Kinetic Resolution of Racemic 4-Substituted Chroman-2-ones Through Asymmetric Lactone Hydrogenation

Abstract

Open AccessCCS ChemistryRESEARCH ARTICLES29 Feb 2024Kinetic Resolution of Racemic 4-Substituted Chroman-2-ones Through Asymmetric Lactone Hydrogenation Xiong Wu, Hai-Tao Yue, Xiao-Dong Zuo, Xiao-Hui Yang, Pu-Cha Yan, Jian-Hua Xie and Qi-Lin Zhou Xiong Wu State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071 , Hai-Tao Yue State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071 , Xiao-Dong Zuo State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071 , Xiao-Hui Yang State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071 , Pu-Cha Yan *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Zhejiang Jiuzhou Pharmaceutical Co., Ltd., Taizhou, Zhejiang 318000 , Jian-Hua Xie *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071 and Qi-Lin Zhou State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071 https://doi.org/10.31635/ccschem.024.202303801 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Esters are abundant in natural and synthetic products and their conversion into primary alcohols holds great importance in fine chemical synthesis. However, achieving asymmetric hydrogenation (AH) of racemic esters with remote stereocenters via kinetic resolution (KR) remains a formidable challenge due to the difficulties associated with discerning spatially distant stereocenters. To address this issue, we have designed a hydroxy-assisted strategy that introduces a hydroxy group into racemic β-aryl esters to facilitate hydrogenation and enhance chiral discrimination through a lactone form. By employing chiral Ir-SpiroPAP catalysts, we achieved exceptional AH of racemic 4-substituted chroman-2-ones, lactone form of ortho-hydroxylated β-aryl esters, via KR, resulting in impressive selectivity factor (s) values of up to 600. This approach exhibited significant efficacy for racemic chroman-2-ones containing β-aryl, alkenyl, alkynyl, and alkyl groups, enabling the synthesis of chiral γ-aryl primary alcohols and the recovery of chiral β-aryl esters or chroman-2-ones, typically difficult to access using existing methods. The scalability and broad synthetic applications of this method were exemplified by successfully synthesizing chiral drugs (R)-fesoterodine and enrasentan, alongside various chiral intermediates essential for producing chiral drugs and natural products. These promising results highlight the potential of this approach as a powerful tool for synthesizing valuable chiral compounds. Download figure Download PowerPoint Introduction Esters are commonly present in natural and synthetic products, and their conversion to primary alcohols plays a significant role in the production of fine chemicals such as pharmaceuticals, agrochemicals, and fragrances.1,2 Catalytic reduction of esters using molecular hydrogen offers a sustainable and atom-economic alternative to traditional methods involving aluminum or boron hydrides in stoichiometric amounts.3 As a result, catalytic ester hydrogenation has gained considerable attention in recent decades, leading to the development of numerous transition metal catalysts that exhibit exceptional activity and efficiency in converting esters to primary alcohols.4–7 Notably, the utilization of chiral catalysts in the asymmetric hydrogenation (AH) of racemic esters has emerged as a promising strategy for the synthesis of chiral primary alcohols.7 This breakthrough significantly broadens the synthetic applications of ester reductions. However, successful instances, thus far, mainly involve AH of racemic α-substituted esters to access β-chiral primary alcohols via dynamic kinetic resolution (KR).8–15 Only one reported example exists for the AH of racemic esters with remote stereocenters situated nonadjacent to the ester group via KR for the enantioselective synthesis of chiral primary alcohols with a distal stereocenter from the δ-position. In 2014, our research demonstrated the remarkable efficacy of chiral iridium spiro pyridine–aminophosphine (Ir-SpiroPAP) ligand catalysts in catalyzing the AH of racemic δ-hydroxy esters via KR, allowing for the enantioselective synthesis of chiral 1,5-diols and the recovery of chiral δ-hydroxy esters with exceptional enantioselectivities (Figure 1c).16 However, the low reactivity of esters towards hydrogenation and the inherent complexities associated with discerning spatially distant stereocenters have hindered the development of efficient catalytic protocols for the AH of racemic esters containing remote stereocenters through KR. Figure 1 | Selected pharmaceuticals and bioactive natural products, representative methods for the enantioselective synthesis of chiral γ-aryl primary alcohols, and kinetic resolution (KR) of racemic esters via asymmetric ester hydrogenation. Download figure Download PowerPoint KRs are attractive strategies for achieving asymmetric transformations, as they provide enantioselective product generation and precursor recovery.17–21 Notably, the KR of racemic unsaturated substrates via AH has emerged as a prominent approach since its introduction by Noyori and coworkers22 in 1988. This method has successfully resolved a broad range of racemic unsaturated substrates, including olefins,23–27 imines,28,29 ketones,30–33 aldehydes,34 and aromatics,35 enabling efficient synthesis of diverse chiral compounds. However, despite significant progress in this field, there is a scarcity of methods for asymmetrically hydrogenating racemic substrates, particularly racemic esters with a remote stereocenter, through KR, although such transformations can provide new strategies and building blocks for the synthesis of fine chemicals, pharmaceuticals, and natural products.20 We have been actively involved in broadening the application of chiral Ir-SpiroPAP catalysts, renowned for their exceptional activity, efficacy, and enantioselectivity, in catalytic AH.36–38 As part of our program to extend the synthetic utility of these catalysts to racemic esters,9–11 we embarked on an investigation of the AH of racemic β-aryl esters containing a remote benzylic tertiary stereocenter (Figure 1d). Our objective was to utilize KR to selectively synthesize chiral γ-aryl primary alcohols while simultaneously recovering the corresponding ester precursors, chiral β-aryl esters. These compounds are highly valuable as fundamental building blocks for the synthesis of various bioactive chiral compounds. Noteworthy examples include muscarinic receptor antagonists like (R)-tolterodine39–42 and (R)-fesoterodine,43,44 endothelin receptor antagonist enrasentan,45,46 G-protein coupled receptor 40 (GPR40) partial agonist, AMG-837,47,48 as well as bioactive natural products such as cylindrophane F49 (Figure 1a). Despite extensive research on AH for the synthesis of chiral primary alcohols from allylic alcohols since Noyori's group50 pioneering work in 1987, the synthesis of chiral γ-aryl primary alcohols bearing a benzylic tertiary stereocenter is still limited.51–53 Current catalytic asymmetric methods for their preparation often involve laborious multistep sequences. These sequences typically begin with an enantioselective transformation on a functionalized substrate, followed by subsequent adjustment of the oxidation state of the resulting product. As illustrated in Figure 1b, typical examples include AH54,55 and conjugate reduction56 of β,β-disubstituted acrylic acids and derivatives, asymmetric conjugate addition to α,β-unsaturated compounds,57–59 asymmetric β-C-H arylation/alkylation of carboxylic esters and amides,60 asymmetric allylic alkylation61–63 and isomerization64,65 of allylic substrates, as well as asymmetric hydrovinylation of styrenes.66 However, all these methods yielded products that require further redox transformations to obtain the desired compounds. Additionally, successful examples of synthesizing chiral β-aryl acids/esters through AH are also scarce.67–70 Building upon the efficient KR of racemic δ-hydroxy esters16 and the observed facilitation of ester group reduction by γ- and δ-hydroxyl groups generated during the AH of ketoesters71–73 we developed a hydroxy-assisted strategy to enhance chiral discrimination and facilitate AH by introducing a hydroxy group into racemic esters containing a remote stereocenter (Figure 1d). Thus, ortho-hydroxylated racemic β-aryl esters were chosen as substrates to validate our approach. Since these esters form an equilibrium with their lactone forms under base-containing alcohol conditions, we investigated the direct AH of racemic 4-substituted chroman-2-ones, which served as readily available precursors.74 Utilizing the established procedure,16 we obtained moderate enantioselectivity (s-factor of 11) using the Ir-SpiroPAP catalyst (R)- 4a (Figure 1c). However, we made a noteworthy discovery that the catalyst (R)- 4e, incorporating a methyl group at the 6-position of the pyridine ring, exhibited exceptional performance with remarkable selectivity factor (s) values of up to 600 (Figure 1d). Specifically, this catalyst enabled highly efficient KR of diverse racemic chroman-2-ones, particularly those containing alkenyl, and alkynyl groups at the β-chiral stereocenters. This process resulted in the production of chiral γ-aryl primary alcohols and the recovery of chiral β-aryl esters or chroman-2-ones, which are challenging to achieve using existing alternative methods. This article presents the details regarding the AH of racemic 4-substituted chroman-2-ones through KR. Moreover, it discusses the significant implications of this approach in the synthesis of chiral drugs like (R)-fesoterodine and enrasentan, as well as various pertinent chiral intermediates within the field of chiral pharmaceuticals and natural products. Experimental Methods To a 20 mL hydrogenation vessel in an autoclave was added racemic substrates (1.0 mmol), catalyst (R)- 4e (0.5 mL, 0.002 mmol, 0.04 mmol/mL in MeOH), tBuOK (0.12 g, 1.0 mmol) and MeOH (1.5 mL). The autoclave was purged with hydrogen by pressurizing to 5 atm and releasing the pressure. This procedure was repeated three times and then pressurized to 10 atm of H2. The reaction mixture was stirred at room temperature (25–30 °C) until no obvious hydrogen pressure drop was observed, followed by quenching with 1 N HCl (2 mL), and subsequent extraction with ethyl acetate (5 mL × 3). The combined extracts were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with ethyl acetate/petroleum ether (V/V = 1:10 to 1:4) as an eluent to provide the products. The enantiomeric excess (ee) values of all compounds were determined by high-performance liquid chromatography (HPLC) analysis using chiral columns. Further details on experimentation and characterization data are available in the Supporting Information. Results and Discussion Our investigation began with the utilization of racemic 4-phenylchroman-2-one (rac- 1a) as the model substrate (Table 1). Initially, the hydrogenations were conducted using chiral spiro Ir-SpiroPAP catalysts (R)- 475 and KOtBu as the base in EtOH under 20 atm of H2 pressure at ambient temperature (25–30 °C). When catalyst (R)- 4a was used, the hydrogenation proceeded efficiently with a conversion of 47% achieved in 24 h (entry 1). Moreover, this hydrogenation yielded the hydrogenated product (R)- 3a with a 72% ee and the recovered β-aryl ester (S)- 2a with a 61% ee. Calculated values determined the selectivity factor (s) to be 11.76,a Building on this initial finding, we evaluated other chiral Ir-SpiroPAP catalysts (R)- 4b-e, and observed that the substituents on the pyridine ring of the catalysts (R)- 4 significantly influenced both hydrogenation reactivity and selectivity. Catalysts (R)- 4c and 4d, containing 4-tert-butyl and 5-methyl groups on the pyridine ring, did not exhibit enhanced selectivity (entries 3 and 4). However, catalysts (R)- 4e-g, with the substituent located at the 6-position of the pyridine ring, demonstrated improved results with s values ranging from 23 to 34 (entries 5–7). Notably, (R)- 4e exhibited particularly favorable selectivity (s = 34), resulting in the hydrogenated product (R)- 3a with 86% ee and 50% conversion, along with the recovery of ester (S)- 2a with 83% ee after 4 h of hydrogenation of rac- 1a (entry 5). We also evaluated other chiral spiro catalysts such as (R)- 5,77–79 (Ra,R)- 6,80 and (Sa,R,R)- 7.81 (Ra,R)- 6, incorporating a spiro oxazoline-aminophosphine ligand (SpiroOAP), which exhibited similar performance as (R)- 4e (entry 9), while (Sa,R,R)- 7, containing a spiro diphosphine (SDP) and chiral 1,2-diphenyl-1,2-ethylenediamine (DPEN) ligands, failed to yield the desired alcohol product (entry 10). The chiral ruthenium catalyst (R,R)- 8, known for its efficiency in the AH of racemic esters,12 achieved only moderate reactivity and selectivity (s = 11, entry 11). Subsequent investigations, employing different solvents and bases exhibited significant improvement in the resolution outcomes when conducting the process in MeOH with an increased amount of KOtBu (entries 12–17). Specifically, in the presence of 100 mol % KOtBu in MeOH for 2 h, the chiral alcohol product (R)- 3a and the recovered ester (S)- 2a were obtained with 91% ee and 88% ee, respectively, accompanied by 50% conversion and an improved s value of 62 (entry 17). Moreover, by reducing the catalyst loading of (R)- 4e to 0.1 mol %, the AH of rac- 1a achieved a conversion of 49% within 8 h, exhibiting consistent selectivity without any noticeable decrease ((R)- 3a, 91% ee; (S)- 2a, 88% ee, s = 62, entry 21). Importantly, the AH of rac- 2a using (R)- 4e under the given conditions produced comparable results (8 h, 49% conversion, (R)- 3a, 46% yield, 90% ee; (S)- 2a, 47% yield, 88% ee; s = 59, entry 22). These results highlighted the similarity between the direct hydrogenation of racemic 4-substituted chroman-2-ones and the ring-opening of racemic β-aryl esters. Table 1 | Optimization of the Reaction Conditions for Asymmetric Hydrogenation Entry Cat* Base Solvent Time (h) Conv (%)b ee (%)c Sd (R)- 3a (S)- 2a 1 (R)- 4a KOtBu EtOH 24 47 72 61 11 2 (R)- 4b KOtBu EtOH 6.5 47 67 60 9 3 (R)- 4c KOtBu EtOH 32 43 65 50 7 4 (R)- 4d KOtBu EtOH 31 42 68 49 8 5 (R)- 4e KOtBu EtOH 4 49 86 83 34 6 (R)- 4f KOtBu EtOH 4 47 82 76 23 7 (R)- 4g KOtBu EtOH 8 43 85 64 24 8 (R)- 5 KOtBu EtOH 12 48 74 70 14 9 (Ra,R)- 6 KOtBu EtOH 32 48 84 82 29 10 (Sa,R,R)- 7 KOtBu EtOH 32 >5 – – – 11 (R,R)- 8 KOtBu EtOH 24 46 70 64 11 12 (R)- 4e NaOtBu EtOH 4 49 85 81 31 13 (R)- 4e LiOtBu EtOH 4 53 78 89 24 14 (R)- 4e K2CO3 EtOH 8 55 80 65 18 15 (R)- 4e KOtBu MeOH 7 50 90 89 57 16 (R)- 4e KOtBu nPrOH 3 53 88 82 40 17e (R)- 4e KOtBu MeOH 2 50 91 88 62 18f (R)- 4e KOtBu MeOH 12 42 93 68 56 19g (R)- 4e KOtBu MeOH 2 53 80 92 29 20h (R)- 4e KOtBu MeOH 4 45 90 78 45 21i (R)- 4e KOtBu MeOH 8 49 91 88 62 22j (R)- 4e KOtBu MeOH 8 49 90 88 59 aReaction conditions: 2.0 mmol scale, [rac- 1a] = 0.5 M, 0.5 mol % of catal., [base] = 0.1 M, Solvent (4.0 mL), room temperature (25–30 °C). bDetermined by 1H NMR. cDetermined by HPLC using chiral columns. dCalculated conversion (C) and selectivity factors (s): C = ee 2a/(ee 2a + ee 3a), s = ln[(1 − C)(1 − ee 2a)]/ln[(1 − C)(1 + ee 2a)] (see, footnote a). e[KOtBu] = 0.5 M. f0 °C, [KOtBu] = 0.5 M. g50 °C, [KOtBu] = 0.5 M. h10 atm, [KOtBu] = 0.5 M. i0.1 mol % of (R)- 4e, [KOtBu] = 0.5 M. jUsed rac- 2a as a substrate, [KOtBu] = 0.5 M. 1H NMR, proton nuclear magnetic resonance; HPLC, high-performance liquid chromatography. Under these optimized conditions, we investigated the applicability of the method to a series of racemic 4-arylchroman-2-ones rac- 1a-r (Scheme 1). These AHs yielded chiral primary alcohols (R)- 3a-r with 81–99% ee, along with the recovery of optically active methyl esters (S)- 2a-r with 82–98% ee, at 46–53% conversions. Notably, these transformations exhibited excellent s values ≥600. Substrates with substituents at positions 5 and 8 of the chromanone ring exhibited enhanced selectivity. Particularly, rac- 1j, containing 5,8-dimethyl groups displayed exceptional selectivity with an s value up to >600. Consequently, this led to the yield of chiral primary alcohol (R)- 3j and the recovery of ester (S)- 2j with 89% ee and >99% ee at 49% conversion. Furthermore, higher selectivity was observed for 4-arylchroman-2-ones with 4-methyl (rac- 1k, s = 125) and 2-methoxy (rac- 1n, s = 210) groups at the 4-phenyl ring. Scheme 1 | Asymmetric hydrogenation (AH) of racemic 4-arylchroman-2-ones rac-1 via kinetic resolution (KR). Reaction conditions: 1.0 mmol scale, [rac-1] = 0.5 M, 0.1 mol % of catalyst, [base] = 0.5 M, Solvent (2.0 mL), room temperature (25–30 °C). The conversions were determined by 1H NMR, isolated yields, and the ee values were determined by HPLC using chiral columns. 1H NMR, proton nuclear magnetic resonance; HPLC, high-performance liquid chromatography. Download figure Download PowerPoint Motivated by the remarkable outcomes achieved with catalyst (R)- 4e, we embarked on an investigation into the AH of racemic 4-alkenylchroman-2-ones rac- 9, aiming to produce chiral primary alcohols and β-aryl esters with alkenyl-substituted tertiary benzylic stereocenters (Scheme 2). Replicating similar reaction conditions, our initial focus was directed toward the hydrogenation of racemic 4-styrylchroman-2-one (rac- 9a). This reaction led to the production of chiral primary alcohol (R)- 10a in 49% yield and 89% ee, along with chroman-2-one (S)- 9a in 50% yield and 88% ee (50% conversion, s = 50). These outcomes align with those obtained from the AH of racemic 4-arylchroman-2-ones rac- 1. Additionally, it is worth noting that no over-hydrogenation product was observed, affirming the inertness of (R)- 4e towards double bonds within the β-alkenyl group under the employed hydrogenation conditions. Consequently, our investigation was expanded to encompass various racemic 4-alkenylchroman-2-ones rac- 9b-l, yielding chiral primary alcohols (R)- 10b-l (89–96% ee) and the recovery of chroman-2-ones (S)- 9b-l (88–94% ee) with exceptional ee values and selectivity factors (s = 50–151) at 47–51% conversions. Among the substrates examined, those featuring a methoxy group at the 8-position of the chromanone ring or a bromine or methoxy group at the 4-phenyl ring showed significantly higher selectivity, with a maximum s value of 151, observed for the hydrogenation of rac- 9g. Scheme 2 | Asymmetric hydrogenation (AH) of racemic 4-alkenylchroman-2-ones rac-9 via kinetic resolution (KR). Reaction conditions: 1.0 mmol scale, [rac-9] = 0.5 M, 0.1 mol % of catal., [base] = 0.5 M, Solvent (2.0 mL), room temperature (25–30 °C). The conversions were determined by 1H NMR, isolated yields, and the ee values were determined by HPLC using chiral columns. 1H NMR, proton nuclear magnetic resonance. Download figure Download PowerPoint A subsequent investigation was conducted to achieve the AH of racemic 4-alkynylchroman-2-ones rac- 11, aiming to obtain optically active chiral primary alcohols and β-aryl esters with alkynyl-substituted tertiary benzylic stereocenters (Scheme 3). Compared to other unsaturated bonds like C=C and C=O, the C≡C bond exhibited higher activity in the catalytic reduction reactions.82–85 Consequently, achieving AH of the ester group in 4-alkynyl substituted β-aryl esters presented significant challenges. Under identical reaction conditions, the AH of racemic 4-(prop-1-yn-1-yl)chroman-2-one (rac- 11a) was investigated. The catalyst (R)- 4e also demonstrated high selectivity in hydrogenating the ester group while preserving the triple bond of the alkynyl moiety. As a result, chiral primary alcohol (R)- 12a was obtained in 48% yield and 89% ee. Simultaneously, chiral chroman-2-one (S)- 11a was recovered with 50% yield and 88% ee (49% conversion, s = 49). Subsequently, various racemic 4-alkynylchroman-2-ones rac- 11b-o were examined directly using the catalyst (R)- 4e under comparable reaction conditions. These hydrogenations produced chiral primary alcohols (R)- 12a-o chroman-2-ones (S)- 11a-o with 89–98% ee and 86–96% ee, respectively, and at 43–51% conversions with s values of up to 392. These results indicated that substrates with bulky alkyl groups or 4-bromophenyl substituents in their alkynyl moieties exhibited higher selectivity factors, with s values of 128 and 392, respectively, observed for the hydrogenation of the alkyl-alkynyl substrate rac- 11c and the aryl-alkynyl substrate rac- 11g. However, the introduction of substituents on the phenyl ring slightly reduced the selectivity factors (s = 42–74). Scheme 3 | Asymmetric hydrogenation (AH) of racemic 4-alkynylchroman-2-ones rac-11 via kinetic resolution (KR). Reaction conditions: 1.0 mmol scale, [rac-11] = 0.5 M, 0.1 mol % of catal., [base] = 0.5 M, Solvent (2.0 mL), room temperature (25–30 °C). The conversions were determined by 1H NMR, isolated yields, and the ee values were determined by HPLC using chiral columns. 1H NMR, proton nuclear magnetic resonance; HPLC, high-performance liquid chromatography. Download figure Download PowerPoint The substrate scope was further expanded to include racemic 4-alkylchroman-2-ones rac- 13 (Scheme 4). Using optimized conditions, a range of 4-alkylchroman-2-ones rac- 13a-j underwent hydrogenation with (R)- 4e to produce chiral primary alcohols (R)- 14a-j (86–96% ee) and chroman-2-ones (S)- 13a-j (83–93%) with good to excellent enantioselectivities and s values of up to 131 at 41–51% conversions. Generally, substrates with bulkier 4-alkyl groups exhibited higher selectivity the substrate rac- containing a yielded chiral primary alcohol (R)- in 47% yield and ee, along with the recovery of chroman-2-one (S)- in 49% yield with ee, at conversion with a s value of Notably, substrates rac- with groups demonstrated significant selectivity factors ranging from to resulting in chiral primary alcohols (R)- and chroman-2-ones (S)- with benzylic stereocenters with ee and ee, This approach offers an efficient method for chiral compounds containing benzylic which as in Scheme 4 | Asymmetric hydrogenation (AH) of racemic 4-alkylchroman-2-ones via kinetic resolution (KR). Reaction conditions: 1.0 mmol scale, = 0.5 M, 0.1 mol % of catal., [base] = 0.5 M, Solvent mL), room temperature (25–30 °C). The conversions were determined by 1H NMR, isolated yields, and the ee values were determined by HPLC using chiral columns. 1H NMR, proton nuclear magnetic resonance; HPLC, high-performance liquid chromatography. Download figure Download PowerPoint To the scalability and applicability of this we conducted enantioselective hydrogenations and the resulting products as chiral intermediates for the enantioselective synthesis of pharmaceuticals and natural products (Scheme 5). hydrogenation of rac- was by using the catalyst (S)- 4e under optimized reaction conditions. Subsequently, the resulting reaction mixture was with to provide (S)- in 50% yield and ee, along with the recovery of chroman-2-one (R)- with yield and 91% ee (Scheme The recovered (R)- as a chiral for the enantioselective synthesis of a muscarinic receptor antagonist employed in Additionally, the hydrogenated product (S)- be into its via 3 to hydrogenation of rac- using catalyst (S)- 4e resulted in the production of (S)- with 48% yield and 89% ee, and the recovery of ester (R)- in yield with ee (Scheme The recovered ester (R)- was reduced with (R)- in (S)- and (R)- as intermediates for the enantioselective synthesis of such as and its Furthermore, a hydrogenation of rac- using catalyst (R)- 4e chiral alcohol (R)- and ester (S)- 15 with 50% yield and 91% ee, 47% yield and ee, (Scheme The recovered ester (S)- 15 underwent with followed by a to the group from the phenyl ring, to produce ester (S)- 16 with The yielding ester (S)- 16 is a valuable chiral for the synthesis of a and Moreover, the hydrogenation of rac- bearing a tertiary benzylic stereocenter, proceeded with catalyst (S)- 4e (Scheme of the reaction mixture with the hydrogenated product (S)- was obtained in 50% yield with 90% ee, while ester (R)- was recovered in 47% yield with ee. Subsequently, using the procedure to the group from the phenyl ring, ester (R)- was to ester (S)- as a chiral for a receptor with 90% Scheme 5 | synthesis of the chiral intermediates of (R)- and (R)- and and Download figure Download PowerPoint Moreover, the recovered chiral β-aryl esters bearing tertiary benzylic stereocenters remarkable as chiral building blocks in the synthesis of chiral pharmaceuticals and natural products. To their synthetic we ester (R)- into muscarinic antagonist for (Scheme The conversion by (R)- to a reduction of its ester group using an excess of yielding (R)- in Subsequently, of (R)- with over under hydrogen followed by using successfully (R)-fesoterodine in Subsequently, we employed ester (S)- which was using (R)- 4e as the catalyst for the synthesis of enrasentan, an antagonist of endothelin The of (S)- and by in the presence of an reaction leading to the of hydroxy ester with (Scheme A subsequent of hydroxy ester by led to the of product in This was followed by a reaction involving with and of the resulting hydroxy group with with Thus, a procedure for the enantioselective synthesis of from ester (S)- was Additionally, we conducted a synthesis of employing ester (S)- (Scheme with the of ester (S)- using followed by the resulting product with methyl resulting in the of (S)- 23 in Subsequently, a of (S)-

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