Catalytic Kinetic Resolution and Desymmetrization of Amines

Abstract

Optically active amines represent critically important subunits in bioactive natural products and pharmaceuticals, as well as key scaffolds in chiral catalysts and ligands. Kinetic resolution of racemic amines and enantioselective desymmetrization of prochiral amines have proved to be efficient methods to access enantioenriched amines, especially when the racemic or prochiral amines were easy to prepare while the chiral ones are difficult to be accessed directly. In this Account, we systematically summarized the development of kinetic resolution and desymmetrization of amines through nonenzymatic asymmetric catalytic approaches in the last two decades.

1 Introduction

2 Kinetic Resolution of Amines

2.1 Kinetic Resolution of Amines via Asymmetric Transformations of the Amino Group

2.1.1 Asymmetric N-Acylations

2.1.2 Asymmetric N-Alkylation

2.1.3 Asymmetric N-Arylation

2.1.4 Other Asymmetric N-Functionalizations

2.1.5 Asymmetric Dehydrogenation of Amines

2.1.6 Selective C–N Bond Cleavage of Amines

2.2 Kinetic Resolution of Amines via Asymmetric Transformations without Amino Group Participating

3 Enantioselective Desymmetrization of Amines

3.1 Desymmetrization of Diamines

3.2 Desymmetrization of Prochiral Monoamines

4 Conclusion and Outlooks

Biographical Sketches

Xiaoyu Yang was born in Taicang city of Jiangsu Province (P. R. of China), which is a small city next to Shanghai. He studied chemistry at Nanjing University and received his BSc degree in 2007. He then joined Prof. Biao Yu’s group at Shanghai Institute of Organic Chemistry (SIOC) and worked on the total synthesis of naturally occurring glycoconjugates. After obtaining his PhD, he moved to University of California, Berkeley and joined Prof. Dean Toste’s group as a postdoctoral researcher in 2013 and studied the development of asymmetric catalysis and selective protein modification methods. In 2016, he began his independent research at ShanghaiTech University as an assistant professor. His current research interests mainly focused on the development of new methodologies for asymmetric catalysis, particularly on development of novel kinetic resolution strategies and methods.

Introduction

Chiral amines represent critically important chiral moieties in biologically active natural products and pharmaceuticals, because of their inherent ability for hydrogen-bonding formation. According to statistics, about 35% of the top 200 small-molecule drugs sold in 2020 contains chiral amine subunits.[1] In addition, enantioenriched amines have been widely used as resolving agents, chiral organocatalysts, and ligands in asymmetric synthesis.[2] Consequently, the asymmetric synthesis of structurally diverse chiral amines through asymmetric catalytic approaches has drawn numerous amounts of interest.[3] In the recent decades, a number of practical protocols for asymmetric synthesis of chiral amines have been developed, such as asymmetric reduction of imines and enamines,[4] asymmetric additions of imines,[5] and others.[6] However, the catalytic enantioselective synthesis of amines still faces the challenges of relatively limited substrate scope when compared with the scope for racemic ones.

Kinetic resolution (KR) is a reliable method to give access to valued enantioenriched compounds from their racemic mixture.[7] The principle of KR relies on the different reaction rates of two enantiomers of a racemate with a chiral reagent, catalyst, or other material, which would give the fast-reacting enantiomer in the product form and the slow-reacting enantiomer recovered (Figure [1, a]). Although the maximum yields for one chiral product cannot exceed 50%, one advantage for KR reactions is that the enantiopure starting material (SM, >99% ee) could always be obtained if the reactions are allowed to proceed to sufficient conversion. Consequently, KR is still a practical protocol to access chiral products, especially when the direct enantioselective synthesis is challenging while the racemic synthesis is more convenient. It is worth mentioning that since the enantiomeric excess (ee) values of the products decrease and the ee values of the recovered SM increase as the reaction proceeds to high conversions, selectivity factor[8] (s or s-factor) has been postulated to describe the efficiency of a KR reaction, which is defined as the ratio between the reaction rate of the fast-reacting enantiomer and the slow-reacting enantiomer (s = k _fast/k _slow). In general, a KR process can be operatively useful if the s > 10, though the recovered SM may be obtained in relatively low yields. While an s-factor greater than 50 is required for a KR reaction, which would provide both the reaction product and recovered SM with high enantioselectivities at ca. 50% conversion (e.g., s = 58, ee_s = 90% ee and ee_p = 90% ee). In contrast, with the rapid racemization of the racemic substrates under the reaction conditions (k_rac >> k_fast >> k_slow ), the dynamic kinetic resolution (DKR) could be realized, which could give access to the enantioenriched product in up to 100% yield[9] (Figure [1, b]). However, although numerous reports have been emerged in the last two decades, the substrate and reaction scope for DKR of amines have been limited to the asymmetric ring-opening of azlactones[10] and asymmetric hydrogenation of α-amino ketones,[11] the details of which will not be discussed in this Account.

In the last decades, a variety of useful KR methods have been disclosed, especially the asymmetric acylations enabled by either enzymatic or small-molecule catalyst, which have been widely utilized in the KR of alcohols in both academia and industry.[7c] [12] However, the KR of amines through asymmetric N-acylation protocol is more challenging compared with the KR of alcohols, because of the relatively high nucleophilicity of amines, which may lead to the nonstereoselective background reactions without the engagement of chiral catalysts. Nevertheless, a series of ingenious methods have been developed for the KR of amines in the last two decades by chemists. However, this topic has not been specially and comprehensively reviewed in the recent years.[13] Herein, we provide a comprehensive and up-to-date review on the development of KR of amines using nonenzymatic asymmetric catalytic methods, which could be categorized into two subgroups based on the reaction sites of these asymmetric reactions (Figure [1, c]). The first type is asymmetric functionalization of the amino group, which includes various asymmetric N-substitutions, asymmetric hydrogen transfers of the amino group, and the asymmetric C–N bond cleavage. The second type is the asymmetric transformation without amino group participation, in which the amino group usually plays as a directing group.

The enantioselective desymmetrization has proved to be a highly efficient way to deliver enantioenriched products from relatively simple achiral starting materials.[14] Different from the KR process, the strategy of desymmetrization utilizes the prochiral or meso-substrates, which destructs the symmetrical elements of SM under the guidance of chiral catalysts and could give access to one chiral product up to 100% yield (Figure [2, a]). However, similar to KR process, most asymmetric methods involved in the desymmetrization process do not affect the original (prochiral) stereocenters in the SM, therefore a number of asymmetric methods have been successfully applied in both KR and desymmetrization of amines. In this Account, we classified the advances of enantioselective desymmetrization of amines into two categories based on the types of amines substrates: 1) the prochiral or meso-diamines, which usually utilized the asymmetric N-functionalization approaches; and 2) the prochiral monoamines, which generally used the amino group as the directing group in asymmetric C–H functionalizations (Figure [2, b]).

It is also worth mentioning that the methods for KR and desymmetrizations of aziridines[15] and azetines[16] are not included in this Account, since these types of specialized amines usually undergo the asymmetric ring-opening reactions for KR and desymmetrizations, which possess big differences with the methods for other amine substrates included in this Account.

Kinetic Resolution of Amines

Kinetic Resolution of Amines via Asymmetric Transformations of the Amino Group

The asymmetric N-functionalizations are the most straightforward strategy for KR of amines, however, which is relatively more challenging when compared with the KR of alcohols, since the inherent basicity, strong nucleophilicity, and strong coordination abilities with metals of the amino groups. Nevertheless, a series of elegant asymmetric catalytic methods have been disclosed for the KR of amines through this strategy by organic chemists in the last two decades.

Asymmetric N-Acylations

In 2001, Fu and co-works reported the first effective KR of primary amines through nonenzymatic N-acylations. The key to the success of their approach relied on the utilization of a planar-chiral DMAP catalyst (PPY*, cat-1) and an O-acylated azlactone 2 as the acylating agent, which afforded moderate to good s-factors for the benzylic primary amines 1 [17] (Scheme [1]). A plausible two-step reaction mechanism was also proposed: 1) catalyst PPY* reacts rapidly with the acylating agent, producing an ion-pair intermediate (step 1), which is the resting state of the catalytic cycle; 2) in the subsequent stereochemistry-determining step, the methoxycarbonyl group is transferred to the amine, thus furnishing the carbamate and regenerating PPY* (step 2).

In 2006, Fu and co-works reported the first nonenzymatic KR of indolines 4 by developing a new planar-chiral PPY catalyst (cat-2), in which both the 2-substituted indolines and 2,3-disubstituted indolines were kinetically resolved with good enantioselectivities[18] (Scheme [2]). It is worth mentioning that the application of the previous conditions for benzylic primary amines could not afford any desired N-acylation products of indolines, probably because of their relatively low nucleophilicity. Interestingly, modification of the catalyst with a more bulky cyclopentadienyl group (cat-2) could improve both the reactivity and stereoselectivity of this reaction, and LiBr and 18-crown-6 were also suggested to be critical for this KR reaction.

In 2006, Birman and co-workers reported the KR of 2-oxazolidinones 7 via catalytic enantioselective N-acylations (Scheme [3, a]).[19] A variety of 4-substituted and 4,5-disubstituted oxazolidinones could be kinetically resolved with high s-factors upon treatment of racemic 7 with acid anhydride and a chiral isothiourea catalyst cat-3 (BTM). It is worth noting that the 4-alkyl-substituted oxazolidinones could not afford the expected N-acylation products, probably due to the absence of π–π interactions between the substrates and the catalyst. In 2012, the Birman group successfully expanded the scope of this KR approach to more diverse lactams, thiolactams, and their heterocyclic derivatives[20] (Scheme [3, b]). In addition, the density functional theory (DFT) calculations suggested that the reaction proceed via N-acylation of the lactim tautomer and the cation–π interactions play a crucial role in the chiral recognition of lactam substrates.

Interestingly, in 2013, the same group reported the KR of N-acyl-thiolactams 9 via catalytic enantioselective deacylation upon the treatment of isothiourea catalyst cat-3 and MeOH (Scheme [4]).[21] The authors observed the diminishment of s-factor of the KR reaction of 9d with time, which suggested that the deacylated product 10d may undergo slow acyl group exchange with the unreacted (R)-9d as well, resulting in the diminishment of KR performance.

In 2009, Seidel and co-works reported the KR of primary amines through merging nucleophilic and hydrogen-bonding catalysis (Scheme [5]).[22] In this reaction, a novel chiral intermediate was proposed by the authors, in which the binding of benzoate anion of the acyl pyridinium species with the chiral thiourea catalyst dominate the stereoselectivity of this KR reaction. By the combinational use of DMAP and a chiral thiourea catalyst cat-5, the asymmetric N-acylation of primary benzylic amines 11 with benzoic anhydride proceed efficiently to afford the products 12 with moderate to good s-factors. Later, the authors reported the modifications of both the H-bonding catalyst (with cat-6) and the nucleophilic catalyst (with cat-7) could dramatically improve the KR performances of these N-acylation reactions.[23]

Later, Seidel and co-works successfully expanded the scope of this dual catalysis method to more diverse racemic amine substrates, such as primary propargylic amines 13 [24] (Scheme [6, a]), allylic amines 14 [25] (Scheme [6, b]), and 1,2-diaryl-1,2-diaminoethanes 15 [26] (Scheme [6, c]) by minor modifications of the nucleophilic catalysts.

In 2010, Miller and co-works reported the KR of thioformamides through a peptide-catalyzed asymmetric N-acylations (Scheme [7]).[27] The reaction of various thioformamides 16 with Boc₂O enabled by histidine-containing pentapeptide catalyst cat-8 proceeded smoothly with moderate to good s-factors, affording the recovered SM with good enantiomeric ratios. It is worth noting that the corresponding formamides exhibited relatively low reactivities and stereoselectivities under these conditions. The obtained chiral product 17a was a practical building block, which could be converted into formamide 18a by acidic cleavage of the Boc group and exchange of S-to-O, and the carbamate 19a via oxidative hydrolysis.

In 2011, Bode and co-works reported an ingenious protocol for KR of cyclic secondary amines through the cooperative catalysis of an achiral N-heterocyclic carbene catalyst (cat-9) and a new chiral hydroxamic acid catalyst (cat-10, Scheme [8]).[28] A series of 2-substituted piperidines, piperazines, and morpholines were selectively amidated upon the treatment of mesitylsubstituted α′-hydroxyenone 21 as the acylating agent under the cocatalyzed conditions, which afforded moderate to good selectivity factor (Scheme [8, a]). Later, the Bode group reported more environmentally friendly conditions (using i-PrOAc as solvent) and modified catalyst for the catalytic KR of cyclic secondary amines.[29] A remote substitution of the chiral hydroxyamic acid catalyst (cat-11) improved selectivities of 6- and 7-membered N-heterocycles and expanded the substrate scope to piperazinones and diazepanones, which were unreactive under prior conditions (Scheme [8, b]). In 2015, the same group reported the KR of disubstituted piperidines via this cooperative catalysis protocol. A series of 2,3-disubstituted, 2,4-disubstituted, and 2,5-disubstituted piperidines were screened under these conditions; interestingly, the cis- and trans-stereoisomers gave distinct reactivities and selectivities[30] (Scheme [8, c]). Detailed experimental and computational studies revealed a strong preference for the acylation of conformers in which the α-substituent occupies the axial position.

The reaction mechanism was studied and a possible mechanism for cooperatively catalyzed selective N-acylation of cyclic secondary amines was proposed by the authors (Scheme [9]). In the first catalytic cycle, N-heterocyclic carbene catalyst cat-9 binds with 21 through nucleophilic addition, retro-benzoin, β-protonation, and keto-enol tautomerism to produce the key acyl azolium intermediate 23. In the second catalytic cycle, the acyl azolium 23 reacted with chiral hydroxyamic acid catalyst cat-10 to give the real active acylating agent 24, which was well confirmed by independently preparing this compound and employing it as a stoichiometric reagent. Finally, selective acylation of 24 with cyclic secondary amines fulfilled the KR process and released the catalyst. It is worth mentioning that the Bode group also developed a series of elegant methods for KR of nitrogen heterocycles via using a reusable polymer-supported chiral hydroxyamic acid derived acylating reagents.[31]

In 2017, Spivey and co-workers reported the KR of 2-substituted indolines 25 via asymmetric N-sulfonylation (Scheme [10]).[32] The key to the success of this protocol was the use of a novel atropisomeric 4-DMAP-N-oxide catalyst cat-12 as the nucleophilic catalyst and 2-isopropyl-4-nitrophenylsulfonyl chloride (26) as the sulfenylation reagent, which is critical to the stereodiscrimination and enables facile deprotection of the sulfonamide products 27. A qualitative model rationalized that 2,3-disubstituted indolines require cis-stereochemistry for efficient KR.

Besides the chiral amines bearing N-containing stereocenters, axially chiral arylamines are another type of enantioenriched amines, which have been widely used in chiral catalysts and ligands. In 2020, Shi and co-workers reported the asymmetric synthesis of oxindole-based axially chiral styrenes bearing an aniline moiety through catalytic KR[33] (Scheme [11, a]). A wide range of racemic styrenes 28 were kinetically resolved by the chiral phosphoric acid (CPA, cat-13) catalyzed asymmetric amidation of the aniline moiety with azlactone 29, which provided both the recovered 28 and the amidation products 30 with high enantioselectivities. Notably, the recovered axially chiral aniline (R_a )-28a could be readily converted into a thiourea derivative 31, which was proved to be an excellent chiral organocatalyst for the asymmetric [4+2] cycloaddition between ortho-quinone methide 32 and malononitrile 34 (Scheme [11, b]) and the asymmetric [2+4] cyclization of 2-benzothiazolimines.[34]

Asymmetric N-Alkylation

In 2009, Hou and co-works reported the KR of 2-substituted indolines 35 via Pd-catalyzed asymmetric allylic amination with allyl carbonate 36 using Trost’s chiral ligand cat-14, which represented the first KR of nucleophiles via transition-metal-catalyzed allylic substitution (Scheme [12]).[35] The scope of indolines with different substituents was investigated, and the results indicated that 2-aryl-substituted indolines could be resolved with high s-factors, while the 2-alkyl-substituted ones (35b) only afforded moderate s-factors.

In 2013, Maruoka and co-works reported the KR of axially chiral 2-amino-1,1′-biaryls 38 by phase-transfer-catalyzed asymmetric N-allylation enabled by a binaphthyl-derived chiral quaternary ammonium salt catalyst (cat-15, Scheme [13]).[36] A series of N-sulfonylated 2-amino-2′-hydroxy-1,1′-binaphthyl (NOBIN) derivatives selectively underwent the N-allylation reactions with allyl iodide under the optimal phase-transfer-catalyzed conditions, affording moderate to good s-factors. Moreover, the KR of the 1,1′-binaphthyl-2,2′-diamine (BINAM) type substrate 38d and the enantioselective desymmetrization of the diamine compound 39e further expanded the utility of this catalytic asymmetric method.

In 2014, Tan, Liu, and co-works reported the KR of axially chiral BINAM derivatives 40 via a chiral Brønsted acid catalyzed imine formation and transfer-hydrogenation cascade process (Scheme [14]).[37] A series of BINAM derivatives were kinetically resolved through the CPA (cat-16) catalyzed imine formation with aryl aldehyde 41 and the cascade reduction by Hantzsch ester 42, which afforded good to excellent KR performances (with s-factors up to >300). Extensive exploration of the substrate generality indicated that the aromatic stacking interaction may play a crucial role in achieving excellent enantioselectivities, since the 2- naphthaldehyde exhibited the best KR performance. Furthermore, the bulky N-sulfonyl group (2-naphthylsulfonyl group) has also been proved to be critical for the high s-factors obtained for these KR reactions.

In 2019, Kürti, Zhao, and co-works reported the KR of biaryl amino phenols via an organocatalytic asymmetric N-alkylation (Scheme [15]).[38] The combinational use of a commercially available chiral amine catalyst (cat-17, (DHQD)₂AQN) and MBH carbonate reagent 45 enabled the practical KR of a series of NOBIN analogues 44, generating the recovered SM with excellent enantioselectivities. Notably, extensive substrate scope investigation indicated that the substitutions on the amino group and the free hydroxyl group played a critical role in enantioselectivity control. In addition, this method also provided an efficient synthesis of axially chiral N-aryl sulfonamides via atroposelective N-alkylations.

In 2020, in the work of asymmetric conjugate addition of cyclic amines with α,β-unsaturated ester, Seidel and co-workers disclosed the efficient KR of 2-aryl substituted cyclic amines 47 via asymmetric N-alkylations with commercially available benzyl acrylate (Scheme [16]).[39] A novel bifunctional selenourea–thiourea Brønsted acid catalyst cat-18 was identified in the course of this study. Mechanistic studies suggested these reactions proceeded through reversible C–N bond formation to form a β-amino enolate, which is followed by rate- and enantioselectivity-determining protonation by the thiourea catalyst.

Asymmetric N-Arylation

In 2013, Cai and co-works reported the KR of α-amino ester derivatives 50 via copper-catalyzed enantioselective intramolecular N-arylation (Scheme [17]).[40] Under the catalysis of CuI and chiral BINOL-derived ligands, the KR of 2-amino-3-(2-iodoaryl)propionates (with cat-19) and 2-amino-4-(2-iodoaryl)butanoates (with cat-20) through intramolecular N-arylation proceed with high s-factors (up to 245), generating both 2,2-disubstituted indolines and 1,2,3,4-tetrahydroquinolines with excellent enantioselectivities. It is worth mentioning that this work represents the first highly efficient KR of α-tertiary amines (amines bearing an N-containing tetrasubstituted stereocenter).

In 2021, Shi and co-works reported the KR of cyclic secondary amines 52 through low-temperature (as low as –50 °C) nickel-catalyzed C–N cross-coupling with aryl chlorides (Scheme [18]).[41] A wide range of 2-alkyl and aryl-substituted tetrahydroquinolines, as well as piperidine, tetrahydroisoquinoline, and dihydrobenzoazepines, served as suitable substrates in the asymmetric N-arylation reactions with various aryl chlorides 53, which afforded good to excellent KR performances (with s-factors up to >300). The key to the success of this reaction is the development of a bulky yet flexible chiral N-heterocyclic carbene (NHC) ligand (cat-21), which is leveraged to drive both oxidative addition and reductive elimination with low barriers and control the enantioselectivity.

Other Asymmetric N-Functionalizations

In 2016, Seidel and co-workers reported the KR of 2-substituted indolines via a chiral Brønsted acid catalyzed asymmetric Povarov reaction, which also achieved the asymmetric synthesis of polycyclic heterocycles with four stereogenic centers with excellent enantio- and diastereoselectivities (Scheme [19]).[42] Under the catalysis of CPA cat-22, one enantiomer of the racemic indolines 55 reacted preferentially with the aromatic aldehydes bearing a pendent dienophile 56, which resulted in the highly enantio- and diastereoselective formation of polycyclic heterocycles 57.

In 2017, List and co-works reported the KR of primary amines via chiral Brønsted acid catalyzed condensation between an amine and a carbonyl compound (Scheme [20]).[43] 1,3-Diketones 59 were crucial in such a process as they reacted efficiently with racemic α-branched amines 58 to furnish the relatively stable and enantioenriched enaminones 60, making the process much less reversible. A series of benzylic amines, as well as the aliphatic amines, could be kinetically resolved with good to high s-factors. Remarkably, this work represented the first KR of aliphatic primary amines through small-molecule catalysis.

In 2020, with our continuous research in asymmetric aminations of anilines with azodicarboxylates,[44] our group disclosed the KR of BINAMs and NOBINs via CPA-catalyzed asymmetric triazane formations with azodicarboxylates (Scheme [21]).[45] Interestingly, one enantiomer of a series of NOBIN derivatives and N-protected BINAMs reacted preferentially with dibenzyl azodicarboxylate 62 to afford the N-amination triazane products 63 in the presence of CPA catalyst cat-22, which provided high to excellent s-factors. Moreover, this method was also applicable to the KR of protecting-group-free BINAM 61d, which gave the recovered (S)-61d with high enantioselectivity, and a mixture of the triazane product 63d and the bistriazane product 63d′. Nonetheless, the facile catalytic hydrogenation of this mixture readily returned the (R)-61d with high ee value, thus achieving the enantiodivergent access to both enantiomers.

In 2016, Yamamoto and co-workers reported the catalytic asymmetric synthesis of N-chiral amine oxides, in which the KR of γ-amino alcohols was also achieved through this protocol[46] (Scheme [22]). A variety of racemic γ-amino alcohols 64 bearing a pre-existing α- or β-stereocenter adjacent to the amino group could be resolved efficiently enabled by the bimetallic catalyst (in situ generated from Ti(Oi-Pr)₄ and cat-24) catalyzed N-oxidations with tert-butyl hydroperoxide (TBHP), providing both tertiary amines and the corresponding N-oxides 65 with good to high enantioselectivities. It is noteworthy that the hydroxy group located at the γ-position with respect to the N-stereocenter is the key to the success of this approach, which played the role of directing group.

In 2021, Liu and co-workers reported the KR of indolines through asymmetric oxygenation to produce enantiopure hydroxylamines involving N–O bond formation[47] (Scheme [23]). With the common hydrogen peroxide as the oxidant, a wide range of racemic 2,3,3-trisubstituted indolines 66 were kinetically resolved with high s-factors enabled by the chiral dimeric titanium catalyst cat-25, which produced both the recovered indolines (R)-66 and hydroxylamines 67 with high enantioselectivities. It is noteworthy that indolines bearing two adjacent stereocenters at the C2 and C3 positions (66e) were also compatible with this oxidative KR method, and both the trans- and cis-configured substrates gave good KR performances.

Inspired by the development of highly efficient KR of α-tertiary alcohols via asymmetric intramolecular dehydrative condensations,[48] recently, our group disclosed the KR of α-tertiary benzylamines via CPA-catalyzed intramolecular dehydrative cyclizations[49] (Scheme [24]). A range of 2-N-trifluoroacetyl-substituted α-tertiary benzylamines 68 were kinetically resolved with high efficiencies enabled by CPA cat-26 via this protocol, which simultaneously delivered chiral hydroquinazolines 69 bearing C4-tetrasubstituted stereocenters. Control experiment suggested that the 2-N-trifluoroacetyl group is critical for this transformation, in which other N-acyl groups, even the N-perfluoalkylacyl group, could not provide the desired hydroquinazoline products under these conditions.

Asymmetric Dehydrogenation of Amines

Oxidative kinetic resolution (OKR) is a KR method that is based on an asymmetric dehydrogenative or oxygenation reaction of racemic substrates, which eliminate the stereocenters of the starting material. However, in contrast to the well-developed OKR protocols for secondary alcohols, the corresponding method for amines by oxidation to imines has posed several challenges, such as the low oxidation potential and the Lewis basicity of amines.

In 2013, Akiyama and co-workers reported the oxidative KR of 2-substituted indolines 70 enabled by chiral phosphoric acid catalyst cat-22 [50] (Scheme [25, a]). After screening of a series of imines as hydrogen acceptor, the ketimine 71 has proved to provide the optimal KR performance. A wide array of racemic 2-alkyl- and 2-aryl-substituted indolines were amenable with the OKR protocol, generating the recovered indolines with excellent enantioselectivities. In 2015, the same group extended this OKR approach to more diverse cyclic secondary amines, including 2-alkyl- and 2-aryl-substituted tetrahydroquinolines and dihydrobenzoxazine 73c and dihydrobenzothiazine 73d (Scheme [25, b]).[51] In 2020, Akiyama and co-workers reported the OKR of acyclic secondary amines 75 with modified conditions, in which an aldimine 76 was chosen as the optimal hydrogen acceptor (Scheme [25, c]).[52] The authors indicated that the ratio of the amine substrate to the resolving reagent (75/76 = 1:2) was the key to the success of the reaction.

With their continuous studies on KR of cyclic amines, in 2016, Akiyama and co-workers disclosed an intriguing KR of 2-substituted indolines 70 based on a CPA-catalyzed self-redox reaction (Scheme [26]).[53] 2-Hydroxy-5-methoxybenzaldehyde (77, 0.3 equiv) was used as the resolving reagent in the presence of catalytic amount of CPA (R)-cat-27 in these reactions. The mechanism of this KR reaction involved the reversible condensation of racemic indoline 70c with aldehyde 77 to generate iminium intermediates INT-A, in which the (S)-INT-A was more reactive toward the asymmetric hydrogen-transfer reaction with (S)-70c, thus giving recovered (R)-70c, N-alkylation product (S)-78a, and indole as products. This KR strategy featured the use of less than 0.5 equiv of resolving reagents, enabling the synthesis of a series of 2-substituted indolines in good yields and high enantioselectivities.

In 2019, Liu and co-workers reported a nonenzymatic chiral iron complex cat-28 catalyzed dehydrogenative KR of cyclic secondary amines with air as an oxidant[54] (Scheme [27]). This economical and practical method is applicable to a range of cyclic secondary amines, including 5,6-dihydrophenanthridines 79a–d and 1,2-dihydroquinolines 79e,f bearing various α-aryl and alkyl substitutions. Notably, this KR protocol is also applicable to advanced intermediate of bioactive molecules that are difficult to access by other existing asymmetric catalytic methods.

Selective C–N Bond Cleavage of Amines

In 2008, You and his co-workers reported the KR of cis-4-formyl-β-lactams 81 via chiral N-heterocyclic carbene (NHC) catalyzed asymmetric ring-expansion reactions (Scheme [28]).[55] A series of racemic cis-4-formyl-β-lactams bearing C-2 aryl substitution underwent selective ring-expansion reactions in the presence of NHC catalyst cat-29 to give the succinimide derivatives 83, thus remaining the recovered β-lactams 82 with high enantioselectivities (after reduction with NaBH₄). However, the succinimide products 83 were obtained with poor enantioselectivities, which is probably because of its facile racemization under the basic reaction conditions. A plausible reaction mechanism was also proposed: after the formation of the Breslow intermediate INT-B, the selective ring opening of β-lactam released the amide nucleophile INT-C, which achieved the KR process. The amide nucleophile INT-D, as an equilibrium form of INT-C, then underwent the intramolecular cyclization to give succinimide 83 and release the carbene catalyst to finish the catalytic cycle.

In 2012, Tian and co-workers reported the KR of N-benzylic sulfonamides through asymmetric substitutions with thiols (Scheme [29]).[56] In the presence of 10 mol% of chiral phosphoric acid cat-30, a series of racemic N-benzylic sulfonamides 84 bearing N-(3-indolyl)methyl moiety underwent the selective substitution with benzyl thiol, affording the recovered (S)-84 with excellent ee values. However, it is worth mentioning that the sulfide products 85 were obtained in their racemic form. The reaction was suggested to proceed in an S_N1 manner on the basis of kinetics studies.

In 2015, Tian and co-workers disclosed the KR of primary allylic amines via palladium-catalyzed asymmetric allylic alkylations (Scheme [30]).[57] A range of primary allylic amines 86 were kinetically resolved through [Pd(allyl)Cl]₂/(S)-BINAP-catalyzed asymmetric allylic alkylation with malononitriles 87, which provided both the recovered allylic amines (S)-86 and the α-branched allyl-substituted malononitriles 89 with high enantioselectivities. It is worth noting that the mesitylsulfonyl hydrazide 88 played the role of accelerating the allylic alkylation reactions, which was believed to form a more reactive allylic diazene intermediate after its coupling with 86 and following oxidation.

Kinetic Resolution of Amines via Asymmetric Transformations without Amino Group Participating

Besides the relatively traditional methods for KR of amines via asymmetric functionalizations of the amino group, a number of ingenious protocols for KR of amines have also been disclosed recently through the asymmetric transformations without amino group participation. Nevertheless, most of these methods still relied on the asymmetric transformations of the functional groups adjacent to the N-containing stereocenter.

In 2008, Onomura and co-workers reported the KR of racemic N-protected α-amino aldehydes through the asymmetric oxidation of the aldehyde group to an ester[58] (Scheme [31]). A series of cyclic and acyclic α-amino aldehydes 90 were selectively oxidized upon the treatment of NIS and Cu(II)/(R,R)-Ph-BOX (cat-31) in MeOH, which produced both the α-amino esters 91 and aminoaldehyde dimethyl acetals 92 with good to high enantioselectivities, corresponding to s-factors up to 129. In addition, the same group also reported the KR of β-amino alcohols and α-amino aldehydes using the same chiral copper catalyst through an electrochemical oxidation process; however, only moderate s-factors were obtained under these conditions.[59]

In 2011, Birman and co-workers reported the KR of α-substituted alkanoic acid derivatives via chiral homobenzotetramisole (HBTM) catalyzed enantioselective esterification[60] (Scheme [32]). A series of α-aryl-, α-aryloxy/alkoxy-, α-halo-, α-azido-, and α-phthalimido-alkanoic acids (93a–e) were kinetically resolved upon the treatment of dicyclohexylcabrodiimide (DCC), di(1-naphthyl)methanol 94, and HBTM catalyst cat-32, which provided the recovered acid (R)-93 and the corresponding esters 95 with good to high enantioselectivities. The authors proposed that the racemic α-substituted alkanoic acids (±)-93 were first converted into the corresponding anhydride 96 upon treatment with DCC, which was followed by the attack of cat-32 to afford the activated chiral intermediate INT-E. The preferred addition of alcohol 94 with one diastereomer of INT-E afforded the ester 95, while the unreactive diastereomeric INT-E gave the acid (R)-93 upon aqueous workup. The dependence of asymmetric induction on the nature of the alcohol employed clearly indicated that the addition of alcohol with INT-E being the enantio-determining step.

In 2009, Hou and co-workers reported the KR of 2-substituted 4-quinolinones via palladium-catalyzed asymmetric allylic alkylations[61] (Scheme [33, a]). A variety of 2-aryl- and 2-alkyl-substituted racemic 2,3-dihydro-4-quinolinones 97 were efficiently resolved through the Pd(II)/SiocPhox ligand cat-33 catalyzed asymmetric allylic alkylation with allyl phosphate 98, which generated both the recovered SM and the C-3 allylation products 99 with high enantioselectivities and diastereoselectivities as well (with s-factors up to 145). In 2014, Hou, Ding, and co-workers extended the utilities of this method to the KR of 2-substituted 2,3-dihydro-4-pyridones 100 [62] (Scheme [33, b]). Commercially available (S)-P-Phos (cat-34) and allyl carbonate 101 were identified as the optimal chiral ligand and resolving agent in this allylic alkylative KR protocol, which afforded both the recovered SM and 2,3-disubstituted dihydro-4-pyridones 102 with good enantioselectivities (with s-factors up to 43). Notably, with this protocol, a catalytic asymmetric total synthesis of indolizidine (–)-209I was accomplished for the first time.

In 2009, Stanley and co-workers disclosed the KR of pyrazolidinones via copper-catalyzed asymmetric Diels–Alder cycloaddition (Scheme [34]).[63] A variety of racemic α,β-unsaturated pyrazolidinone imides 103 were kinetically resolved through the Cu(II)/chiral bisoxazoline ligand cat-35 catalyzed asymmetric [4+2] cycloadditions with cyclopenta-1,3-diene, which provided the recovered pyrazolidinones (S)-103 with good to high enantioselectivities. In addition, treatment of the recovered (S)-103a with lithium alkoxide of p-methoxybenzyl alcohol (LiOPMB) facilely cleaved the imide moiety and gave the pyrazolidinone 105a with retained ee value.

In 2014, Chi and co-workers reported a NHC-catalyzed enantioselective and diastereoselective [3+4] cycloaddition of azomethine imines with enals (Scheme [35]).[64] When the racemic azomethine imines 106 were used as the limiting reagent, the asymmetric [3+4] cycloadditions with enal 107 enabled by NHC catalyst cat-36 under oxidative conditions (with quinone 109 as the oxidant) provided the recovered (S)-106 and the dinitrogen-fused seven-membered heterocyclic products 108 with good to high enantioselectivities (with s-factor up to 336). It is impressive that the substrate’s chiral center, which is remote to the NHC catalyst, can be effectively resolved by this method.

In 2014, Yu and co-workers reported a highly efficient KR of racemic benzyl amines through enantioselective C–H iodination (Scheme [36, a]).[65] A wide array of N-Tf-protected racemic benzyl amines (including simple arylalkyl amines, α-amino acids and β-amino alcohols) were kinetically resolved through Pd(OAc)₂/Bz-Leu-OH (cat-37) catalyzed iodination with I₂ at room temperature, which provided the recovered benzylamines (S)-110 and the ortho-iodinated benzyl amines 111 with high enantioselectivities (with s-factors up to 244). A great number of transformations of the chiral iodinated amine 110c demonstrated the utilities of this KR method to access a diverse range of chiral amines.

With their continuous research interest on the asymmetric C–H functionalization, in 2016, the Yu group reported the KR of racemic benzylamines through Pd-catalyzed enantioselective C–H cross-coupling reactions (Scheme [36, b]).[66] Both recovered benzylamines (S)-112 and chiral ortho-arylated benzylamines 113 were obtained in high enantiomeric purity enabled by Pd(II) catalyst and mono-N-protected α-amino-O-methylhydroxamic acid ligand (MPAHA, cat-38), which proceeded through a KR process of enantioselective ortho-arylation with aryl boronic esters. Notably, the use of a readily removable N-nosyl (Ns) protecting group as the directing group is a crucial practical advantage.

In 2021, Gulías and co-workers reported the KR of α-branched allyltriflamides through a formal [4+2] cycloaddition initiated by a Pd(II)-catalyzed C–H activation process (Scheme [37]).[67] A wide range of highly substituted allylic amines 114 were kinetically resolved through the asymmetric formal [4+2] cycloadditions with allenes enabled by Pd(OAc)₂ catalyst and monoprotected amino acid ligand cat-39 under oxidative conditions (with the presence of Cu(OAc)₂), which gave both the recovered allyltriflamides (S)-114 and the tetrahydropyridines 115 with good to high enantioselectivities. Notably, this work represents a rare example for enantioselective C–H activation of the alkenyl C–H bonds.

In 2016, Fan, Chen, and their co-workers reported the highly efficient asymmetric construction of indolines via enantioselective hydrogenation of 1H-indoles and 3H-indoles enabled by chiral cationic Ru-diamine catalyst (R,R)-cat-40 [68] (Scheme [38]). Moreover, a robust and efficient KR of racemic 3H-indoles 116 bearing different substituents at C3 position was realized by this approach, which afforded the indolines 117 and the recovered 3H-indoles (–)-116 with both high diastereo- and enantioselectivity.

In 2017, Hou and co-workers reported the KR of 2-substituted 1,2-dihydroquinolines by asymmetric Cu-catalyzed borylation under mild conditions (Scheme [39]).[69] A series of chiral 3-boryl-1,2,3,4-tetrahydroquinolines 119 as well as the recovered 2-substituted 1,2-dihydroquinolines (S)-118 were afforded with high enantioselectivities upon the treatment of racemic 118 with B₂Pin₂ under the catalysis of CuI/phosphine ligand cat-41. Notably, this approach was successfully applied in the asymmetric synthesis of a selective estrogen-receptor modulator.

In 2021, Wang and co-workers reported the KR of 2-substituted 1,2-dihydroquinolines through Rh-catalyzed asymmetric hydroarylation (Scheme [40]).[70] A variety of arylboronic acids were selectively coupled with racemic dihydroquinolines 120 enabled by Rh(I)/phosphine ligand cat-42, which afforded the enantioenriched 2,3-diaryl-tetrahydroquinolines 121 as well as the recovered 120 with high enantiomeric purity (with s-factors up to >500).

In 2021, Ratovelomanana-Vidal and co-workers reported the KR of 2-substituted 2,3-dihydro-4-quinolinones via Rh-catalyzed asymmetric transfer hydrogenation[71] (Scheme [41, a]). The catalytic transfer hydrogenation of a series of 2-aryl substituted 2,3-dihydro-4-quinolinones 122 using Rh-catalyst cat-43 and HCO₂H/DABCO as hydrogen source provided both the recovered tetrahydro-4-quinolinones (S)-122 and tetrahydro-4-quinolols 123 with excellent enantioselectivities. Recently, the Liu group reported the KR of N-protecting-group-free 2-substituted 2,3-dihydro-4-quinolinones via Ru-catalyzed asymmetric hydrogenation[72] (Scheme [41, b]). A variety of 2-aryl- and 2-alkyl-substituted 2,3-dihydro-4-quinolinones 124 were efficiently resolved through the catalytic enantioselective hydrogenation (40 bar) using RuPHOX (cat-44) as catalyst, which gave both the recovered (S)-124 and the tetrahydro-4-quinolols 125 with excellent enantiomeric purity.

In 2021, Wang and co-workers reported the KR of spiroindolines through Ir-catalyzed asymmetric allylative ring-opening reaction[73] (Scheme [42]). A series of racemic spiroindolines 126, which were derived from the dearomative Heck reaction, were kinetically resolved through the Ir/(P,olefin)-ligand cat-45 catalyzed asymmetric allylative ring-opening reaction with allylic alcohol 127 to afford the recovered (R)-126 and the medium-sized lactams 128 with excellent enantioselectivities. The authors proposed that the mechanism of this reaction proceed through the selective addition of alkene with chiral Ir-allyl species to deliver a tertiary cation intermediate INT-F, which was followed by a C–C bond fragmentation and an alcohol trapping to give the medium-sized lactam.

In 2019, in our work of asymmetric synthesis of biaryl diamines and biaryl amino alcohol derivatives through enantioselective C–H aminations of anilines and phenols, we disclosed that the KR of axially chiral biaryl derivatives could also be realized with high efficiencies using this protocol[44b] (Scheme [43]). Treatment of the racemic biaryls 129 with dibenzyl azodicarboxylate 62 enabled by CPA catalyst cat-22 afforded the axially chiral recovered (S)-129 and the aniline para-amination products 130 with high to excellent enantioselectivities, corresponding to s-factors up to 246.

In 2021, our group reported the first KR of hydroquinolines 131 bearing α,α-disubstitution through the CPA-catalyzed asymmetric remote C–H aminations with azodicarboxylates[74] (Scheme [44]). A series of racemic tetrahydroquinolines, dihydroquinolines, and 5,6-dihydrophenanthridines bearing α,α-disubstitutions were efficiently resolved through the CPA (cat-46 or cat-47) catalyzed asymmetric remote C–H aminations with azodicarboxylate 62 at –40 °C, which provided both the recovered heterocycles ent-131 and the hydrazine-substituted products 132 with high enantiomeric purity. Notably, the obtained hydrazine-substituted products (S)-132c could undergo the deamination reaction upon treatment with KOH solution at 75 °C, thus achieving the facile enantiodivergent synthesis of both enantiomers of these valued N-containing heterocycles with α,α-disubstitution.

Encouraged by the high performance for KR of 2,2-disubstituted hydroquinolines via asymmetric C–H aminations, recently our group extended this approach to the KR of more challenging acyclic α-tertiary propargylic amines (Scheme [45]).[75] A wide range of aryl and alkyl groups at the α-position, as well as the alkynyl and N-aryl variants of the propargylic amines 133 were well compatible with this reaction, providing excellent KR performances (with s-factors up to 111). More encouragingly, KR reaction of α-tertiary amine bearing an α-cyano group 135 (the Strecker reaction product) could also be readily fulfilled using this method, which provided both recovered (S)-135 and the amination product 136 with high enantioselectivities.

In addition, this KR protocol is also applicable in the KR of functional group containing amines. Recently, we disclosed the efficient KR of N-aryl β-amino alcohols 137 through this asymmetric C–H amination method (Scheme [46]).[76] Instead of dibenzyl azodicarboxylate, the use of diethyl azodicarboxylate (138) as the amination reagent gave the optimal KR performance, which provided the amination products 139 as well as the recovered amino alcohols 137 with high enantioselectivities in the presence of CPA cat-26. Moreover, α,β-disubstituted β-amino alcohols bearing two adjacent chiral stereocenters were also compatible with this method, which gave access to both trans- and cis-diastereomers with high KR performances.

Inspired by the KR of racemic arylamines via asymmetric C–H aminations, we envisioned that other asymmetric aromatic electrophilic substitution reaction may also be utilized in the KR of aromatic amines. In 2021, our group reported the KR of 2,2-disubstituted hydroquinolines 131 through asymmetric C–H halogenations, which gave access to products with more synthetic utilities (Scheme [47]).[77] Both dihydroquinolines and tetrahydroquinoline bearing α,α-disubstitutions were kinetically resolved upon treatment with NBS enabled by CPA catalyst cat-48 at –78 °C, which afforded the recovered (R)-131 and the C6-brominated products 140 with high enantiomeric purity. In addition, a one-pot stepwise brominative KR and boronation reaction was performed on racemic 131e, which gave access to (R)-131c and the C-6 Bpin-substituted product 141e with good KR performance. It is noteworthy that this one-pot stepwise protocol could overcome the difficulties encountered in separation of the SM and brominated products.

Enantioselective Desymmetrizations of Amines

Enantioselective desymmetrization is a powerful method to give access to complex optically active products from relatively simple achiral or meso-substrates. Although the enzymatic asymmetric N-acylations have been widely studied in desymmetrization of 1,2- and 1,3-diamines,[78] the corresponding nonenzymatic approaches have been less explored.

Desymmetrizations of Diamines

In 2004, Taguchi and co-workers reported the enantioselective desymmetrization of meso-1,2-diamines 142 via asymmetric Pd-catalyzed N-allylation (Scheme [48]).[79] Both cyclic and acyclic meso-1,2-diamines were compatible with the optimal asymmetric N-allylation conditions ((allyl-Pd-Cl)₂ as catalyst and Trost ligand (cat-49) as the chiral ligand), which produced the chiral mono-N-allylated 1,2-diamine products 143 in good yields and enantioselectivities. Later in 2006, the same group reported the modifications of the asymmetric N-allylation conditions to give access to the mono-N-allylated 1,2-diamine products 143 with improved enantioselectivities.[80]

With the excellent performance of the dual small-molecule-catalysis approach for KR of primary amines via asymmetric N-acylations, in 2011, Seidel and co-workers disclosed the enantioselective desymmetrization of meso-1,2-diamines using this protocol[81] (Scheme [49]). Treatment of a series of meso-1,2-diaryl-1,2-diaminoethanes 144 with Bz₂O at –78 °C enabled by the catalysis of DMAP and a chiral thiourea catalyst cat-6 afforded the mono-N-acylated products 145 in good yields and high enantioselectivities.

In 2020, del Pozo and co-workers reported the desymmetrizations of 2-substituted 1,3-diamines through asymmetric intramolecular aza-Michael reaction[82] (Scheme [50]). A series of 2,2-disubstituted 1,3-propanediamines 146 bearing an α,β-unsaturated ketone moiety at the C-2 position underwent the asymmetric intramolecular aza-Michael reaction enabled by chiral primary amine catalyst cat-50, which gave access to 2,5,5-trisubstituted piperidines 147 with excellent enantioselectivities and moderate to good diastereoselectivities. It is worth mentioning that the vinyl sulfonamide moiety is key to the good diastereoselectivities of these reactions, which could also be facilely removed by ozonolysis. In addition, this intramolecular asymmetric aza-Michael reaction approach was also applicable for the desymmetrization of prochiral amines bearing two α,β-unsaturated ketone-moiety-containing chains.[83]

With our continuous research on asymmetric C–H aminations of anilines, in 2021, our group described an highly efficient desymmetrization strategy of 1,3-propanediamines 148 via CPA-catalyzed para-amination of anilines (Scheme [51]).[84] Both 2-substituted and 2,2-disubstituted N-phenyl 1,3-propanediamines were feasible under the asymmetric amination conditions with dibenzyl azodicarboxylate 62 enabled by CPA catalysts (cat-51 or cat-52), which afforded the desymmetrized 1,3-propanediamines 149 in moderate to good yields and high enantioselectivities. Moreover, we also demonstrated that the substituted hydrazine group could be facilely converted into various useful functional groups, such as –NH₂, –I etc., while retaining the enantiopurity of the products.

Desymmetrization of Prochiral Monoamines

Alongside with the KR of racemic benzylamines via Pd-catalyzed C–H iodination and arylation, these two enantioselective methods are also applicable in the desymmetrization of diarylmethylamines. In 2013, Yu and co-workers reported the asymmetric synthesis of diarylmethylamines 151 through Pd and mono-N-benzoyl-protected amino acid (MPAA, cat-37) enabled desymmetrization through enantioselective C–H iodonations[85] (Scheme [52, a]). It is worth noting that the substrates 150 bearing ortho-substituted phenyl groups could afford the chiral amine products in good yields with excellent enantioselectivities, while the substrates with meta- and para-substituted phenyl groups only gave the products as a mixture of mono- and di-iodinated products. In 2015, the Yu group disclosed the desymmetrization of the N-nosyl-substituted diarylmethylamines 152 through Pd/MPAA-catalyzed enantioselective ortho-C–H cross-coupling with arylboronic acid pinacol esters (Ar-BPin)[86] (Scheme [52, b]). Notably, in these reactions, both ortho- and meta-substituted substrates gave monoarylated products (153a–c), while the unsubstituted or para-substituted ones provided the diarylated products predominantly (153d). Nevertheless, all these products could be afforded with excellent enantioselectivities.

In 2018, the Yu group reported the desymmetrization of alkyl amines through Pd-catalyzed enantioselective γ-C(sp³)–H activation (Scheme [53, a]).[87] A series of aryl- and vinyl-boron reagents 155 were selectively coupled with N-Tf-protected alkyl amines 154 catalyzed by Pd(OAc)₂ coupled with chiral acetyl-protected aminomethyl oxazoline ligands (cat-53 and cat-54), which produced the γ-arylated and alkenylated amines 156 with excellent enantioselectivities. Moreover, this enantioselective γ-C(sp³)–H activation approach was also applicable in the KR of racemic alkyl amines 157, which gave the γ-arylated products 158 with high enantiomeric purity and the recovered alkyl amines (R)-157 with moderate to high enantioselectivities, corresponding to s-factors up to 233 (Scheme [53, b]).

In 2019, Xu and Ke et al. reported the enantioselective desymmetrization of diarylmethylamines 159 through Ir-catalyzed C(sp²)–H borylation with B₂Pin₂ (Scheme [54]).[88] The key to the success of this reaction was the development of a family of novel chiral bidentate boryl ligands cat-56, which could be readily synthesized from commercially available (S,S)-1,2-diphenyl-1,2-ethanediamine. In addition, this protocol was also feasible in the KR of diarylmethylamines bearing two different aryl groups, which provided good to high s-factors (160d–f). However, generally low conversions were afforded in these KR reactions, thus only giving access to the borylated products with high enantioselectivities.

In 2019, Xu and co-workers reported the desymmetrization of prochiral sulfonamides via an asymmetric oxidative C–H/N–H carbonylation process[89] (Scheme [55, a]). A bimetallic Pd/Cu-based catalyst with mono-N-protected amino acid ligand was developed for the enantioselective C–H carbonylation of both prochiral diarylmethylamines and 1,3-diaryl-2-propanamines 161, which generated lactam-type products 162, such as isoindoline-1-ones and isoquinoline-1-ones, in high yields and enantioselectivities. In the same year, Xia and co-workers reported a similar work of desymmetrization of 1,3-diaryl-2-propanamines 163 through Pd-catalyzed asymmetric C–H carbonylation[90] (Scheme [55, b]). With the commercially available l-pyroglutamic acid (l-pGlu-OH) as the chiral ligand and CO as the carbonyl source, a variety of isoquinolinones 164 were successfully obtained in moderate to good yields and high enantioselectivities.

Despite the fact that a series of different enantioselective C–H activation processes have been developed for diarylmethylamines, these methods all relied on the asymmetric ortho-C–H bond activation of the aryl groups. In 2018, Yu and co-workers reported the desymmetrization of prochiral amines through Pd-catalyzed enantioselective remote meta-C–H arylation and alkylation (Scheme [56]). The key to the success of these transformations is the utilization of a catalytic amount of chiral norbornene derivative (+)-NBE-CO₂Me as chiral transient mediator (CTM), which could intercept the ortho-palladium intermediate via migratory insertion and thus affect meta-C–H activation (INT-G in Scheme [56, c]). A series of diarylmethylamines 155 and aryl iodides were compatible with this reaction, which afforded the desymmetrized meta-C–H-arylated amines 166 with high enantioselectivities (Scheme [56, a]). In addition, the 1,3-diaryl-2-propaneamines 167 were also feasible substrates in this reaction via the formation of a six-membered metallacycle, which could undergo either enantioselective desymmetrization or KR process to give the meta-arylated/alkylated amine products 168 with good to high enantiomeric purity (Scheme [56, b]).

In 2020, Phipps and co-workers reported another ingenious example of desymmetrization of diarylmethylamines through Ir-catalyzed enantioselective meta-C–H borylation[91] (Scheme [57]). A common bipyridine ligand with a sulfonate group paring with a chiral cation derived from quinine cat-57 was developed in this work, which rendered the efficient asymmetric meta-C–H borylation of 169 with B₂Pin₂ and provided the chiral amine products 170 with high enantioselectivities and regioselectivities. In addition, this method was also applicable in the desymmetrization of phosphinamides through enantioselective meta-C–H borylation, which gave the P-chiral products 171a in good yields and stereoselectivities. Mechanistic studies suggested that both the hydrogen-bonding interaction between the sulfonate group of the bipyridine ligand with the N–H group of substrates and the ion-pairing interaction of the sulfonate group with the chiral ammonium cation played critical roles in modulating the reactivity and stereoselectivity of these reactions.

Besides the enantioselective remote desymmetrization of diarylmethylamines enabled by chiral TM catalysts, the Miller group disclosed the remote desymmetrization of bis(pyridine)methylamines via asymmetric organocatalyzed pyridine N-oxidation in 2019 (Scheme [58]).[92] A series of methylamines bearing bis(3-pyridyl) moieties (172) were examined under the asymmetric N-oxidation reaction with H₂O₂ enabled by an aspartic acid containing peptide catalyst cat-58, which gave access to the chiral monopyridine-N-oxide products 173 with good to high enantioselectivities. It is worth mentioning that the bulky N-pivaloyl group is critical to the high enantioselectivities of these reactions (173e).

Conclusion and Outlooks

In conclusion, kinetic resolution and enantioselective desymmetrization have turned out to be useful strategies to access enantioenriched amines, especially when the racemic or prochiral amine substrates are easy to prepare while the direct enantioselective synthesis is challenging. In this Account, we have systematically summarized the development of KR and desymmetrization of amines through nonenzymatic asymmetric methods in the last two decades. Starting from the traditional asymmetric N-acylation methods, numerous elegant catalytic asymmetric methods, including various asymmetric N-functionalizations and asymmetric transformations without amino group participation, have been successfully applied in the KR of racemic amines and desymmetrizations of prochiral amines, which gave access to optically active amines with diverse structures.

However, despite great progress have been made in the last decades, there are still some limitations need to be overcome. First, the stereoselectivities for some KR process are still not so satisfying (with s-factor < 50), which usually could only provide the recovered SM with high enantioselectivities. Secondary, from the point of view of substrate scope, most developed methods realize the goal of KR or desymmetrizations of α-secondary amines (amines bearing two α-nonhydrogen substituents). Although our recently reported KR protocol through asymmetric electrophilic amination of anilines successfully realized the KR of both cyclic and acyclic α-tertiary amines, more diverse methods are still in high demands. Third, from the point view of methodology development, most reported KR methods still rely on the asymmetric functionalizations of the amino group for KR and desymmetrization. Encouragingly, recent advances based on the asymmetric transformations without amino group participation have been emerged as a novel and powerful strategy for both KR and desymmetrization of amines, which could be enabled by both chiral transition-metal catalysis and asymmetric organocatalysis. We envision that more practicable KR and desymmetrization methods for enantioenriched amine preparation could be developed based on this strategy. Lastly, although the KR of amines represent a practicable protocol to access optically active amines with broad scope, the inherent yield limitation (<50% yield) of this tactic cannot be ignored. DKR has proved to be an ideal way to overcome this limitation, however, whose scope was rather limited because of the challenging cooperation between the racemization process and the KR process. Nevertheless, we believe that the development of novel DKR protocols of amines is still one direction for further development.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank the past and present members of the Yang group for their contributions for the development of the KR and desymmetrization methods of amines, which have been presented in this Account.

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Corresponding Author

Publication History

Received: 18 January 2022

Accepted after revision: 07 March 2022

Accepted Manuscript online:
07 March 2022

Article published online:
13 April 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

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