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This tutorial account describes the design of chiral spiro iridium catalysts bearing spiro pyridine–aminophosphine ligands, and their preparation and application in the asymmetric hydrogenation of ketones and β-aryl-β-ketoesters.
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... catalytic asymmetric hydrogenation is one of the most e ffi cient and convenient methods for the preparation of optically active compounds, and has been applied in the industrial synthesis of pharmaceuticals and agrochemicals. 1 Recently we developed a new type of chiral spiro iridium catalysts bearing tridentate spiro pyridine – aminophosphine (abbreviated as SpiroPAP, Fig. 1) ligands and found these chiral iridium catalysts were extremely e ffi cient for the hydrogenation of ketones and β -ketoesters, producing the corresponding chiral alcohols and chiral β -hydroxy esters in excellent yields and enantioselectivities (up to 99.9% ee) with TON ’ s up to millions ( ca . 4 550 000). This highly e ffi cient catalytic asymmetric hydrogenation has been successfully applied in the synthesis of pharmaceuticals and pharmaceutical intermediates. In this tutorial account, we describe the design and synthesis of chiral iridium catalysts Ir-( R )-SpiroPAP and their applications in the asymmetric hydrogenation of ketones and β -ketoesters. Since Noyori and co-workers reported that chiral RuCl 2 (diphosphine)(diamine) complexes were highly e ffi cient catalysts for the asymmetric hydrogenation of ketones, 3 research on the catalytic asymmetric hydrogenation of ketones has been focused on the development of chiral ruthenium catalysts bearing diphosphine and diamine ligands. 4 Recently, we developed a new type of chiral spiro ligand containing phosphine and amine moieties, named as SpiroAP (Fig. 2), and found their iridium complexes were highly active for the asymmetric hydrogenation of ketones. 5 The turnover frequencies (TOF) of the hydrogenation were as high as 37 000 h − 1 , however, the turnover numbers (TON) reached only 10 000. 5 b The Ir-SpiroAP catalyst was unstable under a hydrogen atmosphere and quickly transformed into an inactive iridium dihydride species with two SpiroAP ligands. To prohibit the coordination of the second SpiroAP ligand to the iridium atom of the catalyst, we introduced an additional coordinating pyridine moiety to the SpiroAP, making it a tridentate ligand named SpiroPAP. 2 a This modification led us to develop a novel chiral spiro iridium catalyst with exceptionally high stability and activity for the hydrogenation of ketones. The Ir-( R )-SpiroPAP catalyst with 3,5- tert -butyl groups on the P -phenyl rings and a 3-methyl group on the pyridinyl ring was demonstrated to be the best choice. 2 a Under the optimal reaction conditions (0.02 mol% Ir-( R )-SpiroPAP, [KO t Bu] = 0.02 M; [substrate] = 2.1 M, 10 atm of initial H 2 pressure, in anhydrous EtOH at room temperature for 20 min to 4 hours), a series of alkyl aryl ketones were hydrogenated to chiral alcohols in quantitative yields with 96 – 99.9% ee (Fig. 3). This is an extremely e ffi cient asymmetric hydrogenation and the TON ’ s are up to millions. For example, in the asymmetric hydrogenation of acetophenone the catalyst loading can be reduced to 0.0001 mmol% (S/C = 1 000 000) and 100% conversion with 98% ee was obtained under 50 atm of initial H 2 pressure at room temperature for 30 hours. On further reduction of the catalyst loading to 0.00002 mol% (S/C = 5 000 000) the hydrogenation gave 91% conversion under an initial 100 atm of H 2 pressure at room temperature for 15 days. The enantio- selectivity of the reaction remained at 98% ee, showing that the catalyst was very stable. Encouraged by these results we investigated the catalysts Ir-( R )-SpiroPAP for the hydrogenation of functionalized ketones such as β -ketoesters. Previous reports in the literature have shown that the chiral RuX 2 (diphosphine) (X = Cl or Br) complexes are by far the most popular catalysts for the hydrogenation of β -ketoesters, 4 and the RuCl 2 (diphosphine)(diamine) complexes are inert for this hydrogenation. 3 a The major reason for the inertness may be that the RuCl 2 (diphosphine)(diamine) catalyst needs a strong base such as KO t Bu to activate it. However, the strong base enolizes the β -ketoester substrate instead of activating the catalyst. Because the aro- matic N – H of the catalysts Ir-SpiroPAP is more acidic than the aliphatic N – H of the catalysts RuCl 2 (diphosphine)(diamine), the catalysts Ir-SpiroPAP can be activated by a relatively weak base such as the enolate salt of a β -ketoester. We evaluated the catalysts Ir-SpiroPAP for the hydrogenation of β -ketoesters and found they are also highly e ffi cient for the hydrogenation of the challenging substrates β -aryl- β -ketoesters. Under the optimal reaction conditions (0.1 mol% Ir-( R )SpiroPAP, [KO t Bu] = 0.02 M; [substrate] = 1 M, 8 atm of initial H 2 pressure, in anhydrous EtOH at room temperature for 25 min to 4 hours), a range of β -aryl- β -ketoesters were hydrogenated by the catalyst Ir-( R )-SpiroPAP to yield the corresponding chiral β -hydroxy esters in 93 – 98% yields with 96 – 99.8% ee (Fig. 3). 2 b The TON ’ s of these hydrogenations were up to millions. For example, when the catalyst loading was reduced to 0.001 mol% (S/C = 100 000), the hydrogenation of ethyl 3-oxo-3-phenylpropanoate under 50 atm of initial H 2 pressure at room temperature for 19 hours a ff orded the chiral ethyl 3-hydroxy-3-phenylpropanoate in 98% yield with 98% ee. The catalyst loading can be further reduced to as low as 0.00067% mol% (S/C = 1 500 000) and the ...
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... Nevertheless, typical procedures toward the synthesis of chiral alcohols using asymmetric reduction of ketones and hydration of nitriles suffer from some drawbacks, such as the use of high atmospheric pressure, scarce heavy metals as catalysts, the need for inert atmosphere conditions and purification steps (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). For instance, (S)-4a was obtained through enantioselective hydrogenation of 2a using iridium as a catalyst under 15 atm pressure, inert atmosphere, after 20 h with ee 98% (13). ...
... Nevertheless, typical procedures toward the synthesis of chiral alcohols using asymmetric reduction of ketones and hydration of nitriles suffer from some drawbacks, such as the use of high atmospheric pressure, scarce heavy metals as catalysts, the need for inert atmosphere conditions and purification steps (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). For instance, (S)-4a was obtained through enantioselective hydrogenation of 2a using iridium as a catalyst under 15 atm pressure, inert atmosphere, after 20 h with ee 98% (13). Wessjohann and coworkers synthesized 4a as a racemic compound via the Reformatsky reaction catalyzed by chromium under an inert atmosphere (15). ...
Asymmetric synthesis of optically pure (S)-3-hydroxy-3-phenylpropanamide derivatives from o-, m- and p-substituted benzoylacetonitrile was achieved by two enzymatic one-pot protocols, the simultaneous and the sequential two-step linear cascade promoted by alcohol dehydrogenase (ADH) and nitrile hydratase (NHase). A set of commercially available ADHs and NHases were individually screened, followed by the investigation of the impact of the order of the biocatalyst addition and the effect of the substrate’s substituent. While NHases were able to hydrate o-, m-, and p-substituted electron withdrawing and electron donating substituents, the ADH was selective for the p-substituted ones. To overcome the absence of ADH catalytic activity towards beta-ketoamides, a less active NHase was employed, and the desired p-substituted products were obtained in high conversions (>99%) and ee (>99%) in the simultaneous and sequential cascade modes. Both strategies lead to optically pure (S)-3-hydroxy-3-phenylpropanamide p-substituted derivatives without the isolation of intermediates, minimizing the environmental impact and offering a greener approach.
... Fortunately, the corresponding chiral benzyl alcohols are indeed easy to access through well-developed asymmetric hydrogenation strategies. [47][48] The accessibility to construct an enantioenriched dialkyl carbinol center bearing two aliphatic substituents with minimally differentiated steric and electronic properties demonstrated that this reaction could supplement longstanding methods, including the kinetic resolution of racemic alcohols and asymmetric hydrogenation of ketones. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 This article presented here has been accepted for publication in CCS Chemistry and is posted at the © 2021 Chinese Chemical Society. ...
Chiral dialkyl carbinols and their derivatives are significant synthetic building blocks in organic chemistry and related fields. The development of convenient and efficient methods to access these
compounds has long been an important endeavor. Herein, we report a NiH-catalyzed reductive hydroalkylation and hydroarylation of enol esters and ethers. α-Oxoalkyl organonickel species were generated in situ in a catalytic mode and then participated in cross-coupling with alkyl or aryl halides. This approach enabled C(sp3)–C(sp3) and C(sp3)–C(sp2) bond formation under mild reductive conditions with simple operations, thereby boosting a broad substrate scope and good functional compatibility. Esters of enantioenriched dialkyl carbinols were accessed in a catalytic asymmetric version. Mechanistic studies demonstrated that this reaction proceeded through a syn-addition of Ni–H intermediate to an enol ester with high regio- and enantioselectivity.
... In this J o u r n a l P r e -p r o o f Journal Pre-proof contribution, Ir-complexes modified by potentially tridentate P,N,N ligands constitute a unique class of chiral catalysts due to their extremely high activity and selectivity, structural modularity and high substrate tolerance ( Figure 1). Recently, Zhou and coworkers developed spiro pyridine-aminophosphine (SpiroPAP) based Ir-catalysts that were utilized in the asymmetric hydrogenation of simple [8] and functionalized ketones (ketoesters [9,10,11], ketoacids [12], α-amino-ketones [13]) with outstanding activities (eg. TOF > 100 000 h -1 for acetophenone) and enantioselectivities (>99% ee). ...
A novel, highly modular approach has been developed for the synthesis of new chiral P,N,N ligands with the general formula Ph2P(CH3)CH(CH2)mCH(CH3)NHCH2CH2(CH2)nN(CH3)2 and Ph2P(CH3)CHCH2CH(CH3)NHCH2(CH2)n-2-Py (m, n = 0, 1). The systematic variation of their PN and NN backbone led to the conclusion that the activity, chemo- and enantioselectivity in the hydrogenation of α,β-unsaturated ketones are highly dependent on the combination of the two bridge lengths. It has been found that a minor change in the ligand's structure, i. e. varying the value of m from 1 to 0, can switch the chemoselectivity of the reaction, from 80% CO to 97% CC selectivity.
A pressure gauge was incorporated into a two‐chamber glass H‐tube to continuously monitor the pressure inside a reactor when working with gases. The ex situ generated H2, D2, acetylene and CO2 were tested in pressure gauge reactors, and calibration curves were plotted. A series of unsaturated compounds with two or more double C=C bonds accessible for hydrogenation were synthesized for hydrogenation. The hydrogenation proceeded well due to constant pressure control, and the desired products were isolated in good yields. The same hydrogenation procedures were then carried out using steel autoclaves to verify the results and compare them. Surprisingly, almost the same results were obtained, confirming the effectiveness of self‐made glass reactors. The hydrogenation mechanism was further investigated using D‐labeled reagents. The kinetics of hydrogenation was studied both in manometric glass reactors and in steel autoclaves, which showed a similar nature of the main process in both reaction units. Thus, the created reactors can be effectively used in barometric transformations instead of steel autoclaves in appropriate cases.
Chiral secondary alcohols, serving as essential structural motifs, hold significant potential for diverse applications. The exploration of effective synthetic strategies toward these compounds is both attractive and challenging. Herein, we present an asymmetric oxa‐Michael reaction involving aliphatic alcohols as nucleophiles and β‐fluoroalkyl vinylsulfones catalyzed by bifunctional phosphonium salt (BPS), achieving high yields and excellent enantioselectivities (up to 98 % yield and 98 % ee). Additionally, a sequential process including asymmetric oxa‐Michael and debenzylation, facilitated by BPS/Lewis acid cooperation, was revealed for synthesizing diverse chiral secondary alcohol compounds in high yields (81–88 %) with consistent stereoselectivities. Furthermore, mechanistic explorations and subsequent results unveiled that the enantioselectivity originates from hydrogen‐bonding and ion‐pair interactions between the BPS catalyst and the substrates.
Chlorohydrins and oxaheterocycles are synthetically valuable building blocks for diverse natural products and therapeutic substances. A highly efficient Ir/f-phamidol-catalyzed asymmetric hydrogenation of ω-chloroketones was successfully developed, and various chlorohydrins and oxaheterocycles were obtained divergently with excellent yields and enantioselectivities (up to >99% yield and >99% ee). Synthetic utilities of this divergent transformation were demonstrated by gram-scale synthesis of key intermediates of several enantiomerically enriched drugs via this catalytic methodology.
ConspectusCatalytic asymmetric hydrogenation is one of the most reliable, powerful, and environmentally benign methods for the synthesis of chiral molecules with high atom economy and has been successfully applied in the industrial production of pharmaceuticals, agrochemicals, and fragrances. The key to achieving highly efficient and highly enantioselective hydrogenation reactions is the design and synthesis of chiral catalysts.Our recent studies involving iridium complexes of bidentate chiral spiro aminophosphine ligands (Ir-SpiroAP) have revealed that adding another coordinating group on the nitrogen atom to form a tridentate ligand can provide catalysts with markedly higher stability, enantioselectivity, and efficiency. Specifically, chiral Ir-SpiroAP catalysts bearing an added pyridine group (designated Ir-SpiroPAP) exhibit high activity and excellent enantioselectivity in the asymmetric hydrogenation of a wide range of carbonyl compounds, including aryl ketones, β- and δ-ketoesters, α,β-unsaturated ketones and esters, and racemic α-substituted lactones, as well as highly electron-deficient alkenes such as α,β-unsaturated malonates and analogues. The efficiency of the Ir-SpiroPAP catalysts is extremely high: in the hydrogenation of aryl ketones, turnover numbers reach 4.5 million, which is the highest value reported to date for a molecular catalyst. Moreover, when a thioether or a bulky triarylphosphine group is added to afford tridentate ligands designated SpiroSAP and SpiroPNP, respectively, the resulting iridium catalysts show high efficiency and enantioselectivity for asymmetric hydrogenation of β-alkyl-β-ketoesters and dialkyl ketones, which are challenging substrates. Furthermore, chiral spiro catalysts containing an added oxazoline moiety (Ir-SpiroOAP) show high enantioselectivity for asymmetric hydrogenation of α-keto amides and racemic α-aryloxy lactones. The above-described catalysts have been used for enantioselective synthesis of chiral pharmaceuticals and other bioactive compounds.We have shown that chiral spiro ligands that combine a rigid skeleton with tridentate coordination stabilize iridium catalysts. The careful tailoring of the substituents on the ligand creates a chiral environment around the active metal center of the catalyst that can precisely discriminate between the two faces of a substrate carbonyl group. These factors are key for controlling the activity, enantioselectivity, and turnover numbers of asymmetric hydrogenation catalysts. We expect that catalysts based on iridium, and other transition metals, coordinated by tridentate chiral ligands with a rigid skeleton will find more applications in asymmetric hydrogenation and other asymmetric transformations.
In recent years, Pd-catalyzed cross-coupling reactions have been used widely as expeditious reactions in various fields of chemistry. Traditionally, these cross-coupling reactions have been carried out by using different phosphine ligands. Though the phosphine ligands have been extensively used, they suffer from many limitations like poor air, moisture, and thermal stability. Hence, in recent years phosphine-free ligands such as N-heterocyclic carbenes and amines have attracted countless attention in the field of catalysis. Unfortunately, the ligands having only N as a donor atom can activate aryl iodides and bromides, while aryl chlorides are less reactive. Hence, the P–N ligands containing functional moiety, with donor N or P atom have been prepared and used for different organic transformations. An even more effective mixed donor P, N-ligands have many advantages in asymmetric catalysis because of the distinctly different characteristics like a ‘soft’ P-ligand as a π-acceptor and a ‘hard’ N-ligand as a σ-donor. This compressive review highlights the results of the highly active ligands and complexes containing N in combination with P as a donor atom.
Herein, we report the first enantioselective total synthesis of the highly complex hamigeran diterpenoid (-)-hamigeran F and its rearrangement product. The synthetic strategy features key steps of asymmetric hydrogenation, Horner-Wadsworth-Emmons olefination, and intramolecular Friedel-Crafts acylation to construct the [6,6,5]-tricyclic skeleton bearing three consecutive stereocenters, a sequence of steps involving Rosenmund reduction, Wittig reaction, dihydroxylation to assemble the α-acetoxy ketone group, and an intramolecular aldol reaction to build the tetracyclic core structure.
