Asymmetric Hydrogenation of Tetrasubstituted α,β-Unsaturated Ketones: Access to Chiral 2‑Substituted Cyclopentyl Aryl Ketones

Abstract

Asymmetric hydrogenation of tetrasubstituted alkenes is an important but challenging research topic. Herein, we report an efficient iridium-catalyzed asymmetric hydrogenation of tetrasubstituted α,β-unsaturated ketones for the synthesis of chiral 2-substituted cyclopentyl aryl ketones, an important chiral structural motif for the preparation of chiral pharmaceuticals and bioactive molecules. The reaction proceeded very well with good functional group compatibility and delivered the hydrogenated products in high yields and stereoselectivities (up to 99% yield, >20:1 dr and 99% ee). In addition, the reaction could be carried out on a gram-scale, and all four stereoisomers of the hydrogenated products bearing two contiguous stereocenters were obtained. Furthermore, the hydrogenated product can be transformed into the ERβ agonist Erteberel, and the reaction pathway was also studied via deuterium-labelling experiments.

Chiral cyclopentanes bearing two contiguous stereogenic centers are widely found in natural products and biologically active molecules and are also important building blocks, − in which chiral 2-substituted cyclopentyl aryl ketones are important members (Figure a). − For example, compound A has potential neuroleptic activity, and compound B is a selective diacyl glycerolacyltransferase-1 inhibitor. , Erteberel is an ERβ agonist developed by Eli Lily and Company, and its synthesis is derived from 2-arylcyclopentyl aryl ketone. However, examples for the efficient synthesis of chiral 2-substituted cyclopentyl aryl ketone are relatively rare, − and most of the reported methods suffer from low stereoselectivities and yields or require chiral starting materials and multiple steps. The importance of such a molecular structural motif makes the development of general and efficient methods for its synthesis an important goal in chemical synthesis.

1.

Selected examples of bioactive molecules and the catalytic asymmetric hydrogenation reactions. (a) Bioactive molecules containing or derived from 2-substituted cyclopentyl aryl ketones. (b) Asymmetric hydrogenation of tetrasubstituted α,β-unsaturated ketones.

The transition-metal-catalyzed asymmetric hydrogenation of tetrasubstituted alkenes provides direct access to useful chiral compounds bearing two contiguous stereogenic centers. − Comparing the asymmetric hydrogenation of di- and trisubstituted alkenes, the asymmetric hydrogenation of tetrasubstituted alkenes is more challenging and less reported. In 1995, a notable breakthrough for the asymmetric hydrogenation of tetrasubstituted alkenes came from Burk and co-workers, and since then the asymmetric hydrogenation of tetrasubstituted alkenes has gained much attention. However, the reported successful examples are heavily substrate dependent. Our group has focused on transition-metal-catalytic asymmetric hydrogenation reactions for many years, − and considering the importance of the chiral 2-substituted cyclopentyl aryl ketones, we designed an asymmetric hydrogenation of tetrasubstituted α,β-unsaturated ketones for the synthesis of such chiral compounds. Differing from acyclic α,β-unsaturated ketone, 2-substituted cyclopentyl aryl ketones are very prone to epimerization in the presence of acids or bases, so it is more challenging to obtain such chiral compounds in excellent results. − In 2012, May and co-workers reported a Rh-catalyzed asymmetric hydrogenation of tetrasubstituted α,β-unsaturated ketones for the synthesis of chiral 2-arylcyclopentyl aryl ketones (Figure b, top). The additive is necessary to suppress epimerization of the products and to improve the reactivity of the reaction. It also should be noted that in order to obtain the hydrogenated products with good results, an ortho-substituted group on the phenyl ring is essential. Considering that the iridium-catalyzed asymmetric hydrogenation of CC bonds usually proceeds under neutral reaction conditions and as additive-free, − we conceived it could suppress the epimerization of the products. Therefore, we reported herein an iridium-catalyzed asymmetric hydrogenation of tetrasubstituted α,β-unsaturated ketones for the synthesis of chiral 2-arylcyclopentyl aryl ketones as additive-free (Figure b, bottom).

The tetrasubstituted α,β-unsaturated ketone 1a was selected as the model substrate for this iridium-catalyzed asymmetric hydrogenation reaction (Table ). Dichloromethane (DCM), which always gave better results for the iridium-catalyzed asymmetric hydrogenation of alkenes, was used for the examination of the ligands. , First, the commercially available phosphine-oxazoline (PHOX) ligands L1-L4 were tested for the reaction (entries 1-4). To our delight, the reaction proceeded very well and delivered the hydrogenated product 2a in 97% ee with 18:1 dr when using L1 as the ligand (entry 1). Then, the axis-unfixed biphenylphosphine-oxazolines (BiphPHOX) developed by our group, which showed excellent performance in the iridium-catalyzed asymmetric hydrogenation of some tri-substituted alkenes, − were also examined for this reaction. However, no good results were obtained (see the Supporting Information for details). It is well known that the solvent usually has an important effect on the reaction, and so different solvents were investigated, with chlorobenzene giving the best result (99% conversion, >20:1 dr and 98% ee) (entry 6). The reaction did not proceed well when shortening the reaction time or reducing the catalyst loading (entries 9-11).

1. Reaction Conditions Screening .

^aReaction conditions: substrate 1a (0.2 mmol), [Ir­(cod)­(L)]­BAr_F (5 mol %), solvent (2 mL), H₂ (50 bar).

^bDetermined by ¹H NMR spectra.

^cDetermined by HPLC using a chiral column.

^d24 h.

^e[Ir­(cod)­(L1)]­BAr_F (3 mol %).

^f[Ir­(cod)­(L1)]­BAr_F (1 mol %).

With the optimized reaction conditions in hand (Table , entry 6), the substrate scope for this iridium-catalyzed asymmetric hydrogenation reaction was examined (Table ). First, the R¹ group was examined with R being a phenyl group, the optimized reaction conditions showed good functional group compatibility, and all the products were obtained with excellent results. When R¹ was a phenyl ring with different substituents at the para-position, the hydrogenated products 2b-f were obtained in excellent yields (95-99%), excellent diastereomeric ratios (>20:1 dr), and excellent enantioselectivities (97-99% ee), regardless of the electronic nature of the substituent on the phenyl ring. The substrates bearing the Cl or Me group at the meta-position on the phenyl ring could also give the desired hydrogenated products (2g and 2h) in quantitative yields with 15:1 and >20:1 dr, respectively, and with excellent enantioselectivities (98% ee). The asymmetric hydrogenation of a substrate with a piperonyl was hydrogenated in 92% yield with >20:1 dr and 98% ee (2i). A substrate substituted with 2-naphthyl gave the hydrogenated product (2j) with excellent results (99% yield, 19:1 dr and 97% ee). Furthermore, heteroaromatic rings, such as 2-thienyl and 3-methylthiophen-2-yl, were also tolerated in the reaction and provided the corresponding hydrogenated products (2k and 2l) in excellent yields (98%) with excellent diastereomeric ratios (>20:1 dr) and in 97% and 98% ee, respectively. In addition, substrates where R¹ was methyl, ethyloxy, or methylamino were also tested in the reaction, but the hydrogenated products were obtained with poor results (see the Supporting Information for details).

2. Substrate Scope .

^aReaction conditions: Substrate 1 (0.2 mmol), [Ir­(L1)­(cod)]­BAr_F (5 mol %), and PhCl (2 mL) under H₂ (50 bar) at 30 °C for 48 h; isolated yields; the dr values were determined by the crude ¹H NMR spectra; ee values were determined by HPLC using a chiral column.

^b[Ir­(L1)­(cod)]­BAr_F (10 mol %).

^cDCM as solvent.

Next, the substituted group R on the substrate was examined for this asymmetric hydrogenation reaction with R¹ being a phenyl ring (Table ). When R was a phenyl ring bearing different substituents at the para- or meta-position, the reaction proceeded very well and delivered the corresponding hydrogenated products (2m-2w) in excellent yields (94-99%) with excellent diastereomeric ratios (>20:1 dr) and excellent enantioselectivities (95−99% ee). A substrate with a fluorine at the ortho-position on the phenyl ring gave the hydrogenated product (2x) in 90% yield with >20:1 dr and with 93% ee. Substrates where R was a heteroaromatic ring such as 2-thienyl or alkyl methyl were also examined in the reaction, and to our delight, the corresponding hydrogenated products (2y and 2z) were obtained in satisfactory results. The absolute configuration of the product 2f was determined to be (1S,2R) by X-ray single crystal diffraction.

Some bioactive molecules bearing chiral cyclopentanes with two contiguous stereogenic centers possess trans-dihydrogen scaffolds, and the reported hydrogenation reaction only delivers the cis-dihydrogen as products. To expand the versatility of the developed method in the synthesis of chiral cyclopentanes bearing two contiguous stereogenic centers, and considering our group’s interest in stereodivergent systhesis, − we intended to synthesize all four stereoisomers of the hydrogenated products. We speculated that the hydrogenated product could be transformed into the trans-products via epimerization, as the cyclopentanes bearing two trans-dihydrogen stereogenic centers are thermodynamically stable. To our delight, with the addition of the organic base 1,5-diazabicyclo[4.3.0]­non-5-ene (DBU) and solvent (DMF/ethylene glycol) into the reaction mixture when the hydrogenation reaction was completed, the trans-product was prepared with excellent results (99% yield, >20:1 dr and 98% ee). Then, with a combination of the adjustment of the catalyst’s configuration and the epimerization of the hydrogenated products, all four stereoisomers were obtained with excellent results (Figure a).

2.

Access to all four stereoisomers and the derivatization of the hydrogenated products. (a) Access to all four stereoisomers. (b) Gram-scale reaction and derivatization. (c) Synthesis of benzo-fused tricyclic compound. (d) The synthesis of the ERβ agonist Erteberel.

To further explore the applications of the developed method, a gram-scale reaction and derivatization of the hydrogenated products were carried out (Figure b). The gram-scale reaction proceeded very well, giving the corresponding hydrogenated product in 96% yield with 98% ee and 14:1 dr, and the product could be obtained in 99% ee with >20:1 dr via recrystallization. The carbonyl of the hydrogenated product 2a can be reduced to the corresponding alcohol in the presence of NaBH₄, giving product 3 bearing three contiguous stereocenters in 99% ee with 10:1 dr. Product 2a could also be transformed to amide 4 via condensation and Beckmann rearrangement in 76% yield with >20:1 dr and 99% ee. Furthermore, the deuterated product 5 was obtained in 95% yield in the presence of the catalyst and D₂. − In addition, the benzo-fused tricyclic compound 6 was synthesized from the hydrogenated product 2w in the presence of H₃PW₁₂O₄₀ (Figure c). Finally, we also tried to synthesize the hydrogenated product 8, which is an important intermediate for the synthesis of the ERβ agonist Erteberel (LY500307) developed by Eli Lily and Company. However, when compound 7 was subjected to the standard reaction conditions, the hydrogenated product 8 was obtained with poor results. Through the ligand screening, the hydrogenated product 8 could be obtained in 98% yield with >20:1 dr and 91% ee when using L3 (Ph-PHOX) as the ligand (Figure d).

To investigate the reaction pathway of this transformation, a deuterium-labelling experiment was conducted (Figure ). When the reaction was conducted under D₂, deuterated product 2a- d was obtained, and the percentages of deuterium atoms on the hydrogenated alkene carbons were 88% and 86%, respectively (Figure a). In addition, H/D exchange occurred with the hydrogen atoms on the ortho-position on the phenyl ring adjacent to the carbonyl group. To verify the origin of the hydrogen atom on the hydrogenated alkene carbons of product 2a- d , deuterated substrate 1a- d was prepared and subjected to the standard reaction conditions in the presence of D₂ (Figure b). As a result, no hydrogen atom was observed at the hydrogenated alkene carbons of product 2a- d . These results indicate that the hydrogen atom on the hydrogenated alkene carbons in product 2a- d in Figure a originates from the hydrogen atom at the ortho-position of the phenyl ring adjacent to the carbonyl group.

3.

Deuterium-labelling experiments and the proposed reaction pathway for H/D exchange. (a) The reaction of 1a was performed in the presence of D₂. (b) The reaction of the deuterium-labelled substrate 1a- d was performed in the presence of D₂. (c) The reaction of 1l was performed in the presence of D₂. (d) The proposed reaction pathway for the H/D exchange.

In order to verify whether the H/D exchange process has an effect on the reactivity and stereoselectivity on the reaction, substrate 1l was subjected to the standard reaction conditions under a D₂ atmosphere. The reaction proceeded smoothly with no H/D exchange occurring and delivered the corresponding hydrogenated product 2l- d with >20:1 dr and 98% ee (Figure c). These results demonstrate that the H/D exchange process has no effect on the reactivity and stereoselectivity of the reaction. In addition, a possible reaction pathway for the H/D exchange was provided (Figure d). − First, the Ir­(III)-complex I is generated from the Ir­(I)-complex via oxidative addition in the presence of D₂. Complex I coordinates with substrate 1a to give complex II, which then transformed to the five-membered metallacycle III. Subsequently, H/D exchange in metallacycle III occurs to deliver complex IV. Finally, the deuterium-labelled product 1a- d ₁ is produced with regeneration of complex I. Product 1a- d ₁ undergoes the above process again to give product 1a- d .

In summary, we have developed an iridium-catalyzed asymmetric hydrogenation of tetrasubstituted α,β-unsaturated ketones, delivering a variety of 2-substituted cyclopentyl aryl ketones with excellent results (up to 99% yield, >20:1 dr and 99% ee). All four stereoisomers can be obtained by altering the catalyst configuration and epimerization of the hydrogenated products. The reaction could be carried out on a gram-scale, and the hydrogenated products can be easily derivatized. In addition, the developed method could be used for the efficient asymmetric synthesis of the ERβ agonist Erteberel developed by Eli Lily and Company. Furthermore, the reaction pathway was also studied via deuterium-labelling experiments.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/prechem.2c00010.

• Experimental procedures and characterization data for all reactions and products, including ¹H, ¹³C NMR, HRMS, and HPLC spectra, and crystallographic data for CCDC 2117619 (PDF)

The authors declare no competing financial interest.