Recent advances in the metal-catalyzed asymmetric alkene hydrogenation of cyclic conjugated carbonyl compounds

Abstract

The transition metal-catalyzed asymmetric hydrogenation of carbon–carbon double bonds is recognized as one of the most straightforward methods for the preparation of stereopure compounds. Chiral cyclic motifs have widespread applications in organic synthesis and can also be prepared via this strategy. This review summarizes the recent advances (2016–2023) in the stereoselective metal-catalyzed hydrogenation of cyclic α,β-unsaturated ketones, lactams and lactones since considerable developments in this regard were made. The applications of these methodologies in synthesis are also outlined where relevant.

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Min Tan

Min Tan received her B.Eng. (Bachelor of Engineering) in Applied Chemistry from Southwest Petroleum University and then she continues to pursue M.Eng. (Master of Engineering) in Chemical Engineering and Technology at Southwest Petroleum University. She focuses on catalyzing asymmetric hydrogenation reactions.

Bram B. C. Peters

Dr Bram B. C. Peters obtained his B.Sc. in Chemistry from the University of Applied Sciences Utrecht and subsequently moved to Sweden to conduct his MSc studies in Organic Chemistry at Stockholm University. He received his Ph.D in 2023 from the same university under the guidance of prof. Pher G. Andersson with a thesis on catalytic asymmetric hydrogenation. Bram currently occupies a Senior Scientist position in Medicinal Chemistry at Sprint Bioscience.

Pher G. Andersson

Pher G. Andersson was born in 1963 in Växjö, Sweden. He was educated at Uppsala University where he received his B.Sc. in 1988 and his Ph.D. in 1991. After postdoctoral research at Scripps Research Institute with Prof. K. B. Sharpless, he returned to Uppsala where he became Docent in 1994 and full Professor in 1999. Since 2010 he also holds the position of Honorary Professor at the University of KwaZulu-Natal, South Africa. As of January 2013, he is Professor of Organic Chemistry at Stockholm University. His main research interests involve organometallic chemistry, stereoselective synthesis, and asymmetric catalysis.

Taigang Zhou

Taigang Zhou was born in 1982 in Chengdu, China. He received his B.Eng. from Xihua University in 2005 and M.Eng. from Chongqing University in 2008. From 2008 to 2012 he undertook Ph.D studies at Uppsala University under supervision of Professor Pher G. Andersson. From 2013 to 2015, he worked as a postdoctoral researcher with Professor Zhangjie Shi at Peking University. Since 2016 he has been a professor in the Southwest Petroleum University. His current research interests focus on asymmetric catalysis, heterogeneous catalysis, catalytic dehydrogenation, and hydrogen storage in a liquid organic hydrogen carrier.

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1. Introduction

Chiral cyclic compounds play an important role in modern organic chemistry and such skeletons are widely present in pharmaceuticals,¹ chiral ligands for metal catalysis² and natural products.³ It is precisely the widespread application of these scaffolds that attracts a vast interest in the development of new methodologies to prepare cyclic compounds in stereopure form.

The metal-catalyzed asymmetric hydrogenation of alkenes is one of the most efficient methods for the installation of stereocenters on a ring system. Typically, high reactivity, high stereoselectivity, and high atom-economy make hydrogenation an attractive method in view of other methodologies for this purpose. Selecting the proper metal catalyst and chiral ligand is crucial for the success of the hydrogenation and the reduction of each cyclic olefin often requires individual catalyst screening and fine-tuning of conditions. Historically, the asymmetric hydrogenation of olefins is dominated by the platinum group transition-metal catalysts based on rhodium, ruthenium and iridium. However, recent advances that utilize catalysts based on other metals such as iron,⁴ nickel⁵ and cobalt⁶ have begun to emerge and continue to prove themselves successful in the hydrogenation of cyclic alkenes.

α,β-Unsaturated cyclic carbonyl compounds are a subclass of cyclic alkenes and the current research status of the metal-catalyzed asymmetric hydrogenation is central to this review. The chiral products obtained after asymmetric hydrogenation are interesting beccause the remaining carbonyl group, which is not reduced, can either be retained in the final product or participate in the continuation of the synthesis. However, there are a number of challenges associated with the hydrogenation of cyclic α,β-unsaturated carbonyl compounds. (1) Conjugation results in a more electron deficient alkene which might account for a slower hydrogenation rate. (2) Rigidity in the substrate can complicate coordination to the catalyst and a dependency of the ring size on the level of stereoinduction can sometimes be observed. (3) The conformation of the alkene with respect to the carbonyl group is locked in these substrates. The presence of a coordinating carbonyl group in proximity to the olefin can assist in complexation of the C=C π-bond by formation of a bidentate chelate. As a consequence of a locked conformation, this might result in an unfavorable chelate for hydrogenation to proceed. On the other hand, the presence of a carbonyl group does allow the use of catalysts that are unable to hydrogenate minimally functionalized cyclic olefins that do not possess a coordinating group in vicinity to the alkene.

In 2016, Zhang and coworkers⁷ communicated an extensive overview of the asymmetric hydrogenation of nonaromatic cyclic substrates. Since then, the research field has continued to advance, leading to not only expansion in substrate scope and the communication of new catalysts, but also a number of dual reductions via dynamic kinetic resolution due to the presence of an enolizable carbonyl group.⁸ The spine of this review consists of metal-catalyzed hydrogenations of cyclic substrates bearing a carbonyl group in conjugation developed from 2016 onwards. The content is categorized by type of carbonyl group (ketone, ester and amide). The specific category of the hydrogenation of cyclic enamides is not part of this review since it was recently reported in detail elsewhere.⁹ Likewise, non-conjugated unsaturated cyclic carbonyl compounds and enolesters are excluded.

2. α,β-Unsaturated cyclic ketones

The asymmetric hydrogenation of cyclic enones differs from that of other carbonyl-containing substrates because of the additional challenge of controlling chemoselectivity. From a general perspective, catalysts suitable for alkene hydrogenation reduce the C=O π-bond to a lesser extent and vice versa. Thus, high chemoselectivity to each respective double bond is typically achieved. Nevertheless, methodologies developed in recent years have focused on hydrogenating both alkenes and ketones for the simultaneous installation of multiple stereogenic centers. The chemoselective hydrogenation of alkenes and double hydrogenations are discussed in the following section.

The development of efficient chiral ligands constitutes a central role in asymmetric catalysis. However, in recent years, ligand backbones have been expanded for the preparation of chiral cyclic ketones via asymmetric hydrogenation. Catalysts are most frequently evaluated against α-alkylidene cyclic ketones S1. Recent efforts of these hydrogenations are summarized in Scheme 1.

Scheme 1 Asymmetric hydrogenation of exo-cyclic α,β-unsaturated ketones.

In 2018, Zhang¹⁰ reported the use of an Ir/In-BiphPHOX L1a catalyst for the hydrogenation of α-alkylidene cyclobutenones which presented the first preparation of chiral cyclobutanones by metal-catalyzed asymmetric hydrogenation (up to 98% ee). The inherent challenge in facial discrimination associated with small ring systems for this type of enones was resolved by using this catalyst. Interestingly, this axially-unfixed biphenyl phosphine-oxazoline ligand exists as an equilibrating mixture of diastereomers in solution. However, this mixture, upon complexation with [Ir(COD)Cl]₂, forms only one diastereomeric catalyst.

The characteristic challenge of controlling the stereoinduction in the hydrogenation of small and rigid ring systems became clear in the hydrogenation of 5-membered exo-cyclic enones reported by Andersson¹¹ (Ir/phosphine-thiazole L2a, 76% ee), Verdaguer & Besora & Diéguez¹² (Ir-MaxPHOX L3, 94% ee), Liu & Zhang¹³ (Ir/Rong-Phos L4, up to 64% ee) and Ye & Hou¹⁴ (Rh/f-spiroPhos L5, 90% ee). Interestingly, in the third case, an enantiodivergent hydrogenation was attained by inversion of the chirality at the nitrogen donor in the bidentate ligand. The mixture consisting of two diastereomeric RongPhos-iridium complexes could easily be separated by column chromatography in most cases.

The majority of new catalysts were evaluated against the hydrogenation of the 6-membered analogous. In most cases, the corresponding chiral ketone was obtained in good stereopurity installed by phosphine-thiazole¹¹L2a (Andersson, 99% ee), MaxPHOX¹²L3 (Verdaguer & Besora & Diéguez, 97% ee), phosphite-oxazoline¹⁵L6–7 (Pàmies & Diéguez, 96% ee and up to 98% ee, respectively), ZhaoPhos¹⁶L8 (Lv, 91% ee), phosphite-sulfoximine¹⁷L9 (Pàmies & Diéguez, 95% ee), phosphite-selenoether¹⁸L10a (Alberico & Pàmies & Diéguez, 85% ee), phosphinite-thioether¹⁹L11a (Margalef & Pericàs & Diéguez, 88% ee), phosphine-imidazole²⁰L12a (Andersson, >99% ee) and f-spiroPhos¹⁴L5 (Ye & Hou, 96% ee) ligated catalysts.

In two publications, the Andersson group communicated that the hydrogenation of cycloheptenone analogoues can easily be controlled and the desired product could be obtained in 99% ee using either Ir/phosphine-thiazole¹¹L2a or Ir/phosphine-imidazole²⁰L12a catalysts.

Moreover, the same authors²⁰ disclosed an interesting finding in stereoconvergancy (Scheme 2). It was found that the chiral product with the same absolute configuration at the α-carbon could be formed in 99% ee regardless whether the hydrogenation started from the pure (E)-alkene (E)-S1, the pure (Z)-alkene (Z)-S1, or any mixture between these two geometries. It was proposed that these substrates undergo a chelating mechanism which, together with the residence of the chelating functional group at the prochiral terminus of the olefin, accounted for the convergent outcome. In addition, this efficient enantioconvergent hydrogenation was also found tolerant to linear substrates bearing other chelating functional groups (carbonyl, sulfone and phosphonate).

Scheme 2 Enantioconvergent hydrogenation of α-prochiral enones.

A number of simple cyclic enones S2 bearing an endo-cyclic C=C double bond have also been hydrogenated (Scheme 3). Manoury & Diéguez²¹ prepared a series of planar chiral ferrocenyl phosphine-thioether L13 iridium catalysts that gave up to 85% ee. Complete control over the chirality at the stereogenic sulfur atom was attained for most ligands upon complexation with [Ir(COD)Cl]₂. Holz & Börner²² prepared a large library of novel P-chirogenic XantPhos ligands L14–15 which corresponding rhodium catalysts were evaluated in the hydrogenation of isophorone and 3,3,5-trimethylcyclohexanone could be formed up to 96.5% ee.

Scheme 3 Asymmetric hydrogenation of endo-cyclic α,β-unsaturated ketones.

In 2021, Wen & Zhang²³ developed an efficient rhodium/ZhaoPhos L8 catalytic system for the asymmetric hydrogenation of predominantly β-prochiral cyclopentenones S3 (up to 99% ee, Scheme 4). Efficient catalysts for this transformation had not been established prior to this report and a long-standing interest was thus realized. The authors proposed that hydrogen bonding between the thiourea motif and the enone carbonyl contributed to the success in reactivity and stereoselection of this particular ZhaoPhos ligand. In the same year, Xie & Zhang²⁴ reported the use of an axially-unfixed biphenylphosphine-oxazoline ligand L1b for the iridium-catalyzed synthesis of β-chiral indanones P3 and thereby further expanded the substrate scope for cyclopentenone derivatives (up to 95:5 e.r.). This method provides an efficient route for the formal synthesis of (S)-Tolterodine and (+)-Indatraline. A β-aryl cycloheptanone S3 was hydrogenated by rhodium/ZhaoPhos catalysis in 97% ee by Lu.²⁵ The chiral product of the reduction was further used in the enantioselective total synthesis of salimabromide.

Scheme 4 Asymmetric hydrogenation of β-disubstituted cyclopentanones and cycloheptanones.

More functionalized chiral cyclic ketones were prepared by contributions from Andersson,²⁶ Zheng & Zhang & Yao,²⁷ Ye & Hou¹⁴ and Tan & Ding & Chen & Zhang.²⁸ Baylis–Hillman adducts²⁶S4 were efficiently hydrogenated by Ir/phosphine-thiazole L2b or Ir/phosphine-imidazole L12b complexes to give stereoenriched cyclic β-hydroxy ketones P4 up to 93% ee (Scheme 5a). In the same study, a correlation between the acidity of N,P-iridium complexes and the nature of the heterocyclic nitrogen donor in the ligand backbone was made on the basis of DFT ΔpK_a calculations. Chiral chromanones P5 bearing a carboxylic acid in the β-position with respect to the ketone were obtained by the hydrogenation of chromones S5 using a JosiPhos SL-J216-1 L16a ligated rhodium complex.²⁷ This catalyst exhibited high efficiency (up to 10 000 TON) and stereoselectivity (up to 99% ee). This method provides a reliable synthetic path to key skeletons of many drug candidates for neurocognitive deficits and also towards a novel kind of bridged [3.2.1] tricyclic lactone skeleton, that can serve as a new class of chemical entity for drug design (Scheme 5b). A computational study showed that the presence of a carboxylate group in the substrate played an important role for the catalyst's stereodifferentiating ability. Chromes²⁹ constructed with a stereogenic center at the α-carbon were in turn synthesized by a Ir/PHOX catalyzed hydrogenation following a known protocol.

Scheme 5 Asymmetric hydrogenation of additionally functionalized endo-cyclic enones.

A Rh/f-spiroPhos L5-catalyzed highly chemo- and enantioselective hydrogenation of 2-CF₃-chromen/thiochromen-4-ones S6 was successfully established achieving excellent selectivity and high turnover numbers (up to 99.9% ee, up to 11 800 TON, Scheme 5c).¹⁴ Increased hydrogen pressure and prolonged reaction time led to further hydrogenation of chromones S6 obtaining chromols P6b with two chiral centers. A series of novel atropoisomeric diphosphine ligands L17 (TanPhos) were prepared by Tan & Ding & Chen & Zhang²⁸ and tested in the rhodium catalyzed asymmetric hydrogenation of α-dehydro amino ketones S7 yielding the desired product P7 in up to 99% ee (Scheme 5d). X-ray diffraction of Pd-TanPhos complexes showed that the chiral ligand exhibit a smaller bite angle compared to the commercially available BINAP, SDP and O-SDP diphosphines.

Control over the hydrogenation of tetrasusbsituted olefins can sometimes be more challenging compared to trisubstituted analogs as a result of the increased steric encumbrance of the carbon–carbon double bond. Nevertheless, a few successful methodologies have been developed in recent years for the hydrogenation of tetrasubstituted cyclic enones. A high degree of cis-addition of molecular hydrogen to a π-bond accounts for the typically high diastereomeric ratio observed in these hydrogenations. Yuan & Deng & Zhang³⁰ established a highly stereoselective Ir/PHOX L18a catalyzed hydrogenation of 2-substituted cyclopentyl aryl ketones S8 (up to 99% ee, >20 : 1 dr, Scheme 6a). The trans product diastereomer could be accessed by a thermodynamically driven epimerization of the installed stereogenic center at the α-carbon by DBU giving up to >20 : 1 dr (retained ee). Using this modification together with both enantiomeric forms of the iridium catalyst, all four product stereoisomers P8 were prepared in a stereodivergent manner and in the same degree of stereopurity. Additionally, an important intermediate for the synthesis of the ERβ agonist Erteberel (LY500307) was prepared using this methodology.

Scheme 6 Asymmetric hydrogenation of tetrasubstituted cycloalkenes.

Song & Qin³¹ developed an Ir/spiro phosphoramidite L19 complex catalyzed asymmetric hydrogenation of tetrasubstituted α,β-unsaturated cyclic acylpyrazoles S9 bearing a variety of β-alkyl substituents to give 1,2-cis carbo- or heterocycles P9 in high stereopurity (Scheme 6b, up to 99% ee). It was proposed that the acylpyrazole motif serves as a key directing group by coordinating to the active Ir-complex. Later, they utilized the above outlined hydrogenation as a key step in the enantioselective total synthesis of the (−)-mitragynine, (−)-quinine and (+)-quinidine alkaloids.³²

Endo-cyclic tetrasubstituted cyclic ketoesters S10 underwent hydrogenation catalyzed by an Ir/SpiroPAP L20a complex in the presence of KOtBu and under 10 atm H₂, as reported by Xie³³ (Scheme 7). However, this reaction suffered from over-reduction into the saturated alcohol M1b which was previously reported for analogous substrates under similar conditions.³⁴ Therefore, it was deemed essential to oxidize the mixture in the same pot leading up to 82% yield of the ketone. These β-ketoesters P10 were isolated in excellent stereopurity (up to 98% ee) bearing a cis relationship as a result of the alkaline reaction conditions. A similar approach³⁵ was undertaken by the same group to reduce an iPr-substituted β-ketoester on a >10 gram scale (>99% ee, >99 : 1 dr). The reduced product was then further used in the divergent asymmetric total synthesis of mulinane diterpenoids.

Scheme 7 Asymmetric hydrogenation of endo-cyclic tetrasubstituted cyclic enones.

Exo-cyclic tetrasubstituted cyclic enones S11 were also hydrogenated (up to 99% ee, up to >25 : 1 dr) catalyzed by Ir/aminophosphine-oxazoline L21 complexes under 100 bar H₂, as reported by Besora & Diéguez³⁶ (Scheme 8).

Scheme 8 Asymmetric hydrogenation of exo-cyclic tetrasubstituted cyclic enones.

The asymmetric hydrogenation of dienes holds additional interesting features compared to the hydrogenation of a single alkene. First, a regioselective monohydrogenation allows the preparation of stereoenriched products in which a synthetically useful alkene is retained. Alternatively, a stereoselective double hydrogenation offers the opportunity to install multiple stereogenic centers in one single operation. The hydrogenation of cyclic dienones has been a topic of interest in recent years leading to a number of elegant methodologies.

Xie & Ding³⁷ optimized a regioselective monohydrogenation of dienone S12 catalyzed by an Ir/In-BiphPHOX L1a complex, directed to the alkene in the (s)-cis conformation (94% ee, Scheme 9a). This hydrogenation was performed on a gram scale and with high regiocontrol (95% isolated yield). The chiral product P12 was then used in the divergent total synthesis of crinipellins. The finding that a cyclic enolether could be retained was in line with Andersson's observations involving 1,4-cyclohexadienes that lack a ketone group in conjugation to the diene.³⁸

Scheme 9 Regioselective monohydrogenation of a cyclic dienones.

Andersson studied the effect of conformational freedom of conjugated carbonyl compounds on the rate of asymmetric hydrogenation in more detail. It was found that substrates able to adopt the (s)-cis conformation underwent a rate acceleration in comparison with (s)-trans conformed analogues. Using this effect, a novel regioselective monohydrogenation of dienes S13 was devised that tolerates dienones with olefins bearing similar electronic properties (Scheme 9b).³⁹ Interestingly, the regioselection was powerful enough to invert the convential reactivity order in iridium-catalyzed hydrogenation (di > tri > tetra) leaving the least substituted endo-cyclic alkene untouched in the chiral product.

A nickel-catalyzed desymmetric hydrogenation of cyclohexadienones was developed by Wen & Zhang⁴⁰ (Scheme 10). With the Ni(OTf)₂/(S,S)-Ph-BPE L22 catalytic system, a series of γ,γ-disubstituted cyclohexadienones S14 was transformed to the corresponding cyclohexenones P14 and thereby installing a chiral all-carbon quaternary center at the γ-position in excellent enantioselectivities (up to 99% ee). The key intermediate of natural products (−)-cannabispirenones A and B was obtained with this method in one step.

Scheme 10 Nickel-catalyzed desymmetric hydrogenation of cyclohexadienones.

In pursuit of the interest to install multiple stereogenic centers at once, cyclic α,α′-dialkylidene ketones S15 bearing two alkenes in the (s)-cis conformation and with various ring sizes were efficiently reduced (Scheme 11). These reactions were catalyzed by Ir/PHOX⁴¹L18b (Ding, up to >99% ee, up to >20 : 1 dr) or Ir/iPr-BiphPHOX⁴²L1c (Zhang, up to >99.9% ee, up to >20 : 1 dr) catalysts and liberated the desired product P15 in high stereopurity. A stepwise dissociative mechanism leads to a trans relationship between the substituents at the α/α′-position. Products containing an ortho-bromo substituent could further undergo a TiCl₄ catalyzed spirocyclization reaction to furnish 1,1′-spirobiindane motifs. These motifs were in turn transformed into a privileged class of chiral ligands which were evaluated in a number of metal-catalyzed reactions.

Scheme 11 Asymmetric hydrogenation of α,α′-dialkylidene ketones.

High chemoselectivity for the hydrogenation of either the alkene or carbonyl group is often attained when enones are used. This mainly results from the fact that not only the catalyst structures, but also the reaction conditions, to hydrogenate each unsaturated functional group differs largely. From a generalized perspective, olefins are most often reduced via an innersphere mechanism operating under pH neutral conditions in non-coordinative solvents. On the contrary, ketones are best hydrogenated via an outersphere mechanism enabled by bifunctional ligand-cooperative catalysts performed in polar solvents and by the assistance of a base. Therefore, there exist only a few asymmetric hydrogenations in which both π-bonds are reduced in the same pot. Despite the rarity, a significant number of contributions have been made in recent years that start from cyclic enones.

In 2016, a Rh/(R)-QuinoxP* L23a catalyzed hydrogenation of α-dehydroamino ketones S16 was reported by Zhang & Zhang⁴³ to furnish chiral cyclic β-amino alcohols P16 containing two contiguous stereogenic centers (up to 99% ee, up to 16 : 1 dr, Scheme 12a). A series of control experiments revealed that these substrates underwent hydrogenation in a stepwise manner, starting with the reduction of the alkene. The facial selection in the hydrogenation of the intermediate product was directed by the chelating amide to form products with a trans-relationship. Using the method, an important intermediate in the synthesis of a potent inhibitor of apoptosis (IAP) antagonist was prepared. Chromones S17 substituted at the β-carbon were hydrogenation by Liu⁴⁴ into chiral chromanols P17 following the same order of reductions (Scheme 12b). The used trimetallic Ru-PHOX-Ru L24-Ru catalyst showed good activity (S/C up to 1000) and produced these products with high control over the stereoselective outcome (up to 99.9% ee, up to >20 : 1 dr). Two chiral products were further derivatized with excellent preservation of the installed chirality. In another report,⁴⁵ the same catalyst was used to hydrogenate one single substituted cyclopentenone into a saturated alcohol (2 : 1 dr), which sequential reduction proceeded via the allylic alcohol.

Scheme 12 Stereoselective and stepwise double hydrogenation of cyclic enones.

A large portion of the recently developed double hydrogenation methodologies followed an olefin hydrogenation/dynamic kinetic resolution sequence. Herein, a (non-)stereoselective hydrogenation of the C=C double bond takes place first, followed by a continuous racemization of the stereogenic carbon in α-position with respect to the ketone. The stereochemical relationship of the final product is then installed by the catalyst in the consecutive hydrogenation of the carbonyl group, which is not only stereoselective but also exhibits a large rate difference between both enantiomers of the α-chiral ketone.

Following this concept, numerous substituted chromanols and tetrahydronaphthols bearing two newly installed vicinal stereogenic centers at once were efficiently prepared and with excellent control over the stereoselective outcome (Scheme 13). Substrates S18a, S18b bearing both an endo-cyclic or an exo-cyclic alkene were successfully reduced under either transfer hydrogenation or direct hydrogenation conditions. These hydrogenations were catalyzed by ancillary η⁵-arene tethered TsDPEN-rhodium L25 (Phansavath & Ratovelomanana-Vidal,⁴⁶ up to >99% ee, up to >99 : 1 dr), Noyori-Ikariya type ruthenium L26 (Domingos & Costa,⁴⁷ up to >99 : 1 er, up to >95 : 5 dr), Ir/f-Ampha L27 (Lv,⁴⁸ up to >99% ee, up to >20 : 1 dr, up to S/C = 20 000) and Rh/C10-BridgePhos L28 (Zhang,⁴⁹ up to 99.9% ee, up to >20 : 1 dr) complexes. Interestingly, this last example operates under pH neutral conditions, rather than the pH adjusted conditions in the other examples. It is suggested on the basis of DFT calculations that the racemization takes place on the rhodium complex and proceeds via a stereomutation (or named chiral assimilation) to convert the slow-reacting enantiomer into the fast-reacting enantiomer.

Scheme 13 Stereoselective double hydrogenation/DKR of cyclic enones.

An interesting olefin hydrogenation/DKR sequence is reported by Xie³⁴ in which the reaction started from a tetrasubstituted cyclic β-ketoester S19 (Scheme 14). This Ir/SpiroPAP L20a catalyzed hydrogenation furnishes chiral cycloalkanols P19 with three contiguous stereogenic centers and the achieved degree of stereocontrol is noteworthy (up to >99% ee, up to >99 : 1 dr).

Scheme 14 Stereoselective double hydrogenation/DKR of tetrasubstuted cyclic enones.

The asymmetric hydrogenation of cyclic α,β-unsaturated ketones was extensively studied. The most successful catalytic systems employ Ir complexes as the active species. α-Alkylidene cycloalkanones can be reduced with high enantioselectivities using a variety of bidentate N,P-chelating ligands such as BiphPHOX, phosphine-thiazole, phosphine-imidazole, MaxPHOX, phosphite-oxazoline, phosphite-sulfoximine, phosphite-selenoether and phosphinite-thioether. Rh complexes exhibit high catalytic activity with P,P-chelating ligands (ZhaoPhos, f-spiroPhos, XantPhos, TanPhos, (R)-QuinoxP* and C10-BridgePhos) in the hydrogenation of mostly additionally functionalized cyclic enones. Lastly, a few Ru catalysts were utilized for the dual reduction of enones and also a P,P-Ni catalyst was reported for a desymmetric hydrogenation.

3. α,β-Unsaturated lactams

Chiral lactams are important skeletons for medicinal chemistry purposes. Like the enones, most newly developed catalytic system were evaluated against lactams bearing a conjugated exo-cyclic alkene with different ring sizes. The asymmetric hydrogantion of both N-protected (Ar, Bn, PMP, Me, Boc, Ac) and protecting group free examples S20 were communicated leading to the preparation of a series of different chiral lactams P20 in recent years (Scheme 15).

Scheme 15 Asymmetric hydrogenation of exo-cyclic α,β-unsaturated lactams.

The Ir/In-BiphPHOX L1a catalytic system reported by Zhang¹⁰ for the hydrogenation of cyclobutenones was also found efficient for the preparation of lactam analogous (up to 98% ee). This methodology presented the first synthesis of these chiral motifs by asymmetric hydrogenation.

The Ir/Rong-Phos L4 enantiodivergent hydrogenation based on the chirality at the nitrogen donor developed by Liu & Zhang¹³ was applicable to a number of N-benzylated 5-membered α,β-unsaturated lactams. Both enantiomers of the chiral lactam could efficiently be prepared using this methodology in high enantiomeric excess (up to 98% ee). Additionally, the P-stereogenic Ir/MaxPHOX L3 complex showed good results for the same purpose as shown by Verdaguer & Besora & Diéguez¹² on one example (95% ee). The oxaspirocyclic phosphine-oxazoline (O-SIPHOX L29a) ligated iridium complex developed by Chen & Zhang⁵⁰ was less efficient in the hydrogenation of a trisubstituted exo-cyclic α,β-unsaturated lactam despite the good reactivity (8% ee). In turn, Ir/O-SIPHOX L29b catalyst was proven to suit the hydrogenation of 1-methylene-tetrahydro-benzo[d]azepin-2-one type α,β-unsaturated lactams, constructed with an exo-cyclic terminal alkene, and was used for the asymmetric synthesis of lorcaserin (up to 99% ee).

A large number of structurally diverse catalysts were found applicable to the asymmetric hydrogenation of 6-membered α,β-unsaturated lactams. Contributions in this regard were made by Andersson⁵¹ (Ir/phosphine-thiazole L30, 94% ee), Pàmies & Diéguez (Ir/phosphite-sulfoximine¹⁷L9, up to 96% ee, Ir/phosphite-oxazoline L6,^15aL7,^15b up to >99% ee), Verdaguer & Besora & Diéguez¹² (Ir/MaxPHOX L3, up to >99% ee), Besora & Diéguez⁵² (Ir/phosphite-thioether L31, 97% ee), Margalef & Pericàs & Diéguez¹⁹ (Ir/phosphinite-thioether L11b, up to 99% ee), Alberico & Pàmies & Diéguez¹⁸ (Ir/phosphite-thioether L10b, 95% ee), and Lv¹⁶ (Rh/ZhoaPhos L8, up to 95% ee). In the majority of cases excellent control over the stereoselective outcome was attained. Interestingly, the Ir/phosphine-thiazole L30 catalyst reported by Andersson⁵¹ was successful in the hydrogenation of a secondary, unprotected, substrate. Huang & Hou⁵³ demonstrated that the Rh/f-spiroPhos L5 catalysts could be used for the efficient hydrogenation of CF₃-containing α,β-unsaturated lactams (Scheme 15, up to TON = 10 500). Both 5- and 6-membered lactams of this kind were reduced in high enantioselectivity (up to 99.9% ee).

Moving to substrates S21 bearing endo-cyclic alkenes, a range of unprotected 7-membered β-substituted α,β-unsaturated lactams⁵⁴ were reduced in high control over the stereochemistry by Rh/ZhaoPhos L8 catalysis (Scheme 16, up to >99% ee). These olefins were easily prepared by a Beckmann rearrangement and were transformed into substituted caprolactams upon hydrogenation of the C=C bond. The same catalyst was found applicable to the hydrogenation of 5-membered analogous⁵⁵ providing the chiral product up to 99% ee. Interestingly, N-unprotected substrates were hydrogenated with similar efficiency as corresponding analogous protected with Boc, Me, tBu, Bn, Ph, and PMP. The quest for efficient catalytic systems for the preparation of chiral 3,4-dihydro-2-quinolones by hydrogenation of 2-quinolones was reported by Glorius.⁵⁶ The SINpEt-ligated L32 ruthenium catalyst performed well under 10 bar hydrogen atmosphere (up to 98 : 2 er, Scheme 16).

Scheme 16 Asymmetric hydrogenation of endo-cyclic lactams.

Proceeding with more functionalized α,β-unsaturated lactams, the Ir/BiphPHOX L1c catalyzed hydrogenation of benzoxazinones S22 was reported by Yuan & Zhang⁵⁷ (Scheme 17). The desired chiral 1,4-benzoxazin-3-ones P22 were prepared in satisfactory stereopurity (up to 99% ee) using an up to S/C = 1000 ratio. Additionally, three bioactive molecules were prepared from these reduced products. Zhang & Yin,⁵⁸ Yan & Xie⁵⁹ and Liao & Zhou⁶⁰ demonstrated the use of Rh/JosiPhos L16b, Ir/SpiroPAP L20 (TON up to 28 000) and Pd/(R,R)-QuinoxP* L23b catalysts, respectively, for the asymmetric hydrogenation of tetrasubstituted α,β-unsaturated lactams S23 bearing an ester functional group in the α-position (Scheme 18). Good control over the stereochemical outcome was attained in both cases (up to 93% ee, up to 16 : 1 dr, up to 99% ee, up to >20 : 1 dr and 90% ee, respectively). The trans/cis ratio in the final products P23 was suggested to arise from a thermodynamic epimerization of the α-stereocenter under the reaction conditions. In addition, (+)-femoxetin, (−)-paroxetine and MPR3160 were synthesized by Zhang & Yin and Yan & Xie using their developed hydrogenation protocol. Chiral 1,5-benzothiazepinones S24 were prepared by Ru/SINpEt L32 (Glorius⁶¹) and Rh/ZhoaPhos L8 (Wen & Zhang⁶²) catalysis (Scheme 19). Both catalytic systems furnished these corresponding medicinally relevant motifs in high stereopurity (up to 95% ee and up to >99% ee, respectively). It is worth mentioning that in the latter case the hydrogenation started most from N-unprotected substrates.

Scheme 17 Ir/BiphPHOX catalyzed asymmetric hydrogenation of benzoxazinones.

Scheme 18 Asymmetric hydrogenation of tetrasubstituted α,β-unsaturated lactams.

Scheme 19 Preperation of 1,5-benzothiazepines by catalytic asymmetric hydrogenation.

Functionalized substrates constructed with an additional carbonyl carbon in the ring system could also be reduced by catalytic asymmetric hydrogenation. Chiral succinimides⁶³P25 were obtained by a Rh/ZhoaPhos L8 catalyzed hydrogenation (Scheme 20a). This catalyst was efficient in terms of reactivity (up to TON = 2000) and stereoselectivity (up to >99% ee) and was tolerant to N-unprotected substrates. It was proposed that hydrogen-bonding interactions between the thiourea motif in the ligand and the carbonyl carbon in the maleinimide contributes to the activation of these substrates. Further reduction of the two carbonyl groups in the chiral product yielded a potent α-2-adrenoceptor antagonist analogue. Additionally, Liu & Zhang¹³ explored the stereodivergent Ir/Rong-Phos L4 catalyzed hydrogenation of two α-alkylidne succinimides S26 leading to the desired reduced product in up to 92% ee (Scheme 20b).

Scheme 20 Synthesis of chiral succinimides by catalytic asymmetric hydrogenation.

A diverse set of chiral hydantoins (and also thiazolidinediones) were yielded after an Ir/In-BiphPHOX L1a catalyzed hydrogenation in good enantiomeric purity (up to 98% ee), as demonstrated by Yuan & Zhang⁶⁴ (Scheme 21). Here, the olefinic precursors were protected by 2,6-dichlorobenzyl at the nitrogen shared between both carbonyl groups. The new method of Yuan & Zhang provided an efficient synthesis route to an inhibitor of HIV protease. A Pd/BINAP L33 catalyzed hydrogenation was performed on unprotected substrates (Wang,⁶⁵Scheme 21) for the same purpose, although with inferior control over the stereoselective outcome (up to 90% ee). Similarly, Michon & Agbossou-Niedercorn⁶⁶ reported the use of a Pd/(R,R)-QuinoxP* L23b catalyzed hydrogenation for the preparation of L-Valine starting from a 5-methylenhydantoin (70% ee, Scheme 21). Both these Pd-catalyzed hydrogenations benefited from the assistance of a chiral Brønsted acid in catalytic amounts. Alternatively, Hou & Zhang⁶⁷ used a Rh/f-spiroPhos L5 complex for the preparation of analogous hydantoins and were able to install the stereogenic center in up to 99.9% ee, in which the use of protecting groups was also avoided. The ring system in this last methodology could also be enlarged to furnish a series of chiral 2,5-di-ketopiperazines (up to 99.9% ee, Scheme 21).

Scheme 21 Synthesis of chiral hydantoins and analogous compounds by catalytic asymmetric hydrogenation.

Interestingly, one example by Hou & Zhang⁶⁷ involved the hydrogenation of a 3,6-dibenzylidene-2,5-di-ketopiperazine S28 which reduction liberated exclusively one stereoisomer (99.9% ee, Scheme 22a). Prior to this entry, Han & Ding⁶⁸ studied the Ir/SpinPHOX L34 catalyzed hydrogenation of these motifs for the efficient synthesis of cyclic dipeptides P28. A number of conformationally rigid cyclic dipeptides P28 were obtained in excellent stereochemical purity (up to 98% ee, >99% de, Scheme 22b). The stereochemical cis-relationship in the product was proposed to arise from a non-dissociative hydrogenation pathway. Even larger macrocyclic peptides P29 constructed with 4 stereogenic centers could be prepared in a single operation by a Rh/DuanPhos L35 catalyzed hydrogenation, as showcased by Wiest & Dong⁶⁹ (Scheme 22c). Based on a combined experimental and theoretical study it was proposed that these substrates underwent a cascade and unidirectional dissociative hydrogenation with excellent stereocontrol (>99% ee, 20 : <1 dr). This work by Wiest & Dong presents an interesting study involving molecular recognition between the substrate and an artificial metal catalyst.

Scheme 22 Stereoselective multi-hydrogenations for the preparation of cyclic peptides.

A variety of α,β-unsaturated lactams were successfully hydrogenated using different catalytic systems. The greatest success was achieved using P,P-Rh ligand complexes such as Rh/ZhaoPhos and Rh/f-spiroPhos. N,P-Ir complexes were mostly tested in the asymmetric hydrogenation of exo-cyclic α,β-unsaturated lactams that often proceeded in high stereoselectivity. P,P-chelating Pd complexes (such as (R,R)-QuinoxP* and BINAP) and Ru catalyst coordinated with SINpEt also showed excellent activity in certain cases.

4. α,β-Unsaturated lactones

Similar to the cyclic enones and α,β-unsaturated lactams in the sections above, catalysts were also extensively screened against α,β-unsaturated lactones S30 bearing an exo-cyclic alkene (Scheme 23). 5-membered α,β-unsaturated lactones were hydrogenated in varying degree of stereocontrol. A rhodium catalyst ligated with a ZhoaPhos L8 diphosphine ligand hydrogenated terminal and trisubstituted motifs of this kind in 82%⁷⁰ and 79%¹⁶ ee, respectively. The same terminal alkene was also targeted by Zakarian⁷¹ (Ru/BINAP L33) which hydrogenated product (96% ee) was used in the total synthesis of unsymmetrically oxidized nuphar thioalkaloids. Iridium based catalysts were sometimes found more efficient for the purpose of hydrogenating 5-membered exo-cyclic lactones and complexes based on O-SIPHOX⁵⁰L29a (Zhang, 42% ee), phosphite-sulfoximine¹⁷L9 (Pàmies & Diéguez, 92% ee), MaxPHOX¹²L3 (Verdaguer & Besora & Diéguez, up to 99% ee), and phosphite-oxazoline^15aL6 (Pàmies & Diéguez, 99% ee) frameworks were reported.

Scheme 23 Asymmetric hydrogenation of exo-cyclic α,β-unsaturated lactone.

A large portion of catalyst communicated for the hydrogenation of 6-membered analogous were well-performing and good to highly stereoselective. Yuan & Zhang⁵⁷ (Ir/BiphPHOX L1c, 68% ee), Pàmies & Diéguez (Ir/thioether-carbene, -phosphinite, and -phosphite L36–37,⁷² Ir/phosphite-sulfoximine¹⁷L9, Ir/phosphite-oxazoline^15aL6, 28% ee, 97% ee, 99% ee, >99% ee, respectively), Alberico & Pàmies & Diéguez¹⁸ (Ir/phosphite-selenoether L10a, 94% ee), Margalef & Pericàs & Diéguez¹⁹ (Ir/phosphinite-thioether L11a, up to 98% ee), Besora & Diéguez⁵² (Ir/phosphite-thioether L31, up to >99% ee), Verdaguer & Besora & Diéguez¹² (Ir/MaxPHOX L3, up to 98% ee), Manoury & Diéguez²¹ (Ir/phosphine-thioether L38, 84% ee), and Lv¹⁶ (Rh/ZhaoPhos L8, up to 99% ee) contributed in this regard and prepared the desired chiral lactones by catalytic asymmetric hydrogenation.

A few hydrogenations targeting simple α,β-unsaturated lactones S31 constructed with an endo-cyclic alkene were reported. Chiral γ-butyrolactones P31 were accessed by a stereoselective Rh/ZhoaPhos L8 catalyzed hydrogenation (Lang & Chen & Zhang,⁷⁰Scheme 24a). Subjection of γ-butenolides S31 (Scheme 24a) or γ-hydroxybutenolids S32 (Scheme 24b) to the hydrogenation both afforded the desired product in high stereopurity (up to 98% ee, up to 99% ee). This strategy was applicable to the concise syntheses of the pharmaceutical drugs brivaracetam and arctigenin that demonstrated the practical usefulness. A nickel-catalyzed asymmetric hydrogenation of α,β-unsaturated esters S31 was developed by Shevlin & Chirik⁷³ based on a high-throughput experimentation approach (Scheme 24a). Although the majority of the scope involved linear substrates, the Ni/Me-DuPhos L39 catalytic system was also tested against an unsaturated 5-membered lactone S31 giving 82% ee. The nature of the catalytically active species in this hydrogenation was proposed to be a trimetallic (Me-DuPHOS)₃Ni₃(OAc)₅I cluster. Impressively, complete reduction of the endo-cyclic C=C π-bond was obtained using only 1 mol% of nickel precursor.

Scheme 24 Synthesis of chiral γ-butyrolactones.

Trisubstituted 3-benzoylaminocoumarins S33 were efficiently reduced by a Rh/C10-BridgePhos L28 catalyzed hydrogenation and high stereopurity of the chiral 3-amino dihydrocoumarins P33 was achieved (up to 99.7% ee, Zhang,⁷⁴Scheme 25). X-ray analysis of different Rh/BridgePhos complexes (C8 to C12) revealed that C10-BridgePhos L28 exhibited a slightly larger dihedral angle along the biaryl backbone compared to the other ligands. It was observed that π–π stacking interactions between the biphenyl ring and the P-phenyl ring were enhanced as a consequence of this enlarged dihedral angle in the backbone. Ultimately, it was proposed that this provides the best coordination environment for these rigid cyclic substrates making C10-BridgePhos L28 the superior ligand. By comparison, no catalytic activity was observed when a CoCl₂/(S,S)-Ph-BPE L22⁷⁵ catalyst was used for the hydrogenation of a 3-benzoylaminocoumarin (Scheme 25). A large number of bioactive molecules were obtained through further derivatization of chiral products obtained after the Rh/C10-BridgePhos catalyzed hydrogenation.

Scheme 25 Asymmetric hydrogenation of 3-benzoylaminocoumarins.

Chiral dihydrobenzoxazinones P34 were synthesized by a stereoselective Rh/DTBM-SegPhos L40 catalyzed hydrogenation. Dong⁷⁶ reported the smooth preparation of these motifs under 20 bar hydrogen atmosphere in up to >99% ee (Scheme 26). The thiourea bisphosphine based ligand ZhaoPhos L8 was proven successful in the rhodium catalyzed asymmetric hydrogenation of maleic anhydrides⁷⁷S35 (up to 99% ee, Dong & Zhang, Scheme 27). Complete consumption of starting material was achieved within 30 min of reaction time under 1 bar of hydrogen atmosphere for most substitution patterns using this protocol (up to TON = 3000). A chiral product of this hydrogenation was then further derived into a key intermediate in the synthesis of the hypoglycemic drug mitiglinide.

Scheme 26 Synthesis of chiral dihydrobenzoxazinones by asymmetric hydrogenation.

Scheme 27 Asymmetric hydrogenation of maleic anhydrides.

Tetrasubstituted coumarins S36 bearing an ester or acylamine in α-position were successfully hydrogenated using a Ir/SpiroPAP L20b and Pd/(R,R)-QuinoxP* L23b complex (Scheme 28a). This methodology reported by Yan & Xie⁵⁹ and Liao & Zhou⁶⁰ prepared the corresponding dihydrocoumarins P36 in up to 98% ee and up to >20 : 1 dr, up to >99% ee in 2–24 h. The alkaline reaction conditions accounted for the trans-relationship between both substituents. As last, A rhodium catalyst ligated with ArcPhos L41 was reported for the hydrogenation of tetrasubstituted dehydroamino acid derivatives⁷⁸S37 (Claverie & Tang, Scheme 28b). A range of α-acylamino-β-alkyl tetrahydropyranones P37 with two contiguous stereogenic centers were easily synthesized using this protocol (up to 96% ee, TON = 1000).

Scheme 28 Asymmetric hydrogenation of tetrasubstituted α,β-unsaturated lactones.

Numerous catalytic systems were developed and evaluated in the asymmetric hydrogenation of a broad range of α,β-unsaturated lactones. Rh catalysts, in combination with ZhaoPhos, BINAP, C10-BridgePhos, DTBM-SegPhos and ArcPhos, reduced a variety of substitution patterns in high stereoselectivity. N,P-Ir complexes were found as good catalysts to hydrogenate α-alkylidene lactones with satisfactory control over the stereoselective outcome. The use of Ni and Co catalysts with P,P-chelating ligands (Me-DuPhos and Ph-BPE, respectively) was in some cases tested as an alternative to established transition-metal based catalysts.

5. Conclusion

To conclude, extensive research efforts have been invested in recent years (2016–2023) in the development of new methodologies for the asymmetric hydrogenation of cyclic alkenes conjugated with a carbonyl group. This led to the communication of new ligand structures, an expansion in substrate scope, and the establishment of multi-hydrogenations. Often high control over the stereoselective outcome was attained and a broad range of chiral cyclic ketones, alcohols, lactams and lactones were synthesized. Although base metal-catalyzed hydrogenation of olefins is an emerging area within stereoselective synthesis, the most successful examples of recent years for the hydrogenation of cyclic alkenes are still catalyzed by the well-established platinum group metal (Ir, Rh and Ru) based catalytic systems. In addition, there is still more need for efficient hydrogenations of tetrasubstituted cyclic olefins. Despite that good progress is this regard was made during the past years, a larger diversity in substitution pattern is still desired. We hope that more applications of these recently developed methodologies in total synthesis of natural products and the preparation of pharmaceutically relevant compounds will also be demonstrated in the near future.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors thank the Sichuan Science and Technology Program (No. 2021YFH0161, 2021ZYCD005), the National Natural Science Foundation of China (No. 21811530004), the Science and Technology Project of Southwest Petroleum University (No. 2021JBGS07), the Swedish Foundation for International Cooperation in Research and Higher Education (STINT 31001557 & CH2017-7226), the Swedish research Council (VR), the Knut and Alice Wallenberg foundation (KAW 2016:0072 & 2018:0066) and the Stiftelsen Olle Engkvist Byggmästare for their financial support. We thank Dr Thishana Singh, School of Chemistry and Physics, University of Kwazulu-Natal, South Africa, for proofreading and editing the manuscript.

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Footnote

† These authors contributed equally to this work.

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