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DOI: 10.1055/s-0040-1707188
Ni-Catalyzed Intramolecular Reductive 1,2-Dicarbofunctionalization of Alkene: Facile Access to Podophyllum Lignans Core
This work was supported by the National Natural Science Foundation of China (21772078 and 21472075) and the Fundamental Research Funds for the Central Universities (2682019CX70, 2682019CX71, and 2682020CX55). We also thank Science and Technology Department of Sichuan Province (2020JDRC0021).
In memory of Prof. Xuan Tian
Abstract
The facile access to the tetracyclic skeleton of podophyllotoxin, a medicinally important lignan natural product, was efficiently achieved via a unique intramolecular alkylarylation of the tethered alkene in a dihalide under mild conditions using reductive nickel catalysis.
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Over the past decade, reductive cross-electrophile couplings catalyzed by nickel complex have evolved into a versatile method for the formation of carbon–carbon bonds under the mild conditions.[1] Notably, recent progress towards reductive 1,2-dicarbofunctionalization of alkenes received more attentions because two vicinal C–C bonds across unactivated or electronically biased olefins could be installed simultaneously by this strategy.[2] As shown in Scheme [1] (top), an aromatic halide with a olefin side chain will cyclize first, then followed by the interception of another electrophile.[3] Meanwhile, nickel-catalyzed intermolecular three-component dicarbofunctionalization reactions under reductive conditions appeared as well.[4]
We were earlier involved in the field of reductive coupling trigger by nickel complex.[5] In particular, our interests focused on the undeveloped area: fully intramolecular reactions and their synthetic applications for total synthesis of bioactive natural products and pharmaceuticals.[5a] [d] , [5`] [g] [h] [i] In this work, a dihalide 1 bearing a double bond in the molecule was designed (Scheme [1], bottom), and a tandem cyclization across this double bond would occur to deliver a tetracyclic skeleton 2 embedded in Podophyllum lignans through a single operation. As a representative member of this family, podophyllotoxin (3, Scheme [2]) has been used for the treatment of angogenital warts. Its sugar derivatives have also been developed as chemotherapy drugs. The described transformation herein was thus very valuable for a rapid access to the core structure of this medicinally important molecule.[6] Especially, several radical cyclzation-based routes had been reported.[6j] [t]
The precursor for this fully intramolecular 1,2-dicarbofunctionalization of alkene was prepared according to the synthetic route demonstrated in Scheme [3] and Scheme [4]. Firstly, an aryl lithium reagent derived from easily synthesized 3,4,5-trimethoxyl bromobenzene[5f] was added into a solution of commercially available 6-bromopiperonal. The generated diaryl carbinol was then converted into the corresponding iodide via Br–Li exchange protocol. Through an oxidative reaction mediated with pyridinium dichromate (PDC), the desired diaryl ketone 4 was thus obtained in 43% overall yield. Next, one-carbon homologation of ketone 4 was carried out. The initial epoxidation proceeded smoothly under Corey–Chaykovsky reaction conditions, and the resulting epoxide 5 could further rearrange to diaryl acetaldehyde 6 under ZnI2.[7] Upon subjection of this labile aldehyde to the ylide, which was generated in situ from (methoxylmethyl)triphenylphosphonium chloride,[8] the enol methylether 7 was produced accordingly in 65% overall yield. Notably, only one flash column chromatography was necessary during the conversion of the ketone 4 into 7.
With sufficient amounts of enol ether 7 in hand, the synthesis of β-bromo acetals 8 was pursued. This seeming routine task proved to be challenging, which was partly attributed to a competitive bromination on the electron-rich benzene ring. After extensive experiments with various reagents, such as Br2 and NBS, it was found that the employment of 2,4,4,6-tetrabromo-2,5-cyclohexadienone (TBCD)[9] afforded a fairly good regioselectivity, providing β-bromo acetals 8 as a mixture of diastereomers in 79% yield (Scheme [4]).[10]
The stage was then set for the intramolecular 1,2-alkylarylation of alkene 8. Ethyl crotonate (EC), which played a critical role in our previous studies,[5i] was still found to be a best ligand for this fully intramolecular coupling under reductive conditions (Scheme [5]). Two separable products 9 and 10 with the core of Podophyllum lignans were obtained in a combined yield of 77%. As shown in the Supporting Information, the relative stereochemistries of these two diastereomers were assigned by 1H–1H COSY and NOESY spectra, respectively. The typical tetralin structure embedded in 9 and 10 paves the way for the stereodivergent synthesis of this family of natural products.[5h] [11]
In summary, a diaryl ketone based approach for the synthesis of enol ether 7 was developed, which secured the supply for the designed bicyclization precursor 8. This bromoiodide under reductive nickel catalysis constructed two vicinal C(sp 3)–C(sp 3) and C(sp 3)–C(sp 2) bonds across the tethered alkene, therefore establishing the core of podophyllotoxin as a therapeutic agent. We believed that this fully intramolecular conjunctive cross-coupling would find new utilities in the context of natural products synthesis.
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Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0040-1707188.
- Supporting Information
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References and Notes
- 1a Knappke CE. I, Grupe S, Gärtner D, Corpet M, Gosmini C, Jacobi von Wangelin A. Chem. Eur. J. 2014; 20: 6828
- 1b Moragas T, Correa A, Martin R. Chem. Eur. J. 2014; 20: 8242
- 1c Weix DJ. Acc. Chem. Res. 2015; 48: 1767
- 1d Wang X, Dai Y, Gong H. Org. Chem. Front. 2015; 2: 1411
- 2 For a review, see: Ping Y, Kong W. Synthesis 2020; 52: 979
- 3a Anthony D, Lin Q, Baudet J, Diao T. Angew. Chem. Int. Ed. 2019; 58: 3198
- 3b Kuang Y, Wang X, Anthony D, Diao T. Chem. Commun. 2018; 54: 2558
- 3c Wang K, Ding Z, Zhou Z, Kong W. J. Am. Chem. Soc. 2018; 140: 12364
- 3d Xu S, Wang K, Kong W. Org. Lett. 2019; 21: 7498
- 3e Jin Y, Wang C. Chem. Sci. 2019; 10: 1780
- 3f Jin Y, Wang C. Angew. Chem. Int. Ed. 2019; 58: 6722
- 3g Qin X, Lee MW. Y, Zhou JS. Angew. Chem. Int. Ed. 2017; 56: 12723
- 4 García-Domínguez A, Li Z, Nevado C. J. Am. Chem. Soc. 2017; 139: 6835
- 5a Yan C.-S, Peng Y, Xu X.-B, Wang Y.-W. Chem. Eur. J. 2012; 18: 6039 ; corrigendum: Chem. Eur. J. 2013, 19, 15438
- 5b Xu X.-B, Liu J, Zhang J.-J, Wang Y.-W, Peng Y. Org. Lett. 2013; 15: 550
- 5c Peng Y, Luo L, Yan C.-S, Zhang J.-J, Wang Y.-W. J. Org. Chem. 2013; 78: 10960
- 5d Peng Y, Xu X.-B, Xiao J, Wang Y.-W. Chem. Commun. 2014; 50: 472
- 5e Luo L, Zhang J.-J, Ling W.-J, Shao Y.-L, Wang Y.-W, Peng Y. Synthesis 2014; 46: 1908
- 5f Peng Y, Xiao J, Xu X.-B, Duan S.-M, Ren L, Shao Y.-L, Wang Y.-W. Org. Lett. 2016; 18: 5170
- 5g Xiao J, Wang Y.-W, Peng Y. Synthesis 2017; 49: 3576
- 5h Xiao J, Cong X.-W, Yang G.-Z, Wang Y.-W, Peng Y. Org. Lett. 2018; 20: 1651
- 5i Xiao J, Cong X.-W, Yang G.-Z, Wang Y.-W, Peng Y. Chem. Commun. 2018; 54: 2040
- 5j Luo L, Zhai X.-Y, Wang Y.-W, Peng Y, Gong H. Chem. Eur. J. 2019; 25: 989
- 5k Ouyang Y, Peng Y, Li W.-DZ. Tetrahedron 2019; 75: 4486
- 6a Peng Y. Lignans, Lignins, and Resveratrols. From Biosynthesis to Total Synthesis: Strategies and Tactics for Natural Products. Zografos AL. John Wiley & Sons; Hoboken: 2016. Chap. 10, 331-379
- 6b Liu Y.-Q, Yang L, Tian X. Curr. Bioact. Compd. 2007; 3: 37
- 6c Sellars JD, Steel PG. Eur. J. Org. Chem. 2007; 3815
- 6d Ting CP, Tschanen E, Jang E, Maimone TJ. Tetrahedron 2019; 75: 3299
- 6e Hajra S, Garai S, Hazra S. Org. Lett. 2017; 19: 6530
- 6f Ting CP, Maimone TJ. Angew. Chem. Int. Ed. 2014; 53: 3115
- 6g Wu Y, Zhao J, Chen J, Pan C, Li L, Zhang H. Org. Lett. 2009; 11: 597
- 6h Stadler D, Bach T. Angew. Chem. Int. Ed. 2008; 47: 7557
- 6i Wu Y, Zhang H, Zhao Y, Zhao J, Chen J, Li L. Org. Lett. 2007; 9: 1199
- 6j Reynolds AJ, Scott AJ, Turner CI, Sherburn MC. J. Am. Chem. Soc. 2003; 125: 12108
- 6k Berkowitz DB, Choi S, Maeng J.-H. J. Org. Chem. 2000; 65: 847
- 6l Hadimani SB, Tanpure RP, Bhat SV. Tetrahedron Lett. 1996; 37: 4791
- 6m Bush EJ, Jones DW. J. Chem. Soc., Chem. Commun. 1993; 1200
- 6n Van Speybroeck R, Guo H, Van der Eycken J, Vandewalle M. Tetrahedron 1991; 47: 4675
- 6o Andrews RC, Teague SJ, Meyers AI. J. Am. Chem. Soc. 1988; 110: 7854
- 6p Macdonald DI, Durst T. J. Org. Chem. 1986; 51: 4749
- 6q Gensler WJ, Gatsonis CD. J. Am. Chem. Soc. 1962; 84: 1748 ; see also ref. 5h in this article
- 6r Li J, Zhang X, Renata H. Angew. Chem. Int. Ed. 2019; 58: 11657
- 6s Lazzarotto M, Hammerer L, Hetmann M, Borg A, Schmermund L, Steiner L, Hartmann P, Belaj F, Kroutil W, Gruber K, Fuchs M. Angew. Chem. Int. Ed. 2019; 58: 8226
- 6t Kolly-Kovač T, Renaud P. Synthesis 2005; 1459
- 7 Snyder SA, Wright NE, Pflueger JJ, Breazzano SP. Angew. Chem. Int. Ed. 2011; 50: 8629
- 8 Gibson SE, Guillo N, Middleton RJ, Thuilliez A, Tozer MJ. J. Chem. Soc., Perkin Trans. 1 1997; 447
- 9 Kato T, Ichinose I, Kamoshida A, Kitahara Y. J. Chem. Soc., Chem. Commun. 1976; 518 ; and references cited therein
- 10 In a 100 mL round-bottom flask, enol ether 7 (1.50 g, 3.1 mmol) was dissolved in anhydrous CH2Cl2 (35 mL) and cooled to 0 °C. To this solution was added TBCD (97%, 1.57 g, 3.7 mmol, 1.2 equiv) portionwise, and the mixture was stirred for 30 min at 0 °C. A solution of allyl alcohol (3.6 mL, 62 mmol, 20.0 equiv) in CH2Cl2 (5 mL) was then added dropwise, and the resulting mixture was gradually warmed to room temperature and stirred further for 9 h. The reaction was quenched with saturated aqueous NaHCO3 (3 mL), Na2SO3 (3 mL), and stirred further for 30 min. The resulting mixture was extracted with CH2Cl2 (2 × 50 mL), and the combined organic layers were washed with water (2 × 15 mL) and brine (15 mL), respectively, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petroleum ether/EtOAc = 10:1 → petroleum ether/EtOAc = 4:1) on silica gel to afford 8 (1.519 g, 79% yield) as a yellow oil. Rf = 0.36 (petroleum ether/EtOAc = 2:1). IR (film): νmax = 2930, 2838, 1590, 1504, 1479, 1461, 1422, 1383, 1326, 1265, 1229, 1128, 1037, 929, 845, 792, 736, 701, 685, 582 cm–1. 1H NMR (400 MHz, CDCl3): δ (major isomer) = 7.19 (s, 1 H), 6.99 (s, 1 H), 6.52 (s, 2 H), 5.93 (s, 1 H), 5.89 (s, 1 H), 5.86–5.80 (m, 1 H), 5.35 (dd, J = 17.2, 1.6 Hz, 1 H), 5.13 (dd, J = 10.8, 1.6 Hz, 1 H), 4.76 (d, J = 10.8 Hz, 1 H), 4.55 (dd, J = 11.2, 2.8 Hz, 1 H), 4.26 (dd, J = 13.2, 4.8 Hz, 1 H), 4.00 (d, J = 2.4 Hz, 1 H), 3.88 (dd, J = 12.8, 5.2 Hz, 1 H), 3.76 (s, 6 H), 3.74 (s, 3 H), 3.31 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.3 (2 C), 148.7, 147.3, 137.23, 137.17, 135.6, 133.8, 119.0, 116.7, 107.0, 105.3 (2 C), 102.0, 101.8, 90.5, 69.7, 60.8, 57.7, 57.3, 56.21 (2 C), 56.17 ppm. HRMS (ESI): m/z calcd for C23H26O7 79BrINa+ [M + Na]+: 642.9799; found: 642.9791.
- 11 Xiao J, Nan G, Wang Y.-W, Peng Y. Molecules 2018; 23: 3037
For selected examples, see:
For reviews, see:
For past syntheses of podophyllotoxin (3), see:
For chemoenzymatic syntheses of podophyllotoxin (3), see:
For a synthesis of deoxypodophyllotoxin, see:
Publication History
Received: 17 May 2020
Accepted: 16 June 2020
Article published online:
17 July 2020
© 2020. Thieme. All rights reserved
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
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References and Notes
- 1a Knappke CE. I, Grupe S, Gärtner D, Corpet M, Gosmini C, Jacobi von Wangelin A. Chem. Eur. J. 2014; 20: 6828
- 1b Moragas T, Correa A, Martin R. Chem. Eur. J. 2014; 20: 8242
- 1c Weix DJ. Acc. Chem. Res. 2015; 48: 1767
- 1d Wang X, Dai Y, Gong H. Org. Chem. Front. 2015; 2: 1411
- 2 For a review, see: Ping Y, Kong W. Synthesis 2020; 52: 979
- 3a Anthony D, Lin Q, Baudet J, Diao T. Angew. Chem. Int. Ed. 2019; 58: 3198
- 3b Kuang Y, Wang X, Anthony D, Diao T. Chem. Commun. 2018; 54: 2558
- 3c Wang K, Ding Z, Zhou Z, Kong W. J. Am. Chem. Soc. 2018; 140: 12364
- 3d Xu S, Wang K, Kong W. Org. Lett. 2019; 21: 7498
- 3e Jin Y, Wang C. Chem. Sci. 2019; 10: 1780
- 3f Jin Y, Wang C. Angew. Chem. Int. Ed. 2019; 58: 6722
- 3g Qin X, Lee MW. Y, Zhou JS. Angew. Chem. Int. Ed. 2017; 56: 12723
- 4 García-Domínguez A, Li Z, Nevado C. J. Am. Chem. Soc. 2017; 139: 6835
- 5a Yan C.-S, Peng Y, Xu X.-B, Wang Y.-W. Chem. Eur. J. 2012; 18: 6039 ; corrigendum: Chem. Eur. J. 2013, 19, 15438
- 5b Xu X.-B, Liu J, Zhang J.-J, Wang Y.-W, Peng Y. Org. Lett. 2013; 15: 550
- 5c Peng Y, Luo L, Yan C.-S, Zhang J.-J, Wang Y.-W. J. Org. Chem. 2013; 78: 10960
- 5d Peng Y, Xu X.-B, Xiao J, Wang Y.-W. Chem. Commun. 2014; 50: 472
- 5e Luo L, Zhang J.-J, Ling W.-J, Shao Y.-L, Wang Y.-W, Peng Y. Synthesis 2014; 46: 1908
- 5f Peng Y, Xiao J, Xu X.-B, Duan S.-M, Ren L, Shao Y.-L, Wang Y.-W. Org. Lett. 2016; 18: 5170
- 5g Xiao J, Wang Y.-W, Peng Y. Synthesis 2017; 49: 3576
- 5h Xiao J, Cong X.-W, Yang G.-Z, Wang Y.-W, Peng Y. Org. Lett. 2018; 20: 1651
- 5i Xiao J, Cong X.-W, Yang G.-Z, Wang Y.-W, Peng Y. Chem. Commun. 2018; 54: 2040
- 5j Luo L, Zhai X.-Y, Wang Y.-W, Peng Y, Gong H. Chem. Eur. J. 2019; 25: 989
- 5k Ouyang Y, Peng Y, Li W.-DZ. Tetrahedron 2019; 75: 4486
- 6a Peng Y. Lignans, Lignins, and Resveratrols. From Biosynthesis to Total Synthesis: Strategies and Tactics for Natural Products. Zografos AL. John Wiley & Sons; Hoboken: 2016. Chap. 10, 331-379
- 6b Liu Y.-Q, Yang L, Tian X. Curr. Bioact. Compd. 2007; 3: 37
- 6c Sellars JD, Steel PG. Eur. J. Org. Chem. 2007; 3815
- 6d Ting CP, Tschanen E, Jang E, Maimone TJ. Tetrahedron 2019; 75: 3299
- 6e Hajra S, Garai S, Hazra S. Org. Lett. 2017; 19: 6530
- 6f Ting CP, Maimone TJ. Angew. Chem. Int. Ed. 2014; 53: 3115
- 6g Wu Y, Zhao J, Chen J, Pan C, Li L, Zhang H. Org. Lett. 2009; 11: 597
- 6h Stadler D, Bach T. Angew. Chem. Int. Ed. 2008; 47: 7557
- 6i Wu Y, Zhang H, Zhao Y, Zhao J, Chen J, Li L. Org. Lett. 2007; 9: 1199
- 6j Reynolds AJ, Scott AJ, Turner CI, Sherburn MC. J. Am. Chem. Soc. 2003; 125: 12108
- 6k Berkowitz DB, Choi S, Maeng J.-H. J. Org. Chem. 2000; 65: 847
- 6l Hadimani SB, Tanpure RP, Bhat SV. Tetrahedron Lett. 1996; 37: 4791
- 6m Bush EJ, Jones DW. J. Chem. Soc., Chem. Commun. 1993; 1200
- 6n Van Speybroeck R, Guo H, Van der Eycken J, Vandewalle M. Tetrahedron 1991; 47: 4675
- 6o Andrews RC, Teague SJ, Meyers AI. J. Am. Chem. Soc. 1988; 110: 7854
- 6p Macdonald DI, Durst T. J. Org. Chem. 1986; 51: 4749
- 6q Gensler WJ, Gatsonis CD. J. Am. Chem. Soc. 1962; 84: 1748 ; see also ref. 5h in this article
- 6r Li J, Zhang X, Renata H. Angew. Chem. Int. Ed. 2019; 58: 11657
- 6s Lazzarotto M, Hammerer L, Hetmann M, Borg A, Schmermund L, Steiner L, Hartmann P, Belaj F, Kroutil W, Gruber K, Fuchs M. Angew. Chem. Int. Ed. 2019; 58: 8226
- 6t Kolly-Kovač T, Renaud P. Synthesis 2005; 1459
- 7 Snyder SA, Wright NE, Pflueger JJ, Breazzano SP. Angew. Chem. Int. Ed. 2011; 50: 8629
- 8 Gibson SE, Guillo N, Middleton RJ, Thuilliez A, Tozer MJ. J. Chem. Soc., Perkin Trans. 1 1997; 447
- 9 Kato T, Ichinose I, Kamoshida A, Kitahara Y. J. Chem. Soc., Chem. Commun. 1976; 518 ; and references cited therein
- 10 In a 100 mL round-bottom flask, enol ether 7 (1.50 g, 3.1 mmol) was dissolved in anhydrous CH2Cl2 (35 mL) and cooled to 0 °C. To this solution was added TBCD (97%, 1.57 g, 3.7 mmol, 1.2 equiv) portionwise, and the mixture was stirred for 30 min at 0 °C. A solution of allyl alcohol (3.6 mL, 62 mmol, 20.0 equiv) in CH2Cl2 (5 mL) was then added dropwise, and the resulting mixture was gradually warmed to room temperature and stirred further for 9 h. The reaction was quenched with saturated aqueous NaHCO3 (3 mL), Na2SO3 (3 mL), and stirred further for 30 min. The resulting mixture was extracted with CH2Cl2 (2 × 50 mL), and the combined organic layers were washed with water (2 × 15 mL) and brine (15 mL), respectively, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petroleum ether/EtOAc = 10:1 → petroleum ether/EtOAc = 4:1) on silica gel to afford 8 (1.519 g, 79% yield) as a yellow oil. Rf = 0.36 (petroleum ether/EtOAc = 2:1). IR (film): νmax = 2930, 2838, 1590, 1504, 1479, 1461, 1422, 1383, 1326, 1265, 1229, 1128, 1037, 929, 845, 792, 736, 701, 685, 582 cm–1. 1H NMR (400 MHz, CDCl3): δ (major isomer) = 7.19 (s, 1 H), 6.99 (s, 1 H), 6.52 (s, 2 H), 5.93 (s, 1 H), 5.89 (s, 1 H), 5.86–5.80 (m, 1 H), 5.35 (dd, J = 17.2, 1.6 Hz, 1 H), 5.13 (dd, J = 10.8, 1.6 Hz, 1 H), 4.76 (d, J = 10.8 Hz, 1 H), 4.55 (dd, J = 11.2, 2.8 Hz, 1 H), 4.26 (dd, J = 13.2, 4.8 Hz, 1 H), 4.00 (d, J = 2.4 Hz, 1 H), 3.88 (dd, J = 12.8, 5.2 Hz, 1 H), 3.76 (s, 6 H), 3.74 (s, 3 H), 3.31 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.3 (2 C), 148.7, 147.3, 137.23, 137.17, 135.6, 133.8, 119.0, 116.7, 107.0, 105.3 (2 C), 102.0, 101.8, 90.5, 69.7, 60.8, 57.7, 57.3, 56.21 (2 C), 56.17 ppm. HRMS (ESI): m/z calcd for C23H26O7 79BrINa+ [M + Na]+: 642.9799; found: 642.9791.
- 11 Xiao J, Nan G, Wang Y.-W, Peng Y. Molecules 2018; 23: 3037
For selected examples, see:
For reviews, see:
For past syntheses of podophyllotoxin (3), see:
For chemoenzymatic syntheses of podophyllotoxin (3), see:
For a synthesis of deoxypodophyllotoxin, see: