The chromanes have been respresnted an important subclass of benzopyran structural units, which are key core structures and widely distributed in many natural products, biologically active compounds and drugs [1]. Their great contributions as significant scaffolds have been exhibited with a broad range of biological activities, such as treatment of stomach, aldose reductase inhibitors, anti-cancer, anti-bacterial and anti-arrhythmic (Fig. 1) [2].

Owing to the great importance of these privileged chromanes motifs, much attraction has been obtained to develop efficient synthetic methods. Therefore, some asymmetric catalytic methodologies for the constrution of chiral chromanes promoted by transition metal catalysis and organocatalysis have been well established in the past decades [1i, 2b, 3-13], such as asymmetric cascade reactions involving ortho-hydroxycinnamaldehydes [1i, 3] or ortho-nitrovinylphenols [2b, 4] substrates, asymmetric intramolecular [4+2] cyclization of ortho-quinone methides with olefins [5] or aldehydes [6], asymmtric conjugate addition of alkynes to 3-alkoxycarbonylcoumarines [7], dynamic kinetic asymmetric acylation of 2-chromanols [8], intramolecular desymmetric aryl C—O coupling reaction of 2-(2-haloaryl)-1, 5-diols [9], asymmetric 6-exo-trig Michael addition-lactonization of enone-acid [10], intramolecular ylide annulation [11], allenylidene-ene reactions [12]. Asymmetric catalytic reduction is a direct and powerful synthetic methodology to construct chiral molecules [14]. However, there are limited asymmetric reduction examples concerning the synthesis of chiral chromanes [15, 16]. In 2017, Zhang and coworkers described a highly efficient Ir-catalyzed asymmetric hydrogenation of substituted 2H-chromenes and substituted benzo[e][1,2]oxathiine 2, 2-dioxides in high yields with excellent enantioselectivities [15a]. Zhou and coworkers realized Ni-catalyzed asymmetric (transfer) hydrogenation of α, β-unsaturated esters with excellent results, which involved the example of synthesis of chiral 4-substituted chromane [16]. Encouraged by these great achievements and in the continuation of our efforts in the field of asymmetric catalytic hydrogenation, we herein developed Rh-catalyzed asymmetric hydrogenation of (E)-2-(chroman-4-ylidene)acetates to afford a series of chiral 4-substituted chromanes with high yields and excellent enantioselectivities (up to 99% yield, 98% ee), the gram-scale hydrogenation could be proceeded efficiently in the presence of 0.02 mol% catalyst loading (TON = 5000) (Scheme 1).

We began our initial studies of Rh-catalyzed asymmetric hydrogenation of model substrate ethyl (E)-2-(chroman-4-ylidene)acetate 1a, which was investigated in the presence of various chiral diphosphine ligands, 50 atm H₂ in CH₂Cl₂. As shown in Table 1, the bisphosphine-thiourea ligands L1 and L2 were applied (Fig. 2), which were developed by our group [17], could promote this Rh-catalyzed asymmetric hydrogenation to provide the desired product 2a in full conversion and excellent enantioselectivities (>99% conversion, 95%–97% ee, Table 1, entries 1 and 2). The axially chiral bisphosphine ligands (S)-SegPhos and (S)-Binap displayed poor catalytic activity and asymmetric induction (5%–9% conversions, 18%–20% ee, Table 1, entries 3, 5). Although moderate enatioselectivities could be obtained employing (Rc, Sp)-DuanPhos and (S, S)-Me-DuPhos as the ligands, very poo conversions were given (6%–13% conversions, 56%–60% ee, Table 1, entries 4, 6). Among the ligands probed, the ligand ZhaoPhos L1 was proved to be the best with regard to both conversion and enantioselectivity for this Rh-catalyzed hydrogenation.

Solvents always played an important role in asymmetric catalytic reactions. As shown in Table 2, the Rh/ZhaoPhos L1-catalyzed asymmetric hydrogenation of model substrate ethyl (E)-2-(chroman-4-ylidene)acetate 1a was then investigated in different solvents. Interestingly, nearly these solvents provided the same enantioselectivity. We found that toluene, CH₂Cl₂ and 1, 2-dichloroethane (DCE) led to high conversions and excellent enantioselectivities (98% ~ >99% conversions, 97% ee, Table 2, entries 1, 3, 6). In addition, moderate to good conversions were observed with other polar solvents, such as tetrahydrofuran (THF), 1, 4-dioxane and ⁱPrOH (60%–82% conversions, Table 2, entries 8–10). Although MeOH, EtOH and CHCl₃ allowed this transformation to proceed with high enantioselectivities, 28%–40% conversions were detected (Table 2, entries 4, 5, 7). Therefore, CH₂Cl₂ was the optimal solvent for this Rh-catalyzed asymmetric hydrogenation. To our delight, when the hydrogen pressure was reduced from 50 atm to 10 atm, this hydrogenation could be still performed smoothly with the same results (>99% conversion, 97% ee, Table 2, entry 3 vs. entry 11).

After the optimized reaction conditions were established, we focused on the exploration of the substrate scope generality. These reaction results were summarized in Scheme 2, a variety of substituted (E)-2-(chroman-4-ylidene)acetates were hydrogenated to give the corresponding desired chiral 4-substituted chromanes. Whether the electron-deficient or electron-rich groups were at C6-position of the substrates, they were hydrogenated smoothly to prepare products (2b-2d) in high yields and excellent enantioselectivities (>99% conversion, 95%–97% yields, 96%–98% ee). In addition, other substrates with methyl or isopropyl ester groups were applied into this Rh-catalyzed asymmetric hydrogenation. The methyl (E)-2-(chroman-4-ylidene)acetate (1e) was hydrogenated to give the product (2e) with low conversion and moderate enantioselectivity (38% conversion, 30% yield, 82% ee). The isopropyl (E)-2-(chroman-4-ylidene)acetate (1f) with bulky steric hindrance was difficult to be hydrogenated in this catalytic system, and trace conversion was detected. The oxygen atom of the model substrate ethyl (E)-2-(chroman-4-ylidene)acetate 1a was switched to carbon atom forming substrate ethyl (E)-2-(3, 4-dihydronaphthalen-1 (2H)-ylidene)acetate 1g, which was hydrogenated well to afford product 2g with full conversion, 96% yield and 96% ee. In addition, the alkyl substrate 1h also gave the corresponding product 2h in high yield and moderate enantioselectivity (>99% conversion, 99% yield, 73% ee). However, the substrate (1i) with substituted group on the benzene ring at C7-position almost did not work in this reduction, trace conversion was observed.

Encourged by these promising results, the benzo-seven-membered substrate was further investigated in this catalytic system. And we found that ethyl (E)-2-(6, 7, 8, 9-tetrahydro-5H-benzo[7]annulen-5-ylidene)acetate 1j was an excellent substrate pattern, which was hydrogenated efficiently to provide the desired product 2j with >99% conversion, 97% yield and 94% ee (Scheme 3).

In order to demonstrate the synthetic utility of this asymmetric catalytic methodology, a gram-scale Rh/ZhaoPhos L1-catalyzed asymmetric hydrogenation of model substrate 1a was performed in the presence of 0.02 mol% catalyst loading (S/C = 5000) under 50 atm H₂, and product 2a was readily obtained in comparable yield nearly without loss of enantioselectivity (>99% conversion, 96% yield, 95% ee, Scheme 4a). The enantioenriched hydrogenation product 2a can be easily converted into other useful chiral molecules. For example, the ester group of the product 2a was hydrolyzed smoothly, affording the chiral carboxylic acid 3 in 84% yield and without loss of ee value (Scheme 4b) [18]. In addition, the reduction of product 2a with LiAlH4 furnished chiral alcohol 4 in nearly quantitative yield and 98% ee (Scheme 4b) [6b].

In conclusion, we successfully developed a highly efficient Rh/ZhaoPhos-catalyzed asymmetric hydrogenation of (E)-2-(chroman-4-ylidene)acetates to construct a series of chiral 4-substituted chromanes with high yields and excellent enantio-selectivities (up to 99% yield, 98% ee). Moreover, the gram-scale hydrogenation could be performed well in the presence of 0.02 mol% catalyst loading (TON = 5000), and hydrogenation product transformations were conducted to access other important compounds, such as chiral carboxylic acid and chiral alcohol.

The authors declare no competing financial interest.

We are grateful for the financial support from the National Natural Science Foundation of China (Nos. 21432007, 21502145, 21602172), Wuhan Morning Light Plan of Youth Science and Technology (No. 2017050304010307), the Fundamental Research Funds for and the Central Universities (No. 2042018kf0202), Shenzhen Nobel Prize Scientists Laboratory Project (No. C17783101), Science and Technology Innovation Committee of Shenzhen (No. KQTD 20150717103157174) and SZDRC Discipline Construction Program. The Program of Introducing Talents of Discipline to Universities of China (111 Project) is also appreciated.

Supplementary material related to this article canbefound, in the online version, at doi:https://doi.org/10.1016/j.cclet.2020.01.001.