Recent Advances in the Enantioselective Synthesis of Chiral Amines via Transition Metal-Catalyzed Asymmetric Hydrogenation

Chiral amines are key structural motifs present in a wide variety of natural products, drugs, and other biologically active compounds. During the past decade, significant advances have been made with respect to the enantioselective synthesis of chiral amines, many of them based on catalytic asymmetric hydrogenation (AH). The present review covers the use of AH in the synthesis of chiral amines bearing a stereogenic center either in the α, β, or γ position with respect to the nitrogen atom, reported from 2010 to 2020. Therefore, we provide an overview of the recent advances in the AH of imines, enamides, enamines, allyl amines, and N-heteroaromatic compounds.


INTRODUCTION
Chiral amines are key structural motifs present in a wide variety of natural products, drugs, and other biologically active compounds ( Figure 1). 1,2 Around 40−45% of the small molecule pharmaceuticals and many other industrially relevant fine chemicals and agrochemicals contain chiral amine fragments. Moreover, chiral amines can be used as resolving agents, chiral auxiliaries, or building blocks for the asymmetric synthesis of more complex molecules, including natural products. Therefore, the great demand for enantiomerically enriched amines in the life sciences has driven the development of innovative and sustainable synthetic routes toward their efficient preparation. 3 Despite the widespread relevance of chiral amines, traditional synthetic methods such as resolution are still being used. To overcome their intrinsic limitations, the use of catalytic methods has been widely investigated in recent decades, with asymmetric catalysis being a key research field in modern synthetic chemistry. 4,5 Although biocatalytic 6 and organocatalytic 7 stategies have gained importance, the catalytic approach based on transition metals is still, arguably, the method most widely used. 8 The design and synthesis of modular chiral ligands have allowed the preparation of novel metal complexes whose properties have been fine-tuned to afford highly active and efficient catalysts.
A relevant number of new metal-catalyzed transformations for the synthesis of chiral amines have been reported. Important achievements have been made in enantioselective methods involving, among others, reductive amination, 9−12 hydroamination, 13−15 allylic amination, 16 or isomerization reactions. 17,18 The metal-catalyzed enantioselective alkyl addition to imines has also been explored. 19 Nonetheless, the asymmetric reduction of unsaturated compounds continues to be the most fundamental means of introducing chirality. 20 In this regard, the asymmetric reduction of imines 21,22 (via hydrosilylation or transfer hydrogenation, for example) provides an attractive route to chiral amines. However, direct asymmetric hydrogenation (AH) of unsaturated nitrogenated compounds is probably the most powerful and efficient strategy. AH offers excellent atom economy, with almost no waste or byproducts, and thus is a highly sustainable and "green" strategy for attaining optically active amines. 23 Due to all these advantages, AH has become one of the major disciplines in homogeneous catalysis. 24 Transition metal-catalyzed AH frequently shows excellent chemo-, regio-, and enantioselectivity, and it is considered a versatile and a reliable tool for the synthesis of chiral drugs. 25 The AH of challenging organic substrates such as unfunctionalized olefins, 26,27 nonaromatic cyclic alkenes, 28 tetrasubstituted olefins, 29 and (hetero)arenes 30−34 has been extensively studied, reaching high levels of enantiocontrol. However, and in spite of the long-standing problems being partially solved, many challenges remain. Moreover, the environmental need to use more economical and accessible first-row transition metals (Mn, Fe, Co, and Ni) arises as a new complex task in a field dominated by Rh, Ir, and Ru since its origins.
Focusing on the enantioselective synthesis of chiral amines, important advances have been reported in the last ten years, many of them based on the AH of imines, 35−39 enamines, and derivatives 39−41 and N-heteroarenes. 30 −32 These advancements are largely driven by a plethora of new chiral phosphorus ligands, 42 including phosphino-oxazolines 43 and P-stereogenic phosphines. 44,45 In addition, other chiral phosphine-free metal catalysts, bearing N-heterocyclic carbenes 46 or C,N-and N,Nbased ligands, have also shown outstanding catalytic activity. 47 Thanks to these breakthroughs, a wide range of previously not easily accessible chiral amines have been obtained with excellent enantioselectivities.
The development of new efficient routes for chiral amine synthesis has a strong and direct impact on medicinal chemistry and the pharmaceutical industry. 48 Indeed, recent years have witnessed an increase in the synthesis of new chiral amino building blocks due to the great demand for expanding the chemical space in drug discovery platforms. 49 AH has also found widespread use at the industrial level. The pioneering work of Chemical Reviews pubs.acs.org/CR Review Knowles,50,51 Horner, 52 and Kagan, 53 followed by the great success of the Monsanto Company 54 with the production of L-DOPA, opened up industrial-scale synthesis using AH. 55 −57 In 2009, Merck implemented a highly efficient and sustainable enantioselective synthesis of sitagliptin via rhodium-catalyzed AH on a manufacturing scale. 58 In 2011, Pfizer developed the multikilogram synthesis of the amino acid imagabalin hydrochloride (PD-0332334), used for the treatment of generalized anxiety disorder (GAD), via AH. 59 Another landmark in the field was the rhodium-catalyzed AH of β-cyanocynnamic esters 60 to produce pregabalin (Lyrica), which is an important drug for the treatment of fibromyalgia and epilepsy. 61 The present review focuses on the syntheses of chiral amines bearing a stereogenic center in either the α, β, or γ position with respect to the nitrogen atom reported between 2010 and 2020. Therefore, we provide an overview of the recent advances in the AH of the following substrates: (a) imines, (b) enamides, (c) enamines, (d) allyl amines, and (e) N-heteroaromatic compounds ( Figure 2). Despite the fact that asymmetric reductive amination (ARA) is one of the most convenient methods for the prepration of chiral amines, this topic will not be covered specifically in this review since ARA has been extensively reviewed recently. 10−12

ASYMMETRIC HYDROGENATION OF IMINES
The asymmetric hydrogenation of prochiral imines 35−40 is the most direct and efficient approach to prepare valuable α-chiral amines. 62 It has been used at industrial scale, exemplified by the multiton-scale production of the herbicide (S)-metolachlor. 63 Imines are more challenging substrates than their oxygenated analogs, namely ketones, due to the easy hydrolysis, the presence of E,Z stereoisomers, and nucleophilicity. Thus, extensive efforts have been devoted to the development of efficient synthetic procedures. In recent decades, considerable progress has been made in the AH of both N-protected and unprotected 64 imines. While ruthenium has provided excellent results in asymmetric transfer-hydrogenation reactions, iridium has shown better performance for the direct hydrogenation of imines. 65 −67 In addition, catalytic systems based on earth-abundant metals such as iron or cobalt have started to give competitive results. 68 2.1. N-Aryl Imines 2.1.1. N-Aryl Aryl Alkyl Imines. Several examples of the AH of N-aryl imines derived from acetophenones have been reported, reaching excellent levels of enantioselectivity. The reduction of acetophenone phenyl imine (S1, Scheme 1) is the standard substrate for this chemistry.
In 2009, de Vries, Feringa, and co-workers reported the iridium-catalyzed AH of N-aryl imines using readily available (S)-PipPhos as chiral monodentate phosphoramidite ligand (C1, Scheme 1). 69 With the model substrate S1, they obtained a product of 87% ee, but the selectivity increased significantly using ortho-methoxyphenyl imines (S2b) as substrates. This work demonstrated that, although bidentate chiral ligands were considered a superior class in AH, modular monodentate ligands might also be highly efficient in certain cases. 70 X. Zhang and co-workers used chiral diphosphine DuanPhos in the preparation of iridium catalysts C2. 71 The AH of the standard substrate gave 93% ee. Similar substrates with substitutions in the aryl groups gave 90−93% ee.
Iridium complexes bearing phosphino-oxazoline chiral ligands have been widely used in the AH of N-aryl imines. 72, 73 Zhou's 74 and Ding's 75 groups, respectively, developed chiral complexes with a spiranic backbone C3a and C4a. Both reported high activity and achieved chiral amines in up to 97% ee. Pfaltz also showed that phosphino-oxazoline ligands provide an excellent platform for the iridium-catalyzed reduction of Naryl imines. In 2010, he reported a range of Ir−P,N chiral complexes (SimplePHOX, C5) that were readily accessible by a short and convenient synthesis. 76 The AH of S1 with C5 gave a product of 96% ee. In 2016, Riera and Verdaguer developed a novel family of chiral P-stereogenic phosphino-oxazoline ligands called MaxPHOX. 77 These modular ligands are prepared from three different building blocks: an amino alcohol, an amino acid, and a P-stereogenic phosphinous acid. 78 The key advantage of the Ir-MaxPHOX catalysts (C6a) resides in their structural diversity, which is conferred by four possible configurations and diverse substitution patterns. This feature allows fine-tuning of the catalyst for each specific reaction. Moreover, the absolute configuration of the P-center is crucial and has a great impact on catalytic activity. Using these Ir-MaxPHOX complexes, the AH of acyclic N-aryl ketimines smoothly proceeded with high enantiocontrol (up to 96% ee) at 1 bar of hydrogen. 79 Ruthenium catalyst C7, first developed by Ohkuma and coworkers in 2012, afforded very high enantioselectivities on the model substrate S1 (97% ee) (Scheme 1). 80 The Xyl-Skewphos/ DPEN-Ru complex C7 was applied to the AH of a range of imines derived from aromatic and heteroaromatic ketones with a TON as high as 18,000 to afford chiral amines in up to 99% ee.
Sterically hindered N-aryl imines are difficult substrates. In 2001, X. Zhang and co-workers described Ir/f-binaphane as an excellent catalyst for the AH of sterically hindered N-aryl alkylarylamines. 82 Later, in 2012, Hu reported an extended substrate scope by using the iridium complex derived from phosphine-phosphoramidite ligand L1a (Scheme 2). 83,84 The corresponding chiral amines P3, which are important building blocks in organic synthesis and agrochemistry, were obtained in good to excellent enantioselectivities.
2.1.2. N-Aryl Dialkyl Imines. In contrast to aromatic imines, successful examples of the AH of imines derived from aliphatic ketones (S4) are rare and usually with low chiral induction. In 2008, Xiao pioneered the field with the highly efficient cooperative catalysis between the ruthenium complex C9 and achiral phosphoric acid (HA) (Scheme 3). 85 In 2011, Beller and co-workers demonstrated that performing ligand-free AHs without the use of precious metal catalysts was possible. 86 The combination of an achiral iron complex (Knolker's catalyst, C10) with HAs enabled smooth hydrogenation for a wide range of N-aryl imines, including S1 and the dialkyl imine S4a. Similarly, in 2013, Xiao reported a family of achiral iridium-(Cp*) complexes containing diamine ligands that, in combination with a chiral HA, gave access to highly active catalysts (C11−C12) for the AH of N-aryl imines derived from both aryl and aliphatic ketones. 87,88 While C11 was chosen as the best catalyst for S1 (98% ee, Scheme 3), for imine S4c the highest enantioselectivity was observed using C12, which is the best catalyst reported to date for these substrates.
2.1.3. N-Aryl α-Imino Esters. The synthesis of enantiomerically pure α-amino acids and their derivatives is of great importance in pharmaceutical and synthetic chemistry. 89 Chiral α-aryl glycines, in particular, have found wide applicability in the synthesis of significant antibacterial and cardiovascular drugs, such as amoxicillins and nocardicins. 90 Several highly efficient asymmetric catalytic methods such as the asymmetric Strecker 91 or Sharpless aminohydroxylation have been developed. 92 Despite being a logical approach, the AH of the corresponding α-imino esters has scarcely been addressed, presumably because of the relatively poor reactivity of these types of imino substrates toward hydrogenation. In 2006, X. Zhang and co-workers reported the first rhodiumcatalyzed AH of S5 using a P-stereogenic diphosphine L2 (TangPhos), providing chiral glycines P5 with high yields and enantioselectivities (Scheme 4). 93 However, the scope of this method was limited to p-methoxyphenyl (PMP)-protected αimino esters. To overcome this constraint, Hu described the iridium-catalyzed AH of α-imino esters S6 with unsymmetrical hybrid chiral ferrocenylphosphine-phosphoramidite ligand L3 for the synthesis of optically active α-aryl glycines P6 (Scheme 4). 94 The method features high asymmetric induction (up to 96% ee), with the iodo-substituent of the binaphthyl unit playing a fundamental role in the enantioselectivity.
To avoid the use of precious metals, in 2020, W. Zhang and co-workers reported an efficient nickel-catalyzed AH of N-aryl imino esters S7, affording chiral α-aryl glycines P7 in high yields and enantioselectivities (up to 98% ee) using a P-stereogenic dialkyl phosphine ligand, BenzP* L4 (Scheme 4). 95 The reaction was performed on a gram scale at a low catalyst loading (S/C up to 2000). The preparation of two synthetic drug intermediates showcased the applicability of the method.
2.1.4. Exocyclic N-Aryl Imines. Typically, the AH of exocyclic ketimines derived from 1-tetralone or 4-chromanone exhibited low enantioselectivities, presumably due to the conformational strain upon metal coordination. 96,97 In 2011, Zhou and Bao reported a highly enantioselective palladiumcatalyzed hydrogenation using a catalytic amount of a Brønsted acid as activator (D-DTTA). 98 By using C 4 -TunePhos L5a as a chiral ligand, this catalytic system provided straightforward access to enantioenriched cyclic amines P8a and P8b (86−95% ee, Scheme 5), which are privileged structural motifs present in a large number of drugs and natural compounds. 99 Iridium-based catalytic systems were also used in this transformation. First, Bolm's group made a significant advance in the iridiumcatalyzed AH of exocylic imine S8a. They introduced a novel class of C 1 -symmetry sulfoximines as chiral ligands that, once coordinated, yielded the corresponding chiral amine adduct in 91% ee. 100 Although it was a single example, the catalytic system also gave excellent results for acyclic N-aryl imines. Later, in 2014, Qu and co-workers reported a family of air-stable Pstereogenic dihydrobenzooxaphosphole oxazoline ligands (La-lithPhos). 101 In particular, Ir/L6 was chosen as the best catalyst for the AH of S8a, which afforded up to three examples of P8a in enantiopure form (Scheme 5).

N-Alkyl Imines
Chiral N-methyl or N-alkyl amine is a frequent pharmacophore in many pharmaceuticals and drugs, and despite other successful approaches, 102,103 direct AH is the most convenient process. In sharp contrast with the good results obtained with N-aryl ketimines, the development of the AH of N-alkyl ketimines has been more difficult. The high basicity and nucleophilicity of the corresponding N-alkyl amines as reaction products often results in catalyst deactivation. Pfaltz pioneered the use of Ir-PHOX catalysts for the AH of the N-methyl imine of acetophenone, albeit with low enantioselectivity. 73 Later, in 2013, he discovered that the catalyst in the hydrogenation of N-aryl imine is actually an iridacycle that forms upon reaction with the imine substrate. 104 Prompted by this finding, and inspired by the excellent activity that Ir-MaxPHOX catalysts showed in the AH of N-aryl imines, 79 Riera and Verdaguer's laboratory recently reported a highly efficient AH of N-alkyl imines S9 using iridacycle C13 prepared fromMaxPHOX and the phenyl imine of benzophenone (Scheme 6). 105 This catalyst allowed the first direct hydrogenation of methyl and alkyl imines derived from acetophenones in very mild conditions and in high enantioselectivity (up to 94% ee).
The AH of N-alkyl α-aryl furan-containing imines is a straightforward route to a wide range of unnatural N-alkyl aryl alanines. In this regard, Mazuela et al. reported that, using a Ir/ (S,S)-f-Binaphane-L7 as catalyst, up to 22 N-alkyl imines were efficiently hydrogenated, providing chiral amines P10 (up to 90% ee), which can be further easily transformed into amino acids (Scheme 7). 106 The effect of substituents on the nitrogen was remarkable, as the use of large alkyl substituents led to a significant decrease of enantioselectivity.
Fan described the phosphine-free, chiral, cationic Ru/ MsDPEN complex C14a which was a highly active catalyst for the AH of a range of acyclic and exocyclic N-alkyl ketimines (Scheme 8). 107 By using BAr F as counterion, a broad range of often problematic substrates S11 were efficiently hydrogenated with low catalyst loadings, albeit with the use of Boc 2 O to avoid catalyst inhibition. Moreover, this system also operates under solvent-free conditions, thus providing a highly sustainable platform to optically active amines P11. The same group later reported a similar ruthenium complex that, together with a phosphoric acid as additive via cooperative catalysis, was also an efficient catalyst for the hydrogenation of N-alkyl ketimines S11 in the absence of Boc 2 O. 108 Previously, in 2009, Ding and co-workers designed a new family of spiro phosphino-oxazoline chiral ligands that were successfully applied to the iridium-catalyzed AH of N-aryl imines. 75 Of note, the catalytic system is also applicable for N-alkyl imines (Scheme 8). Actually, both acyclic (S12) and exocyclic (S13) imines were efficiently hydrogenated with high levels of enantioselectivity using two distinct precatalysts (diastereoisomers C4b and C4c, respectively) and without the need of additives.
Phosphine ligands containing spiro scaffolds 109 such as f-spiroPhos L8, first reported by Hou and co-workers, 110 emerged as a new and powerful class of chiral ligands for asymmetric catalysis. In 2016, this group reported a highly efficient AH of diarylmethanimines, which are challenging substrates due to the difficulties to distinguish between two sterically similar aryl groups (Scheme 9). 111 Hou detailed that, by using Ir/L8 as catalyst, a variety of chiral diarylmethylamines P14 were obtained with excellent enantioselectivities (up to 99% ee) and high TON. Previously, L8 had also been successfully applied to the rhodium-catalyzed AH of α,β-unsaturated nitriles, 112 among other examples.

Cyclic N-Aryl Imines
The AH of N-heteroarenes is one of the most important ways to access chiral N-heterocyclic compounds (see section 6). For instance, a direct strategy to obtain chiral indolines would be the direct AH of the corresponding indoles. However, indoles are a challenging class of substrates and their AH was unsuccessful for many years. 113 In this field, Fan and Rueping's groups simultaneously reported two independent catalytic systems that were highly efficient for the AH of 3H-indoles (Scheme 10). Fan and co-workers described a highly efficient enantioselective synthesis of 2-alkyl and 2-aryl indolines (P15a) via AH using Ru diamine catalysts C14b and C14c, respectively. 114 The catalytic reaction proceeded smoothly at low H 2 pressure and with a high enantioselectivity (>99% ee in the best cases). Both the counteranion and the solvent played a crucial role in catalytic performance. On the other hand, Rueping reported a highly enantioselective iridium-catalyzed AH of 3H-indoles S15 by using chiral diphosphine ligand L9a. 115 A wide range of valuable disubstituted and spirocyclic 2-aryl indolines P15b were prepared in excellent results, albeit at elevated H 2 pressure. Previously, the same group provided an operationally simple route to other biologically relevant heterocyclic compounds, such as dihydrobenzodiazepines, by AH. 116 The enantioselective synthesis of seven-membered Ncontaining heterocycles has attracted considerable attention during recent decades, as they are versatile pharmacophores in medicinal chemistry. In 2012, Fan and co-workers reported that two Ru/diamine catalysts were highly efficient in the AH of benzodiazepines S16 (Scheme 11). 117 Interestingly, an achiral anion influenced both the nature and the coordination effect and reversed the sense of the asymmetric induction. After an exhaustive catalyst screening, C14d was chosen for benzodiazepine-bearing aryl substituents, while C14e was used for alkyl groups. In the first case, both enantiomers were obtained using the same ligand but in the presence of different achiral counteranions. Recently, they also reported that the iridium complex C15 is a highly active catalyst for the AH of benzodiazepines S17 bearing aryl substituents (Scheme 11). 118 For both catalytic systems, the corresponding optically active dihydrobenzodiazepines were obtained with good to excellent diastereoselectivity and excellent enantioselectivity. The same group reported other catalysts, including dendritic phosphinooxazoline iridium complexes, which proved highly efficient for both the partial and total AH of benzodiazepines. 119 −121 Zhou's group used Ir chiral complexes also for the AH of benzodiazepines. They reported that Ir/C 4 -TunePhos-L5a is a highly active catalytic system for the AH of both pyrrole-and indole-fused benzodiazepines S18, reporting a moderate to excellent level of enantioselectivity (Scheme 11). 122 Moreover, by switching to chiral ligand L10, outstanding results were also obtained for the AH of benzodiazepinones S19, thus offering a highly versatile catalytic approach for a range of chiral cyclic amines present in numerous important natural products and drugs. In addition, the same group later reported an iridiumcatalyzed AH/oxidative fragmentation cascade for the synthesis of chiral dihydrobenzodiazepinones.
A number of successful examples of the AH of some benzofused seven-membered cyclic imines for the preparation of chiral benzazepines and benzodiazepines have recently been reported. 123 −126 X. Zhang and co-workers described a highly efficient AH of dibenzoazepine hydrochlorides S20 catalyzed by Rh/ZhaoPhos-L11a (Scheme 12). 127 The corresponding chiral seven-member cyclic amines P20 were obtained in high yields and excellent enantioselectivities (>99% ee in the best cases).
Interestingly, control experiments revealed that the anionbonding interaction between the chloride ion of the substrate and the thiourea motif of L11a played a key role in enantioselectivity. The same reaction conditions were also useful for the AH of oxazepines.
Another important family of CN-containing heterocycles are benzoxazines and derivatives (S21−S22). At the beginning of this decade, Beller, 128 Ohkuma, 129 and Zhou's 130 groups reported advances in the transition metal-catalyzed AH of this class of compounds. Later, in 2014, Fan expanded the catalytic application of Ru/MsDPEN complexes. In fact, C14f and C14g were excellent catalysts for the highly enantioselective AH of 3aryl-and 3-styryl-substituted benzoxazines S21, respectively (up to 99% ee, Scheme 13). 131 In contrast to previous work 130 where 3-styryl-substituted benzoxazines were completely hydrogenated, this catalytic system showed an exquisite 1,2-selectivity with an appropriate counterion (C14g). On the other hand, the main drawback of this method is that ortho-substituted aryl substituents in benzoxazines S21 were not compatible. Unfortunately, when using these substrates, the reaction could not take place, probably due to undesired steric effects. In addition, the AH of 3-alkyl-substituted benzoxazines is underdeveloped. 129 Moving to iridium catalysis, Vidal-Ferran designed a new phosphine-phosphite ligand L12, which, once coordinated to iridium, provided a highly active Ir(I) catalyst for the AH of 3aryl-substituted benzoxazines (S21a), benzoxazinones (S22), and benzothiazinones (S23) (up to 99% ee, Scheme 13). 132,133 The iridium catalyst with L12 was also the first-ever reported catalyst for the AH of quinoxalinones and N-substituted quinoxalinones S24a (Scheme 14). More recently, Peng and co-workers reported a highly enantioselective palladiumcatalyzed AH of S24b. 134 Using (R)-SegPhos L9b as the chiral ligand, and performing the reaction in HFIP, a wide array of optically active 3-trifluoromethylated dihydroquinoxalinones P24 were synthesized (>99% ee in the best cases, Scheme 14). However, the substituent on the aromatic ring impaired the reaction. In this regard, the introduction of a methyl group at the 5-position on the phenyl ring inhibited the reaction due to the steric effect.
The AH of related nonaromatic systems such as 5,6dihydropyrazin-2-ones S25 was recently reported by Yang, W. Zhang, and co-workers 135 using a phosphine-oxazoline RuPHOX ligand (L13). The corresponding chiral piperazin-2ones P25 were obtained in good yields and with moderate to good enantioselectivities (Scheme 15).

Cyclic N-Alkyl Imines
The great progress achieved in the AH of activated and N-aryl imines contrasts with the often problematic AH of N-alkyl imines. Buchwald's group reported the titanocene-catalyzed AH of cyclic N-alkyl imines back in 1994. 136 In 2008, Xiao and coworkers identified a Rh(III)-diamine complex (C16) as a highly active catalyst for the AH of cyclic N-alkyl imines S26 to give bioactive tetrahydro-β-carbolines 137 P26 in optically pure form (>99% ee in the best cases, Scheme 16). 138 Remarkably, both aryl and alkyl substituents were well-tolerated, and mostly no differences in terms of enantioselectivities were observed.
Dihydro-β-carbolines have been used to synthesize natural products. In 2020, Tang, Chen, and co-workers reported a concise asymmetric total synthesis of two examples of the Eburnamine−Vincamine alkaloids (Scheme 17). 139 These syntheses featured a highly stereoselective iridium-catalyzed hydrogenation/lactamization cascade using f-binaphane L7 as a chiral ligand, thus allowing a stereocontrolled assembly of the C20/C21 adjacent chiral centers in P27.
Chiral cationic Ru-MsDPEN complexes have also been employed in the AH of cyclic N-alkyl imines. In particular, Fan disclosed that C14a was an efficient catalyst for the AH of S28 to provide chiral cyclic amines P28a in excellent yields and enantioselectivities (Scheme 18). 140 The same authors used a similar catalytic system for the AH of dibenzo[c,e]azepine derivatives to afford seven-membered cyclic amines with moderate to excellent enantioselectivities. 141 However, in both cases, the use of Boc 2 O was required to prevent in situ catalyst deactivation. To circumvent this issue, Hou recently reported that the complex of iridium and (R,R)-f-spiroPhos L8 as the catalyst allowed the smooth hydrogenation of a range of 2-aryl cyclic imines S28 to P28b under mild conditions without any additive (Scheme 18). 142 Hou also reported the synthesis of free cyclic amines via intramolecular reductive amination using a chiral iridium complex derived from L8. 143 Previously, in 2010, X. Zhang reported an iridium-based catalytic system for the direct AH of S28 without in situ N-protection, albeit with lower enantioselectivities. 144 Optically active 2-aryl pyrrolidines and piperidines are an important class of structural units in many natural products and pharmaceuticals ( Figure 3). 145,146 In particular, chiral amines containing a pyridyl moiety, such as nicotine and its derivatives, 147 are very common in alkaloid natural products and pharmaceuticals. However, the transition metal-catalyzed AH of pyridyl-containing unsaturated compounds remained a great challenge due to the strong coordinating ability of the pyridine moiety, which led to catalyst deactivation. To overcome this limitation, in 2015, Xu, Zhu, Zhou, and co-workers reported a highly efficient protocol to facilitate the exploration of nicotine-derived bioactive compounds. 148 By using iridium catalyst C3b with a chiral spiro phosphine-oxazoline ligand (SIPHOX), a wide variety of chiral amines P29 were attained in excellent yields and enantioselectivities via direct catalytic AH of 2-pyridyl cyclic imines S29 (Scheme 19).
Tetrahydroisoquinolines (THIQs) are an important class of alkaloids present in many pharmaceutical drugs ( Figure  4). 149,150 Therefore, the development of new enantioselective methods for their synthesis is highly desired. To this end, Zhou's group used ligand L14 from the family of spiro-ligands SIPHOS for the enantioselective synthesis of THIQs. In 2012, they developed a highly efficient iridium-catalyzed AH of 3,4dihydroisoquinolines (DHIQs) S30 with good to excellent enantioselectivities (Scheme 20). 151 The scope of the reaction was limited to alkyl substituents. 138,152 X. Zhang's laboratory developed an alternative catalytic system using the iodinebridged dimeric iridium complex with (S,S)-f-Binaphane L7. 153 This catalyst was applied to the AH of a wide range of 3,4dihydroisoquinolines (S30) including, for the first time, those bearing aryl substituents. The corresponding THIQs P30b were Scheme 18. Synthesis of Chiral 2-Aryl Pyrrolidines and Piperidines via AH afforded with excellent enantioselectivities and high TON (Scheme 20). Unfortunately, due to steric hindrance, the enantioselectivities varied dramatically with the substrates bearing a 1-ortho-substituted phenyl ring. To overcome this limitation, several catalytic systems were reported as alternatives. 154−156 Of note, Wang, Jiang, S. Zhang, and co-workers reported a direct, simple, and efficient protocol toward enantioenriched chiral 1-aryl-substituted THIQs P30c. 157 For this purpose, they applied novel JosiPhos-type binaphane ligand (t-Bu-ax-JosiPhos) L15 to the iridium-catalyzed AH of 1-arylsubstituted DHIQs S30 (Scheme 20). Interestingly, the new ligand adopted the privileged properties of both JosiPhos and fbinaphane in terms of rigidity and electron-donating ability. Moreover, the use of 40% HBr (aqueous solution) as an additive dramatically improved the asymmetric induction of the catalyst. In 2020, the same catalytic system was applied to the AH of sterically hindered cyclic imines P30d, achieved with good to excellent enantioselectivities (74−99% ee) (Scheme 20). 158 This novel family of chiral ligands was also applied to the iridium-catalyzed AH of acyclic N-aryl imines. 159 In 2013, Zanotti-Gerosa's group (Johnson-Matthey) described a novel approach to the synthesis of the urinary antispasmodic drug solifenacin (Scheme 21). 160 After an exhaustive optimization process, the group demonstrated the feasibility of the process for the AH of the hydrochloride salt S31. The use of this salt increased reactivity in the presence of the iridium catalyst with chiral ligand (S)-P-Phos (L16). The robustness of the protocol was proved by reproducing it on 200 g scale to give P31 in 95% yield and 98% ee.
The AH of iminium salts is the method of choice for obtaining tertiary amines in terms of simplicity and atom economy. In this regard, Zhou's group described an efficient and convenient method using Ir/(R)-SegPhos L9b for the AH of cyclic iminium salts bearing a dihydroisoquinoline moiety S32 (Scheme 22). 161 The corresponding chiral tertiary amines P32 were afforded in good to excellent yields and with up to 96% ee.  from ketones and the inhibitory effect of the amine products on the metal catalysts partially prevented their widespread use in AH. To overcome these limitations, N-sulfonyl imines, which are more stable than aryl or alkyl imines, emerged as a useful alternative. Moreover, the strong electron-withdrawing character of the sulfonyl group reduces the probability of eventual catalyst deactivation. In 2006, X. Zhang and co-workers reported an important breakthrough in the field: palladium-catalyzed AH using TangPhos (L2). 162 N-sulfonyl imines S33 (including exocyclic imines) were efficiently hydrogenated with high levels of enantioselectivity (>99% ee in the best cases, Scheme 23). However, high H 2 pressure was required to hydrogenate the CN bond with full conversion. Aiming to design a catalytic system able to work at low pressure, Laishram, Fan, and coworkers recently reported a cocatalytic system based on Pd and using Zn(OTf) 2 as an essential additive. 163 The combination of this Lewis acid, Pd(OAc) 2 , and the axially chiral diphosphine MeO-Biphep (L17a) furnished the corresponding N-sulfonyl amines P33b, which show high activity and optical purity working under 1 bar of H 2 (Scheme 23).
Palladium-based catalysts had a strong impact on AH. 164 Furthermore, palladium-catalyzed processes involving tandem or cascade reactions are advantageous for the exploration of highly reactive intermediate species. In 2014, Zhou's group reported an efficient palladium-catalyzed AH via hydrogenation of an intermediate generated from the acid-catalyzed aza-Pinacol rearrangement of S34 (Scheme 24). 165 Using the axially chiral ligand (S)-SegPhos L9b, up to 13 examples of chiral fivemembered exocyclic amines P34 were obtained in moderate to high yields and excellent enantioselectivities (up to 97% ee).
Imines bearing small substituents, such as methyl or ethyl groups connected to the carbon atom, have been widely used as substrates. In sharp contrast, the AH of sterically demanding imines (from ketones bearing bulky substituents) or other αheteroatom-substituted imines is still rare. W. Zhang expanded the frontiers of the AH of N-sulfonyl imines by employing the Pstereogenic diphosphine Quinox-P* (L18a), 166 previously designed by Imamoto (Scheme 25). In 2018, the group reported the palladium-catalyzed AH of sterically hindered N-tosylimines under 1 bar of H 2 pressure with high catalytic activities (S/C up to 5000) and excellent enantioselectivities (up to 99% ee, Scheme 25, P35a). 167 This methodology was also applied to dialkyl N-tosyl imines and N-sulfonyl α-iminoesters 168 with the same level of enantiocontrol. W. Zhang and co-workers also described the AH of α-iminosilanes 169 (up to 99% ee, Scheme 25, S35d), albeit using higher H 2 pressures. The low activity of earth-abundant transition metal catalysts has prevented their broad adoption in AH. 170 Undeterred by this challenge, W. Zhang's group recently demonstrated that the combination of nickel complexes with QuinoxP* L18a allows the AH of Nsulfonyl imines S35a with high catalytic activity (S/C = 10500) and exquisite enantiocontrol (>99% ee in the best cases, Scheme 25). 171 Chemical Reviews pubs.acs.org/CR Review A similar catalytic system using Ph-PBE (L19) as a ligand was recently reported by Lv and co-workers (Scheme 26). 172 The nickel-catalyzed chemoselective AH of α,β-unsaturated ketoimines S36 afforded chiral allylic amines P36 in excellent yields and enantioselectivities. The last two examples confirm that nickel can be an effective transition metal for AHa concept also disclosed by Chirik 173 and Hamada. 174 Other α-heteroatom N-sulfonyl imines have also been explored. Zhou and co-workers disclosed the palladiumcatalyzed AH of a series of linear and cyclic α-iminophosphonates. 175 The combination of Pd/(R)-DifluorPhos-L20 as catalyst provided an efficient route to obtain optically active αamino phosphonates P35e with up to 97% ee (Scheme 27).
2.5.2. Cyclic N-Sulfonyl Imines. Sulfamidates (P37 and P38) and sultams (P39 and P40) are privileged building blocks in medicinal chemistry and useful chiral auxiliaries and ligands in asymmetric catalysis. They can be synthesized through the AH of the corresponding imines S37−S40 (Scheme 28). Zhou and co-workers reported an efficient AH of cyclic N-sulfonyl imines using Pd(CF 3 CO 2 ) 2 /(S,S)-f-binaphane-L7 as catalyst, to afford the corresponding chiral amines in high enantioselectivity (up to 99% ee). 176,177 The catalytic system was valid for both sulfamidates and sultams, and it was further extended to the AH of benzo-fused imines S38 and S40. Fan reported a previous version of this transformation using ruthenium catalysts, but with lower enantiomeric ratios. 178 An example of the importance of chiral sulfamidates as drug building blocks is the Merck's synthesis of MK-3207. 179 The chirality of the benzylic stereocenter was introduced via the palladium-catalyzed AH of the cyclic sulfamidate imine S37a using either L7 or JosiPhos (L21a) as chiral ligands (Scheme 29).
More recently, in 2019, Dong, X. Zhang, and co-workers performed the iridium-catalyzed AH of S37 using ZhaoPhos (L11a) to attain sulfamidates P37b with excellent activities and enantioselectivities (Scheme 30). 180 ZhaoPhos is a family of chiral bifunctional diphosphine-thiourea ligands based on the synergistic cooperation between transition metal catalysis and organocatalysis. 181 The substrate scope was limited to aryl or heteroaryl substituents. In contrast, the combination of Ni/L19, which gave excellent results for the AH of α,β-unsaturated ketoimines, 172 is an alternative for the AH of S37 bearing both aryl and alkyl substituents. 182 Several chiral cyclic sulfamidates P37 were prepared, even at gram scale, in high enantiomeric purity. The same catalytic system was used in the highly efficient AH of cyclic N-sulfonyl ketimino esters S38c, among other S38atype substrates, which had not been disclosed before (Scheme 31). 183 This transformation led to the facile synthesis of various chiral α-monosubstituted α-amino acid derivatives with excellent results.
Another strategy for the synthesis of cyclic sultams is the AH of enesulfonamides S41. In 2011, Zhou's group reported an innovative transformation, using a catalytic system based on Pd/ JosiPhos-type ligands. 184 JosiPhos-L21b and WalPhos-L22a, in particular, were excellent chiral ligands for enesulfonamides S41 bearing aryl and alkyl substituents, respectively (Scheme 31). Interestingly, labeling experiments confirmed that the hydrogenation was conducted via N-sulfonylimine intermediates. Later, in 2015, the same group reported the enantioselective synthesis of sultams by a palladium-catalyzed formal hydrogenolysis of racemic N-sulfonyloxaziridines with up to 99% ee. 185

N-Phosphinyl Imines
As described before, palladium complexes bearing diphosphine ligands are highly effective catalysts for the AH of N-sulfonyl imines in fluorinated solvents such as TFE (trifluoroethanol) or HFIP (hexafluoroisopropanol). Similarly, other activated imines, such as N-phosphinyl imines, are also suitable substrates for this catalytic system. After the pioneering work of Blaser, 186 Zhou described the highly efficient palladium-catalyzed AH of activated imines, including N-diphenylphosphinyl ketimines. 187 These ketimines (S42) were hydrogenated using L9b as a chiral ligand (Scheme 32), attaining excellent levels of enantioselectivity (up to 99% ee). The reaction showed a dramatic solvent effect, as only TFE led to high conversion toward P42.
Alternatively, Liu, Huang, and co-workers designed a phosphino-oxazoline ligand (L23) for the ruthenium-catalyzed AH of S42 (Scheme 32). 188 The catalytic system exhibited good activity and excellent enantioselectivity, providing an efficient and mild approach to optically active secondary amines P42. Using iron as earth-abundant transition metal, Morris and coworkers reported that an unsymmetrical iron P-NH-P′ complex (C17, Scheme 32) gave excellent enantioselectivity for the AH of prochiral N-phosphinyl imines S42, but with poorer activity than the previous catalytic systems. 189 The same group had previously foreseen that these iron-hydride catalytic species were highly active toward the AH of polar bonds. 190 Nonetheless, the system failed when using dialkyl-substituted or exocyclic N-phosphinyl imines, which remains as a current challenge in the field.

N-Acyl Imines
In 2010, Mikami and co-workers reported a catalytic AH of acyclic ketimines S43 bearing a perfluoroalkyl chain as substituent (Scheme 33). 191 The introduction of fluorine into molecules enhances their lipophilicity, metabolic stability, and bioavailability, thus remarkably affecting the physicochemical properties. 192−194 Using a Ir/L24b (a 3,5-dimethylphenyl analog of BINAP, L24a) as catalytic system, four examples of chiral perfluoroalkyl amines were obtained with excellent enantioselectivity. Moreover, this work established an important precedent in the field, as the direct AH of N-acyl imines is still rare. 195 A novel strategy for the AH of β,γ-unsaturated γ-lactams S44a was described by Liu, W. Zhang, and co-workers using iridium catalysis in combination with a phosphoramidite ligand L25 and I 2 (Scheme 34). 196 The chiral γ-lactams P44 were obtained in excellent yields and enantioselectivities. Mechanistic studies detailed that the reduced products were obtained via the hydrogenation of N-acyliminium cations, rather than directly by the hydrogenation of S44a. Therefore, using the same catalytic system, these chiral γ-lactams were also prepared via in situ elimination/AH of racemic γ-hydroxy-γ-lactams S44b. 197 A related iridium-catalyzed AH of cationic species was recently reported by Wen, X. Zhang, and co-workers for the enantioselective synthesis of chiral N,O-acetals (Scheme 35). 198 Under acidic conditions, O-acetylsalicylamides S45 underwent cyclization to generate cationic intermediates, which were subsequently hydrogenated by an iridium complex bearing a ZhaoPhos ligand (L11b), thus obtaining P45 in excellent yields and enantioselectivities.
The same group recently reported the nickel-catalyzed AH of 2-oxazolones (S46) to afford 2-oxazolidinones in excellent yields and enantioselectivities (Scheme 36). 199 Interestingly, deuterium labeling experiments and DFT calculations were conducted to reveal the catalytic mechanism for this hydro-genation, which indicated an equilibrium between the enamine and its imine isomer, with the latter being the substrate of choice for the asymmetric 1,2-addition of Ni(II)-H.

N-Heteroatom-Substituted Imines
The hydrogenation of other N-heteroatom imines, such as hydrazones or oximes, remains a challenge. In 2015, Zhou and co-workers reported the enantioselective synthesis of cyclic and linear chiral trifluoromethyl-substituted hydrazines via the palladium-catalyzed AH of N-acyl and N-aryl hydrazones (S47 and S48, Scheme 37). 200 Currently, many compounds bearing a hydrazine moiety, such as atazanavir or azacastanospermine, show pharmacological activity. By using Pd/(S)-SegPhos L9b as a catalyst and TFA as an essential additive, chiral hydrazines P47 and P48 were obtained in excellent yields and up to 97% ee. A year later, the same authors reported that, by using the bulkier DTBM-SegPhos (L9c) as a chiral ligand, the palladium-Scheme 37. Palladium-Catalyzed AH of α-Aryl Hydrazones and α-Alkyl Hydrazones Scheme 38. Palladium-Catalyzed AH of Fluorinated Aromatic Pyrazol-5-ols via the CH-Tautomer Scheme 39. Sequential Palladium-Catalyzed AH/Hydrogenolysis of α-Hydrazono Phosphonates Chemical Reviews pubs.acs.org/CR Review catalyzed AH of α-alkyl hydrazones S49 proceeded smoothly, thus affording the corresponding fluorinated hydrazines P49 in excellent enantioselectivities (Scheme 37). 201 In addition, the same laboratory reported the palladiumcatalyzed AH of fluorinated aromatic pyrazol-5-ols S50 (Scheme 38). 202 The key for the success of this transformation is the Brønsted acid-promoted tautomerization, thus capturing the active form, followed by enantioselective hydrogenation. A wide variety of substituted pyrazolidinones P50 were synthesized with up to 95−96% ee using (S)-MeO-Biphep (L17a) as the chiral ligand.
In 2017, Beletskaya and co-workers reported a convenient one-pot procedure for the asymmetric synthesis of α-amino phosphonates, which are also important structural motifs in many bioactive compounds. Using a combination of Pd and biaryl chiral ligand L17b, the AH of α-hydrazono phosphonates S51 proceeded with high enantiocontrol. 203 Subsequent cleavage of the N−N bond after the addition of Pd/C and methanol into the crude reaction mixture afforded the optically active P51 (Scheme 39).
Alternatively, Schuster and co-workers described the ruthenium-catalyzed AH of hydrazones S54 using a Walphostype ligand L22b (Scheme 41). 206 The method allowed access to versatile chiral hydrazine building blocks P54 containing aryl, heteroaryl, cycloalkyl, and ester substituents, and the protocol was demonstrated on >150 g scale. The use of Rh complexes in the AH of hydrazones had been described early this decade, but with lower ee values. 207,208 The use of chiral Ir complexes in the AH of hydrazones was described by X. Zhang, using f-binaphane as the chiral ligand. Of note, they reported a direct catalytic asymmetric reductive amination of simple aromatic ketones with phenylhydrazide, thus offering an attractive route for the synthesis of chiral hydrazine-derived compounds. 209 In 2019, W. Zhang and co-workers disclosed, for the first time, the efficient cobalt-catalyzed AH of CN bonds. 210 Although the use of cobalt as an earth-abundant transition metal in AHs was first pioneered by Chirik, the scope was limited to CC or  211−213 Interestingly, the success of this reaction relies on the presence of an NHBz group (S55, Scheme 41), which acts as a directing group. The reactivity and enantioselectivity were further enhanced by assisted coordination to the cobalt atom and π−π nonbonding interactions between the phenyl groups on the substrates and the chiral diphosphine (S,S)-Ph-BPE L19. The resulting chiral nitrogencontaining compounds P55 were attained in high yields and excellent enantioselectivities (95−98% ee).
In 2020, Lefort and co-workers reported the first example of a regio-and enantioselective AH of a CN−NC motif. 214 As shown in Scheme 42, the prochiral benzodiazepine S56 was efficiently hydrogenated using a chiral catalyst based on Ir and a Walphos bisphosphine L22c. No undesired hydrogenation of the CN double bond in the 1,2-position was observed. Using the optimal conditions, the AH was performed on a kilogram scale leading to the production of P56, an intermediate of BET The AH of oximes and their derivatives remained a longstanding problem. To solve this gap in the field, X. Zhang and coworkers proposed the rhodium-catalyzed AH of oxime acetates S57 (Scheme 43). 215 Unexpectedly, the reaction led to the formation of chiral acetamide P57 as the major product, thus affording a new strategy for the straightforward synthesis of chiral acetamides from oxime derivatives. After an exhaustive screening of phosphine ligands, JosiPhos L21c was found to give the highest enantioselectivity (up to 91% ee). The main limitations of this approach are the moderate activity, as well as the low enantiocontrol, in the case of ortho-substituted groups on the aromatic ring.
The AH of N-hydroxy-α-imino phosphonates S58 was studied by Goulioukina et al. 216 using the Pd/BINAP (L24a) as catalytic system, first reported by Amii and co-workers. 217 The synthesis of chiral P58 was achieved in up to 90% ee (Scheme 43). The catalytic reaction was performed using a Brønsted acid (CSA) as an activator and TFE as solvent. However, the scope was limited to phenyl and para-substituted aromatic rings.
The selective reduction of an oxime to the corresponding chiral hydroxylamine derivative remains a challenge in this field because of undesired cleavage of the weak N−O bond. In this regard, in 2020, Cramer and co-workers described a methodology to overcome this limitation. He reported a robust cyclometalated Ir(III) complex C18 bearing a chiral cyclopentadienyl ligand as an efficient catalyst for this transformation (Scheme 44). 218 Using MsOH as activator, this acid-assisted AH of oximes S59 avoids overreduction of the N−O bond via CN reduction after substrate protonation, thus accessing valuable chiral N-alkoxy amines P59 in excellent yields and enantioselectivities.

Unprotected Imines
The transition metal-catalyzed AH of N-unprotected imines 64 has been widely pursued. X. Zhang's laboratory, in collaboration with Merck, developed the first efficient and atom-economic iridium-catalyzed AH of unprotected ketimines using HCl as Brønsted acid to activate the substrate. 219 Ketimine hydrochlorides S60 were efficiently hydrogenated using Ir/(S,S)-f-Binaphane L7, although in high catalyst loading (5 mol %). Later, in 2014, Wang, Anslyn, X. Zhang, and co-workers improved this transformation in terms of TON using Rh/ ZhaoPhos (L11a) as catalyst. Taking advantage of the anion binding interaction between the thiourea and chloride counter-ion, chiral amines P60a were afforded in high yields and enantioselectivities (Scheme 45). 220 The iridium-catalyzed AH of substituted benzophenone imines S60 was also efficiently conducted in X. Zhang's group. 221 Enantioenriched diarylmethylamines P60b were obtained using a monodentate phosphoramidite L26 and rather harsh reaction conditions (100 atm H 2 , Scheme 45). Substitution at the 2-position on the aryl group in S60 is essential to achieve good enantiocontrol.
It is worth mentioning that direct asymmetric reductive amination (ARA) has become an important branch of asymmetric hydrogenation. However, as stated in the Introduction, this topic is not covered here since it has been comprehensively reviewed very recently. 10−12

ASYMMETRIC HYDROGENATION OF ENAMIDES
In 1972, Kagan, Dang, and co-workers reported the first example of the AH of N-protected enamines, using the chiral ligand DIOP. 53 Although the enantioselectivity was only moderate, this work opened a door toward the enantioselective synthesis of chiral amines. Knowles, 222 Noyori, 223 and Burk 224 strongly contributed to the field by introducing DIPAMP, BINAP, and DuPhos ligands, respectively. Since then, many highly efficient Rh catalysts bearing chiral diphosphine ligands have been developed. In addition, at the beginning of the century, Reetz, Feringa, and Zhou's groups independently demonstrated that Rh complexes bearing monodentate phosphorus chiral ligands were also highly efficient catalysts. 225−227 The direct catalytic AH of enamides is, arguably, the method of choice for the synthesis of amino acids and chiral amines bearing a stereogenic center in the α or β position to the nitrogen atom.
3.1. Acyclic N-Acyl Enamines 3.1.1. Chiral Rh Catalysts. The presence of a coordinating group adjacent to the CC makes N-acyl enamines ideal substrates for rhodium-catalyzed AH, which very often induces very high enantioselectivity. 228 In contrast to imines, the use of iridium complexes in the AH of acyclic N-acyl enamines is uncommon. 229 Nevertheless, the chiral ligand makes a critical contribution to the achievement of high activity and selectivity. Consequently, the development of more efficient ligands for a range of catalytic processes is still a vital research topic. During the past decade, new families of chiral phosphines, 230 including monodentate phosphines, 231−234 bis(aminophosphine)-type ligands, 235−237 phosphino-phosphite (P-OP), 238−244 phosphino-phosphoramidite, 245−252 spiroketal 253,254 or supramoleculartype 255−259 biphosphines, and others, 260,261 have found widespread use in the rhodium-catalyzed AH of N-acyl enamines. 262 Scheme 45. Metal-Catalyzed AH of N-Unprotected Imines Chemical Reviews pubs.acs.org/CR Review Among these, the past decade has witnessed the development of P-stereogenic electron-rich alkyl phosphines as highly proficient ligands. 44,45,263−265 Figure 5 shows the most relevant Pstereogenic ligands used in the rhodium-catalyzed AH of benchmark enamides (Table 1). These chiral ligands have stood out from others in the AH of standard N-acylenamines such as methyl α-acetamidoacrylate (MAA, S61), (Z)-methyl a-acetamido-3-phenyl acrylate (Z-MAC, S62), β-dehydroamino acids (S63), 266 and N-(1-phenylvinyl)acetamide (PVA, S64).
In 2004, Hoge and co-workers established an important breakthrough in the field by preparing a C 1 -diphosphine with three-hindered quadrants (trichickenfootphosTCFP, L27). 267−269 This ligand showed very high enantioinduction for a wide variety of N-acyl enamines (S61−S64, Table 1).  However, TCFP is difficult to handle in air, which explains why it has received little attention in asymmetric catalysis. To overcome this limitation, Imamoto recently prepared a crystalline, air-stable analog of TCFP by replacing the tertbutyl groups in the nonstereogenic phosphorus atom for the bulkier 1-adamantyl (L28). 270 Its catalytic activity on the rhodium-catalyzed AH of enamides afforded excellent enantioselectivities for the substrates tested, including β-keto enamides (S65). 271 In 2010, Riera and Verdaguer's laboratory reported the first synthesis of optically pure, borane-protected primary and secondary aminophosphines. 272 These compounds were found to be valuable P-stereogenic building blocks for the preparation of new chiral aminodiphosphine ligands. The synthesis and catalytic evaluation of small-bite angle MaxPHOS ligand (L30) was first described. 273 Indeed, MaxPHOS is a nitrogen-containing analog of TCFP (L27). However, and in contrast to L27, the presence of an -NH-bridge between the two phosphine moieties allows the NH/PH tautomerism to take place. The protonation of MaxPHOS led to the stable PH form of the ligand, which turned into air-stable compounds both in the solid state and in solution. The complex Rh/L30 proved to be a highly enantioselective and robust system for the AH of a wide range of N-acyl enamines (Table 1). Later, a new class of Pstereogenic C 2 -symmetric ligands with a hydrazine backbone was also disclosed by Riera and Verdaguer. 274 L31, in particular, showed excellent catalytic performance in the rhodiumcatalyzed AH of several benchmark substrates (Table 1). C 2 -symmetric P-stereogenic ligands have been widely used in AH. Stephan's laboratory performed the rhodium-catalyzed AH of a wide spectrum of representative enamides using L32 and L33 (SMS-Phos) as chiral ligands. 275,276 Both catalytic systems showed excellent enantioselectivities (>99% ee for several model substrates; Table 1). The catalytic activity of the ligand was markedly affected by the nature of its aryl substituents in terms of both bulkiness and electronic properties. Of note, t-Bu-SMS-Phos L33 outperformed other reported ligands (Table 1), although the enantioselectivity dropped considerably when using tetrasubstituted vinyl acetamides. 277 In 2010, Tang designed and synthesized a novel family of chiral bisdihydrobenzooxaphosphole ligands (BIBOP, L34). 278,279 Their ease of preparation and excellent air stability make BIBOP a practical ligand. Moreover, it can also be highly modular by fine-tuning the substituents at the 4,4′-positions. The rhodium-catalyzed AH of various N-acyl enamines using BIBOP ligands was exploited, including in kilogram scale. 280 When using Rh/L34 in the AH of benchmark substrates, the corresponding chiral amines were attained in excellent enantioselectivities ( Table 1). The same group later developed a similar ligand named WingPhos (L35), and the introduction of 9-anthracenyl substituents conferred a deeper chiral pocket. 281 Other ligands were efficiently applied to the rhodium-catalyzed AH of (E)-β-aryl enamides, which is a class of substrates that remained underdeveloped. 282,283 More recently, a novel class of benzooxaphosphole ligands (BABIPhos, L36) has been reported. 284 The high catalytic performance of these ligands was showcased in rhodium-catalyzed AH, although for S63 the enantioselectivity achieved was lower than with BIBOP.
The use of P-stereogenic N-phosphine-phosphinite ligands is still rare. Recently, Dieguez's laboratory developed a family of these ligands (L37) that has been applied in rhodium-catalyzed AH. 285 By choosing the appropriate ligand for each substrate family, benchmark enamides were hydrogenated, giving excellent results (Table 1).
Between 1998 and 1999, Imamoto pioneered the use of the tert-butylmethylphosphine synthon in C 2 chiral diphosphines with the development of BisP* and MiniPHOS. 286−288 Afterward, he improved the ligand design by introducing this P-stereogenic synthon into many other ligands such as QuinoxP* (L18a), BenzP* (L4), and DioxyBenzP* (L29). 289−291 These conformationally rigid ligands are crystalline solids and, once coordinated to Rh, exhibited excellent enantioselectivities in the AH of a broad range of enamides and other functionalized alkenes (Table 1). L18a showed unbeatable enantioselectivities when acetamido acrylates and vinyl acetamides were used but gave poor conversion for the AH of βketo enamide S65. In contrast, L4 and L29 gave the best results reported to date with S65.
As an example of a synthetic application, Evano's group recently developed a short and modular total synthesis of Conulothiazole A in 7 steps and 30% overall yield. 292 One of the key steps was an efficient rhodium-catalyzed AH of a 2-enamidothiazole S66 (Scheme 46) using (S,S)-QuinoxP* L18a. The catalytic system was extended to a variety of 2-enamidoheteroarenes with excellent results (up to 99% ee), thus providing efficient access to 2-aminoethyl-arenes, which are useful building blocks in medicinal chemistry. Of note, the rhodium-catalyzed AH of acetamidoacrylates or vinylacetamides has been widely used as a powerful tool in total synthesis of natural products 293,294 and for the preparation of drugs and pharmacologically active compounds. 295−302 At the beginning of the decade, X. Zhang and co-workers reported the preparation of an electron-donating P-stereogenic biphospholane ligand (ZhangPhos, L38) for the rhodiumcatalyzed AH. 303,304 The group had also previously reported other P-stereogenic ligands with C 2 -symmetry, such as TangPhos (L2) 305,306 or DuanPhos (L39), 307,308 among others. 309 Compared to those, ZhangPhos is conformationally more rigid, and it achieved better or similar enantioselectivities (up to 99% ee, Table 1). Moreover, L38 exhibited extremely high reactivity (up to 50 000 TON) in the rhodium-catalyzed AH of a wide range of N-acyl enamines and had the advantage that both enantiomers can be prepared by asymmetric synthesis. Nevertheless, Rh-DuanPhos is a highly versatile catalytic system that was used in many other functionalized substrates. Wiest, Dong, and co-workers recently applied this chiral catalyst in the cascade hydrogenation of cyclic dehydropeptides controlled by catalyst−substrate recognition. 310 Previously, X. Zhang, Lv, and co-workers used this catalyst for the efficient AH of β-acetylamino vinylsulfides S67, 311 α-CF 3 -enamides S68, 312 α-dehydroamino ketones S69, 313,314 aliphatic dienamides S70 315 and S71, 316 and cyclic dienamides S72 (Scheme 47). 317 The resulting chiral amines were afforded in excellent yields and enantioselectivities. Furthermore, other challenging functionalized substrates, such as tetrasubstituted enamides, were hydrogenated in a highly enantioselective manner. In particular, the AH of α-acetoxy β-enamido esters S73 318 and βacetoxy α-enamido esters S74 319 for the preparation of syn amino alcohols was conducted using Rh/DuanPhos catalyst, achieving excellent results (Scheme 47). In 2015, the same group also reported the highly regio-and enantioselective synthesis of γ,δ-unsaturated amido esters P75 by AH of conjugated enamides using Rh/TangPhos-L2 (Scheme 48). 320 In addition, the AH of tetrasubstituted enamides in Z form was also accomplished by the same laboratory (Scheme 49). 321 However, in this case, Rh-DuanPhos-L39 gave poor conversion for S76. In contrast, JosiPhos ligand L21b afforded a set of anti β-amino alcohol derivatives P76 in excellent yields and enantioselectivities. Simultaneously, scientists at Merck reported a concise, enantio-and diastereoselective route to novel nonsymmetrically substituted N-protected β,β-diaryl-αamino acids and esters through the AH of tetrasubstituted enamides S77 (Scheme 49). 322 Again, JosiPhos ligands (L21d and L21e) allowed complete stereocontrol over the two vicinal stereogenic centers. Remarkably, an example of S77 was previously hydrogenated by Ramsden and co-workers for the asymmetric synthesis of an intermediate of denagliptin. 323 The rhodium-catalyzed AH of other tetrasubstituted enamides has also been investigated. A noteworthy example was the asymmetric synthesis of the cannabinoid-1 receptor inverse agonist taranabant, reported by a Merck team in 2009. 324 Another important transformation in this section is the rhodium-catalyzed AH of α-amino acrylonitriles S78, as it provides a concise route to the synthesis of chiral α-acylamino nitriles P78 (Scheme 50). These compounds are versatile synthetic intermediates, and they can be direct precursors of valuable α-amino acids. X. Zhang and co-workers recently reported that Rh-Me-DuPhos (L40a) is an efficient catalyst for this transformation, thus furnishing P78 in excellent yields and enantioselectivities. 325 Previously, the same group described the highly enantioselective rhodium-catalyzed AH of β-acylamino acrylonitriles S79 using TangPhos (L2) or QuinoxP* (L18a) as chiral ligands (Scheme 50). 326,327 Interestingly, in both cases, the hydrogenation of an E/Z mixture gave excellent enantioselectivities, thus making it unnecessary to isolate the substrate's isomers.
In 2019, W. Zhang and co-workers described a powerful strategy for the preparation of enantioenriched chiral α-amido aldehydes, which have many potential applications in organic synthesis and medicinal chemistry. Using a rhodium complex of a P-stereogenic biphosphine ligand ((R,R)-BenzP*, L4), αformyl enamides S80 were hydrogenated in a highly chemo-and enantioselective manner (up to >99.9% ee, Scheme 51). 328 Under different hydrogen pressures, the preparation of highly enantioenriched β-amido alcohols is also plausible. The method can be carried out on a gram scale, thus demonstrating its high efficiency and practicability. Although the AH of enamido esters, vinyl acetamides, or related compounds has received the most attention in the field, the AH of other α-and β-functionalized enamides constitutes a privileged methodology in the design of new pharmaceuticals and agrochemicals. In 2010, Mikami and co-workers described the enantioselective synthesis of α-(perfluoroalkyl)amines via the rhodium-catalyzed AH of enamides S81, which can be prepared by perfluoroalkylation of nitriles with Ti/Mgreagents. 329 By using ChiraPhos L41, acyclic perfluoroalkyl sec-amines were furnished with excellent enantioselectivities (Scheme 52). Also in 2010, Benhaim et al. reported the first enantioselective synthesis of β-trifluoromethyl α-amino acids using rhodium-catalyzed AH with TCFP (L27). 330 Another type of well-established chiral scaffold is β-amino phosphine derivatives. Hu and co-workers recently reported an unprecedented, catalytic AH of β-phosphorylated enamides S82 (Scheme 53). 331 The method used rhodium catalysis derived from an unsymmetrical hybrid chiral phosphine-phosphoramidite ligand (L42). A wide range of aromatic and alkylic enantioenriched β-acetamidophosphine oxides P82 were efficiently prepared. These compounds could be readily hydrolyzed and reduced, thus providing an efficient route to important chiral β-aminophosphines.
Optically active αand β-amino phosphonic acid derivatives can also be prepared by means of AH. In fact, in 2011, Ding designed a family of chiral monodentate phosphoramidite (DpenPhos) ligands that were found to be highly efficient in the rhodium-catalyzed AH of enamides S83 and S84 (Scheme 53). 332 Of note, when L43 was used, a set of chiral amino phosphonates P83 and P84 were prepared with excellent results. In several cases, the enantioselectivity values obtained were higher than those reported previously. 333,334 Organoboron compounds are also important due to their unique physical, chemical, and biological properties. However, the preparation of chiral α-aminoboronic acids, as mimics of chiral amino acids, is not trivial. In 2020, W. Zhang and X. Zhang independently pioneered this field describing the rhodiumcatalyzed AH of α-boryl enamides (S85) using the P-stereogenic diphosphines L4 and L39, respectively (Scheme 54). 335,336 Critical to the success of this method was the chelate coordination of the amido group to rhodium and the nonbonding interactions between the substrate and the ligand. Whereas by using L4 the method was limited to aryl substituents in the β position, the use of L39 allowed an expanded substrate scope, as alkyl substituents were also well tolerated. Chiral αamidoboronic esters P85 were furnished in quantitative conversion and excellent enantioselectivity. Exquisite chemoselectivity was observed as no protodeboronation was detected.
While the hydrogenative synthesis of chiral α-substituted amines has been widely addressed, synthetic methodologies for the preparation of β-chiral amines are rare. Only a few examples have been reported, mostly by AH of dehydroamino acids. 337,338 The AH of β-branched simple enamines remained a longstanding challenge due to the difficulties related to the stereocontrol of the reaction. To overcome this issue, in 2018, W. Zhang and co-workers disclosed the first catalytic protocol using a Rh complex bearing a diphosphine ligand with a large bite angle (SDP, L44). 339 β-Branched simple enamides with a (Z)-configuration (S86) were efficiently hydrogenated to optically pure β-chiral amines P86 in quantitative yields and with excellent enantioselectivities (Scheme 55).
3.1.2. Ni and Co Catalysts. The limited availability, high cost, and toxicity of noble metals stimulated the research in their replacement with earth-abundant, inexpensive first-row transition metals. However, challenges such as different reaction mechanism and unexpected deactivation of the catalyst prevented their widespread use in asymmetric hydrogenation. 340,341 While dozens of examples using Rh catalysis have been reported during the past decade, the use of earth-abundant transition metals has just started showing practical efficiency in AH. In 2020, W. Zhang and co-workers reported a highly efficient nickel-catalyzed AH of 2-amidoacrylates (Scheme 56). 342 In contrast to the AH with Rh catalysts, where the amido-assisted activation strategy allowed attainment of high activity and enantioselectivity, Ni catalysts cannot utilize this approach as they have their own coordination modes. However, W. Zhang envisioned that other interactions between the substrate and catalyst would lead to high catalytic activity. Interestingly, when using S87 bearing an ortho-methoxysubstituted benzoyl group and Ni/BIPHEP-type ligand (L17c), the AH occurred smoothly and the corresponding chiral α-amino acid esters P87 were afforded in excellent enantioselectivities (up to 96% ee).
Nickel-catalyzed AH has also been used in the synthesis of chiral β-amino acid derivatives. Lv and X. Zhang and co-workers reported a highly enantioselective hydrogenation of (Z)-β-(acylamino)acrylates S88 to provide enantiomerically pure βamino acid derivatives P88 using a commercially available binapine ligand (L45) (Scheme 57). 343 High enantioselectivities were obtained even using Z/E isomeric mixtures. The same catalytic system proved to be fruitful for many other functionalized enamides, including benchmark substrates. 344 In 2018, Lv and co-workers expanded its use for the Ni-catalyzed AH of βacetylamino vinylsuflones S89 (Scheme 57). 345 The methodology showed good compatibility with substituted (Z)-isomers and Z/E isomeric mixtures, thus being an alternative to the previously reported protocol using Rh/TangPHOS-L2. 346 The resulting chiral sulfones P89 were obtained in high yields and excellent enantioselectivities, in gram scale in the presence of only 0.2 mol % of catalyst. This catalyst also showed high activity toward the AH of β-acylamino nitroolefins S90. These are usually challenging substrates for AH due to the weak binding affinity of the olefins with the electron-withdrawing nitro group, and in fact, only a few examples have been reported involving precious transition metal catalysts. 347−349 Despite this, Chung, X. Zhang, and co-workers showed that Ni/Binapine could be used as catalyst to attain chiral β-amino nitroalkanes P90 with excellent enantioselectivity (>99% ee in the best cases) and high TONs using mild conditions (Scheme 57). 350 Finally, Lv also reported the AH of tetrasubstituted β-enamino-α-fluoro esters S91 in high yields and excellent diastereo-and enantioselectivities using Ni/L45 (Scheme 57). 351 Interestingly, key experiments revealed the critical role of acidic solvent in modulating the reaction pathway, as well as for the control of Scheme 55. Enantioselective Synthesis of β-Stereogenic Amines via AH Chemical Reviews pubs.acs.org/CR Review diastereoselectivity. This method provides a highly straightforward and concise route to α-fluoro-β-amino esters P91. 352 Cobalt has also gained great importance during the past decade in the field of AH. Chirik's laboratory has pioneered the use of cobalt complexes bearing chiral diphosphines to attain hydrogenative processes with extraordinary activity and enantioselectivity. 353,354 In 2019, the group demonstrated that cobalt complexes bearing DuPhos-type ligand (L40b) efficiently hydrogenated MAA S61 in excellent enantioselectivity (Scheme 58). 355 More importantly, the reaction was carried out using MeOH, an industrially preferred green solvent which is often a poison for reduced earth-abundant metals, and without the use of additives. Other α,β-unsaturated carboxylic acids, including di-, tri-, and tetra-substituted acrylic acid derivatives, as well as dehydro-α-amino acid derivatives, were hydrogenated using Co/BenzP*-L4 (Scheme 58). 356 Chiral carboxylic acids, including bioactive ones such as Naproxen, (S)-Flurbiprofen, and a D-DOPA precursor P92, were attained in high yields and enantioselectivities. Again, protic solvents such as MeOH were identified as optimal, and Zn dust was used stoichiometrically. The group had previously described the Co-catalyzed AH of enamides using zinc-activation, which promoted straightfroward single-electron reduction to enable the catalytic process (Scheme 58). 357 The optimized protocol, using Co/L19, exhibited high activity and enantioselectivity and allowed the asymmetric synthesis of the epilepsy drug levetiracetam (P93) at 200-g scale with only 0.08 mol % of catalyst loading.

Endocyclic N-Acyl Enamides
In contrast to acyclic enamides, which have been extensively studied, the AH of cyclic enamides remained a challenge before the past decade. Despite that, the resulting chiral cyclic amines are very useful structural motifs that can be found in a range of bioactive molecules. 358 An example of this class of substrates are cyclic α-dehydro amino ketones (S94, Scheme 59). In 2016, W. Zhang and co-workers reported that P-stereogenic chiral ligand L18b, using Rh catalysis, efficiently hydrogenated S94 to chiral Scheme 56. Nickel-Catalyzed AH of 2-Amidoacrylates Scheme 57. AH of β-Functionalized N-Acyl Enamines Using the Ni/Binapine System Chemical Reviews pubs.acs.org/CR Review cyclic trans-β-amino alcohols P94a via a one-pot sequential AH with excellent enantioselectivities and diastereoselectivities. 359 The same group achieved rhodium-catalyzed partial hydrogenation using small-bite angle ligand TFCP (L27) in a completely chemoselective manner (Scheme 59). 360 Thus, chiral α-amino ketones P94b were exclusively obtained with excellent results, and both synthetic protocols were scaled up to gram scale. In contrast, the AH of cyclic β-keto enamides remains unexplored, with only one precedent in the literature and with very limited scope. 361 Another family of long-standing challenging substrates are cyclic enamides derived from tetralones and chromanones. The resulting chiral amines are highly desirable as they are precursors of therapeutic drugs. In this regard, the AH of cyclic enamides has typically relied on the use of Rh and Ru catalysts. 362 −365 Among the most successful examples, Ratovelomanana-Vidal and co-workers reported up to 96% ee in the reduction of S95 (Scheme 60). The method employed Ru catalysis in combination with binap-type ligand SynPhos L46. 366,367 Later, Tang and co-workers described the use of WingPHOS ligand (L35) in the rhodium-catalyzed AH of cylic enamides S95, which yielded the corresponding chiral amines P95 in up to 98% ee (Scheme 60). 281 However, these methods suffer from harsh reactions conditions such as high H 2 pressure or heating. In this regard, iridium catalysis, which has scarcely been used in the AH of Nacyl enamides and other alkenes bearing a metal-coordinating group, offered an excellent alternative. In 2016, Verdaguer, Riera, and co-workers reported the highly enantioselective iridium-catalyzed AH of cyclic enamides S95 and S96, derived from αand β-tetralones (Scheme 60). 77 They optimized the iridium complexes bearing P-stereogenic phosphino-oxazoline ligands (C6a or C6b). These catalytic systems provided the highest selectivity reported to date for the reduction of these substrates. The resulting chiral amines P95 and P96 were obtained in 99% ee. Moreover, the process was carried out in environmentally friendly solvents such as MeOH and EtOAc without loss of selectivity and under very mild conditions (3 bar of H 2 ). When the ligand was replaced with a P-stereogenic phosphino-imidazole ligand, the enantioselectivity decreased considerably. 368 Dieǵuez and co-workers also reported the iridium-catalyzed AH of cyclic enamides S95 and S96 in  369,370 The same group further extended this methodology using other modular ligands. 371−374 Overall, these protocols allowed an efficient route to the asymmetric synthesis of 2-aminotetralines and 3-aminochromanes, key structural units in many biologically active agents such as rotigotine, terutroban, and nepicastat ( Figure 6). 375,376 The AH of tetrasubstituted endocyclic enamides 29 has been a focus of great attention over the last years. The resulting chiral cyclic amines with a substitution at the 2-position are important motifs in many bioactive molecules and drugs (Figure 7).
In 2017, Lv, X. Zhang, and co-workers developed a highly enantioselective hydrogenation of cyclic N-acyl enamines S97 to provide optically pure cycloalkyl amides P97a using Rh-Binapine (L45) as catalyst (Scheme 61). 377 The resulting chiral amides had an aryl substituent in the vicinal position. The methodology could be applied to prepare biologically active compounds. More recently, in 2019, Tang, in collaboration with a team from Pfizer, demonstrated that an electron-rich Pstereogenic bisphosphorus ligand with deep chiral pockets (ArcPHOS, L48) could be applied to the rhodium-catalyzed AH of S97 bearing alkyl substituents at the 2-position (Scheme 61). 378 Consequently, chiral amides P97b were attained in excellent yields and enantioselectivities. The methodology was showcased by a concise synthesis of Tofacitinib (Figure 7). Previously, Stumpf and co-workers reported a multikilogram scale asymmetric synthesis of the enantiomerically pure fluoropiperidine P97c via AH using a Ru/JosiPhos (L21a) catalyst with high enantiomeric excesses (Scheme 61). 379 This fluorinated aminopiperidene is also present as a structural motif in the antibacterial clinical candidate AZD9742. In fact, researchers at AstraZeneca have recently reported its enantioselective synthesis by means of AH using [((S)-BINAP)RuCl 2 ](p-cymene). 380 Chiral cyclic β-amino acids, 381 such as cispentacin (Figure 7), are important in the synthesis of β-peptides. In 2003, X. Zhang and co-workers pioneered the AH of tetrasubstituted cyclic β-(acylamino)acrylates using the chiral biaryl ligand C 3 -TunaPhos. 382 Following this path, Zhou's group hydrogenated tetrasubstituted cyclic β-(arylsulfonamido)acrylates. Using Pd/ DuanPhos-L39 as catalyst, a range of five-membered chiral βamino acid derivatives P97d were obtained in excellent yields and enantiomeric excesses (Scheme 61). 383 More recently, the Scheme 60. Metal-Catalyzed AH of Cyclic Enamides Derived from αand β-Tetralones  Chemical Reviews pubs.acs.org/CR Review same group described the asymmetric hydrogenation of carbocyclic aromatic amines using a ruthenium-DuPhos (L40b) complex as catalyst. 384

N-Sulfonyl Enamines
Little attention has been devoted to the AH of N-sulfonyl enamines, and only a few examples can be found in the literature. 385,386 Following the latter example (P97d, Scheme 61), the enantioselective synthesis of chiral amino acids via AH of noncyclic αand β-(arylsulfonamido)acrylates is of great importance. In 2005, a team from Merck published the synthesis of an anthrax lethal factor inhibitor via ruthenium-catalyzed AH of S98 (Scheme 62). 387 Catalyst screening identified that JosiPhos L21d and the bis-thiophene atropoisomeric ligand L49 gave excellent enantioselectivities. Later, in 2016, Sato, Saito, and co-workers reported nickel-promoted regioselective carbox-ylation of internal enamides to afford a range of α-substituted βaminoacrylates S99. These were then subjected to the rhodiumcatalyzed AH using Walphos ligand L22d. Chiral amino acid derivatives P99 were furnished in a highly enantioselective manner (Scheme 62). 388 On the other hand, the AH of cyclic Nsulfonyl enamines is rare. To the best of our knowledge, there is only one example in the literature, reported by Andersson's group, using iridium complexes bearing chiral P,N ligands. 389 However, the method was hampered by low conversions and moderate enantioselectivities with a very narrow scope.

Other Enamides
The AH of N-phthaloyl enamides is a promising method for the preparation of chiral amines. Apart from serving as a directing group, the phthalimido functionality can be easily removed under mild conditions. In 2006, X. Zhang and co-workers Chemical Reviews pubs.acs.org/CR Review reported the highly enantioselective hydrogenation of α-aryl Nphthaloyl enamides using rhodium catalysts derived from TangPhos (L2) (Scheme 63). 390 The resulting chiral α-methyl, aryl N-phthalimides P100 were generally obtained in excellent enantioselectivities, but these dramatically decreased for substrates bearing an ortho-substituent on the aromatic ring. In contrast, the preparation of enantioenriched α-methyl, alkyl N-phthalimides using AH has not yet been explored. Later, the authors reported the use of the same chiral ligand L2 in the rhodium-catalyzed AH of N-phthaloyl dehydroamino acid esters, thus affording highly valuable chiral αor β-amino acid derivatives with good to excellent enantioselectivities. 391 The rhodium-catalyzed AH of heterocyclic β-aminoacrylates S101 was accomplished by Gallagher and co-workers in 2016 (Scheme 64). 392 By using WalPhos L22d as a chiral ligand, several pyrrolidine and piperidone variants were efficiently hydrogenated, providing chiral heterocyclic amino acids P101 with high enantioselectivity. The use of the carboxylic acid was essential for the success of the reaction. Similarly, the AH of β,γunsaturated γ-lactams was described by Liu, W. Zhang, and coworkers, although the hydrogenation proceeded via Nacyliminium cations. 196 On the other hand, Ding, Han, and co-workers recently described the double asymmetric hydrogenation of 3,4dialkylidene-2,5-diketopiperazines using an iridium-SpinPhox (C4) complex as catalyst. 393 The enantioselective synthesis of chiral 2-oxazolidinones, widely used as Evans' chiral auxiliaries, has attracted considerable attention for the construction of new chiral building blocks and the development of new asymmetric transformations. An alternative to the conventional approach, limited to easily accessible chiral β-amino alcohols, is the direct AH of 2-oxazolones. In this regard, in 2018, Glorius and coworkers reported an innovative protocol for the rutheniumcatalyzed AH of S102 using L50 as precursor of the NHC ligand (Scheme 65). 394 A variety of chiral 2-oxazolidinones P102 were obtained in excellent enantioselectivities (up to 96% ee). The formal synthesis of (−)-aurantioclavine was demonstrated as a synthetic application. X. Zhang's group previously reported the rhodium-catalyzed AH version of this transformation using TangPhos L2, albeit with moderate enantioselectivities and restricted mainly to substrates bearing electron-donating groups on the aryl ring. 395

ASYMMETRIC HYDROGENATION OF ENAMINES
Although great progress has been made in the transition metalcatalyzed asymmetric hydrogenation of N-protected enamides, the introduction and removal of the protecting group reduce the overall efficiency of the method and limit its applications in the synthesis of optically active amines. To overcome this drawback, significant efforts have been devoted to the development of new chiral catalysts for the direct AH of enamines, including N-alkyl, N-aryl, or unprotected amines. 40 . This protocol allowed the hydrogenation of both endocyclic 398 (S104) and exocyclic 399 (S105) enamines in excellent enantioselectivities under very mild conditions (1 bar of H 2 and RT). Pfaltz also contributed to the field using phosphino-oxazoline ligands for the iridium-catalyzed AH of S103-type substrates, albeit with lower ee values. 400 In 2009, a team from Merck applied the direct AH of alkylated enamines to the synthesis of an HIV integrase inhibitor (Scheme 67). 401 Using Rh and a JosiPhos ligand (L21e), a mixture of imine/enamine S106 was efficiently hydrogenated, affording P106, a direct precursor of the target drug, in 90% ee. Interestingly, a deuterium labeling study suggested that the AH proceeds predominantly via the enamine tautomer.

N-Aryl Enamines
The enantioselective synthesis of N-aryl β-enamino esters was first studied in 2005, when X. Zhang and co-workers developed an enantioselective strategy based on the rhodium-catalyzed AH of N-aryl enamines S107 (Scheme 68). 402 Chiral N-arylsubstituted β-amino acid derivatives P107a were obtained in moderate to excellent enantioselectivities (79−96% ee) using a P-stereogenic ligand (TangPhos, L2). However, the reaction was highly substrate-dependent, and S107 bearing a CF 3 as high electron-withdrawing group showed poor conversion. To overcome this limitation, Peng recently reported an alternative approach using Pd/L19 as catalyst. 403 Chiral β-fluoroalkyl βamino acid derivatives P107b were obtained in good yields and excellent enantioselectivites (Scheme 68). The use of p-anisic acid, which can promote the tautomeric transformation between imines and enamines, enhanced both the activity and enantioselectivity. The authors speculated that the hydro- In 2009, Zhou and co-workers described the first highly enantioselective AH of exocyclic unprotected enamines S108 by using Ir/(S)-L17a/I 2 as catalytic system (Scheme 69). 404 The resulting chiral amines P108 were afforded in excellent yields and up to 96% ee.

Unprotected Enamines
The AH of unprotected enamines has scarcely been studied because the transition metal catalyst is usually poisoned by the nucleophilic amino group. However, the direct AH of these substrates is highly desirable to avoid redundant introduction and subsequent removal of protecting groups and also for the preparation of pharmacologically relevant compounds. In 2004, a team from Merck reported the first example of catalytic AH of unprotected β-enamine esters and amides (S109), using Rh-JosiPhos complexes as catalysts (Scheme 70). 405 Ligand L21d gave the best results in the AH of enamine esters, while L21a gave the highest rates and enantioselectivities for the AH of enamine amides. β-Amino acids derivatives P109a were attained in excellent yields and enantioselectivities, thus proving that the N-acyl group is not always a prerequisite for such transformations.
The applicability of this protocol in late-stage functionalization was showcased by the asymmetric synthesis of Sitagliptin (P110, Scheme 71), which was implemented on a manufacturing scale. 58 P110 was obtained in 98% yield and 95% ee (improved to >99% ee by recrystallization) using (R C ,R p )-L21a. More recently, Chikkali and co-workers reported that Rh complexes bearing chiral FerroLANE ligands also catalyze the AH of S110 to yield sitagliptin with excellent enantioselectivity (98% ee). 406 The asymmetric synthesis of P110 was also accomplished via direct asymmetric reductive amination (ARA) with unprecedented levels of asymmetric induction. 407 In addition, Ru catalysis has been successfully applied in both ARA or direct AH of unprotected enamines for the preparation of other pharmacologically relevant compounds. 408,409 The rhodium-catalyzed AH of unprotected β-enamine phosphonates was described by Dong, X. Zhang, and coworkers (Scheme 70). 410 By using Rh/TaniaPhos-L52, the method provided an efficient route to free β-amino phosphonates P109b, which are important intermediates in biochemistry and pharmaceuticals. This work provided an alternative to the protocol previously reported by Ding, in which the amine was necessarily protected by acyl groups (Scheme 53). 332 Also, Ruchelman et al. reported the enantioselective hydrogenation of unprotected β-aminosulfones using Rh catalysis, which afforded a key intermediate of the phosphodiesterase 4 (PDE4) inhibitor Apremilast. 411 Iridium catalysis has also been applied in the AH of unprotected enamines. X. Zhang demonstrated that β-enamine hydrochloride esters S111 can be suitable substrates for AH, despite the fact that primary amines might have a strong inhibitory effect on the iridium catalyst. 412 The combination of Ir/f-binaphane (L7) and the use of hydrochlorides provided direct access to a range of enantiomerically enriched β-amino acids without use of an amino protecting group (Scheme 72).

ASYMMETRIC HYDROGENATION OF ALLYL AMINES
The AH of allyl amines remained relatively underdeveloped before the past decade. Allyl amines are usually considered minimally functionalized olefins as the unsaturated bond lacks close coordinating groups. For this reason, the AH of allyl amines is more challenging if compared to imines or enamines. In the early past decade, a range of new strategies were described for the metal-catalyzed AH of allyl amines, exhibiting high reactivity and enantiocontrol. Thus, the preparation of highly valuable βand γ-substituted chiral amines is now more accessible. In this section, the most important precedents in the field will be described, along with pharmaceuticals and drugs that can be attained by means of the AH of allyl amines ( Figure  8).

N-Phthaloyl Allyl Amines
As previously stated, chiral βand γ-amino acids and their derivatives are important building blocks in the synthesis of pharmaceuticals and other bioactive compounds. Zheng and coworkers reported the first highly enantioselective synthesis of chiral β-aryl-γ-amino acid ester derivatives P112 via rhodiumcatalyzed AH of γ-phthalimido-substituted acrylates 413 using the BoPhoz-type ligand 414,415 L53a (Scheme 73). The method showed high reactivity and enantioselectivity (up to 97% ee) for a range of (Z)-substrates S112. The method was successfully applied to the synthesis of several chiral pharmaceuticals including (R)-rolipram and (R)-baclofen ( Figure 8) with high enantioselectivities. The same group later expanded the applicability of this approach to the asymmetric synthesis of β 2 -amino acids P113 via rhodium-catalyzed AH using another ligand of the BoPhoz family: L53b (Scheme 73). 416 Interestingly, the presence of an N−H proton in the ligand significantly improved the enantioselectivity, whereas the introduction of a P-stereogenic center in the phosphino moiety proved unfruitful and displayed low conversion. The same catalytic system also exhibited excellent ee values for β-Scheme 72. Iridium-Catalyzed AH of β-Enamine Hydrochloride Esters Figure 8. Representative drugs that can be prepared via the AH of allyl amines.
Chemical Reviews pubs.acs.org/CR Review unsubstituted substrates S113 (99% ee). Other protocols for the stereoselective synthesis of chiral β 2 -amino acids include the rhodium-catalyzed AH of β-substituted α-aminomethyl acrylates that Borner and co-workers 417,418 and Qiu and coworkers 419,420 independently reported in this earlier past decade. Chiral amines bearing a β-methyl stereogenic center are extremely interesting as they are present in numerous drugs and pharmaceuticals. The AH of 2-substituted allyl phthalimides is an efficient route toward their preparation. X. Zhang pioneered the field with the ruthenium-catalyzed AH of terminal disubtituted allylphthalimides S114 using C 3 -TunePhos ligand L5b (Scheme 74). 421 Chiral β-alkyl-β-methyl amines P114a were attained in excellent yields and enantioselectivities. However, the scope of this reaction was limited to alkyl substituents, as the hydrogenation of an aromatic substrate gave moderate enantioselectivity. To overcome this limitation, Verdaguer and Riera's laboratory recently reported the highly enantioselective hydrogenation of 2-aryl allyl phthalimides using iridium catalysis (Scheme 74). 422 Ir-MaxPHOX C6b bearing a bulky substituent on the oxazoline ring gave the best enantioselectivities (>99% ee in the best cases for P114b), showing an exquisite functional group tolerance for a range of substrates. Several direct synthetic applications of this catalytic method were disclosed, such as the formal synthesis of (R)-Lorcaserin (Figure 1), which is a marketed anorectic drug, and

N-Sulfonyl Allyl Amines
Verdaguer and Riera's group also reported the iridium-catalyzed AH of N-sulfonyl allyl amines S115, 423 which can be easily prepared by the iridium-catalyzed isomerization of N-tosylaziridines. 424 By using the commercially available iridium catalyst UbaPHOX (C19), first reported by Pfaltz, 425,426 a wide range of chiral β-methyl amines were afforded with good to excellent enantioselectivities (Scheme 75). These compounds are also key intermediates for the preparation of allosteric modulators of AMPA receptor such as LY-404187 ( Figure 8). 427 Iridium complexes bearing chiral P,N ligands were also applied to the catalytic hydrogenation of cyclic N-sulfonyl allyl amines S116, as reported by Andersson and co-workers. 428,389 The reaction was highly substrate-dependent, and an appropriate chiral ligand was used for each case. Substrates S116 bearing aliphatic substituents were efficiently hydrogenated using a phosphino-oxazoline ligand L54 whereas phosphinoimidazole L55 and phosphino-thiazole L56 gave excellent activities and selectivities for aromatic substrates, depending on their electronic properties (Scheme 76). In addition, the methodology was further expanded to the iridium-catalyzed AH of fiveand seven-membered N-heterocyclic olefins. The chiral pyrrolidines, piperidines, and azepanes, which are highly valuable motifs for the synthesis of medicinal compounds and natural products, were attained in excellent enantioselectivities.

Other Allyl Amines
During the past decade, other remarkable examples have also been reported for the highly enantioselective hydrogenation of protected allyl amines. In 2010, a team from Merck described a general method for the ruthenium-catalyzed AH of trisubstituted N-acyl allyl amines S118 using the axially chiral ligand L49, affording chiral β-substituted amines P118 with excellent enantioselectivities (Scheme 77). 430 Optically active amines with remote stereocenters, such as γsubstituted chiral amines, are often key contributors to the potent biological activity of many natural products and pharmaceuticals. Important examples of this class of compounds are dexbrompheniramine, which is an antihistaminic, and tolterodine, an anticholinergic ( Figure 1). γ-Amino acids such as γ-aminobutyric acid (GABA) are also important in medicinal chemistry. Consequently, asymmetric synthesis of chiral derivatives of GABA with appropriate side chains is potentially important for the design of new drug-like molecules with enhanced pharmacological properties. Nevertheless, the direct preparation of γ-substituted chiral amines remains underdeveloped compared to the well-established methods for Scheme 76. Iridium-Catalyzed AH of Cyclic N-Sulfonyl Allyl Amines Scheme 77. Ruthenium-Catalyzed AH of N-Acyl Allyl Amines Chemical Reviews pubs.acs.org/CR Review constructing αand β-substituted chiral amines. In addition, most of the enantioselective syntheses of these compounds are indirect and often require multiple steps. Buchwald's group first reported a direct approach to γ-chiral amines by enantioselective CuH-catalyzed reductive relay hydroamination. 431 Hull and coworkers developed efficient conditions for the highly enantioselective synthesis of γ-branched amines via rhodium-catalyzed reductive amination. 432 Alternatively, the redox neutral asymmetric isomerization of allylic amines is a method of choice with an excellent atom economy, although current methods are hampered by very limited substrate scope. 17,433 In this scenario, the development of new transition metal-catalyzed AH processes to afford enantioenriched γ-substituted amines is extremely desirable. In 2011, Burgess and co-workers reported the asymmetric synthesis of α-methyl-γ-amino acid derivatives via catalytic AH using a carbene−oxazoline iridium complex C20 (Scheme 78). 434 The method of optimization was based on varying peripheral aspects of the substrate rather than optimizing the catalyst via ligand modifications. Following this approach, O-TBDPS-protected allylic substrates gave the best results. Once hydrogenated under mild conditions, chiral γmethyl amines were afforded in high stereocontrol. Antiproducts P119 were formed from the Z-alkenes S119, while the E-isomers S120 gave syn-target compounds P120.
Similarly, Beller and co-workers recently used C21, an iridium-P,N-ligand complex, for the AH of N-acyl endocyclic allyl amines S121 (Scheme 79). 435 Using HFIP as reaction solvent, the reaction proceeded efficiently to afford chiral γmethyl amide P121, which is a key intermediate for the preparation of a common agrochemical building block.
Another type of endocyclic allyl amines, amino acids S122, were hydrogenated by Zhou and co-workers using iridium complexes of P,N-ligands with a spiro backbone (C3c and C3d) (Scheme 80). 436 In particular, C3c was chosen as the best catalyst for N-Boc allyl amines, while C3d was used for N-Me and unprotected allyl amines. The resulting chiral heterocyclic Chemical Reviews pubs.acs.org/CR Review acids P122 were afforded in excellent enantioselectivities, and the potential utility was demonstrated by the concise asymmetric synthesis of (R)-nipecotic acid and (R)-tiagabine ( Figure 8). In fact, chiral cyclic amines with a β-carboxylic acid or derivatives are common structural motifs in many bioactive compounds. For example, the key intermediate for the preparation of a histone deacetylase inhibitor (HDAC, Scheme 81) was obtained via the ruthenium-catalyzed AH of S123 using L17d. 437 This achievement was reported by a team from Roche in 2014. They disclosed that the presence of a carboxylic acid was crucial for the rapid hydrogenation of the unsaturated bond. Chiral γ-lactams are ubiquitous in biological compounds. The antiepilepsy drug Brivaracetam and the PDE-4 inhibitor Rolipram are examples of γ-lactam clinical drugs (Figure 8). These lactams are key building blocks in medicinal chemistry as masked γ-amino acids. In their efforts to prepare γ-lactams in optically pure form, Yin, X. Zhang, and co-workers recently developed the AH of S124 using Rh/ZhaoPhos-L11a (Scheme 82). 438 A wide range of enantioenriched γ-lactams P124 were furnished in excellent yields and enantioselectivities. Interestingly, the catalytic system successfully tolerated a free NH amide group which actually played a positive effect by hydrogen bonding with the thiourea motif of L11a.
Another important drug with a chiral center in the γ-position of the amino group is ramelteon, a selective melatonin MT1/ MT2 receptor agonist. Yamashita's laboratory reported that Rh/ JosiPhos-L21e was a highly effective catalyst for the AH of a key precursor, the unprotected allyl amine S125 (Scheme 83). 439 Interestingly, the primary amino group might act as an Chemical Reviews pubs.acs.org/CR Review anchoring group to the rhodium atom. Chiral amine P125 was smoothly prepared in 92% ee using very mild conditions. Finally, Huang, Geng, Chang, and co-workers recently reported a practical combination of AH and reductive amination in the enantioselective synthesis of the chiral β-aryl amines P126 (Scheme 84). Starting from readily available anilines and α,βunsaturated aldehydes S126, they described a one-pot hydrogenation that involved DRA and AH, using Rh/L9b complex as catalyst. 440 Control experiments revealed that the construction of the C−N bond beforehand helped to pave the way for the subsequent AH of the corresponding N-allyl amine.

ASYMMETRIC HYDROGENATION OF HETEROAROMATIC COMPOUNDS
The direct AH of heteroaromatic compounds provides straightforward access to the corresponding chiral saturated Ncyclic skeletons. This is a less explored area than the AH of prochiral unsaturated amines such as imines or enamides. [30][31][32]441 This may be ascribed to several reasons: (a) the possible deactivation of the chiral catalysts due to the basicity of the nitrogen atom of the aromatic ring; (b) the lack of a coordinating group in simple aromatic compounds; and (c) the increased stability due to the aromaticity of these compounds, which might require harsher conditions. Despite all these issues, remarkable advances have been disclosed during the past Chemical Reviews pubs.acs.org/CR Review decade. In this section, we will review these advances along with the pioneering works and research milestones in this field, focusing mainly on heteroarenes such as quinolines, pyridines, quinoxalines, and indoles.

Quinolines and Derivatives
Optically pure tetrahydroquinolines (THQs) and their derivatives are of great importance due to their pharmaceutical and agrochemical applications, 442 as they are basic units in many natural products. Among the different strategies for their preparation, the AH of quinolines is the most effective. 443 In 2011, Fan, Yu, Chan, and co-workers reported the AH of a wide range of quinoline derivatives (S127) catalyzed by chiral cationic η 6 -arene Ru(II)-diamine complexes (Scheme 85). 444 Interestingly, for 2-alkylquinolines, C22 exhibited outstanding enantioselectivity as P127a (R = alkyl) were attained in excellent enantioselectivities (99% ee for most of the cases). To the best of our knowledge, this is the protocol with the highest level of enantioselectivity for 2-alkyl-substituted quinolines S127a. In contrast, the AH of 2,3-dialkyl quinolines S127b provided a very low ratio of diastereoselectivity. The same authors reported that similar Ru-diamine complexes were capable of efficiently hydrogenating S127a in solvent-free conditions, 445 in neat water, 446 in ionic liquids, 447,448 and in oligo(ethylene glycol)s through host−guest interactions. 449 On the other hand, the AH of 2-aryl-substituted quinolines was more challenging, and only a few examples have been reported. The same group extended the use of these Ru(II)−diamine complexes and found that C14h was a highly active catalyst for the AH of 2-aryl quinolines, affording the corresponding P127a (R = aryl) in excellent yields and enantioselectivities (Scheme 85). 444 Previously, Fan, Xu, and co-workers had already disclosed that air-stable and phosphine-free iridium complexes were also efficient catalysts for the highly enantioselective hydrogenation of quinoline derivatives. 450 Y.-G. Zhou's laboratory reported other important achievements in the field. In 2003, they pioneered the use of iridium complexes bearing axially chiral phosphines that, in combination with I 2 , were found to be highly active in the AH of 2-alkyl quinolines (Scheme 85). 451 In particular, and when using L17a, P127 were obtained in excellent yields and enantioselectivities (up to 96% ee). Using the same catalytic system, the substrate scope was further expanded to a wide range of 2-functionalized quinoline derivatives. 452−457 More importantly, 2,3-dialkylquinolines were also efficiently hydrogenated using the same catalyst, although P127b were furnished from moderate to good enantioselectivities (up to 86% ee). Zhou's group later reported the iridium-catalyzed AH of quinolines activated by Brønsted acids, thus avoiding catalyst activation using I 2 . 458 The highly enantioselective and catalytic hydrogenation of 3alkyl-2-arylquinolines remained a challenging task until 2019, when Hu and co-workers examined the use of structurally finetuned phosphine-phosphoramidite L1-type ligands (Scheme 85). 459 Using L1b as a chiral ligand, a highly diastereo-and enantioselective iridium-catalyzed AH of unfunctionalized 3alkyl-2-arylquinolines was disclosed. The transformation displayed broad functional group tolerance, thus furnishing a wide range of 2,3-disubstituted tetrahydroquinolines P127b in up to 96% ee and with perfect cis-diastereoselectivity. In contrast, the AH of 2,3-diaryl quinolines remains unsolved. In general, the AH of 2,3-disubstituted quinolines represents a more difficult task due to the requirement of diastereocontrol in the construction of two vicinal stereogenic centers. Nevertheless, the AH of functionalized 2,3-disubstituted quinolines with a phthaloyl 460,461 or an ester 462 group at the 3-position and an alkyl group at the 2-position of quinoline has been accomplished.
The chemistry of chiral vicinal diamines and their derivatives has attracted a great deal of interest because they are key substructures in many biologically active compounds. In 2016, Fan and co-workers reported the highly enantioselective synthesis of vicinal diamines by direct AH of 2,2′-bisquinolines S128 (Scheme 86). 463 Using the Ru/diamine complex C14i, the reaction proceeded with very good diastereoselectivity while reaching an unprecedented level of enantioselectivity (>99% ee in the best cases). The resulting chiral vicinal diamines P128 can be used as new chiral ligands. Similarly, the same group later described the use of Ru-complex C22 for the AH of 2-(pyridine-2-yl)quinoline derivatives S129 (Scheme 86). 118 Based on the resulting chiral scaffolds P129, a small library of tunable chiral pyridine-aminophosphine ligands were readily prepared.
In addition, the enantioselective hydrogenation of 2,6bis(quinolinyl) pyridines (PyBQs) or terpyridine-type Nheteroarenes S130 was successfully developed in 2020 by Fan's group using Ru(diamine) complex C14j as catalyst Scheme 86. Ruthenium-Catalyzed AH of 2,2′-Bisquinoline Derivatives Chemical Reviews pubs.acs.org/CR Review (Scheme 87). 464 The method provided partially reduced chiral pyridine-amine-type products P130 in high yields with excellent diastereo-and enantioselectivity, which can serve as a new class of chiral nitrogen-donor ligands. The AH of quinolines using a non-noble metal was also accomplished by Lan, Liu, and co-workers in 2020. Using a chiral pincer manganese catalyst, the AH of quinolines S127a was achieved in high yields and enantioselectivities (up to 97% ee, Scheme 88). 465 Interestingly, an effective π−π interaction between the CN double bond and the imidazole ring of the ligand L58 ensured precise regulation of the enantioselectivity. Undoubtedly, this represents an important precedent for the efficient AH of N-heteroaromatics without the need for precious metals.
Although the catalytic AH of quinolines is the most direct and reliable approach, Mashima, Ratovelomanana-Vidal, Ohsima, and co-workers reported the AH of quinolinium salts using cationic Ir(III) halide complexes with difluorphos (L20). 466 This catalyst system successfully converted both 2-aryl-and 2alkyl-quinolinium salts to the corresponding THQs with excellent enantioselectivities (up to 95% ee). The AH of quinolinium salts has also been applied as the key step for the synthesis of vabicaserin. 467 The asymmetric synthesis of THQs using tandem processes involving hydrogenation has been thoroughly explored in recent years. In 2019, Fan, He, and co-workers reported a novel strategy for the synthesis of chiral vicinal diamines based on a consecutive Ir-or Ru-catalyzed tandem intermolecular reductive amination/asymmetric hydrogenation. 468 Using the appropriate catalyst (C14i or C23), 2-quinoline aldehydes (S131) and feedstock anilines were transformed into a broad range of sterically tunable chiral diamines P131, which were afforded in high yields with excellent enantioselectivity (Scheme 89). The usefulness and practicality of the method were exemplified by the transformation of P131 into sterically hindered chiral Nheterocyclic carbene precursors.
The same group developed a synthetic route to chiral THQs via sequential intramolecular hydroamination and rutheniumcatalyzed AH of anilino-alkynes S132 (Scheme 90). 469 Alternatively, X. Zhang and co-workers reported a one-pot process involving N-Boc deprotection/intramolecular asymmetric reductive amination using S133 (Scheme 90). 470 This latter methodology was also applied to the synthesis of tetrahydroisoquinolines 471 as well as enantioenriched dibenz-[c,e]azepines. 472

Isoquinolines, Pyridines, and Pyridinium Salts
In contrast to quinolines, the transition metal-catalyzed AH of isoquinolines has remained significantly underdeveloped. The resulting products (1,2,3,4-tetrahydroisoquinolines, THIQs) have a stronger basicity and coordination ability, which can lead to a more facile catalyst deactivation. Typically, the strategy most widely used for the AH of substituted isoquinolines was substrate activation via isoquinolinium salts. 473−477 However, the requirement of prior formation of the salt for activation was a considerable limitation. Furthermore, in situ and transient activation using chloroformates 478 or halogenides 479,480 has also been reported. An example of this approach was provided by Zhou's group in 2017 (Scheme 91). 480 By using Ir/(R)-L9b as catalyst, a variety of both isoquinolines and pyridines (S134) were hydrogenated in excellent yields and enantioselectivities. The reaction was promoted using halogenide trichloroisocyanuric acid (TCCA) as traceless activation reagent. Mechanistic studies indicated that hydrogen halide generated in situ acted as the substrate activator. Nevertheless, and although this method avoided the tedious steps of the introduction and removal the activation groups, the reaction conditions were harsh as high temperatures and H 2 pressure were required. To overcome these limitations, Stoltz and co-workers recently reported a highly straightforward method for the iridium-catalyzed AH of 1,3disubstituted isoquinolines S135 under very mild conditions (Scheme 91). 481 The reaction, which involves a commercially available ligand (L21f), proceeded in good yields with high levels of enantio-and diastereoselectivity. The key to the success of this approach was the introduction of a directing group at the C1 position that enabled hydrogenation to occur under mild reaction conditions. As a result, a wide variety of chiral THIQs P135 were prepared in optically pure form, in a broad scope and with a very high tolerance of Lewis basic functionalities. Using a similar catalytic system, the same authors applied this hydrogenation reaction as the key step to the concise total synthesis of (−)-jorunnamycin A and (−)-jorumycin (Scheme 92), which were attained with high efficiency after 15 and 16 steps, respectively. 482 Pyridines are also challenging substrates. Xu and co-workers reported the iridium-catalyzed AH of trisubstituted pyridine derivatives. They described that the iridium complex generated in situ from [Ir(COD)Cl] 2 , difluorPhos-L20, and I 2 was an excellent catalyst for the AH of S137, affording the corresponding chiral amines P137 in excellent yields and enantioselectivities (Scheme 93). 483 The same group reported that P-Phos (L16) could also be used as a chiral ligand without diminishing the reactivity or enantioselectivity. 484 These protocols, which could also be applied to the AH of quinolines, were more efficient than the previous one reported by Zhou's group. 485 To facilitate the AH of pyridines, the activation of pyridine derivatives was first studied. In 2005, Legault and Charette demonstrated that chiral piperidine derivatives could be attained with high enantioselectivities (up to 90% ee) via the AH of Nacyliminopyridinium ylides using a Ir/P,N catalyst. 486 Later, Andersson further developed this methodology with a screening of iridium catalysts with chiral P,N-ligands. 487 In the search for an operationally simple protocol for large-scale synthesis, the Nbenzylpyridinium salts emerged as the best method for pyridine activation. First described by Y.-G. Zhou's group 488 and applied by X. Zhang's 489 and Lefort's laboratories, 490 this method provided a better approach in terms of safety and applicability. Using their catalytic systems, the subsequent iridium-catalyzed AH of these N-benzylpyridinium salts furnished a wide variety of 2-arylpyridines in both high yields and enantioselectivities, but with limited application to 2-alkylpyridines. Qu et al. then reported the use of a new rigid P-stereogenic P,N-ligand L59 for the iridium-catalyzed AH of S138 (Scheme 94). 491 Chiral α-(hetero)aryl piperidines P138a were afforded in high levels of enantioselectivity. Using the same ligand, chiral α-alkyl piperidines P138b were also prepared but with lower enantiocontrol. 492 This catalytic system was also applied in the asymmetric construction of the indenopiperidine core of an 11β-HSD-1 inhibitor. 493 In addition, Mashima and Zhou's laboratories independently reported another strategy for the AH of Brønsted acid-activated multisubstituted pyridines using enantiopure binuclear iridium complexes, thus affording the corresponding chiral piperidines in high diastereo-and enantioselectivities (up to 90% ee). 494,495 Later, Mashima expanded this methodology to the AH of 2-aryl-3-amidopyridinium salts, delivering the corresponding chiral piperidines with high diastereoselectivities and good enantioselectivities (up to 86% ee). 496 These piperidines containing two contiguous centers as structural moieties are present in many neurokinin-1 (NK1) receptor antagonist derivatives, such as (+)-CP-99994 and Vofopitant. Due to the importance of these structural units, X. Zhang and co-workers recently described the AH of 2-aryl-3-phthalimidopyridinium salts S139 driven by the Ir/SegPhos (S)-L9b catalytic system (Scheme 95). 497 Scheme 93. Iridium-Catalyzed AH of Trisubstituted Pyridines Scheme 94. Iridium-Catalyzed AH of Pyridinium Salts Chemical Reviews pubs.acs.org/CR Review Furthermore, the AH of 3-substituted pyridinium salts was developed by Lefort and co-workers using a Rh-JosiPhos catalyst with ee values up to 90%. 498 Working with similar substrates, Y.-G. Zhou's laboratory recently reported a highly enantioselective hydrogenation of 3-hydroxypyridinium salts using Ir/f-binaphane (L7) followed by sequential Swern oxidation, thus furnishing chiral 6-substituted piperidin-3-ones in excellent enantioselectivities (up to 95% ee). 499 On the other hand, in 2018, Peters and co-workers reported an alternative synthesis of piperidines from isoxazolinones by Pd/Ir relay catalytic hydrogenation of the initially formed 3,4-dihydropyridines. 500

Quinoxalines and Pyrazines
The 1,2,3,4-tetrahydroquinoxaline ring system is of great interest as a key structural unit in many therapeutically active compounds. In 2011, Fan's group described that the family of half-sandwich Ru-diamine complexes, which had already been used for the AH of quinolines, were excellent catalysts for the AH of other heteroaromatic compounds such as quinoxalines. In particular, catalyst C14a was used for the enantioselective hydrogenation of 2-alkyl and 2,3-dialkyl quinoxalines S140 with up to 99% ee (Scheme 96). 501 Of note, the bulky and weakly coordinating counteranion (BAr F ) was found to be critical for the high enantioselectivity and/or diastereoselectivity. On the other hand, and using C24, 2-aryl quinoxalines S140c were also hydrogenated in excellent ee values (up to 96% ee, Scheme 96). Later, in 2013, Ohkuma and co-workers reported an alternative protocol for the enantioselective hydrogenation of 2-alkyl quinoxalines using chiral ruthenabicylic complexes. 129 Although this work is the most successful precedent in the field, iridium catalysts had also found use in the AH of quinoxalines. In this regard, Chan, Xu, Fan, and co-workers described a highly efficient AH of quinoxalines using Ir/H 8binapo at low catalyst loading. 502 Later, Ratovelamana-Vidal and Scheme 95. Iridium-Catalyzed AH of 2-Aryl-3-phthalimidopyridinium Salts Scheme 96. Ruthenium-Catalyzed AH of Quinoxalines Chemical Reviews pubs.acs.org/CR Review co-workers described a general AH of a wide range of 2-alkyland 2-aryl-substituted quinoxaline derivatives using a cationic dinuclear triply chloride-bridged Ir(III) complex bearing L20 as a chiral ligand. 503,504 Of note, the efficiency of the catalytic system was demonstrated through a broad scope with excellent enantioselectivities (up to 95% ee, Scheme 96). Mashima and co-workers showed that the use of amines as additives had a positive effect for the iridium-catalyzed AH of quinoxalines. 505 In particular, they found that N-methyl-panisidine (MPA) was the best amine additive for achieving high enantioselectivity. More recently, Nagorny applied new chiral SPIROL-based phosphinite ligands for the iridium-catalyzed AH of heterocycles, including quinoxalines, in good to excellent enantioselectivities. 506 While 2-alkyl-and 2-aryl-substituted quinoxalines have been hydrogenated at useful levels of enantioselectivity, the AH of other derivatives such as quinoxaline-2-carboxylates is still underdeveloped, although the resulting chiral cyclic amino acids are highly valuable. To the best of our knowledge, there is only one example in the literature, affording the corresponding chiral amino acid in moderate enantioselectivity (74% ee). 507 Iridium catalysis was also applied to the AH of pyrrolo/ indolo[1,2-a]quinoxalines (Scheme 97). In 2018, Zhou's laboratory described the highly enantioselective hydrogenation of S141 with Ir/Synphos-L46, providing facile access to chiral P141 with up to 97% ee. 508 However, the addition of acetic anhydride was pivotal for suppressing the rearomatization of hydrogenation products. The system was also applied to the AH of phenanthridines (see section 6.5). The same laboratory  509 In this case, the preparation of the corresponding salt or the addition of a N-protecting group was not required. The reaction was performed under very mild conditions, and it exhibited excellent activity and enantioselectivity when using L17e as a chiral ligand. The group previously reported the enantioselective synthesis of P142 via the iridium-catalyzed AH of pyrrolo[1,2-a]pyrazinium salts, which were prepared after substrate activation using alkyl halides. 510 In 2016, Zhou's laboratory reported a facile method for the synthesis of chiral piperazines P143 through iridium-catalyzed AH of 3-substituted pyrazinium salts S143 using JosiPhos-type ligand L21a (Scheme 98). 511 The system showed broad substrate scope with good to excellent selectivity (up to 92% ee). Furthermore, 2,3-and 3,5-disubstituted pyrazinium salts were also hydrogenated with high yields and enantioselectivities when using the appropriate chiral ligand. To demonstrate the applicability of the methodology, Vestipitant, a potent and selective NK1 receptor antagonist, was prepared in just two steps.
In a similar approach, Mashima and co-workers reported the iridium-catalyzed enantioselective hydrogenation of tosylamidosubstituted pyrazines S144. The addition of N,N-dimethylanilinium bromide (DMA·HBr) enhanced the catalytic activity of the iridium complexes, as well as the enantioselectivity (Scheme 98). 512 Chiral tetrahydropyrazines with an amidine skeleton (P144) were obtained with good to excellent enantioselectiv-Scheme 99. Iridium-Catalyzed AH of N-Protected Indoles Scheme 100. Metal-Catalyzed AH of N-Protected Indoles Using PhTRAP Chemical Reviews pubs.acs.org/CR Review ities (up to 92% ee) using dinuclear triply chloro-bridge Ir(III) complexes bearing chiral difluorPhos (L20). The resulting tetrahydropyrazines P144 are versatile precursors for the preparation of chiral piperazine derivatives without loss of enantioselectivity.

Indoles
Iridium chiral complexes were also applied to the AH of Nprotected indoles to obtain chiral indolines, which are common structures occurring in alkaloids and other natural or synthetic products with biological activity. 513 Pfaltz pioneered the use of cationic Ir complexes derived from PHOX or other chiral P,Nligands in the AH of 2-substituted N-protected indoles S145a (Scheme 99). 514 In particular, C25 gave the highest enantioselectivities, and the results obtained demonstrate that the protecting group (N-Boc, N-acetyl, or N-tosyl) influences both reactivity and enantiomeric excess. Moreover, various examples of 3-substituted indoles were also hydrogenated, using the right combination of catalyst and protecting group. On the other hand, Han, Ding, and co-workers recently reported that Ir/SpinPHOX C4a is an efficient catalyst for the AH of both 2and 3-substituted N-protected indoles (Scheme 99). 515 The corresponding chiral indolines were afforded in excellent yields and enantioselectivities (>99% ee in most cases).
Prior to these iridium complexes, the only suitable catalytic systems known for the AH of N-protected indoles were Ru and Rh complexes bearing the trans-chelating chiral diphosphine (S,S)-(R,R)-PhTRAP ligand (L60), first reported by Kuwano's group. 516 In their work, a wide range of N-protected indoles were hydrogenated with high efficiency, thus providing the corresponding chiral indolines in excellent yields and enantioselectivities. 517 For example, the ruthenium-catalyzed AH of N-Boc 2-substituted (S145a) and N-tosyl 3-substituted indoles (S145b) furnished the corresponding indolines (P145) in excellent yields using L60 (Scheme 100). 518,519 2-Substituted indole esters were also hydrogenated by the groups of Minaard 520 and Agbossou-Niedercorn 521 using Rh complexes bearing PinPhos or WalPhos as catalysts, although only moderate enantioselectivities were achieved.
The methodology developed by Kuwano and co-workers allows the preparation of a wide range of optically active indolines with a chiral center at the 3-position. A team at Bristol-Myers Squibb recently used it in the enantioselective total synthesis of (+)-Duocarmycin SA, which is a potent antitumor antibiotic (Scheme 101). 522 The key tricyclic core was constructed through a highly enantioselective hydrogenation of indole S146 using L60. The progress achieved in the AH of N-protected indoles was in sharp contrast to the AH of simple unprotected indoles, which remain a challenge in organic synthesis. However, significant advances were made in this field in the last ten years.
In 2010, Y.-G. Zhou, X. Zhang, and co-workers developed the first highly enantioselective hydrogenation of simple indoles using Pd/(R)-H 8 -BINAP (L61) with a Brønsted acid (Lcamphorsulfonic acid, L-CSA) as an activator and TFE as solvent (Scheme 102). 523 This methodology provided an efficient route to make chiral indolines from unprotected indoles in excellent enantioselectivities (up to 96% ee). In 2014, Zhou's laboratory reported an extensive substrate scope, including 2-substituted and 2,3-disubstituted indoles (S147). 524 Using the same reaction conditions as the previous work, chiral indolines were prepared in up to 98% ee (Scheme 102). The main drawback of this approach was the low activity and/or enantioselectivity of the 2-aryl-substituted indoles. Interestingly, a mechanistic study using DFT calculations revealed that the hydrogenation occurs through a stepwise, ionic, and outer-sphere mechanism. As an alternative approach, W. Zhang reported that Pd/(S)-C 10 -BridgePhos is a highly efficient catalyst for the AH of 2-, 3-, and 2,3-substituted unprotected indoles. 525 Sulfonic acids were also used as Brønsted acids in the iridiumcatalyzed AH of S147, reported by Vidal-Ferran and co-workers, using a P-OP ligand L12 and THF as solvent (Scheme 102). 526 Enantiomerically enriched indolines P147 were attained in up to 91% ee. The Brønsted acid (rac-CSA), which could be reused by addition of heterogeneous additives, activates the indole ring by breaking its aromaticity. Interestingly, the reaction proceeded by a stepwise process: Brønsted acid-mediated CC isomerization, thus generating the corresponding iminium ion, followed by asymmetric hydrogenation.
Chung and X. Zhang also envisioned a similar strategy. They developed an efficient method to obtain optically pure indolines using a Rh/ZhaoPhos-L11a complex (Scheme 102). 527 Various 2-substituted and 2,3-disubstituted indoles S147 were hydrogenated with high enantioselectivities. By employing HCl as Brønsted acid, an active iminium ion intermediate was formed and reduced. The thiourea anion binding of L11a proved crucial to achieve high enantioselectivity and reactivity.
Fan and co-workers also studied the AH of unprotected indoles using half-sandwich Ru−diamine complexes. In particular, when using C14i with a triflate as counteranion, indolines P147 were afforded in up to 96% ee (Scheme 102). 114 Of note, the reaction was performed under very mild conditions at room temperature and using HFIP as solvent, which significantly influenced catalytic performance. Excellent enantioand diastereoselectivities were obtained for a wide range of indole derivatives. Simultaneously, Touge and Arai and coworkers described that a similar Ru complex with a tetrafluoroborate as counteranion (C14k) also gave excellent yields and enantioselectivities in very mild conditions (Scheme 102). 528 Subsequently, other related transformations using Pd catalysis emerged, including dehydration-triggered AH 529 530 Moreover, 3-(toluenesulfonamidoalkyl)-indoles were synthesized and hydrogenated to form chiral indolines. 531 Of note, Y.-G. Zhou's group recently reported a facile synthesis of chiral indolines through the AH of in situ generated indoles. 532 The reaction was developed through an intramolecular condensation, deprotection, and palladium-catalyzed AH using L61 in a one-pot process (Scheme 103). Chiral 2-alkylsubstituted indolines P148 were furnished in excellent yields and enantioselectivities (up to 96% ee).

Other Heteroaromatic Compounds
In 2011, Zhou, Fan, and co-workers disclosed the first AH of simple unprotected pyrroles. In their work, the Brønsted acidactivation mode was applied to the partial AH of pyrroles S149 (Scheme 104). 533 Using sulfonic acid as activator, a highly enantioselective palladium-catalyzed partial hydrogenation using C 4 -TunePhos (L5a) was reported, providing chiral 2,5disubstituted 1-pyrrolines P149 with up to 92% ee. Previously, Kuwano's group applied the PhTRAP ligand L60 to the ruthenium-catalyzed AH of N-Boc protected pyrroles (Scheme 104). 534 Using this catalytic system, pyrroles S150 were hydrogenated with high ee's to give chiral pyrrolidines P150a or 4,5-dihydropyrroles P150b. The Ru/L60 system was further exploited by Kuwano's group for the AH of other single-ring heteroarenes. Using this catalytic system, oxazoles S151 and N-Boc imidazoles S152 were hydrogenated into the corresponding chiral oxazolines P151 and imidazolines P152, respectively (up to 99% ee, Scheme 105). 535 These hydrogenation products are highly valuable Scheme 105. Ruthenium-Catalyzed AH of Oxazoles, Imidazoles, and Azaindoles Using PhTRAP Scheme 106. Ruthenium-Catalyzed AH of Indolizines and 1,2,3-Triazolopyridines Chemical Reviews pubs.acs.org/CR Review synthetic intermediates, as they can be easily converted to 1,2diamines or β-amido alcohols without loss of enantiopurity. On the other hand, fused aromatic rings consisting of two (or more) heteroarenes are challenging substrates due to the need to control chemoselectivity. Pyrido-fused pyrroles, namely azaindoles, are an important class of this type of substrate. In 2016, Kuwano and co-workers reported the chemo-and enantioselective reduction of 7-azaindoles S153 using Ru/L60 as catalyst (Scheme 105). 536 The reaction occurred exclusively on the fivemembered ring, thus furnishing the corresponding azaindolines P153 with up to 94% ee. Furthermore, the catalyst was also highly active for the AH of 6-, 5-, and 4-azaindoles.
Indolizines are another class of ring-fused heteroaromatic compounds. However, their selective reduction is a difficult task due to the nitrogen atom of the bridgehead position. In fact, the efficient AH of indolizines had not been accomplished until 2013, when Glorius and co-workers described the Ru-catalyzed AH of indolizines S154 using the chiral NHC-ligand L50 (Scheme 106). 537 The corresponding hydrogenated products, indolizidines P154, were afforded in high yields and enantioselectivities, and the applicability of such a methodology was exemplified by the synthesis of unnatural (−)-monomorine in only two steps. In addition, the catalyst was also used for the high-yielding and completely regioselective AH of 1,2,3triazolo-pyridines S155, albeit in low to moderate enantioselectivity (Scheme 106). Later, the same group used this catalytic system for the enantioselective hydrogenation of imidazo[1,2a]pyridines, with enantiomeric ratios of up to 98:2. 538 Very recently, Fan and co-workers have also reported the synthesis of benzo-fused indolizidines and quinolizidines via tandem AH/ reductive amination using a Ru-DPEN catalyst (C14j). 539 In 2015, Glorius and co-workers applied the same catalyst Ru/ L50 for the AH of 2-pyridones S156 into the corresponding enantioenriched 2-piperidones P156 (Scheme 107). 540 How-ever, and even though this was the first related example using a homogeneous catalytic system, the method suffered from low enantioselectivities, and therefore there is still plenty of room for improvement.
The enantioselective hydrogenation of quinozalinones was achieved by Zhou's laboratory, using Pd or Ir catalysis (Scheme 108). First, the group disclosed that Pd/SynPhos [(S)-L46] was an excellent catalyst for the AH of fluorinated quinazolinones (94−98% ee). 541 Later, the substrate scope was expanded to other substituted quinazolinones using iridium catalysis (with L9b), thus allowing the preparation of chiral dihydroquinazolinones P157 in excellent yields and enantioselectivities (Scheme 108). 542 The AH of pyrimidines was first reported by Kuwano and coworkers in 2015. 543 Using an Ir/L21a as catalyst, various 2,4disubstituted pyrimidines S158 were converted into chiral 1,4,5,6-tetrahydropyrimidines P158 in high yield (Scheme 109). Interestingly, lanthanide triflate was used as additive for achieving high enantiocontrol, as well as for activating the heteroarene substrate. Similarly, the AH of 2-hydroxypyrimidines S159 was reported by Zhou's group (Scheme 109). 544 Taking advantage of the lactame-lactime tautomerism of the 2hydroxypyrimidine, the authors developed two distinct catalytic systems for the efficient preparation of cyclic ureas P159, which are highly valuable structural motifs in many pharmacophores and other biologically active compounds. In particular, they reported an efficient Brønsted acid-activated palladiumcatalyzed AH using chiral ligand L21a. By slightly modifying the catalytic system, di-and trisubstituted 2-hydroxypyrimidines were also hydrogenated in good yields. Alternatively, the same laboratory developed the same transformation using iridium catalysis with L7, in which the Brønsted acid was generated in situ. 545 On the other hand, the AH of quinazolinium salts S160 was reported by Mashima and co-workers (Scheme 109). 546 By using halide-bridged dinuclear iridium complexes bearing SegPhos ((S)-L9b) as ligand, the corresponding 1,2,3,4tetrahydroquinazolines P160 were achieved in high enantiomeric excess along with some dihydroquinazolines.
Iridium catalysis was also used for the efficient AH of isoxazolium salts (Scheme 110). Kuwano's laboratory reported that iridium complexes bearing phosphino-oxazoline L62-type ligands were highly active catalysts for the AH of isoxazolium triflates S161. 547 Interestingly, by fine-tuning the oxazoline substituent, isoxazolines P161a or isoxazolidines P161b were selectively obtained in good to high enantioselectivity. Dihydrophenanthridines (DHPDs, P162) are important structural units in natural products and biologically active molecules. In addition, 9,10-dihydrophenanthridine proved to be a regenerable biomimetic hydrogen source, as it was designed as a NAD(P)H analog by Zhou. 548 However, until 2017, the AH of substituted phenanthridines had not been documented. Phenanthridines are heteroarenes formed by three fused aromatic rings. Their hydrogenation is difficult due to the possible dehydrogenative aromatization of the reduced products. Moreover, the strong coordinative nitrogen atom can easily poison the metal catalyst. At that point, Zhou's laboratory reported a highly enantioselective iridium-catalyzed AH of phenanthridines S162 through in situ protection of the reduced products with acetic anhydride to inhibit rearomatization (Scheme 111). 508 This approach was also used for pyrrolo/indolo[1,2-a]quinoxalines, as previously stated (see Scheme 97). Aryl substituents were well-tolerated, and the corresponding DHPDs P162 were attained with excellent yields and enantioselectivities. For alkyl substituents, the level of enantioselectivity was only moderate. Nevertheless, alkyl-substituted phenanthridines S162 had previously been hydrogenated by Yang, Fan, and co-workers in a highly efficient manner (Scheme 111). 549 By using a chiral cationic Ru-diamine complex C14l, the corresponding enantioenriched P162 were obtained. Interestingly, the counteranion was found to be critical for attaining high enantioselectivities (up to 92% ee).
Fan and co-workers further exploited the use of chiral cationic Ru-diamine complexes to the AH of 1,5-and 1,8-naphthyridines (Scheme 112). 550,551 By using the appropriate Ru catalyst, chiral amines containing the 1,2,3,4-tetrahydronaphthyridine ring were afforded in excellent yields and enantioselectivities. In fact, these chiral heterocycles have been used as rigid chelating diamine ligands for asymmetric synthesis and can be found in many biologically active compounds. Previously, in 2013, the same authors reported the highly enantioselective rutheniumcatalyzed AH of 1,10-phenanthroline and its derivatives using Ru-C14j. 552

CONCLUSIONS AND OUTLOOK
The metal-catalyzed asymmetric hydrogenation of prochiral unsaturated amines has been intensively studied in the last ten years, and it continues to be a growing field and a fundamental tool in synthetic organic chemistry. More than four hundred articles have been published since 2010. Although a huge number of catalysts have been described to date, there are some privileged ligands, such as DuanPhos, SegPhos, and ZhaoPhos, able to provide excellent results in a large variety of substrates. Moreover, some modular catalytic systems such as JosiPhos, WalPhos, and the ruthenium DPEN have also proved highly versatile, through fine-tuning the substituents and counterions. In the last ten years we have witnessed incredible advances and may conclude that asymmetric hydrogenation is, arguably, the cleanest and most convenient methodology for the synthesis of chiral amines. Nevertheless, to overcome the fierce competition of biocatalytic and resolution methodologies, further improvement is needed. In the years to come we might expect further development on the use of nonprecious metals to allow for greener and cheaper processes. On the other hand, catalytic systems that are active and resistant to basic and/or acidic conditions, catalyst deactivation, or poisoning by amines are much needed. These advances and others which we may not foresee now will for sure keep the metal-catalyzed synthesis of chiral amines as a thriving field in the next decade.