Letter Cite This: Org. Lett. 2017, 19, 5920-5923
pubs.acs.org/OrgLett
Enantioselective Iridium-Catalyzed Hydrogenation of α‑Keto Amides to α‑Hydroxy Amides Guoxian Gu,† Tilong Yang,† Ouran Yu,† Hua Qian,† Jiang Wang,† Jialin Wen,† Li Dang,*,†,‡ and Xumu Zhang*,† †
Department of Chemistry, Southern University of Science and Technology, 1088 Xueyuan Road, Nanshan District, Shenzhen, Guangdong 518055, P. R. China ‡ Department of Chemistry and Key Laboratory for Preparation and Application of Ordered Structural Materials of Guangdong Province, Shantou University, Shantou, Guangdong 515063, P. R. China S Supporting Information *
ABSTRACT: A highly enantioselective iridium-catalyzed hydrogenation of α-keto amides to form α-hydroxy amides has been achieved with excellent results (up to >99% conversion and up to >99% ee, TON up to 100 000). As an example, this protocol was applied to the synthesis of (S)-4-(2amino-1-hydroxyethyl)benzene-1,2-diol, the enantiomer of norepinephrine, which is widely used as an injectable drug for the treatment of critically low blood pressure. Density functional theory (DFT) calculations were also carried out to reveal the reaction mechanism. Scheme 1. Asymmetric Hydrogenation of α-Keto Amides Catalyzed by Ir/f-Amphox
nantioenriched α-hydroxy carboxylic acids and their derivatives are an important class of compounds that widely exist in many pharmaceuticals.1 Hence, significant effort has been devoted to the synthesis of chiral α-hydroxy acids and their derivatives, including enantioselective reduction of α-keto acids,2 α-keto esters,3 and α-keto amides.4 Among these three types of substrates, asymmetric hydrogenation of α-keto acids has a relative high enanioselectivity and high turnover numbers.2a In addition, a broad range of α-hydroxy acids with high enanioselectivity have been realized through biocatalysis.2b Enantioselective reduction of α-keto esters was also quite common. Biomimetic catalysis,3h asymmetric Meerwein−Ponndorf−Verley (MPV) reaction,3a asymmetric hydrosilylation,3b Ru-catalyzed asymmetric hydrogenation,3c,d,g and catalytic asymmetric transfer hydrogenation3e,f have been established to prepare chiral α-hydroxy esters, with modest ee’s and turnovers achieved. In contrast, there is no excellent solution for asymmetric hydrogenation of α-keto amides.4 Transition metal catalyzed asymmetric hydrogenation of αketo amides provided an efficient approach to prepare enantioenriched α-hydroxy amides. Herein, we are delighted to report a highly enantioselective and active asymmetric hydrogenation of α-keto amides with a broad substrate scope using an Ir-catalyst (Scheme 1) and utilities of this method for making related pharmaceutical products in a concise manner. Recently, we reported that iridium/f-amphox (ferrocenceaminophosphine oxazoline),5a iridium/f-amphol (ferrocenceaminophosphine alcohol),5b and iridium/f-ampha (ferrocenceaminophosphine acid) 5c complexes could catalyze the enantioselective hydrogenation of simple aromatic ketones to form chiral alcohols. Considering the success of these protocols, we envisioned that these catalyst systems could also promote the asymmetric hydrogenation of α-keto amides.
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© 2017 American Chemical Society
Initially, we targeted α-keto amide 1a as the standard substrate for asymmetric hydrogenation. Three tridentate ligands were examined (Figure 1), and the results are summarized in Table 1. Although all three ligands are excellent for asymmetric hydrogenation of simple ketones, they behave differently in this reaction. f-Ampha and f-amphol exhibited excellent activity, but with poor to moderate enantioselectivities. It is interesting that full conversion and 99%
Figure 1. Ligands screening in Ir-catalyzed hydrogenation of 1a. Received: September 18, 2017 Published: October 26, 2017 5920
DOI: 10.1021/acs.orglett.7b02912 Org. Lett. 2017, 19, 5920−5923
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Organic Letters
With the optimized reaction conditions in hand, we turned our attention to study the substrate scope. As shown in the Scheme 2, excellent ee’s were achieved for a wide range of α-
Table 1. Ligands Screening for Asymmetric Hydrogenation of α-Keto Amides 1aa
Scheme 2. Scope Study for the Asymmetric Hydrogenation of α-Keto Amides with Ir/f-Amphoxa entry 1 2 3 4 5 6 7 8 9
solvent
conv (%)b
ee (%)c
PrOH MeOH THF 1,4-dioxane DCM EtOAc toluene i PrOH i PrOH
>99 trace >99 nr >99 >99 >99 >99 >99
76 nd 74 nd 84 84 85 99 54
ligand f-ampha f-ampha f-ampha f-ampha f-ampha f-ampha f-ampha f-amphox f-amphol
i
a Reaction conditions: 0.2 mmol of substrate, 0.01 mmol % [Ir(COD)Cl]2, 0.021 mmol % ligand, 0.2 mmol % tBuONa, solvent volume = 1.0 mL. bDetermined by 1H NMR analysis. cDetermined by HPLC analysis.
enantioselectivity were obtained when f-amphox was used as the chiral ligand. Subsequently, the effect of solvent and base was examined in detail when f-amphox was used as ligand (Table 2). Toluene Table 2. Screening Solvents and Bases for the Asymmetric Hydrogenation of α-Keto Amide 1a with Ir/f-Amphoxa
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14d
base
conv (%)b
ee (%)c
BuONa BuONa t BuONa t BuONa t BuONa t BuONa t BuONa t BuOLi t BuOK KOH K2CO3 Na2CO3 Cs2CO3 Cs2CO3
>99 >99 nr nr >99 >99 >99 >99 >99 >99 trace nr >99 >99
99 98 nd nd 97 93 99 99 99 99 nd nd 99 99
solvent toluene DCM THF 1,4-dioxane EtOAc MeOH i PrOH i PrOH i PrOH i PrOH i PrOH i PrOH i PrOH i PrOH
t t
a
Reaction conditions: 0.2 mmol of substrate, 0.01 mmol % [Ir(COD)Cl]2, 0.021 mmol % ligand, 0.2 mmol % Cs2CO3, 1.0 mL of iPrOH, 10 atm H2. Ee’s were determined by HPLC analysis. b40 atm of H2. cAll the yields are isolated yield.
keto amides and were found to be insensitive to the nature of substituents on the aromatic rings. Both electron-donating (2b−2e) and electron-withdrawing (2i) substituents were tolerable for the substrates. The position of the substituent groups on the aromatic core of the substrates shows little influence on the reactions (2b vs 2d, 2f vs 2g). Increasing the steric hindrance of the aromatic ring also provided superior results (2l). Particularly, the challenging heterocyclic substrates (2m) also proceeded smoothly affording the desired hydrogenation product with >99% conversion and >99% ee. In addition, the substrates (2n, 2o, 2p) without the benzyl group but with an alkyl on the N-atom can also work efficiently with >99% conversion and ≥99% ee. However, secondary α-keto amides did not work (2q, 2r). Some particular examples (2b, 2d, and 2k) to be noted required a higher H2 pressure for completion. As we expected, this Ir/f-amphox catalytic system is highly efficient in this asymmetric hydrogenation (Table 3). The turnover number was up to 50 000 with a low loading of base at low H2 pressure (Table 3, entry 2). After increasing the base loading and H2 pressure, the TON was even up to 100 000 with 98% ee.
a
Reaction conditions: 0.2 mmol of substrate, 0.01 mmol % [Ir(COD)Cl]2, 0.021 mmol % ligand, 0.2 mmol % base, solvent volume = 1.0 mL. bDetermined by 1H NMR analysis. cDetermined by HPLC analysis. d10 atm of H2. The absolute configuration of 2a was determined by comparing the HPLC with those reported in the literature.4e
and isopropanol were found to achieve both excellent yield and enantioselectivity (Table 2, entry 1 and entry 7), while THF or 1,4-dioxane is not a good choice for the reaction (Table 2, entries 3 and 4). Cs2CO3 and tert-butoxides were found equally efficient while neither K2CO3 nor Na2CO3 works. Here, Cs2CO3 was chosen for further study because it could tolerate more functional groups compared to strong bases. 5921
DOI: 10.1021/acs.orglett.7b02912 Org. Lett. 2017, 19, 5920−5923
Letter
Organic Letters Table 3. Asymmetric Hydrogenation of α-Keto Amide 1a Catalyzed by Ir/f-Amphox in High TONa
entry
s/c
H2 (atm)
base (equiv)
conv (%)b
ee (%)c
1 2 3 4
10 000 50 000 100 000 100 000
10 10 10 40
0.001 0.001 0.02 0.02
>99 >99 70 >99
99 99 98 98
used as an injectable drug for the treatment of critically low blood pressure. We carried out density functional theory (DFT) calculations to study the detailed mechanism for enantioselective hydrogenation of 1a catalyzed by Ir/f-amphox with a base such as t BuONa.7 Ir(III) Na−amidato complex I can be formed by Ir/famphox in the presence of tBuONa [see Supporting Information (SI)].8 As shown in Figure 2, this catalytic reaction takes place with (1) hydride transfer from the Ir center of complex I to the α-keto carbon of 1a and (2) protonation of the alkoxide anion to yield 2a and regenerate the active complex I. The second step is calculated to be the ratedetermining step with less than 14 kcal/mol activation energy9 while the first step controls the enantioselectivity. The hydride transfer leading to the (S)-alkoxide anion has a transition state (TS1S) which is more stable than the one leading to the (R)alkoxide anion by 3.2 kcal/mol, indicating an ee value of 99.1%, which is consistent with the experimental value of 99%. The energy difference between these two transition states comes from the C−H−π interaction and π−π stacking between the famphox ligand and the phenyl group in TS1S as shown in Figure 3,10 together with the steric repulsion5 between the famphox ligand and benzyl amide group in TS1R. The electrostatic interaction stabilizes TS1S and the steric repulsion destabilizes TS1R, resulting in enantioselective hydrogenation. Other possible but unfavorable reaction mechanisms were also studied and shown in the SI. In summary, we have successfully developed the iridium/famphox-catalyzed asymmetric hydrogenation of a wide range of α-keto amides to prepare the corresponding chiral α-hydroxy amides with excellent results (>99% conversion and up to >99% ee). Our catalytic system is extremely reactive; the TON was up to 100 000. DFT data revealed that the noncovalent interactions between the ligand and substrate played an important role in high enantioselectivity. This will be helpful for chemists to understand the role that the ligand plays in the
a
Reaction conditions: 0.2 mmol of substrate, 1.0 mL of iPrOH. Conversion was determined by 1H NMR analysis. cThe ee was determined by HPLC analysis. b
In addition, the asymmetric hydrogenation of 1k in gramscale proceeded smoothly under the optimized reaction conditions (S/C = 10 000, 1.5 g of 1k, 0.11 mg of [Ir(COD)Cl]2, and 0.19 mg of f-amphox). Full conversion and 98% ee were obstained within 24 h (Scheme 3). The Scheme 3. Asymmetric Hydrogenation of N-Benzyl-2-(3,4bis(benzyloxy)phenyl)-2-oxoacetamide 1k on Gram Scale
desired chiral α-hydroxy amide 2k can be further reduced to prepare chiral β-amino alchol 3k. 3k was a candidate start material to prepare (S)-4-(2-amino-1-hydroxyethyl)benzene1,2-diol, the enantiomer of norepinephrine, which is widely
Figure 2. Solvent corrected Gibbs free energy profile for the iridium-catalyzed enantioselective hydrogenation of 1a in tBuONa. 5922
DOI: 10.1021/acs.orglett.7b02912 Org. Lett. 2017, 19, 5920−5923
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Organic Letters
(3) (a) Wu, W.; Zou, S.; Lin, L.; Ji, J.; Zhang, Y.; Ma, B.; Liu, X.; Feng, X. Chem. Commun. 2017, 53, 3232. (b) Ren, X.; Du, H. J. Am. Chem. Soc. 2016, 138, 810. (c) Sun, Y.; Wan, X.; Wang, J.; Meng, Q.; Zhang, H.; Jiang, L.; Zhang, Z. Org. Lett. 2005, 7, 5425. (d) Sun, X.; Zhou, L.; Li, W.; Zhang, X. J. Org. Chem. 2008, 73, 1143. (e) Yang, J. W.; List, B. Org. Lett. 2006, 8, 5653. (f) Yin, L.; Shan, W.; Jia, X.; Li, X.; Chan, A. S.C. J. Organomet. Chem. 2009, 694, 2092. (g) Enders, D.; StÖ ckel, B. A.; Rembiak, A. Chem. Commun. 2014, 50, 4489. (h) Kanomata, N.; Nakata, T. J. Am. Chem. Soc. 2000, 122, 4563. (i) Paule, S. D.; Jeulin, S.; Virginie, R.-V.; Genet, J. P.; Champion, N.; Dellis, P. Eur. J. Org. Chem. 2003, 2003, 1931. (4) (a) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2003, 125, 7825. (b) Concellón, J. M.; Bardales, E. Org. Lett. 2003, 5, 25. (c) Pasquier, C.; Naili, S.; Pelinski, L.; Brocard, J.; Mortreux, A.; Agbossou, F. Tetrahedron: Asymmetry 1998, 9, 193. (d) Stella, S.; Chadha, A. Catal. Today 2012, 198, 345. (e) Mamillapalli, N. C.; Sekar, G. Chem. - Eur. J. 2015, 21, 18584. (f) Pasquier, C.; Pélinski, L.; Brocard, J.; Mortreux, A.; Agbossou-Niedercorn, F. Tetrahedron Lett. 2001, 42, 2809. (g) Chiba, T.; Miyashita, A.; Nohira, H. Tetrahedron Lett. 1993, 34, 2351. (h) Zhao, Q.; Zhao, Y.; Liao, H.; Cheng, T.; Liu, G. ChemCatChem 2016, 8, 412. (i) Cederbaum, F.; Lamberth, C.; Malan, C.; Naud, F.; Spindler, F.; Studer, M.; Blaser, H.-U. Adv. Synth. Catal. 2004, 346, 842. (5) (a) Wu, W.; Liu, S.; Duan, M.; Tan, X.; Chen, C.; Xie, Y.; Lan, Y.; Dong, X.-Q.; Zhang, X. Org. Lett. 2016, 18, 2938. (b) Yu, J.; Long, J.; Yang, Y.; Wu, W.; Xue, P.; Chung, L. W.; Dong, X.-Q.; Zhang, X. Org. Lett. 2017, 19, 690. (c) Yu, J.; Duan, M.; Wu, W.; Qi, X.; Xue, P.; Lan, Y.; Dong, X.-Q.; Zhang, X. Chem. - Eur. J. 2017, 23, 970. (6) Barlow, J. J.; Main, B. G.; Snow, H. M. J. Med. Chem. 1981, 24, 315. (7) Please see the computational details in the Supporting Information. DFT calculations were carried out by using the Gaussian 09 package. Geometric structures of all species in the gas phase were optimized with the M06-2X functional, which has good performance for noncovalent interactions. On the basis of the gas-phase optimized geometries, the solvation effect of iPrOH was incorporated with the PCM solvent model at the M06-L/6-311++G** level of theory. (8) (a) Alkali cations (Na+, K+, Cs+) are necessary for the high activity asymmetric hydrogenation. We choose the Na−amidato complex in this calculated mechanism to save computational cost. (b) Dub, P. A.; Henson, N. J.; Martin, R. L.; Gordon, J. C. J. Am. Chem. Soc. 2014, 136, 3505. (c) Dub, P. A.; Gordon, J. C. ACS Catal. 2017, 7, 6635. (9) IIS is the TOF-determining intermediate and TS2S is the TOFdetermining transition state, according to the energetic span concept introduced by Kozuch and Shaik: (a) Kozuch, S.; Shaik, S. J. Am. Chem. Soc. 2006, 128, 3355. (b) Uhe, A.; Kozuch, S.; Shaik, S. J. Comput. Chem. 2011, 32, 978. (c) Kozuch, S.; Shaik, S. Acc. Chem. Res. 2011, 44, 101. (d) Kozuch, S.; Martin, J. M. L. ACS Catal. 2012, 2, 2787. (10) (a) The noncovalent interaction energy between these two moieties is evaluated as −3.3 kcal/mol by topology analysis of electron density by using Multiwfn program packages: Lu, T.; Chen, F. J. Comput. Chem. 2012, 33, 580. (b) The 3D molecular structures were generated by using CYL-view: CYLview, 1.0b; Legault, C. Y., Université de Sherbrooke, 2009 (http://www.cylview.org).
Figure 3. Geometry information on TS1S and TS1R.
reaction and will be useful to guide the design of ligand synthesis.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02912. General information, typical experimental procedures, HPLC, NMR spectra of the compounds, and computational details (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Guoxian Gu: 0000-0003-3216-0933 Tilong Yang: 0000-0002-9126-8840 Li Dang: 0000-0003-2666-7607 Xumu Zhang: 0000-0001-5700-0608 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by a start-up fund from Southern University of Science and Technology, Shenzhen Peacock Plan (KQTD2015071710315717) and Shenzhen Research Grants (JSGG20160608140847864).
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REFERENCES
(1) (a) Hanessian, S. Total Synthesis of Natural Products: The Chiron Approach; Pergamon: Oxford, 1983. (b) Coppola, G. M.; Schuster, H. F. α-Hydroxy Acids in Enantioselective Synthesis; VCH: Weinheim, Germany, 1997. (c) Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Ed.; Springer: Berlin, Germany, 1999, Vol. I−III. (d) Catalysis Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000. (e) Zhang, Q.-L.; Zhuang, Z.-Y.; Liu, Q.-D.; Zhang, Z.-M.; Zhan, F.-X.; Zheng, G.-X. Org. Process Res. Dev. 2016, 20, 1993. (2) (a) Yan, P.-C.; Xie, J.-H.; Zhang, X.-D.; Chen, K.; Li, Y.-Q.; Zhou, Q.-L.; Che, D.-Q. Chem. Commun. 2014, 50, 15987. (b) Xue, Y.-P.; Zheng, Y.-G.; Zhang, Y.-Q.; Sun, J.-L.; Liu, Z.-Q.; Shen, Y.-C. Chem. Commun. 2013, 49, 10706. 5923
DOI: 10.1021/acs.orglett.7b02912 Org. Lett. 2017, 19, 5920−5923
