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Synthesis of double-13C-labeled imidazole derivatives
Tetrahedron Letters 59 (2018) 3516–3518
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Synthesis of double-13C-labeled imidazole derivatives Hitoshi Ouchi a,f, Tomohiro Asakawa b,f, Kazutada Ikeuchi c, Makoto Inai a, Jae-Hoon Choi d,e, Hirokazu Kawagishi d,e, Toshiyuki Kan a,⇑ a
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan Tokai University Institute of Innovative Science and Technology, 4-1-1, Kitakaname, Hiratsuka-city, Kanagawa 259-1292, Japan c Department of Chemistry, Faculty of Science, Hokkaido University, Kita 10, Nishi 8, Kita-ku, Sapporo 060-0810, Japan d Graduate School of Integrated Science and Technology, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan e Research Institute of Green Science and Technology, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan b
a r t i c l e
i n f o
Article history: Received 18 June 2018 Revised 12 July 2018 Accepted 19 July 2018 Available online 19 July 2018
a b s t r a c t Double-13C-labeled imidazole-4-carboxamide (ICA: 13C2-1) and 5-aminoimidazole-4-carboxamide-1-briboside (AICAr: 13C2-5) were synthesized from stable isotope-labeled sodium cyanide and triethyl orthoformate. The key intermediate, 4-aminoimidazole-5-carboxamide (AICA: 13C2-4), should also provide access to double-13C-labeled histidine and adenosine derivatives via reported methods. Ó 2018 Elsevier Ltd. All rights reserved.
Keywords: Isotope label Fairy chemicals (FCs) Double-label Histidine Adenosine riboside
Stable isotope labeling is useful for NMR analysis [1] and in preparing internal standards for LC-MS detection of biologically active compounds and their metabolites [2]. During the course of studies of the so-called fairy chemicals (FCs) [3–5], which were originally isolated as plant growth stimulators from the fairyring-forming fungus, Lepista sordida, labeled compounds 1–7 were required to confirm the endogenous existence of FCs in plants and to elucidate their biosynthetic pathway. Among these compounds, AICA (4) and its ribotide (AICAR: 6) are common members of the purine metabolic pathway in animals, plants and microorganisms, and AICAR (6) is an intermediate leading to inosine monophosphate (IMP), inosine, hypoxanthine, xanthine and uric acid in the same pathway. On the other hand, AICAr (5) activates adenosine monophosphate-activated protein kinase (AMPK) without affecting the cellular concentrations of ATP, ADP, or AMP [6]. AICAr (5; international nonproprietary name, acadesine) is used as a targeting agent for therapy of patients with acute lymphoblastic leukemia [7]. It is also a potential lead for anticancer as well as diabetes treatment [8], so stable isotope-labeled derivatives should be helpful for drug development. In particular, double-labeled
⇑ Corresponding author. f
E-mail address: [email protected] (T. Kan). Both authors contributed equally to this work.
https://doi.org/10.1016/j.tetlet.2018.07.048 0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
compounds are expected to be useful for detailed analysis without having to take account of the natural abundance (1%) of 13C. As shown in Scheme 1, incorporation of labeled carbons into the imidazole ring was performed with triethyl orthoformate 8 and sodium cyanide as the 13C source. Under acidic conditions, dimerization reaction of methyl urea 9 and 8 proceeded smoothly to afford 10. Condensation of 10 and 11, prepared from 13C-labeled sodium cyanide, also proceeded smoothly through the intermediate 12 to provide the double-labeled imidazole ring compound 13. After removal of the methyl carbamoyl group, deamination of 13 C2-4 was carried out by conversion to the diazoimidazole derivative and hydrogenolysis to give 13C2-1. Next, 13C2-4 was readily converted to 13C2-2 by means of a similar procedure to that used for synthesizing the non-labeled compound [9]. To our knowledge, there is no previous report of the preparation of double-13C-labeled imidazole ring derivatives. Next, we turned our attention to the synthesis of doublelabeled ribosyl FCs. As shown in Scheme 2, direct condensation of ribose derivative 14 with ICA (1) or AICA (4) gave unsatisfactory results, so double-labeled AICA (4) was first converted to hypoxanthine (15) to protect the two nitrogen groups. Upon treatment of 13 C2-4 with triethyl orthoformate, six-membered ring formation proceeded smoothly to afford 15. Coupling reaction of 15 and 14 was performed by in situ protection of the amide group of 15 as trimethylsilyl amide by treatment with N,O-bis(trimethylsilyl)
H. Ouchi et al. / Tetrahedron Letters 59 (2018) 3516–3518
3517
Fig. 1. Structures of fairy chemicals 1–3 and related compounds 4–7.
Scheme 1. Synthesis of double-13C-labeled FCs 1 and 2.
Scheme 3. Potential of labeled imidazoles 1 and 15.
[14], so the synthesis of double-13C-labeled adenosine derivative 20 from 15 should also be straightforward. These compounds should be useful in biological studies as well as for drug development. It is noteworthy that it has recently become possible to search for stable isotope-labeled compounds with SciFinder, which should help to raise awareness of their availability. In summary, we have developed an efficient synthesis of double-13C-labeled imidazole derivative as a key intermediate in the synthesis of double-13C-labeled FCs. It should also be readily convertible to double-labeled histidine and adenosine via reported procedures. Acknowledgments
Scheme 2. Synthesis of double-labeled AICA riboside (13C2-5).
acetamide (BSA) and activation of 14 with trimethylsilyl triflate to give 16. Removal of the C1-unit at the C2 position of inosine derivative 16 was achieved according to our previously reported method for non-labeled compounds [10]. Incorporation of a 2,4dinitrophenyl group on the amide nitrogen of 16 was carried out via nucleophilic aromatic substitution reaction of 1-chloro-2,4dinitrobenzene to give 17. Simultaneous aminolysis reaction of the imidamide ring, acetate and 2,4-dinitrophenyl group was performed by treatment of 17 with ethylenediamine in acetonitrile to give the desired 13C2-5. The availability of this compound as an internal standard should facilitate highly sensitive LC-MS/MS detection of 5; this is important because the World Anti-Doping Agency (WADA) has prohibited the use of AICAr (5) since 2009 [11,12]. In addition, 13C2-5 would be readily applicable as a key intermediate for preparation of double-labeled ICA riboside, AHX riboside (7) and AOH riboside. Further synthetic investigations of labeled FCs are in progress in our laboratory (See Fig. 1). Furthermore, our synthetic double-13C-labeled imidazole derivatives should be readily convertible to the corresponding histidine 19 and adenosine riboside 20 as shown in Scheme 3, since we recently showed that optically active histidine 19 could be synthesized from imidazole carboaldehyde by a combination of HornerWadsworth-Emmons reaction and asymmetric hydrogenation [13]. Thus, ICA (1) should be convertible to 19 via 18. On the other hand, conversion of a purine ring to adenosine has been reported
This work was financially supported by MEXT/JSPS KAKENHI Grant Numbers JP17H03973 and JP17K15424, Grants-in-Aid for Scientific Research on Priority Areas JP16H01160 and 17H06402 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics and Structural Life Science) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.tetlet.2018.07.048. References [1] [2] [3] [4] [5]
[6] [7] [8]
[9]
S. Ohki, M. Kainosho, Prog. Nucl. Magn. Reson. Spectrosc. 53 (2008) 208–226. T. Toyo’oka, J. Pharm. Biomed. Anal. 69 (2012) 174–184. A. Mitchinson, Nature 505 (2014) 298. For review of fairy chemicals, see; H. Kawagishi Biosci. Biotechnol. Biochem. 82 (2018) 752–758. J.-H. Choi, J. Wu, A. Sawada, S. Takeda, H. Takemura, K. Yogosawa, H. Hirai, M. Kondo, K. Sugimoto, T. Asakawa, M. Inai, T. Kan, H. Kawagishi, Org. Lett. 20 (2018) 312–314. C.B. Favero, J.W. Mandell, Brain Res. 1168 (2007) 1–10. B.N. Cronstein, B.A. Kamen, J. Pediatr. Hematol. Oncol. 29 (2007) 805–807. D.J. Cuthbertson, J.A. Babraj, K.J.W. Mustard, M.C. Towler, K.A. Green, H. Wackerhage, G.P. Leese, K. Baar, M. Thomason-Hughes, C. Sutherland, D.G. Hardie, M.J. Rennie, Diabetes 56 (2007) 2078–2084. J.-H. Choi, T. Ohnishi, Y. Yamakawa, S. Takeda, S. Sekiguchi, W. Maruyama, K. Yamashita, T. Suzuki, A. Morita, T. Ikka, R. Motohashi, Y. Kiriiwa, H. Tobina, T. Asai, S. Tokuyama, H. Hirai, N. Yasuda, K. Noguchi, T. Asakawa, S. Sugiyama, T. Kan, H. Kawagishi, Angew. Chem. Int. Ed. 53 (2014) 1552–1555.
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H. Ouchi et al. / Tetrahedron Letters 59 (2018) 3516–3518
[10] K. Ikeuchi, R. Fujii, S. Sugiyama, T. Asakawa, M. Inai, Y. Hamashima, J.-H. Choi, T. Suzuki, H. Kawagishi, T. Kan, Org. Biomol. Chem. 12 (2014) 3813–3815. [11] C. Görgens, S. Guddat, A.-K. Orlovius, G. Sigmund, A. Thomas, M. Thevis, W. Schänzer, Anal. Bioanal. Chem. 407 (2015) 5365–5379.
[12] T. Piper, A. Thomas, N. Baume, T. Sobolevsky, M. Saugy, G. Rodchenkov, W. Schänzer, M. Thevis, Rapid Commun. Mass Spectrom. 28 (2014) 1194–1202. [13] M. Yamashita, K. Shimizu, Y. Koizumi, T. Wakimoto, Y. Hamashima, T. Asakawa, M. Inai, T. Kan, Synlett 27 (2016) 2734–2736. [14] Y. Yafeng, S. Li, P. Wen, J. Chinese, Synth. Chem. 11 (2003) 307–309.
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Synthesis of double-13C-labeled imidazole derivatives Hitoshi Ouchi a,f, Tomohiro Asakawa b,f, Kazutada Ikeuchi c, Makoto Inai a, Jae-Hoon Choi d,e, Hirokazu Kawagishi d,e, Toshiyuki Kan a,⇑ a
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan Tokai University Institute of Innovative Science and Technology, 4-1-1, Kitakaname, Hiratsuka-city, Kanagawa 259-1292, Japan c Department of Chemistry, Faculty of Science, Hokkaido University, Kita 10, Nishi 8, Kita-ku, Sapporo 060-0810, Japan d Graduate School of Integrated Science and Technology, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan e Research Institute of Green Science and Technology, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan b
a r t i c l e
i n f o
Article history: Received 18 June 2018 Revised 12 July 2018 Accepted 19 July 2018 Available online 19 July 2018
a b s t r a c t Double-13C-labeled imidazole-4-carboxamide (ICA: 13C2-1) and 5-aminoimidazole-4-carboxamide-1-briboside (AICAr: 13C2-5) were synthesized from stable isotope-labeled sodium cyanide and triethyl orthoformate. The key intermediate, 4-aminoimidazole-5-carboxamide (AICA: 13C2-4), should also provide access to double-13C-labeled histidine and adenosine derivatives via reported methods. Ó 2018 Elsevier Ltd. All rights reserved.
Keywords: Isotope label Fairy chemicals (FCs) Double-label Histidine Adenosine riboside
Stable isotope labeling is useful for NMR analysis [1] and in preparing internal standards for LC-MS detection of biologically active compounds and their metabolites [2]. During the course of studies of the so-called fairy chemicals (FCs) [3–5], which were originally isolated as plant growth stimulators from the fairyring-forming fungus, Lepista sordida, labeled compounds 1–7 were required to confirm the endogenous existence of FCs in plants and to elucidate their biosynthetic pathway. Among these compounds, AICA (4) and its ribotide (AICAR: 6) are common members of the purine metabolic pathway in animals, plants and microorganisms, and AICAR (6) is an intermediate leading to inosine monophosphate (IMP), inosine, hypoxanthine, xanthine and uric acid in the same pathway. On the other hand, AICAr (5) activates adenosine monophosphate-activated protein kinase (AMPK) without affecting the cellular concentrations of ATP, ADP, or AMP [6]. AICAr (5; international nonproprietary name, acadesine) is used as a targeting agent for therapy of patients with acute lymphoblastic leukemia [7]. It is also a potential lead for anticancer as well as diabetes treatment [8], so stable isotope-labeled derivatives should be helpful for drug development. In particular, double-labeled
⇑ Corresponding author. f
E-mail address: [email protected] (T. Kan). Both authors contributed equally to this work.
https://doi.org/10.1016/j.tetlet.2018.07.048 0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
compounds are expected to be useful for detailed analysis without having to take account of the natural abundance (1%) of 13C. As shown in Scheme 1, incorporation of labeled carbons into the imidazole ring was performed with triethyl orthoformate 8 and sodium cyanide as the 13C source. Under acidic conditions, dimerization reaction of methyl urea 9 and 8 proceeded smoothly to afford 10. Condensation of 10 and 11, prepared from 13C-labeled sodium cyanide, also proceeded smoothly through the intermediate 12 to provide the double-labeled imidazole ring compound 13. After removal of the methyl carbamoyl group, deamination of 13 C2-4 was carried out by conversion to the diazoimidazole derivative and hydrogenolysis to give 13C2-1. Next, 13C2-4 was readily converted to 13C2-2 by means of a similar procedure to that used for synthesizing the non-labeled compound [9]. To our knowledge, there is no previous report of the preparation of double-13C-labeled imidazole ring derivatives. Next, we turned our attention to the synthesis of doublelabeled ribosyl FCs. As shown in Scheme 2, direct condensation of ribose derivative 14 with ICA (1) or AICA (4) gave unsatisfactory results, so double-labeled AICA (4) was first converted to hypoxanthine (15) to protect the two nitrogen groups. Upon treatment of 13 C2-4 with triethyl orthoformate, six-membered ring formation proceeded smoothly to afford 15. Coupling reaction of 15 and 14 was performed by in situ protection of the amide group of 15 as trimethylsilyl amide by treatment with N,O-bis(trimethylsilyl)
H. Ouchi et al. / Tetrahedron Letters 59 (2018) 3516–3518
3517
Fig. 1. Structures of fairy chemicals 1–3 and related compounds 4–7.
Scheme 1. Synthesis of double-13C-labeled FCs 1 and 2.
Scheme 3. Potential of labeled imidazoles 1 and 15.
[14], so the synthesis of double-13C-labeled adenosine derivative 20 from 15 should also be straightforward. These compounds should be useful in biological studies as well as for drug development. It is noteworthy that it has recently become possible to search for stable isotope-labeled compounds with SciFinder, which should help to raise awareness of their availability. In summary, we have developed an efficient synthesis of double-13C-labeled imidazole derivative as a key intermediate in the synthesis of double-13C-labeled FCs. It should also be readily convertible to double-labeled histidine and adenosine via reported procedures. Acknowledgments
Scheme 2. Synthesis of double-labeled AICA riboside (13C2-5).
acetamide (BSA) and activation of 14 with trimethylsilyl triflate to give 16. Removal of the C1-unit at the C2 position of inosine derivative 16 was achieved according to our previously reported method for non-labeled compounds [10]. Incorporation of a 2,4dinitrophenyl group on the amide nitrogen of 16 was carried out via nucleophilic aromatic substitution reaction of 1-chloro-2,4dinitrobenzene to give 17. Simultaneous aminolysis reaction of the imidamide ring, acetate and 2,4-dinitrophenyl group was performed by treatment of 17 with ethylenediamine in acetonitrile to give the desired 13C2-5. The availability of this compound as an internal standard should facilitate highly sensitive LC-MS/MS detection of 5; this is important because the World Anti-Doping Agency (WADA) has prohibited the use of AICAr (5) since 2009 [11,12]. In addition, 13C2-5 would be readily applicable as a key intermediate for preparation of double-labeled ICA riboside, AHX riboside (7) and AOH riboside. Further synthetic investigations of labeled FCs are in progress in our laboratory (See Fig. 1). Furthermore, our synthetic double-13C-labeled imidazole derivatives should be readily convertible to the corresponding histidine 19 and adenosine riboside 20 as shown in Scheme 3, since we recently showed that optically active histidine 19 could be synthesized from imidazole carboaldehyde by a combination of HornerWadsworth-Emmons reaction and asymmetric hydrogenation [13]. Thus, ICA (1) should be convertible to 19 via 18. On the other hand, conversion of a purine ring to adenosine has been reported
This work was financially supported by MEXT/JSPS KAKENHI Grant Numbers JP17H03973 and JP17K15424, Grants-in-Aid for Scientific Research on Priority Areas JP16H01160 and 17H06402 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics and Structural Life Science) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.tetlet.2018.07.048. References [1] [2] [3] [4] [5]
[6] [7] [8]
[9]
S. Ohki, M. Kainosho, Prog. Nucl. Magn. Reson. Spectrosc. 53 (2008) 208–226. T. Toyo’oka, J. Pharm. Biomed. Anal. 69 (2012) 174–184. A. Mitchinson, Nature 505 (2014) 298. For review of fairy chemicals, see; H. Kawagishi Biosci. Biotechnol. Biochem. 82 (2018) 752–758. J.-H. Choi, J. Wu, A. Sawada, S. Takeda, H. Takemura, K. Yogosawa, H. Hirai, M. Kondo, K. Sugimoto, T. Asakawa, M. Inai, T. Kan, H. Kawagishi, Org. Lett. 20 (2018) 312–314. C.B. Favero, J.W. Mandell, Brain Res. 1168 (2007) 1–10. B.N. Cronstein, B.A. Kamen, J. Pediatr. Hematol. Oncol. 29 (2007) 805–807. D.J. Cuthbertson, J.A. Babraj, K.J.W. Mustard, M.C. Towler, K.A. Green, H. Wackerhage, G.P. Leese, K. Baar, M. Thomason-Hughes, C. Sutherland, D.G. Hardie, M.J. Rennie, Diabetes 56 (2007) 2078–2084. J.-H. Choi, T. Ohnishi, Y. Yamakawa, S. Takeda, S. Sekiguchi, W. Maruyama, K. Yamashita, T. Suzuki, A. Morita, T. Ikka, R. Motohashi, Y. Kiriiwa, H. Tobina, T. Asai, S. Tokuyama, H. Hirai, N. Yasuda, K. Noguchi, T. Asakawa, S. Sugiyama, T. Kan, H. Kawagishi, Angew. Chem. Int. Ed. 53 (2014) 1552–1555.
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H. Ouchi et al. / Tetrahedron Letters 59 (2018) 3516–3518
[10] K. Ikeuchi, R. Fujii, S. Sugiyama, T. Asakawa, M. Inai, Y. Hamashima, J.-H. Choi, T. Suzuki, H. Kawagishi, T. Kan, Org. Biomol. Chem. 12 (2014) 3813–3815. [11] C. Görgens, S. Guddat, A.-K. Orlovius, G. Sigmund, A. Thomas, M. Thevis, W. Schänzer, Anal. Bioanal. Chem. 407 (2015) 5365–5379.
[12] T. Piper, A. Thomas, N. Baume, T. Sobolevsky, M. Saugy, G. Rodchenkov, W. Schänzer, M. Thevis, Rapid Commun. Mass Spectrom. 28 (2014) 1194–1202. [13] M. Yamashita, K. Shimizu, Y. Koizumi, T. Wakimoto, Y. Hamashima, T. Asakawa, M. Inai, T. Kan, Synlett 27 (2016) 2734–2736. [14] Y. Yafeng, S. Li, P. Wen, J. Chinese, Synth. Chem. 11 (2003) 307–309.