Recent advances in synthesis of nitrogen-centered chiral compounds

Abstract

Nitrogen-centered chiral compounds are widely found in natural products and pharmaceuticals, and can serve as multifunctional chiral catalysts, reagents, and ligands in asymmetric synthesis. However, the creation of nitrogen stereocenters remains a significant challenge. This difficulty arises from the low energy barrier for pyramidal inversion of the amine lone pair, which leads to rapid racemization. In recent years, breakthroughs in areas such as dynamic kinetic resolution, chiral ligand control, enzymatic catalysis, and organocatalysis have dramatically enhanced the efficiency of accessing configurationally stable nitrogen-centered chiral compounds. Herein, we present a detailed overview of the research progress in this field over the past five years, organized by the coordination number of the nitrogen stereocenter.

This review summarizes efficient synthetic routes to two types of stable nitrogen-centered chiral compounds, classified by the coordination number of the stereogenic nitrogen center.

1. Introduction

Nitrogen-centered chiral compounds refer to those where the nitrogen atom serves as the stereogenic center. Tricoordinate nitrogen possesses three distinct substituents along with one lone electron pair, while tetracoordinate nitrogen is bonded to four different substituents. Both adopt an approximately tetrahedral geometry. They are widely found in natural products¹ and pharmaceuticals,² and can serve as multifunctional chiral catalysts, reagents, and ligands in asymmetric synthesis,³ thus possess significant application value (Fig. 1a).

Fig. 1. (a) Representative examples of nitrogen-centered chiral compounds; (b) nitrogen inversion in trivalent amines.

Nevertheless, the efficient synthesis of nitrogen-centered chiral compounds remains enormously challenging. Most tricoordinate nitrogen centers bearing a lone pair of electrons have low inversion barriers, allowing rapid configurational interconversion at room temperature, which makes enantiomer separation or configurational stability difficult to achieve (Fig. 1b).⁴ Although quaternization to form ammonium salts can improve stability, some ammonium salts, especially iodides and bromides in low-polarity solvents, remain prone to racemization via dealkylation followed by realkylation, or to direct irreversible decomposition.⁵ In early explorations, researchers attempted to obtain optically active compounds with stereogenic nitrogen centers through resolution methods. In 1899, Pope and Peachey resolved allylbenzylmethylphenylammonium salt using camphorsulfonic acid, obtaining the first optically active enantiomers of a quaternary ammonium salt.⁶ In 1908, Meisenheimer resolved N-oxides using d-bromocamphorsulfonic acid.⁷ However, such strategies generally relied on stoichiometric chiral resolving agents, suffered from low enantioselectivity, and possessed a narrow substrate scope.⁸ Consequently, the development of chiral compounds bearing stereogenic nitrogen centers had long proceeded slowly.

In recent years, breakthroughs in areas such as dynamic kinetic resolution, chiral ligand control, enzymatic catalysis, and organocatalysis have dramatically enhanced the efficiency of accessing configurationally stable nitrogen-centered chiral compounds. Zaitseva and Köhler⁹ have comprehensively reviewed the synthetic methodologies of such compounds reported up to 2023, wherein the synthetic approaches were categorized into resolution, enantioselective synthesis and diastereoselective synthesis. Unlike previous reviews, the present review classifies nitrogen stereocenters according to their coordination numbers (tricoordinate and tetracoordinate) and highlights recent breakthroughs in this field. Specifically, it focuses on literature from the past five years reporting significant advances (Fig. 2). Very recently, Sibi and co-workers published an account on the functional utilization of fluxional chirality at nitrogen centers to enhance stereoselectivity in asymmetric catalysis.¹⁰ In contrast, this review focuses on the synthesis and construction of configurationally stable nitrogen stereocenters.

Fig. 2. Synthesis of nitrogen-centered chiral compounds: progress in the past five years.

2. Synthesis of tetracoordinate nitrogen stereocenters

2.1. N-centered quaternary ammonium salts

Since the first report by Tayama and co-workers in 2007 on the efficient optical resolution of N-centered chiral tetraalkylammonium salts via diastereoselective complexation between (R)-BINOL and N-centered chiral β-hydroxy tetraalkylammonium bromides,¹¹ the groups of Suzuki¹² and Tayama¹³ have also obtained such N-centered quaternary ammonium salts through alternative chiral resolution strategies. In 2021, Kitching reported an enantioselective method for synthesizing quaternary ammonium cations by combining BINOL-mediated enantioselective ammonium recognition with reversible racemization of nitrogen stereocenters (Scheme 1).^5b Unlike previous resolution strategies this method enables for the first time the direct construction of stereogenic nitrogen centers in quaternary ammonium salts from simple achiral anilines and alkyl halides in a one-pot process without requiring any additional functional handle. This method offers broad substrate scope, good yields, and high enantioselectivity under thermodynamic control. The process involves reversible alkylation of conformationally labile amines to a dynamic equilibrium, followed by BINOL-mediated selective complexation of the preferred ammonium enantiomer via hydrogen bonding. Mismatched complexes redissolve due to low stability, allowing racemization and re-complexation in a self-correcting cycle that continuously improves enantiopurity. The resulting chiral ammonium cations outperform alkylated cinchona alkaloids in BINOL recognition, presenting new opportunities for nitrogen stereocenters in catalysis, medicine, and materials science.

Scheme 1. Enantioselective synthesis of quaternary ammonium cations.

In 2023, Köhler reported the first enantioselective catalytic method for the synthesis of chiral ammonium ions bearing a stereogenic nitrogen center (Scheme 2).¹⁴ This method employs palladium-catalyzed asymmetric allylic alkylation, exploiting the rapid configurational inversion of tertiary amines via a dynamic kinetic resolution (DKR) strategy to directly and efficiently convert configurationally labile tertiary amines into chiral quaternary ammonium ions with favorable enantioselectivity (up to 80% ee). The reaction is carried out in a polar protic solvent (MeOH/H₂O 1 : 1) using prenyl methyl carbonate as a low-reactivity electrophile. The polar protic solvent stabilizes the ionic products and suppresses background reactions, while the low-reactivity electrophile avoids non-catalyzed alkylation. Among 40 chiral ligands evaluated, the Trost-type ligands, featuring a large bite angle and a flexible scaffold, afforded the optimal results. In addition, the geminal dimethyl group at the allyl terminus significantly suppresses product racemization. This metal-catalyzed dynamic kinetic resolution represents a distinct advance over previous stoichiometric and enzymatic methods, establishing a new catalytic platform for the catalytic synthesis of chiral quaternary ammonium salts bearing nitrogen stereocenters.

Scheme 2. Palladium-catalyzed enantioselective allylation of stereogenic nitrogen centers.

2.2. N-chiral amine oxides

Tetracoordinate nitrogen stereocenters can be constructed not only in N-centered quaternary ammonium salts but also in N-chiral amine oxides. In 2016, Yamamoto and Bhadra¹⁵ reported the direct asymmetric synthesis of N-chiral amine oxides using a bimetallic titanium catalyst, opening an efficient route to both N-chiral amine oxides and optically active γ-amino alcohols. In 2023, Tang and colleagues developed a biomimetic dynamic kinetic asymmetric nitrogen-oxidation strategy, achieving the efficient and highly enantioselective synthesis of N-chiral tertiary amine oxides (Scheme 3).¹⁶ Building on their prior discovery that nonionic alloxan efficiently catalyzes sulfide/amine oxidation with H₂O₂ or O₂, they introduced chiral substituents into the alloxan framework to replicate the FMO chiral cavity.

Scheme 3. The chiral alloxan-catalyzed dynamic kinetic asymmetric N-oxidation of unsymmetrical tertiary amines with H₂O₂ or O₂.

This system employs H₂O₂ or O₂ as green oxidants and relies on hydrogen-bond-mediated dynamic kinetic resolution. It accommodates a broad range of unsymmetric tertiary amines, for example, those bearing various electronic substituents on the phenyl ring, replacing the phenyl with naphthyl or thienyl, or varying N-substituents, to afford N-chiral acyclic tertiary amine oxides in high yields with excellent enantioselectivities. DFT calculations support the following mechanism: chiral alloxan activates H₂O₂ to form a reactive hydroperoxide intermediate, which hydrogen-bonds to the rapidly inverting amine substrate 7-A. Favorable intermolecular interactions between the substrate's adamantyl group and the catalyst's phenyl ring stabilize the (R)-configured complex, locking the nitrogen center. Stereoselective oxygen transfer then proceeds preferentially viaTS2-(R) due to a lower energy barrier, releasing the (R)-N-chiral amine oxide product 8-A and regenerating the catalyst. The amine oxidation step is both stereo-determining and rate-determining.

Despite these remarkable breakthroughs, a general strategy for the highly enantioselective synthesis of nitrogen-stereogenic compounds remains elusive. In particular, organocatalytic approaches that efficiently control the stereochemistry at nitrogen stereocenters are still rare. In 2024, Wu and Zhang reported the first NHC organocatalytic formal desymmetrization strategy, offering an efficient and highly enantioselective route to the long-challenging construction of nitrogen stereocenters (Scheme 4).¹⁷ The NHC catalyst converts an aldehyde into an acyl azolium intermediate, which then undergoes enantioselective esterification with a prochiral diol under the cooperative action of a chiral phosphoric acid cocatalyst, affording chiral N-oxide products. Mechanistic and DFT studies revealed that the diol substrates form stable dimeric aggregates via unique ionic hydrogen bonds (IHB), a key factor enabling highly enantioselective desymmetrization of remote diols. This method accommodates a range of prochiral 1,5-diols bearing various aryl substituents, affording chiral N-oxides with a tetrahedral nitrogen stereocenter in good to excellent yields and high enantioselectivities. Notably, the enantioselectivity of the products decreased markedly with increasing carbon chain length of the 1,5-diols. The resulting products not only serve as novel chiral ligands in asymmetric allylation reactions, demonstrating their potential in chiral ligand design, but also exhibit promising inhibitory activity against phytopathogens, offering valuable lead structures for the development of new antibacterial agrochemicals.

Scheme 4. NHC-catalyzed desymmetrization for chiral N-oxides.

In contrast to the desymmetrization strategy, Ye and co-workers developed an ion-pair catalytic system comprising a chiral bisguanidinium cation and an achiral oxodiperoxomolybdosulfate anion for the asymmetric N-oxidation of various cyclic and acyclic tertiary amines, affording chiral N-oxides (Scheme 5).¹⁸ Using aqueous H₂O₂ as the oxidant and through silyl group modification of the catalyst, the optimal catalyst BG1 was obtained for acyclic tertiary amines, delivering up to 98% yield and 93% enantioselectivity with broad substrate scope. For cyclic tertiary amines, switching to catalyst BG2 also gave excellent catalytic performance. Mechanistically, H₂O₂ oxidizes molybdate in the aqueous phase to generate an active anionic species I, which is captured by the chiral bisguanidinium cation BG²⁺ and transferred into the organic phase, leading to the formation of the oxidizing ion-pair II. The tertiary amine substrate 12-A undergoes oxygen transfer with a side-on peroxo group of II, generating the chiral N-oxide (S)-13-A while the catalyst anion is reduced to its reductive state III. The reduced anion III returns to the aqueous phase and is re-oxidized by H₂O₂ to regenerate I, completing the catalytic cycle. Notably, the N-oxide products can slowly re-oxidize another amine to form racemic product, but the acidic additive KHSO₄ suppresses this side reaction via protonation. Together with the dynamic kinetic resolution (DKR) enabled by the chiral cavity, the system achieves high enantioselectivity. The mild reaction conditions and broad functional-group tolerance highlight the versatility of this method. Moreover, the N-oxides can be converted into a range of medicinally relevant derivatives with high enantiomeric purity, showing potential applications in the modification of existing drugs.

Scheme 5. Chiral bisguanidinium catalyzes asymmetric oxidation of amines to synthesize N-oxides.

2.3. N-chiral amine-boranes via B–N coordination

In 2025, Song and coworkers tackled the underexplored area of constructing nitrogen and boron heteroatomic stereo-centers in organic synthesis (Scheme 6).¹⁹ Unlike previous methods that focus on single heteroatom centers or carbon-only substituted N-stereocenter, they developed a Cu-catalyzed asymmetric B–H insertion reaction that for the first time assembles three consecutive stereocenters on three different atoms (B, N, and C), as well as vicinal B–N diheteroatomic stereocenters and isolated nitrogen stereocenters. This method exhibits broad substrate scope, accommodating a wide range of substituted amine boranes and diaryl diazo-methanes, and furnishes the target products in good to high yields, excellent enantioselectivities (up to 98% ee), and high diastereoselectivities. Mechanistic and DFT studies reveal a kinetic resolution pathway, with stereocontrol originating from π–π interactions between substrates and steric hindrance from the chiral ligand. Moreover, the kinetic resolution pathway affords chiral amine boranes bearing a single nitrogen stereocenter, which can serve as chiral transfer hydrogenation reagents, thereby expanding the structural diversity of chiral molecules.

Scheme 6. Copper-catalyzed asymmetric B–H insertion reaction between racemic amine boranes and diaryl diazomethanes.

3. Synthesis of tricoordinate nitrogen stereocenters

3.1. Diaziridines and N-chiral alkoxyamines

In 2013, Jørgensen reported the first catalytic asymmetric synthesis of diaziridines using a chiral phase-transfer catalyst.²⁰ Not until 2025 did Tan and Houk reported a chiral Brønsted acid-catalyzed enantioselective chlorination strategy, successfully achieving catalytic asymmetric construction of acyclic nitrogen stereocenters (Scheme 7).²¹ This method uses N-alkoxy hydroxylamines as substrates, which undergo catalytic chlorination to generate an N-chloro intermediate I. Rapid stereospecific intramolecular cyclization captures its transient configuration before racemization occurs, resulting in configurationally stable N-alkoxy-1,2-oxazolidines. This method exhibits good compatibility with aromatic rings, heteroaromatic rings, cycloalkyl rings of different sizes, and symmetric dihydroxy structures, achieving target products with excellent yield and enantioselectivity. Additionally, this method is also applicable to complex substrates containing carbon chiral centers, enabling late-stage stereoselective modification of natural products and drug molecule derivatives, and obtaining various stereoisomers by switching the catalyst configuration. Furthermore, this strategy has been further extended to the direct asymmetric synthesis of configurationally stable N-chlorinated aziridines, rapidly obtaining products with high enantiomeric purity under mild conditions. By combining catalytic asymmetric chlorination with intramolecular stereospecific capture, this strategy provides an effective approach for the catalytic asymmetric construction of trivalent nitrogen stereocenters.

Scheme 7. Asymmetric control of nitrogen chirality via CPA-catalyzed enantioselective chlorination.

Meanwhile, List and colleagues achieved the catalytic asymmetric synthesis of acyclic N-stereogenic amines (Scheme 8).²² They employed a class of highly acidic and conformationally confined imidodiphosphorimidate (IDPi) chiral Brønsted acid catalysts to successfully catalyze the asymmetric addition of silyl ketene acetals to in situ-generated silyl nitronium ions, giving anomeric amines that are configurationally stable acyclic N-stereogenic amines. Substrate scope studies revealed that the nitrogen substituents, along with the silyl and ester groups, collectively modulate the yield, enantioselectivity, and configurational stability of the products. Mechanistic investigations confirmed that the reaction proceeds via an anti-periplanar addition pathway and revealed the inadequacy of conventional stereochemical descriptors in this system, leading to the proposal of a novel “enantiolobal differentiation” mechanism, in which the selective attack of the nucleophile on different lobes of the π* orbital ultimately determines the absolute configuration of the nitrogen atom. This work successfully fills a long-standing research gap in the catalytic asymmetric synthesis of acyclic, tricoordinate N-stereogenic centers, which had been previously unattainable due to rapid pyramidal inversion.

Scheme 8. IDPi-catalysed asymmetric addition of silyl ketene acetals to nitronium ions.

3.2. N-chiral fused N-heterocycles

In 2021, Yan reported a new strategy for constructing rigid fused azepine skeletons via an organocatalytic asymmetric annulation reaction (Scheme 9).²³ This method enables the simultaneous and precise control of four types of stereogenic elements in a single transformation: a chiral nitrogen center, C–N axial chirality, C–C axial chirality, and seven-membered ring conformational chirality. The cyclization was efficiently carried out using NBS as the bromination reagent and dichloromethane as the solvent at −78 °C in the presence of chiral squaramide catalyst 3. The method exhibited a broad substrate scope, accommodating various naphthol substituents at different positions as well as diverse carbazole derivatives including symmetric 3,6-disubstituted carbazoles and unsubstituted carbazole. The target products were obtained in 46–92% yields, with >20 : 1 dr and up to 97% ee. In addition, this system can be applied to the kinetic resolution of racemic unsymmetric substrates containing 4-substituted carbazoles to access diastereomers with complementary configurations, further expanding the synthetic utility of this method for constructing complex molecules bearing multiple stereogenic elements. Mechanistically, the catalytic cycle proceeds as follows. Catalyst 3 first coordinates with NBS to generate complex I; the activated NBS then reacts with the substrate through bromination and proton transfer to generate a chiral brominated VQM intermediate. Subsequently, this VQM intermediate undergoes intramolecular electrophilic aromatic substitution at the C1 position of the carbazole moiety via a sp³-hybridized carbocation transition state TS-1, which simultaneously establishes the second stereogenic axis. Finally, proton migration and aromatization afford the enantioenriched azepine product, bringing all four stereochemical elements under precise control within a single molecular scaffold.

Scheme 9. Enantioselective synthesis of compounds with multiple stereogenic elements.

In 2023, Zhu and Luo described a novel strategy for constructing doubly fused triarylamines with configurationally stable nitrogen-stereogenic centers through palladium-catalyzed asymmetric C–H activation and seven-membered-ring formation (Scheme 10).²⁴ In this method, 6/6/7/6 and 6/7/7/6 doubly fused triarylamine scaffolds were designed. The nitrogen atom is rigidly embedded into the helical center, achieving a pyramidal inversion energy barrier as high as 45.4 kcal mol⁻¹. As a result, long-term configurational stability of the nitrogen stereocenter is enabled without the assistance of bulky substituents. Substrate scope investigation revealed that this method exhibits good compatibility with aryl iodides bearing substituents of different electronic natures as well as isocyanides derived from phenothiazine, phenoxazine, and related heterocycles, affording the corresponding products in moderate to excellent yields with high enantioselectivities. X-ray crystallographic analysis determined the absolute configuration of the nitrogen atom as S, and the whole molecule adopted an M helical twist conformation. Moreover, the products could be divergently transformed through cross-coupling, reduction, and oxidation reactions. Mechanistically, the reaction proceeds through a concerted metalation–deprotonation pathway to activate the C–H bond, forming an eight-membered palladacycle intermediate. Subsequent reductive elimination closes the seven-membered ring, and this step is identified as both the rate-determining and enantioselectivity-determining step.

Scheme 10. Pd-catalyzed C–H imidoylation.

In 2023, Zhang reported a new method for the efficient and highly enantioselective synthesis of rigid Tröger's base analogues bearing a nitrogen stereocenter via palladium-catalyzed intramolecular α-arylation (Scheme 11).²⁵ The study employs the home-developed GF-Phos L6 as the chiral ligand, Pd₂(dba)₃ as the palladium source, Cs₂CO₃ as the base, and MeCN as the solvent at 100 °C for 12 hours. This approach enables the simultaneous construction of a carbon stereocenter and a nitrogen stereocenter, successfully overcoming the dual bottlenecks of the configurational lability of nitrogen chirality and the acid instability of traditional Tröger's base, affording a stable N-bridged [3.3.1] ring scaffold in up to 95% yield and 96% ee. DFT calculations and control experiments reveal that the NH⋯O hydrogen bond between the ligand and substrate, along with weak interactions (C–H⋯π) between the substrate C–H bonds and the aromatic ring of the ligand, are the key mechanisms cooperatively controlling the high enantioselectivity. The obtained chiral scaffold is configurationally stable and can serve directly as a chiral phase-transfer catalyst and a precursor for Ir/Pd metallacycles, enabling kinetic resolution, borrowing hydrogen cascade, and imine 1,2-addition. This work provides a new strategy for constructing nitrogen-stereogenic compounds and rigid chiral bridged scaffolds.

Scheme 11. Nitrogen stereocenter via palladium-catalyzed intramolecular α-arylation.

In 2025, Shi employed a catalytic system consisting of Pd(OAc)₂ and l-pyroglutamic acid (l-pGlu-OH) to achieve an enantioselective C–H olefination reaction, successfully synthesizing a series of configurationally stable and non-rigidified N-stereogenic tribenzo[b,d,f]azepines (Scheme 12).²⁶ A broad range of substrates (41 examples) are compatible, providing products in up to 99% yield and >99% ee. Distinct from conventional strategies relying on covalent rigidification or quaternization, the configurational stability of these nitrogen stereocenters primarily originates from the unique saddle-shaped molecular conformation. The synthetic protocol can be readily scaled up to gram-scale, and the products can be conveniently converted into chiral alcohols, carboxylic acids, amides, and other derivatives. Furthermore, these molecules display outstanding CPL properties, with luminescence dissymmetry factors up to 0.011, significantly exceeding those of typical small organic molecules, highlighting their significant application potential in the fields of chiral ligand design and chiroptical materials.

Scheme 12. N-stereogenic tribenzo[b,d,f]azepines via palladium-catalyzed enantioselective C–H olefination.

Recently, Zhang and co-workers reported a dynamic kinetic resolution strategy via enantioselective palladium-catalyzed C–H olefination, which harnesses rapid nitrogen inversion to convert configurationally labile nitrogen stereocenters into stable chiral centers. This method enables efficient synthesis of highly enantioenriched tribenzo[b,d,f]azepines and dibenzo[b,f]azepines (Scheme 13).²⁷ The reaction accommodates a broad range of substrates and alkenes, delivering products in up to 98% yield and up to 99% ee. Mechanistic studies reveal that the palladium catalyst coordinates with the chiral ligand and then undergoes ligand exchange with the racemic substrate to generate an intermediate, which proceeds through a concerted metalation–deprotonation pathway for C–H activation, followed by alkene insertion and β-hydride elimination to complete the catalytic cycle, wherein the C–H activation step is both the rate-determining step and the chirality-determining step. Furthermore, the products exhibit excellent circularly polarized luminescence performance, highlighting their potential for applications in OLEDs and asymmetric catalysis.

Scheme 13. DKR via Pd-catalyzed enantioselective C–H activation for the construction of nitrogen stereocenters.

4. Summary and perspectives

This review systematically summarizes the key advances in the synthesis of nitrogen-stereogenic molecules over the past five years. A series of highly enantioenriched chiral nitrogen-containing frameworks have been established, greatly enriching the structural diversity of this class of compounds. Here, we categorize these systems according to the coordination number of the stereogenic nitrogen center (tricoordinate and tetracoordinate) and provide a comprehensive overview of the synthetic strategies, substrate scopes, and reaction mechanisms for each category.

Against this backdrop, significant challenges remain for both tricoordinate and tetracoordinate nitrogen-stereogenic systems. For tricoordinate systems, controlling configurational stability while achieving efficient stereocontrol remains a fundamental challenge. For tetracoordinate systems, the development of general, practical, and broadly applicable catalytic asymmetric platforms is highly desirable. In addition, the fusion of nitrogen chirality with other stereogenic elements, such as central carbon chirality, axial chirality, and helical chirality, remains largely unexplored, offering a promising route toward structurally diverse and functionally novel chiral molecules. With continued advances in synthetic methodology, nitrogen-stereogenic compounds are expected to find increasingly broad applications in asymmetric catalysis, medicinal chemistry, and functional materials.

Author contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Conflicts of interest

There are no conflicts of interest to declare.

Abbreviations

BINOL

2,2′-Dihydroxy-1,1′-binaphthol

NHC

N-heterocyclic carbene

IHB

Ionic hydrogen bonds

DKR

Dynamic kinetic resolution

IDPi

Imidodiphosphorimidate

NBS

N-Bromosuccinimide

l-pGlu-OH

l-Pyroglutamic acid

CPL

Circularly polarized luminescence

FMO

Flavin-containing monooxygenases

VQM

Vinylidene ortho-quinone methide

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review