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DOI: 10.1055/a-2021-7944
Bioinspired Formal Synthesis of Pancracine via Selective Hydrogenation of an Indole Derivative
This work was supported by the National Natural Science Foundation of China (21971018 and 82225041). The authors gratefully thank the Beijing Municipal Government and Tsinghua University for their financial support.
Abstract
A bioinspired formal synthesis of the montanine-type Amaryllidaceae alkaloid pancracine through selective hydrogenation of a 3-arylindole derivative is disclosed. The key features of this synthesis include a hexahydroindole synthesis by a chemoselective hydrogenation of an aryl-substituted indole and a diastereoselective silyl hydride reduction of an iminium intermediate generated from an enaminone through Tf2O activation. The eight-step assembly of the 5,11-methanomorphanthridine framework represents a novel and efficient strategy that permits one of the shortest syntheses of pancracine reported so far.
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In drug development, sp3-hybridized carbons and heteroatoms are frequently observed in drug molecules[1] and the saturated cores offer a greater possibility of accessing 3D spatial binding sites in target proteins than do planar aromatic scaffolds.[2] In particular, the chiral topology of stereogenic centers can improve various drug-related properties, including solubility, lipophilicity, and stability, and is therefore closely associated with the ultimate clinical success rate.[3] In terms of the atom and step economy, the chemo- and stereoselective hydrogenation of arenes and heteroarenes to give three-dimensional saturated rings with multiple stereocenters has proven to be a powerful but challenging strategy, due to the high activation energy required to break aromaticity.[4]
Hydrogenases are a family of metalloenzymes that participate in the metabolism of hydrogen in organisms such as bacteria, archaea, and eukarya.[5] Theoretically, hydrogenases activate the inert H–H bond (bond enthalpy: 436 kJ/mol) and promote the cleavage of dihydrogen into two protons with the generation of two electrons.[6] Taking the [Fe]H2ase hydrogenase (Figure [1a], right) as an example, H2 is cleaved heterolytically by placing H+ on the ligand O– group and hydride on the Fe center (L = H–), which can then transfer the hydride to substrates.[7] Mimicking hydrogenase enzymes, several organometallic catalysts have been devised to achieve an effective performance in the stereoselective hydrogenation of arenes and hetarenes.[8] For example, ruthenium catalysts with a chiral diamine ligand (Figure [1a], left) promote the highly stereoselective reduction of quinolines,[9] [10] [11] [12] isoquinolines,[13] quinolizidines,[14] benzoxazines,[15] and indoles.[16] [17] The hydrogenation of arenes has also been broadly utilized in total syntheses of natural products,[18] [19] [20] [21] further demonstrating the power of this strategy.
Although more and more researchers are involved in designing homogeneous and heterogeneous catalysts to achieve chemo- and stereoselective hydrogenations of aromatic rings,[22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] the stereoselective perhydrogenation of indole to a saturated [6,5]-fused ring system is less-well explored due to the high energy necessary to break the aromaticity of both the pyrrole and benzene rings. Furthermore, the chemoselective perhydrogenation of indole in the presence of a phenyl substituent to deliver a perhydrogenated indole without affecting the benzene ring is even more challenging (Figure [1b], top). The development of efficient protocols for the construction of hydrogenated indole structures[36–40] is essential for the concise total synthesis of several natural products, such as Sceletium-type, Strychnos-type, and Amaryllidaceae-type alkaloids (Figure [1b], bottom).
To demonstrate the efficiency of a chemoselective indole hydrogenation strategy in the total syntheses of natural products, we chose the montanine-type Amaryllidaceae alkaloid pancracine as our target, as this contains both phenyl and hydrogenated-indole scaffolds. After the first isolation of pancracine in 1968,[41] the antiproliferative activity of pancracine and its derivatives against human solid-tumor cell lines with GI50 ≤ 10 μM has been recently disclosed.[42] [43] With regard to synthetic strategies for pancracine, great efforts have been made to construct the 3-aryl-substituted cis-hydroindoles 2 as critical intermediates through either cycloaddition or transannulation approaches (Scheme [1]).[44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] Here, we present our synthesis of this 3-arylhydroindolone intermediate through a unique chemoselective hydrogenation of the phenyl-substituted indole derivative 11c, which can be efficiently assembled from easily accessible 4-(benzyloxy)-1H-indole.
a Reaction condition: 11, solvent (0.12 M), catalyst, stirring, H2 (1 atm), 24 h.
b Calculated based on the weight fraction of the substrate.
c Isolated yield.
d Reaction concentration: 0.05 M.
e N.D. = not detected.
f Reaction concentration: 0.025 M.
g Reaction concentration: 0.1 M.
h Synthetic details for substrates 11a and 11b are given in the Supporting Information.
Our retrosynthetic analysis of pancracine was based on late-stage oxidation of the known intermediate 12, which was obtained through a Pictet–Spengler cyclization of the 3-arylhexahydroindole 13. We proposed that the key tetrahydroindole intermediate 14c might be generated by a chemoselective hydrogenation of the phenyl-substituted indole derivative 11c, which could be synthesized through Suzuki–Miyaura coupling of commercially available 4-(benzyloxy)-1H-indole (15) and (3,4-methylenedioxyphenyl)boronic acid (16) (Scheme [2]).
To investigate the feasibility of the chemoselective hydrogenation of indole derivatives 11 without affecting the phenyl substituent, we started with the 3-aryl-substituted N-tosyl-4-(benzyloxy)indole 11a as a model substrate. A 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)/trifluoroacetic acid (TFA) mixture and 20 wt% Pd/C catalyst had been developed in our laboratory as optimal reaction conditions for the efficient selective hydrogenation of indole;[58] however, these were unsuccessful in attempts to transform substrate 11a into the desired hydrogenated product (Table [1], entry 1). Investigation of various reaction conditions, including solvent combinations, reaction temperatures, transition metals, and catalyst loadings, resulted in only debenzylated byproduct 17a (entries 2–4). The N-Boc protected substrate 11b was not a suitable substrate for hydrogenation, even by using 50 wt% PtO2 in 200:1 MeOH–AcOH at 50 ℃ for 24 hours (entry 5). To our delight, however, when the unprotected indole substrate 11c was subjected to hydrogenation in 3:1 HFIP–TFA with 20 wt% Pd/C catalyst at 60 ℃ (entry 6), the desired product 14c was obtained, albeit in a low isolated yield (23%). Encouraged by this promising result, we conducted further investigations of the effects of the solvent, temperature, and catalyst loading with 11c as the substrate. First, increasing the catalyst loading to 50 wt% led to a higher yield of 14c (entry 7). Subsequently, a survey of solvent proportions (entries 8–11) revealed that 50:1 HFIP–TFA was the optimal solvent system. Decreasing the reaction temperature to 50 ℃ gave the product 14c in a slightly higher yield (entry 12). However, further decreasing the reaction temperature to 40 ℃ had a negative effect on the yield of the product (entry 13). Either decreasing the catalyst loading (entry 14) or replacing HFIP with other solvents (entries 15 and 16) led to unsatisfactory results. It should be noted that a variety of hydrogenated products with different chemoselectivities were detected during the optimization process, among which the three compounds 17c, 18c, and 19c were identified as byproducts. Under our optimized condition (entry 12), the ratio of 14c/18c/19c was determined by ultraperformance liquid chromatography to be 1:0.2:0.1, and no 17c was detected.[59] The presence of these byproducts further demonstrated the challenge of chemoselective hydrogenation of indole derivatives with phenyl substituents.
a Reaction conditions: 21 (1.0 equiv), Tf2O (x equiv), reductant (2.0 equiv), solvent (0.1 M), 24 h.
b Determined by 1H NMR.
With the optimal chemoselective hydrogenation condition in hand, we began our total synthesis of pancracine (1). The hydrogenation substrate 11c was obtained from the commercially available compound 15 by a two-step synthetic sequence (Scheme [3]) involving protection by N-silylation followed by bromination by NBS at the indole C3 position[60] and a Pd-catalyzed Suzuki–Miyaura coupling reaction with (3,4-methylenedioxyphenyl)boronic acid (16). Chemoselective hydrogenation of 11c under our optimized reaction condition delivered the 3-aryl-substituted tetrahydroindole 14c,[61] [62] which was converted into the N-tosyl enaminone 21.
To complete our synthesis of pancracine, we conducted an investigation of the conversion of the enaminone 21 into the known intermediate 12. First, Tf2O-induced activation of enaminone 21 followed by Et3SiH-mediated reduction of the intermediate 21′ led to two diastereomers, with the undesired product dia-22 as the major diastereomer (Table [2], entry 1). The unfavorable diastereoselectivity was presumably due to steric hindrance by the 3,4-methylenedioxyphenyl group (Table [2], right). Changing the reaction temperature or the amount of Tf2O had no effect on the diastereoselectivity (entries 2–5). A survey of silane reductants (entries 6–10) revealed that EtMe2SiH (entry 9) improved the ratio of the desired diastereomer 22, and the two diastereomers were isolated in a combined 85% yield with 1.4:1 dr.[62] After the removal of the OTf functional group under Pd-catalyzed reductive conditions, we successfully obtained the tricyclic intermediate 13 [46] in only six steps. Further reductive cleavage of the sulfonamide group under sodium naphthalenide conditions and a subsequent Pictet–Spengler reaction in one pot afforded the 5,11-methanomorphanthridine 12, which is an advanced intermediate in Overman’s total synthesis of pancracine.[44] The spectroscopic data of compound 12 were identical to those reports in the literature.[55]
In summary, we have developed an efficient chemoselective hydrogenation protocol for the synthesis of aryl-substituted hexahydroindole skeletons. The preference for hydrogenation of the indole over the phenyl ring showcases the robustness of precise manipulation of aromatic rings based on different electronic properties. The Tf2O-induced enaminone activation and subsequent diastereoselective reduction delivered the key intermediate 22 and permitted the formal synthesis of pancracine (1). The present chemoselective hydrogenation strategy should be applicable to the synthesis of other alkaloids with similar hydroindole skeletons. Our ongoing work is focusing on the stereoselective hydrogenation of aryl-substituted indoles. Hydrogenase-inspired metal–organic catalyst design for asymmetric reduction of arenes is also under investigation.
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Conflict of Interest
The authors declare no conflict of interest.
Acknowledgment
We thank Dr. Gen Li for crucial comments and suggestions. Qingcui Wu is thanked for technical support.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2021-7944.
- Supporting Information
-
References and Notes
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- 62 Procedure for the Selective Hydrogenation of 11c A solution of compound 11c (100 mg, 0.29 mmol, 1.0 equiv) in 50:1 HFIP–TFA (2.5 mL) was stirred in the presence of 50 wt % Pd/C at 50 ℃ under H2 at atmospheric pressure for 24 h. The mixture was then cooled to r.t. and filtered through Celite. The filtrate was basified with sat. aq NaHCO3, and the mixture was extracted with CH2Cl2 (×3). The combined organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure to give a crude residue that was purified by column chromatography (silica gel, 0.5–5% MeOH–CH2Cl2) to give 14c as a light-red solid; yield: 36 mg (48%). 1H NMR (400 MHz, DMSO-d 6): δ = 7.30 (s, 1 H), 6.76 (d, J = 7.9 Hz, 1 H), 6.64 (d, J = 1.5 Hz, 1 H), 6.59 (dd, J = 8.0, 1.6 Hz, 1 H), 5.94 (s, 2 H), 4.06 (dd, J = 11.0, 4.5 Hz, 1 H), 3.87 (t, J = 10.9 Hz, 1 H), 3.22 (dd, J = 10.7, 4.7 Hz, 1 H), 2.43 (t, J = 5.8 Hz, 1 H), 2.38 (t, J = 6.6 Hz, 1 H), 2.11–2.03 (m, 2 H), 1.89 (p, J = 6.3 Hz, 2 H). 13C NMR (101 MHz, DMSO-d 6): δ = 188.86, 169.32, 147.10, 145.22, 139.92, 119.67, 110.98, 107.81, 107.30, 100.54, 54.99, 43.12, 36.31, 23.24, 22.20. Procedure for the Tf2O-Induced Diastereoselective Activation/Reduction Tf2O (28 mg, 0.1 mmol, 2.0 equiv) and EtMe2SiH (8.8mg, 0.1 mmol, 2.0 equiv) were added successively to a stirred solution of compound 21 (21 mg, 0.05 mmol, 1.0 equiv) in anhydrous CH2Cl2 (4 mL) at r.t. The mixture was stirred at r.t. for 24 h then quenched with sat. aq NaHCO3 and extracted with CH2Cl2 (×3). The combined organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue that was purified by column chromatography (silica gel, 1–5% EtOAc–PE) to give compound 22 (79 mg, 36% yield) and dia-22 (108 mg, 49% yield) in a combined 85% yield. 22 1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 8.2 Hz, 2 H), 7.21 (d, J = 8.4 Hz, 2 H), 6.53 (d, J = 8.0 Hz, 1 H), 6.34 (dd, J = 8.0, 1.8 Hz, 1 H), 6.22 (d, J = 1.7 Hz, 1 H), 5.90 (d, J = 0.8 Hz, 2 H), 4.16–4.04 (m, 1 H), 3.90 (dd, J = 10.7, 7.5 Hz, 2 H), 3.35 (dd, J = 10.7, 4.0 Hz, 1 H), 2.65 (dq, J = 12.1, 3.9 Hz, 1 H), 2.41 (s, 3 H), 2.39–2.37 (m, 2 H), 2.09 (d, J = 14.1 Hz, 1 H), 1.79–1.63 (m, 1 H), 1.50 (dd, J = 25.6, 11.5 Hz, 1 H). 13C NMR (101 MHz, CDCl3): δ = 147.76, 146.53, 144.08, 143.92, 133.13, 132.99, 129.58, 127.47, 120.20, 118.0 (q, J C–F = 308.2 Hz), 108.24, 107.08, 101.02, 59.91, 56.39, 42.85, 29.11, 26.44, 21.46, 20.36. 19F NMR (376 MHz, CDCl3): δ = –74.74. dia-22 1H NMR (400 MHz, CDCl3) δ = 7.68 (d, J = 8.3 Hz, 2 H), 7.39 (d, J = 7.9 Hz, 2 H), 6.75 (d, J = 1.0 Hz, 1 H), 6.70 (dd, J = 2.3, 1.0 Hz, 2 H), 5.94 (dd, J = 3.4, 1.5 Hz, 2 H), 3.80 (d, J = 8.1 Hz, 1 H), 3.48 (dd, J = 9.8, 2.4 Hz, 1 H), 3.39–3.35 (m, 1 H), 3.17 (dd, J = 9.8, 8.3 Hz, 1 H), 2.75–2.70 (m, 1 H), 2.47 (s, 3 H), 2.33–2.30 (m, 2 H), 2.15–2.09 (m, 1 H), 1.71–1.65 (m, 2 H). 13C NMR (101 MHz, CDCl3): δ = 147.84, 146.68, 144.46, 143.30, 135.17, 134.99, 130.82, 129.88, 128.18, 121.22, 118.0 (q, J C–F = 321.6 Hz), 107.98, 107.62, 100.99, 61.27, 57.25, 43.36, 28.09, 26.63, 21.57, 20.48. 19F NMR (376 MHz, CDCl3): δ = –74.68.
Corresponding Author
Publication History
Received: 07 January 2023
Accepted after revision: 28 January 2023
Accepted Manuscript online:
28 January 2023
Article published online:
28 February 2023
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References and Notes
- 1 Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257
- 2 Lovering F, Bikker J, Humblet C. J. Med. Chem. 2009; 52: 6752
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- 61 The isolated yield of 14c in a one-gram-scale reaction was 39%.
- 62 Procedure for the Selective Hydrogenation of 11c A solution of compound 11c (100 mg, 0.29 mmol, 1.0 equiv) in 50:1 HFIP–TFA (2.5 mL) was stirred in the presence of 50 wt % Pd/C at 50 ℃ under H2 at atmospheric pressure for 24 h. The mixture was then cooled to r.t. and filtered through Celite. The filtrate was basified with sat. aq NaHCO3, and the mixture was extracted with CH2Cl2 (×3). The combined organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure to give a crude residue that was purified by column chromatography (silica gel, 0.5–5% MeOH–CH2Cl2) to give 14c as a light-red solid; yield: 36 mg (48%). 1H NMR (400 MHz, DMSO-d 6): δ = 7.30 (s, 1 H), 6.76 (d, J = 7.9 Hz, 1 H), 6.64 (d, J = 1.5 Hz, 1 H), 6.59 (dd, J = 8.0, 1.6 Hz, 1 H), 5.94 (s, 2 H), 4.06 (dd, J = 11.0, 4.5 Hz, 1 H), 3.87 (t, J = 10.9 Hz, 1 H), 3.22 (dd, J = 10.7, 4.7 Hz, 1 H), 2.43 (t, J = 5.8 Hz, 1 H), 2.38 (t, J = 6.6 Hz, 1 H), 2.11–2.03 (m, 2 H), 1.89 (p, J = 6.3 Hz, 2 H). 13C NMR (101 MHz, DMSO-d 6): δ = 188.86, 169.32, 147.10, 145.22, 139.92, 119.67, 110.98, 107.81, 107.30, 100.54, 54.99, 43.12, 36.31, 23.24, 22.20. Procedure for the Tf2O-Induced Diastereoselective Activation/Reduction Tf2O (28 mg, 0.1 mmol, 2.0 equiv) and EtMe2SiH (8.8mg, 0.1 mmol, 2.0 equiv) were added successively to a stirred solution of compound 21 (21 mg, 0.05 mmol, 1.0 equiv) in anhydrous CH2Cl2 (4 mL) at r.t. The mixture was stirred at r.t. for 24 h then quenched with sat. aq NaHCO3 and extracted with CH2Cl2 (×3). The combined organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue that was purified by column chromatography (silica gel, 1–5% EtOAc–PE) to give compound 22 (79 mg, 36% yield) and dia-22 (108 mg, 49% yield) in a combined 85% yield. 22 1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 8.2 Hz, 2 H), 7.21 (d, J = 8.4 Hz, 2 H), 6.53 (d, J = 8.0 Hz, 1 H), 6.34 (dd, J = 8.0, 1.8 Hz, 1 H), 6.22 (d, J = 1.7 Hz, 1 H), 5.90 (d, J = 0.8 Hz, 2 H), 4.16–4.04 (m, 1 H), 3.90 (dd, J = 10.7, 7.5 Hz, 2 H), 3.35 (dd, J = 10.7, 4.0 Hz, 1 H), 2.65 (dq, J = 12.1, 3.9 Hz, 1 H), 2.41 (s, 3 H), 2.39–2.37 (m, 2 H), 2.09 (d, J = 14.1 Hz, 1 H), 1.79–1.63 (m, 1 H), 1.50 (dd, J = 25.6, 11.5 Hz, 1 H). 13C NMR (101 MHz, CDCl3): δ = 147.76, 146.53, 144.08, 143.92, 133.13, 132.99, 129.58, 127.47, 120.20, 118.0 (q, J C–F = 308.2 Hz), 108.24, 107.08, 101.02, 59.91, 56.39, 42.85, 29.11, 26.44, 21.46, 20.36. 19F NMR (376 MHz, CDCl3): δ = –74.74. dia-22 1H NMR (400 MHz, CDCl3) δ = 7.68 (d, J = 8.3 Hz, 2 H), 7.39 (d, J = 7.9 Hz, 2 H), 6.75 (d, J = 1.0 Hz, 1 H), 6.70 (dd, J = 2.3, 1.0 Hz, 2 H), 5.94 (dd, J = 3.4, 1.5 Hz, 2 H), 3.80 (d, J = 8.1 Hz, 1 H), 3.48 (dd, J = 9.8, 2.4 Hz, 1 H), 3.39–3.35 (m, 1 H), 3.17 (dd, J = 9.8, 8.3 Hz, 1 H), 2.75–2.70 (m, 1 H), 2.47 (s, 3 H), 2.33–2.30 (m, 2 H), 2.15–2.09 (m, 1 H), 1.71–1.65 (m, 2 H). 13C NMR (101 MHz, CDCl3): δ = 147.84, 146.68, 144.46, 143.30, 135.17, 134.99, 130.82, 129.88, 128.18, 121.22, 118.0 (q, J C–F = 321.6 Hz), 107.98, 107.62, 100.99, 61.27, 57.25, 43.36, 28.09, 26.63, 21.57, 20.48. 19F NMR (376 MHz, CDCl3): δ = –74.68.
