-chiral compounds.

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  In 2017, DiRocco et al. disclosed a catalytic stereoselective phosphorylation of nucleosides using a chiral bicyclic imidazole-derived multifunctional catalyst, achieving the assembly of P-stereogenic nucleotide phosphoramidate prodrugs with high stereoselectivity (99:1) through a dynamic kinetic process (Fig. 5B) [89]. This method not only bypasses the need for chiral auxiliaries or non-racemic phosphorylating agents but also enhances the synthesis of clinically relevant nucleoside analogs like MK-3682, a hepatitis C virus (HCV) polymerase inhibitor. Their work represents a significant advance in the stereoselective synthesis of phosphorus-based prodrugs, with broad applicability in antiviral and anticancer therapies. Subsequently, in 2020, Zhang's group demonstrated that chiral bicyclic imidazole catalysts can be used in the asymmetric catalytic synthesis of Remdesivir, an antiviral drug for treating Ebola virus and COVID-19 (Fig. 5C) [90]. The researchers validated the scalability of this method through a 10-g scale synthesis. The protected Remdesivir was obtained in 89% yield with a diastereomeric ratio of > 99:1. After deprotection with 37% HCl in THF, the desired Remdesivir was obtained in 73% isolated yield. Moreover, the catalyst was successfully regenerated after column chromatography and reused in the next catalytic cycle without any noticeable loss in catalytic efficiency. Additionally, in 2021, Hung, Wong, and co-workers achieved a one-pot synthesis of Remdesivir using a bicyclic imidazole catalyst with dual stereocenters (Fig. 5D) [91]. Employing 20 mol% of the chiral imidazole-cinnamaldehyde-derived carbamate, they performed a 10-g scale synthesis. After protecting group removal and a single recrystallization step, Remdesivir was obtained in 70% yield with a diastereomeric ratio of 99.3:0.7. In 2019, Tang's group demonstrated that chiral bicyclic imidazole catalysts could be effectively applied to carbohydrate compounds, offering a streamlined approach for the selective synthesis of phosphoramidated carbohydrate-based prodrugs and natural products through site- and stereoselective phosphoramidation (Fig. 5E) [92]. Although these represent significant breakthroughs in phosphoramidation—achieving high stereoselectivity at the phosphorus center with a small molecule catalyst, these strategies are limited to chlorophosphoramidates that contain an -NH group.

  Metal-catalyzed phosphoramidation, alongside organocatalytic approaches, has achieved notable progress and plays a pivotal role in the synthesis of P-stereogenic phosphoramidate prodrugs. In 2015, Pertusati's group reported the first copper-catalyzed diastereoselective synthesis of P-stereogenic phosphoramidate prodrugs (Fig. 6A) [93]. Through careful optimization of the metal catalyst, base, and solvent, they achieved selective phosphorylation of unprotected nucleosides, attaining moderate conversion rates and diastereomeric ratios of up to 8.3:1. Prior to this, the diastereoselective synthesis of ProTides often relied on the use of chiral auxiliaries [94, 95] and diastereomerically pure phosphoramidating agents featuring p-nitrophenyl or pentafluorophenyl as leaving groups [96]. Recently, Shang et al. have developed a ligand-enabled, copper-catalyzed method for the stereoselective synthesis of P-stereogenic ProTides (Fig. 6B) [97]. The success of this approach lies in integrating a newly developed chiral diamine ligand with a copper catalyst, forming a chiral metal complex that activates the electrophilic phosphorylating reagent and facilitates a base-promoted nucleophilic substitution pathway. It enables the highly stereoselective synthesis of previously inaccessible (S, R) and (R, S) ProTide derivatives using catalysts of different configurations, achieving diastereomeric ratios of up to 99:1, whereas previous catalytic methods were limited to the synthesis of (R, R) and (S, S) ProTide derivatives. This method has been proven effective for various nucleosides and phosphoramidates and is particularly valuable for the synthesis of clinically relevant ProTides, such as (R)-NUC-3373 and (R)-NUC-7738, whose diastereomeric mixtures are currently being clinically evaluated for the treatment of solid tumors, as well as (R)-Stampidine, which is currently being investigated in Phase I clinical trials for the treatment of HIV.

  Figure 6

  

  Figure 6.  Metal-catalyzed stereoselective synthesis of P‑stereogenic ProTides.

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  5. Conclusion

  The advancements in the catalytic stereoselective synthesis of P‑stereogenic compounds via P-centered nucleophilic substitution have been summarized in this review. Recognized as the most efficient and direct approach to high-value chiral phosphorus molecules, this area holds significant potential for further development. For instance, desymmetrization strategies based on P-centered nucleophilic substitution cannot yet be extended to non-carbon-substituted prochiral phosphorus compounds and are highly dependent on the use of hydrogen-bond-donor catalysts. Due to the high inversion barriers of tertiary phosphines and their derivatives, examples of (dynamic) kinetic transformations in this context remain limited, particularly for chlorophosphoramidates containing an -NH group. Although some existing methods can construct P-stereogenic compounds with non-carbon substituents, they generally involve multi-step processes to introduce chiral auxiliaries, leading to stoichiometric by-products and reduced efficiency. Asymmetric catalysis offers a promising way to streamline these syntheses and minimize by-product formation. However, catalytic asymmetric methods for the construction of non-carbon-substituted P-stereogenic compounds remain largely unexplored. Current research methods, such as the desymmetrization of tertiary phosphorus (targeting distal atoms) and (dynamic) kinetic transformation of secondary phosphines and their derivatives, predominantly focus on fully carbon-substituted species, while therapeutically relevant molecules often contain P-O, P-N, or P-S bonds. Therefore, there is an urgent need to develop novel catalytic systems, whether organocatalytic or metal-catalytic, that can enable the efficient, stereoselective synthesis of P-stereogenic compounds with diverse applications and high pharmaceutical relevance via phosphorus-centered nucleophilic substitution.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Bingbing Dong: Writing – original draft, Investigation, Conceptualization. Junmin Zhang: Funding acquisition, Formal analysis. Xiang-Yu Ye: Writing – original draft. Xuan Huang: Writing – review & editing. Yonggui Robin Chi: Writing – review & editing, Funding acquisition, Formal analysis.

  Acknowledgments

  We acknowledge financial support from the National Natural Science Foundation of China (Nos. 22171187 and 22001173), the Project of Department of Education of Guangdong Province (No. 2020KTSCX116), the Shenzhen Science and Technology Foundation (Nos. 20200812202943001 and KQJSCX20180328100401788), Frontiers Science Center for Asymmetric Synthesis and Medicinal Molecules, Department of Education, Guizhou Province (No. Qianjiaohe KY (2020)004), the Central Government Guides Local Science and Technology Development Fund Projects (Nos. Qiankehezhongyindi (2024)007, (2023)001), Singapore National Research Foundation under its NRF Competitive Research Program (No. NRF-CRP22–2019–0002), Ministry of Education, Singapore, under its MOE AcRF Tier 1 Award (Nos. RG84/22, RG70/21), MOE AcRF Tier 2 (No. MOE-T2EP10222–0006), and MOE AcRF Tier 3 Award (No. MOE2018-T3–1–003), a Chair Professorship Grant, and Nanyang Technological University.

  
  
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  Figure 1  Examples of high-value P-stereogenic compounds.

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  Figure 2  General strategies for constructing P-stereogenic compounds.

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  Figure 3  Desymmetrization strategies for accessing stereogenic P(Ⅴ) targets.

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  Figure 4  The challenge of racemization in tertiary phosphines and their derivatives.

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  Figure 5  Catalytic P(Ⅴ)-centered nucleophilic substitution for high-value P-chiral compounds.

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  Figure 6  Metal-catalyzed stereoselective synthesis of P‑stereogenic ProTides.

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