Highly Enantioselective Hydrogenation of <i>tetra</i> - and <i>tri</i> -Substituted α,β-Unsaturated Carboxylic Acids with <i>oxa</i> -Spiro Diphosphine Ligands

Abstract

Open AccessCCS ChemistryCOMMUNICATION1 Dec 2020Highly Enantioselective Hydrogenation of tetra- and tri-Substituted α,β-Unsaturated Carboxylic Acids with oxa-Spiro Diphosphine Ligands Gen-Qiang Chen#, Jia-Ming Huang#, Bi-Jin Lin, Chuan Shi, Ling-Yu Zhao, Bao-De Ma, Xiao-Bing Ding, Qin Yin and Xumu Zhang Gen-Qiang Chen# *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen 518000 Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen 518000 , Jia-Ming Huang# Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen 518000 , Bi-Jin Lin Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen 518000 , Chuan Shi Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen 518000 , Ling-Yu Zhao Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen 518000 , Bao-De Ma Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen 518000 , Xiao-Bing Ding Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen 518000 , Qin Yin Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen 518000 Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen 518000 and Xumu Zhang *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen 518000 https://doi.org/10.31635/ccschem.020.202000176 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesTrack Citations ShareFacebookTwitterLinked InEmail We herein present the design and synthesis of a structurally unique oxa-spirocyclic diphosphine ligand, termed as O-SDP. The diphosphine ligand O-SDP derived from oxa-spirocyclic diphenols (O-SPINOL) has a relatively larger bite angle compared with that of SDP, and O-SDP has been successfully applied in the ruthenium-catalyzed asymmetric hydrogenation of α,β-unsaturated carboxylic acids under mild reaction conditions. High yields and enantioselectivities were generally achieved for a wide range of substrates (up to 99% yield and >99% ee), and many of the resulting products are key intermediates of important drugs such as Sacubitril, Artemisinin, and Paroxetine. Download figure Download PowerPoint Introduction Asymmetric catalysis is a powerful tool for the rapid construction of single enantiomers both in the laboratory and on an industrial scale, and the development of new ligands plays a pivotal role in the generation and transfer of chirality.1–3 Due to their rigidity and stability, chiral spiro ligands, complementary to axially chiral biaryl ligands, have exhibited tremendous potential and efficacy in asymmetric transformations.4–8 Since the pioneering work by Chan, Jiang, and Sasai et al.,9–12 chiral spiro ligands have developed rapidly in transition metal catalysis. Based on 1,1'-spirobiindane-7,7'-diol (SPINOL), which was reported by Birman and co-workers in 1999,13,14 a great number of ligands such as SDP (spirocyclic diphosphine),15 SIDIM (spiro diimine),16 SpiroAP,17,18 SpiroPAP,19,20 SpiroBox,21,22 and SIPhox23 have been synthesized and applied by Zhou's group, rendering spirobiindane as a privileged scaffold in asymmetric transition metal catalysis.24 Other spiro diphenols have also been synthesized by Zhou, Zhang, Ding, and other groups.25–32 In 2018, we reported a novel and efficient synthesis and resolution of structurally interesting oxa-spirocyclic diphenols (O-SPINOL, >100 g scale), and the related ligand O-SpiroPAP showed excellent efficacy in the dynamic kinetic resolution of Bringmann's lactone.33 The crystal structure of O-SPINOL shows that the introduction of oxygen atoms to the spirocyclic moiety makes a great difference, and the distance between the two phenolic oxygens in O-SPINOL becomes longer compared to that same distance in SPINOL and other related spiro diphenols (Figure 1),13,14,31,32 which is expected to result in a larger bite angle34–40 and higher electron density at the P atoms of the corresponding diphosphine. Herein, we report the design and synthesis of O-SDP as rigid diphosphine with a wider bite angle compared with SDP and its synthetic applications. Figure 1 | Structure comparisons of related spiro diphenols. Download figure Download PowerPoint Results and Discussion Chiral diphosphine ligand O-SDP [(R)- 2] was synthesized from enantiopure (R)-O-SPINOL in high yields according to reported procedures,15,41 as shown in Scheme 1 (for details see the Supporting Information). Remarkably, the racemic diphosphine 2 can be expediently synthesized via the intermolecular SNAr reaction of compound 3, albeit with low yield (Scheme 1). Treatment of (rac)- 2a with equimolar amounts of Pd(CH3CN)2Cl2 provided palladium complex (rac)- 4 in high yield (Scheme 1). Scheme 1 | Synthesis of O-SDP and its palladium complex. Download figure Download PowerPoint A crystal of the complex PdCl2((rac)- 2a) suitable for X-ray diffraction was grown and analyzed. As can be seen from Figure 2, the complex has a square-planar configuration and the eight-membered heterometallocyclic ring formed by the chelation of O-SDP to palladium is highly rigid. In PdCl2((rac)- 2a)), the P-Pd-P bite angle is 99.2°, which is greater than that in PdCl2((R)-SDP) (92.7°)42, and PdCl2((R)-SFDP) (96.7°).43 The Pd-P (2.265 and 2.273 Å) and Pd–Cl (2.328 and 2.343 Å) bond lengths in PdCl2((rac)- 2a) are in the typical range for dichloropalladium complexes bearing diphosphine ligands.44 Figure 2 | XRD structure of the complex (rac)-4. Download figure Download PowerPoint Catalytic enantioselective hydrogenation of α,β-unsaturated carboxylic acids is a straightforward method for the synthesis of chiral carboxylic acids, which are important intermediates for the construction of biologically active compounds (Figure 3), including antidepressant drugs, paroxetine and femoxetine, JAK inhibitors, Gibberellins intermediates, the antidiabetic drug Ertiprotafib, the antimalarial drug Artemisinin, and Sacubitril, which is an antihypertensive drug used in combination with Valsartan. Over the past decades, various Ru(OAc)2(ligand)-type catalysts with chiral diphosphine ligands45–48 and Rh catalysts with chiral phosphorus or nitrogen-containing ligands49–52 have been developed for the hydrogenation of different α,β-unsaturated carboxylic acids in high enantioselectivities. However, the efficiencies of Ru and Rh catalysts are highly substrate dependent. The Ir-SIPHOX system53–55 gives good results for various tri-substituted and tetra-substituted substrates. However, it does not work for challenging cyclic tetra-substituted substrates.56,57 Figure 3 | Selected examples of bioactive compounds derived from chiral carboxylic acids. Download figure Download PowerPoint We evaluated the efficacy of O-SDP, as well as other diphosphine ligands, on the asymmetric hydrogenation of challenging substrate 5a, and the results are summarized in Table 1. Low conversion was achieved using SDP as the ligand (entry 1, Table 1). SegPhos, BINAP, MeO-BIPHEP, and JosiPhos could give good conversions and moderate ee values (entries 2–5, Table 1). It was good to determine that a series of O-SDP ligands could give excellent conversions and enantioselectivities (entries 6–10, Table 1). Table 1 | Evaluation of Various Diphosphine Ligands. The substrate scope of compound 5 was evaluated, and the result is summarized in Scheme 2. For substrates with electron-donating (Me, MeO) or electron-withdrawing groups (Cl, F) on the para position of the phenyl ring, the reaction smoothly proceeded to give the desired products in high yields and enantioselectivities ( 6b– 6e, Scheme 2). The reaction also tolerates meta and ortho substituents on the phenyl ring ( 6f– 6h, Scheme 2). 98% ee was achieved for the β-alkyl substrate 5i using (R)- 2e as the ligand and TFE as a solvent. The reaction also worked well for tri-substituted compound 5j (96% yield, 96% ee). Compound 6k was produced with 96% ee under standard conditions. The five-membered substrate 5l could also be hydrogenated with 97% yield and 94% ee. Scheme 2 | Substrate scope of cyclic unsaturated acids. Download figure Download PowerPoint Zhou's research works have shown that diphosphine with a larger bite angle generally furnish higher enantiocontrol in the hydrogenation of tiglic acids.30,43 Since O-SDP has a larger bite angle than BINAP,58 SDP, and SFDP, we expected comparable or better enantiocontrol in this reaction. Gratifyingly, for the hydrogenation of tiglic acid 7a or α-methyl cinnamic acid 7 b, O-SDP shows superior results (>99% ee obtained in both cases) in terms of enantioselectivity compared with BINAP, SDP, and SFDP (Scheme 3). However, there is not a definitive correlation between the bite angle and enantioselectivity for the hydrogenation of α-methyl cinnamic acid 7b. Scheme 3 | Bite angle effects in the hydrogenation of tiglic acid and α-methyl cinnamic acid. Download figure Download PowerPoint Substrate generality of α-alkyl cinnamic acid derivatives was then evaluated. Both electron-donating (MeO) and electron-withdrawing (F, Cl, Br, or CF3) substituents on the aryl ring at various positions were well tolerated, and the conversion and enantioselectivity were excellent throughout ( 8b– 8i, Scheme 4). Asymmetric hydrogenation of O-containing α,β-unsaturated acids was also examined (Scheme 5). Overall, excellent conversions and enantioselectivities were obtained for all tested α-aryloxy acid substrates ( 10a– 10f, quantitative yields, 91–95% ee). Besides, α-MeO-substituted cinnamic acid 9g is also a suitable substrate, providing the corresponding product 10g in 99% yield and 87% ee. 98% yield and 94% ee were achieved for the cyclic substrate 9h. Scheme 4 | Substrate scope of α-alkyl cinnamic acids. Download figure Download PowerPoint The ligand O-SDP has many potential applications in the synthesis of important drugs and bioactive compounds. Compound 12 is an intermediate for the blockbuster drug, Sacubitril,59,60 after screening of hundreds of chiral ligands, MandyPhos was utilized in the industrial synthesis of compound 12; however, modification of the phenyl group (Ar = 3,5-di-Me-4-MeO-Ph) was necessary to achieve a high dr value. Our ligand O-SDP (Ar = Ph) works well for the hydrogenation of compound 11 (91% yield, >99/1 dr, TON up to 30,000), whereas very poor selectivities were achieved with other diphosphine ligands such as SDP, BINAP, SegPhos, C3-TunePhos, and MeO-BIPHEP (Scheme 6). Scheme 6 | Application of O-SDP in the hydrogenation of Sacubitril intermediate 11. Download figure Download PowerPoint The ligand O-SDP also worked well for the hydrogenation of AA (artemisinic acid) 13 and DHAA (dihydroartemisinic acid) 14 was produced in high diastereoselectivity (Scheme 7, Eq. 1), where it can be used for the synthesis of antimalarial drug, Artemisinin.61 Compounds 6e and 6a are key intermediates of antidepressant drugs, paroxetine and femoxetine (Scheme 7, Eqs. 2 and 3).62 Moreover, our protocol provides a direct entry to the Gibberellins intermediate,63 which has been shown to normally necessitate multiple synthetic steps in an earlier report (Scheme 7, Eq. 4).57 Scheme 7 | Other synthetic elaborations of O-SDP. Download figure Download PowerPoint Conclusions In conclusion, a new series of chiral O-SDP were developed and applied in asymmetric catalysis. Compared with SDP, O-SDP possesses a much wider bite angle and has displayed outstanding performance in Ru-catalyzed asymmetric hydrogenation of challenging cyclic tetra-substituted α,β-unsaturated carboxylic acids. The ligand O-SDP also works well for various tri-substituted substrates. Notably, modifications on the phenyl group of O-SDP are unnecessary to achieve high enantioselectivity. The O-SDP ligand has great potential in the synthesis of blockbuster drugs such as Sacubitril, Artemisinin, and Paroxetine, as well as other bioactive compounds. The unique structure and property of O-SDP will attract further investigations in challenging asymmetric transformations, and the results will be reported in due course. Scheme 5 | Substrate scope of O-containing α,β-unsaturated acids. Download figure Download PowerPoint Supporting Information Supporting Information is available. Conflict of Interest The authors declare no competing interests. Funding Information G.-Q. 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