Min
Tan†
a,
Bram B. C.
Peters†
b,
Pher G.
Andersson
*bc and
Taigang
Zhou
*ad
aCollege of Chemistry and Chemical Engineering, & Institute for Carbon Neutrality, Southwest Petroleum University, Chengdu, Sichuan 610500, China. E-mail: tgzhou@swpu.edu.cn
bDepartment of Organic Chemistry, Stockholm University, Svante Arrhenius väg 16C, 10691, Stockholm, Sweden. E-mail: Pher.Andersson@su.se
cSchool of Chemistry and Physics, University of Kwazulu-Natal, Private Bag X54001, 4000, Durban, South Africa
dTianfu Yongxing Laboratory, Chengdu, Sichuan 610000, China
First published on 27th March 2024
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.
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 CC 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.
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.
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).
A number of simple cyclic enones S2 bearing an endo-cyclic CC 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.
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.
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 ΔpKa 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 10000 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.
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 11800 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.
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.
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).
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
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.
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.
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.
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 CC 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 = 20000) 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.
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).
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.
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 = 10500). 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 CC 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).
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 28000) 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.
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).
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.
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.
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-oxazoline15aL6, 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 CC π-bond was obtained using only 1 mol% of nickel precursor.
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.
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.
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).
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.
Footnote |
† These authors contributed equally to this work. |
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