Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of Chiral β‑Borylated Carboxylic Esters via NickelCatalyzed Asymmetric Hydrogenation Zhengyu Han,†,§ Gang Liu,†,§ Xianghe Zhang,† Anqi Li,† Xiu-Qin Dong,*,† and Xumu Zhang*,‡,† †
Key Laboratory of Biomedical Polymers, Engineering Research Center of Organosilicon Compounds & Materials, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, P. R. China ‡ Department of Chemistry, Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen, Guangdong 518055, P. R. China
Downloaded by ALBRIGHT COLG at 14:58:15:678 on May 22, 2019 from https://pubs.acs.org/doi/10.1021/acs.orglett.9b00994.
S Supporting Information *
ABSTRACT: The highly efficient Ni-catalyzed asymmetric hydrogenation of β-boronic ester substituted-α,β-unsaturated carboxylic esters was successfully developed using (S,S)-Ph-BPE as the ligand. A series of chiral β-borylated carboxylic esters were obtained with high yields (94%−99% yields) and excellent enantioselectivities (89%− 99% ee). The gram-scale asymmetric hydrogenation with a low catalyst loading (0.25 mol %) and synthetic transformation of hydrogenation product demonstrated the great synthetic utility of this methodology.
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neboronic ester. The pioneering work of nickel-catalyzed reduction reported by Hamada,8 Zhou,9 Chirik,10 and our group11 mainly focused on the reduction of amino ketones, α,β-unsaturated carboxylic esters, hydrazones, ketimines, and enamines. To the best of our knowledge, the nickel-catalyzed asymmetric hydrogenation of β-boronic ester substituted α,βunsaturated carboxylic esters is still unexplored. In continuation of our studies, we herein successfully developed nickelcatalyzed asymmetric hydrogenation of β-boronic ester substituted α,β-unsaturated carboxylic esters with up to 99% yield and 99% ee (Scheme 1). The possible reaction mechanism was revealed according to deuteration experiment results.
hiral organoboron compounds have been regarded as an important class of synthetic precursors for the construction of complicated chiral molecules, which went through the efficient formation of the C−Y (Y = C, N, O, etc.) bond from the carbon−boron bond.1,2 Increasing effort has been devoted to the efficient synthesis of chiral organoboron compounds. Some important methods including hydroboration reactions of alkenes,3 metal-catalyzed or metal-free boration reactions of electron-deficient alkenes,4 have been well established to construct the chiral α-boron compounds. Some other synthetic strategies such as lithiation−borylation,5 kinetic resulotion of borylated carboxylic esters,6 and asymmetric hydrogenation7 were also developed. Although some progress has been made, it is still necessary to develop a new and efficient method to synthesize these useful chiral organoboron compounds with high optimal purity. Among the above synthetic strategies, transition-metalcatalyzed asymmetric hydrogenation is a powerful and important method for the synthesis of chiral boronic compounds,7 which always exhibited excellent stereoselectivity and high efficiency with the potential of industrialization. However, the asymmetric hydrogenation was mainly focused on the precious transition metal catalysts based on rhodium7a−c,i and iridium,7d−g which could address the difficulties of high costs and limited resources in nature. Cheap and earth-abundant transition-metal-catalyzed asymmetric hydrogenation of alkenylboronates has always been a goal for chemists to pursue. In 2017, Lu and co-workers reported the cobalt-catalyzed sequential hydroboration/hydrogenation of internal alkynes to obtain chiral boronates, which was a great breakthrough in this field.7h Based on our longstanding research in this field of asymmetric hydrogenation, therefore, we are devoted to developing a cheap first-row transition-metal-catalyzed asymmetric hydrogenation of alke© XXXX American Chemical Society
Scheme 1. Ni-Catalyzed Asymmetric Hydrogenation of βBoronic Ester Substituted α,β-Unsaturated Carboxylic Esters
In our initial study, we utilized ethyl (Z)-3-phenyl-3(4,4,5,5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) acrylate 1a as the model substrate to investigate bisphosphine ligands (Figure 1) in this nickel-catalyzed asymmetric hydrogenation. In order to achieve good solubility of the Ni(OAc)2/diphosphine ligand catalytic system, the catalyst was generated in stiu by mixing Ni(OAc)2/diphosphine ligand in MeOH. As shown in Table 1, Received: March 21, 2019
A
DOI: 10.1021/acs.orglett.9b00994 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Table 2. Screening Solvents for Ni-Catalyzed Asymmetric Hydrogenation of Ethyl (Z)-3-Phenyl-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl) acrylate 1aa
Figure 1. Structures of chiral bisphosphine ligands.
Table 1. Screening Ligands for Ni-Catalyzed Asymmetric Hydrogenation of Ethyl (Z)-3-Phenyl-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl) Acrylate 1aa
entry
solvent
conv (%)b
ee (%)c
1 2 3 4 5 6 7 8 9 10 11d
MeOH EtOH/MeOH = 10:1 TFE/MeOH = 10:1 HFIP/MeOH = 10:1 toluene/MeOH = 10:1 hexane/MeOH = 10:1 CHCl3/MeOH = 10:1 TFE/MeOH = 40:1 HFIP/MeOH = 40:1 HFIP HFIP
Trace Trace 45 33 NR NR NR 62 66 71 >99
NA NA 75 83 NA NA NA 93 94 95 95
a
entry
ligand
conv (%)b
ee (%)c
1 2 3 4 5 6 7
(S)-Bianpine (S)-BINAP (Rc,Sp)-Duanphos t Bu-Josiphos (S,S)-Me-Duphos (S,S)-Ph-BPE (S)-Segphos
10 Trace 14 13 Trace 45 10
54 NA 31 60 NA 75 65
Reaction condition: 0.1 mmol 1a in 1.0 mL solvent, 1.0 mol % Ni(OAc)2/(S, S)-Ph-BPE, 80 atm H2, 80 °C. bDetermined by 1H NMR analysis. cDetermined by HPLC analysis using a chiral stationary phase. dReaction time is 48 h. HFIP is hexafluoroisopropanol. NR = no reaction. NA = not available.
conversions, 93%−94% ee, Table 2, entries 8−9 vs entries 3−4). In order to obtain a better result, the ratio of methanol was further decreased, and 71% conversion and 95% ee were obtained in pure hexafluoroisoporpanol (Table 2, entry 10). When the reaction time was prolonged to 48 h, this hydrogenation was fully finished (>99% conversion, 95% ee, Table 2, entry 11). With the optimized reaction conditions in hand, we focused on the exploration of the substrate generality of this Ni/(S,S)Ph-BPE-catalyzed asymmetric hydrogenation of β-boronic ester substituted α,β-unsaturated carboxylic esters. These reaction results were summarized in Scheme 2. When the carboxylic ester group was changed from ethyl ester (1a) to methyl ester (1b), n-propyl ester (1c), or isopropyl ester (1d), these reactions proceeded smoothly to prepare the corresponding hydrogenation products (2a−2d) with full conversion, 99% yield, 94%−97% ee. These results indicated that the size of the carboxylic ester group has a slight impact on this asymmetric hydrogenation. A series of β-aryl-β-boronic ester substituted α,β-unsaturated esters were then investigated. The substrates bearing an electron-withdrawing (1e−1g), electron-donating (1h−1i, 1k), or electron-neutral (1j) group on the phenyl ring were hydrogenated well to give hydrogenation products (2e− 2k) with excellent results (>99% conversion, 94%−99% yields, 91%−99% ee). We found that the position of the substituted group on the phenyl ring has little influence on the reactivity and enantioselectivity. To our delight, the alkyl substrate (1l) can be smoothly converted to the hydrogenation product (2l) with >99% conversion, 94% yield, and 89% ee. To further investigate the mechanism of this Ni/(S,S)-PhBPE-catalyzed asymmetric hydrogenation, deuterium labeling experiments were carried out. As shown in Scheme 3, the asymmetric hydrogenation of methyl (Z)-3-phenyl-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl) acrylate 1b was explored in (CF3)2CDOD (D-HFIP) solvent. The hydrogenation product 2b-D was obtained with 61% deuteration at the αposition of the methyl ester group. This hydrogenation was conducted in the presence of 75 atm of D2 and HFIP; the
a
Reaction conditions: 0.1 mmol of 1a in 1.0 mL of TFE, S/C = 100, 80 atm of H2, 80 °C, 24 h. The catalyst was precomplexed in MeOH (0.1 mL for each reaction vial). bDetermined by 1H NMR analysis. c Determined by HPLC analysis using a chiral stationary phase. TFE is trifluoroethanol. NA = not available.
(S)-Binapine, (Rc,Sp)-Duanphos, tBu-Josiphos, and (S)-Segphos gave very poor conversion and poor to moderate enantioselectivities (10%−14% conversions, 31%−65% ee, Table 1, entries 1, 3−4, 7). (S)-BINAP and (S,S)-Me-Duphos almost did not promote this hydrogenation, and only trace product was detected (Table 1, entries 2, 5). To our delight, (S,S)-Ph-BPE provided an inspiring result that included moderate conversion and enantioselectivity being achieved (45% conversion, 75% ee, Table 1, entry 6). Compared to other bisphosphine ligands mentioned above, both the reactivity and enantioselectivity were greatly improved. Having found the optimal ligand (S,S)-Ph-BPE, we started to investigate the solvent effect of this Ni-catalyzed asymmetric hydrogenation of model substrate 1a (Table 2). The protic solvents, such as methanol or ethanol, led to trace conversion (Table 2, entries 1−2). This asymmetric transformation did not occur in toluene, CHCl3, and hexane (Table 2, entries 5− 7). When the strong protic solvent hexafluoroisopropanol (HFIP) was applied, better enantioselectivity than that using trifluoroethanol (TFE) was provided (Table 2, entry 4 vs entry 3). We noticed that methanol is an unfavorable solvent for this hydrogenation (Table 2, entry 1). We began to reduce the ratio of methanol in the reaction system, and higher conversions and excellent enantioselectivities were obtained in trifluoroethanol and hexafluoroisoporpanol (62%−66% B
DOI: 10.1021/acs.orglett.9b00994 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Scope Study for the Asymmetric Hydrogenation of (Z)-β-Boronic Ester Substituted α,β-Unsaturated Carboxylic Estersa
Scheme 4. Asymmetric Hydrogenation of (E)-1a
Scheme 5. Gram-Scale Ni-Catalyzed Hydrogenation of (Z)1b and Synthetic Transformation of Product 2b
high conversion and excellent enantioselectivity (92% conversion, 95% ee). As shown in Scheme 5b, synthetic transformation of product 2b was conducted to further demonstrate the synthetic utility. The chiral lactone 3 was easily available through three steps with 67% overall yield and without any loss of ee value.12 Moreover, compound 3 can be efficiently converted to chiral γ-butyrolactone 4,12 which is widely distributed in natural products.13 In conclusion, the Ni/(S,S)-Ph-BPE-catalyzed asymmetric hydrogenation of β-boronic ester substituted α,β-unsaturated carboxylic esters was successfully developed; various chiral βborylated carboxylic esters can be obtained with excellent results (94%−99% yields, 89%−99% ee). The gram-scale asymmetric hydrogenation was performed well in the presence of only a 0.25 mol % catalyst loading. Furthermore, the important intermediate can be easily obtained through this asymmetric catalytic methodology. Further investigations on nickel-catalyzed asymmetric hydrogenation are in progress in our lab.
a
Reaction conditions: 0.1 mmol substrate 1, 1.0 mL HFIP, 1.0 mol % Ni(OAc)2/(S, S)-Ph-BPE, 80 atm H2, 80 °C, 48 h. Conversion was determined by 1H NMR analysis. Ee was determined by HPLC analysis using a chiral stationary phase. bS/C = 50.
Scheme 3. Deuterium Labeling Experiments of Asymmetric Hydrogenation of 1b
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ASSOCIATED CONTENT
S Supporting Information *
product 2b-D′ was obtained with >95% deuteration at the βposition and 16% deuteration at the α-position of the methyl ester group. These results showed that our hydrogenation process should be consistent with the proposed mechanism reported by Chirik.10 In addition, the Ni-catalyzed asymmetric hydrogenation of ethyl (E)-3-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl) acrylate (E)-1a was investigated, affording product 2a with the same configuration and similar enantioselectivity as (Z)-substrate 1a (Scheme 4, 52% conversion, 93% ee). This reaction result illustrated that the Z/E isomeric mixture can be used as the substrate directly. To explore the synthetic potential of this Ni-catalyzed hydrogenation, a gram-scale experiment proceeded under 80 atm of H2 and at 80 °C with only a 0.25 mol % catalyst loading (Scheme 5a). This transformation proceeded smoothly with
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00994. Experimental procedures, NMR and HPLC spectra (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Xiu-Qin Dong: 0000-0002-5045-1198 Xumu Zhang: 0000-0001-5700-0608 C
DOI: 10.1021/acs.orglett.9b00994 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Author Contributions
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§
Z.H. and G.L. contributed equally in this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (Grant No. 21432007, 21502145), Wuhan Morning Light Plan of Youth Science and Technology (Grant No. 2017050304010307), the Fundamental Research Funds for and the Central Universities (Grant No. 2042018kf0202), Shenzhen Nobel Prize Scientists Laboratory Project (Grant No. C17783101), and Science and Technology Innovation Committee of Shenzhen (Grant No. KQTD20150717103157174, JSGG 20170821140353405, and JSGG 20160608140847864). The Program of Introducing Talents of Discipline to Universities of China (111 Project) is also appreciated.
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DOI: 10.1021/acs.orglett.9b00994 Org. Lett. XXXX, XXX, XXX−XXX
