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A novel total synthesis of the bioactive poly-substituted carbazole alkaloid carbazomadurin A

Yuhzo Hieda, Tominari Choshi *, Sayuri Kishida, Haruto Fujioka, Satoshi Hibino *Graduate School of Pharmacy & Pharmaceutical Sciences, and Faculty of Pharmacy & Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japana b s t r a c t

A new total synthesis of the neuronal cell-protecting carbazole alkaloid carbazomadurin A is described.The key step was an allene-mediated electrocyclic reaction involving an indole [b]-bond for the construction of a highly substituted carbazole ring. The E-alkenyl side chain at the C1 position of carbazole was introduced between O-triflate and alkenyl pinacol borate using the Suzuki–Miyaura reaction. SEM groups were cleaved with TBAF and the formyl group was reduced to provide carbazomadurin A.

1. Introduction

Naturally occurring carbazoles are very attractive compounds because of their antioxidant activity.1 The neuronal cell-protecting carbazole alkaloids carbazomadurins A (1) and B (2) were isolated in 1997 from the microorganism Actinomadura madurae 2808-SV1 by Seto and co-workers (Fig. 1).2 The structures of both compounds except the absolute configuration for 2 were assigned based on their spectroscopic data. These compounds protect against glutamate toxicity in neuronal hybridoma N18-RE-105 cells as an in vitro ischemia model. The Knker group achieved the first totalsyntheses of carbazomadurin A (1)3 and B (2)4 by constructing a suitable carbazole framework based on a palladium-catalyzed sequence of the Buchwald–Hartwig amination, followed by oxidativecyclization and subsequent introduction of the alkenyl group at the C1 position using the Stille coupling reaction. In their first total synthesis, the Knker group has also assigned the absolute configuration for 2, which was shown to have an S-configuration at the stereogenic center.We are interested in the synthesis of bioactive condensed heterocyclic compounds including natural products, based on a thermal electrocyclic reaction strategy with either a 6p-electron system or an aza 6p-electron system incorporating an aromatic or heteroaromatic double bond.5–7 In the course of our studies focusing on the development of a thermal electrocyclic reaction of a 6p-electron system including an allene intermediate,5,7 we achieved a new total synthesis of a highly functionalized carbazole alkaloid, carbazomadurin A (1). Our synthetic strategy of carbazomadurin A (1) is outlined in Scheme 1, where a 1,3,8-trioxygenated carbazole framework of 1 is obtained from 2-allenylindole intermediate 5 generated from 2-propargylindole 6. We also hypothesized that an alkenyl side chain with an E configuration at the C1 position of 1 might be introduced by the Suzuki–Miyaura reaction8 using alkenyl pinacol borate 42. Results and discussion We initially attempted a synthesis of the required 7-oxygenated 2,3,4,7-tetrasubstituted indole 13 from the known ethyl 7-isopropoxyindole- 2-carboxylate (7)9 as shown in Scheme 2. Treatment of 7 with a,a-dichloromethyl methyl ether in the presence of TiCl4 at _40 _C10 for 4 h gave 4-formylindole 8. The formyl group of 8



was subsequently reduced to a hydroxymethyl group with NaBH4, which was treated with MOMCl in the presence of N,N-diisopropylethylamine (iPr2NEt) to yield MOM-ether 10. Reduction of the ester moiety of 10 by Red-Al, followed by oxidation of the resulting alcohol by MnO2 afforded the indole-2-carboxaldehyde 12. Further treatment of 12 with I2 in the presence of KOH gave the 7-oxygenated 2,3,4,7-tetrasubstituted indole 13 in six-steps. On the other hand, a pinacol borate 4 to introduce an alkenyl side chain with an E configuration at the C1 of carbazomadurin A (1) was prepared from 5-methyl-1-hexyne (14) in three steps as follows (Scheme 3). Zirconium-catalyzed carboalumination of 5- methyl-1-hexyne (14) with trimethylaluminum in the presence

of zirconocene dichloride as reported by Negishi,11 followed by the addition of I2 afforded the E-alkenyl iodide 153 in moderate yield.Subsequently, the Suzuki–Miyaura reaction8,12 of 15 with bis(pinacolato) diboron in the presence of PdCl2(dppf) afforded the pinacol borate 4 in 48% yield. We then synthesized 1,3,8-trioxygenated 1,2,3,5,8-pentasubstituted carbazoles 23 and 24 from the 2,3,4,7-tetrasubstituted indole 13 (Scheme 4). A Stille coupling reaction of 3-iodoindole 13 with 2- ethoxyvinylstannane13 in the presence of PdCl2(PPh3)2 gave the 3- alkenylindole 16 in good yield. Grignard reaction of 16 with ethynylmagnesium bromide, followed by treatment of the resulting alcohol 17 with MOMCl and iPr2NEt produced the O-MOM-propargyl ether 18 in good yield. We subsequently attempted to constructa poly-functionalized carbazole framework 20 that was equivalent to 3, using an allene-mediated electrocyclic reaction as a key step. When the O-MOM-propargyl ether 18 was heated at 90 _C in the presence of potassium tert-butoxide in tert-butyl alcohol according to the previously reported method7 for allene generation, the expected carbazole 20 was not detected. Alternatively, treatment of 18 with TBAF in THF according to another reported method7b afforded the required carbazole 20 in somewhat low yield (40%). Oxidation of the O-MOM-methyl group14 at the C-5 of 20 with DDQ provided the 5-formylcarbazole 21, which was treated with 4 M HCl in the presence of ethylene glycol in THF to yield the 1- hydroxycarbazole 22. Sequential treatment of 22 with N-phenylbis(trifluoromethanesulfonimide) (PhNTf2) gave the corresponding

triflate 23. Cleavage of ethyl and isopropyl ethers of 23 with BBr3 afforded the 3,8-dihydroxycarbazole, which was immediately protected with SEMCl and iPr2NEt to produce the 3,8-bis-O-SEM-carbazole 24Carbon–carbon bond formations of two kinds of triflates 23 and 24 with the alkenyl pinacol borate 4 were then investigated(Scheme 5). The Suzuki–Miyaura cross-coupling reaction12 of 23 with 4 in the presence of Na2CO3 and Pd(PPh3)4 gave the 1-alkenylcarbazole 25 in an excellent yield. In the case of cross-coupling 24 with 4, the coupling reaction proceeded smoothly in the presence of aqueous Na2CO3 and Pd(PPh3)4 to give 26 in good yield. Although, removal of the ethyl and isopropyl ethers of 25 with BBr3 was attempted, the conversion to the corresponding 27 failed.By contrast, reduction of the formyl group of 26 with DIBAL gave the 5-hydroxymethylcarbazole 28 in good yield. Cleavage of both SEM groups of 28 using TBAF in THF did not provide carbazomadurinA (1). As a result, removal of both SEM groups15 of 26 with TBAF in HMPA gave the expected dihydroxycarbazole 27. Finally, reduction of 27 with NaBH4 in methanol afforded carbazomadurin A (1). The physical and spectroscopic data16 of our synthetic carbazomadurin A (1) were identical with those of reported data.2,3 3. Conclusions The preparation of 2,3,4,7 tetrasubstituted indole 13 for the synthesis of poly-functionalized carbazoles 23 and 24 was achieved from 7 in a six-step sequence. An allene-mediated electrocyclic reaction of the propargyl ether 18 afforded the appropriate substituted carbazole 20, which led to the desired carbazoles 23 and 24. Introduction of the alkenyl side chain to the C1 position of carbazole O-triflates 23 and 24 was successfully achieved by the Suzuki–Miyaura cross-coupling reaction using alkenyl pinacol borate 4. Carbazomadurin A (1) was obtained from the 3,8-O-bisSEM carbazole 26 in two steps. Thus a new total synthesis of carbazomadurin A (1) was completed in two key steps by a synthesis of the suitable substituted carbazole, based on an allene-mediated electrocyclic reaction of a 6p-electron system involving an indole [b]- bond and then the Suzuki–Miyaura reaction. This synthetic strategy is applicable for a series of other functionalized carbazole alkaloids. Acknowledgment This work was supported in part by Grant-in Aid for Scientific Research (C) (No. 15590033) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. References and notes 1. For most recent reviews, see: (a) Chakraborty, D. P.. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: Amsterdam, 1993; Vol. 44, pp 257–364; (b) Knker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303–4428; (c) Knker, H.-J. Top. Curr. Chem. 2005, 244, 115–148; (d) Knker, H.-J.; Reddy, K. R.. In The AlkaloidsCordell, G. A., Ed.; Academic Press: Amsterdam, 2008; Vol. 65, pp 1–430; (e) Knker, H.-J. Chem. Lett. 2009, 38, 8–13. 2. Kotoda, N.; Shinya, K.; Furihata, K.; Hayakawa, Y.; Seto, H. J. Antibiot. 1997, 50770–772. 3. Knker, H.-J.; Knl, J. Chem. Commun. 2003, 1170–1171. 4. Knl, J.; Knker, H.-J. Synlett 2006, 651–653. 5. (a) Hibino, S.; Sugino, E.. In Advances in Nitrogen Heterocycles; Moody, C. J., Ed.; JAI Press: Greenwich, CT, 1995; Vol. 5, pp 205–227; (b) Kawasaki, T.; Sakamoto, M. J. Indian Chem. Soc. 1994, 71, 443–457; (c) Choshi, T. Yakugaku Zasshi 2001121, 487–495; (d) Choshi, T.; Hibino, S. Heterocycles 2009, 77, 85–97. 6. (a) Ohmura, K.; Choshi, T.; Watanabe, S.; Satoh, Y.; Nobuhiro, J.; Hibino, S. Chem. Pharm. Bull. 2008, 56, 237–238; (b) Kohno, K.; Azuma, S.; Choshi, T.;Nobuhiro, J.; Hibino, S. Tetrahedron Lett. 2009, 50, 590–592. and relatedreferences cited therein.7. (a) Choshi, T.; Sada, T.; Fujimoto, H.; Sugino, E.; Hibino, S. Tetrahedron Lett.1996, 37, 2593–2596; (b) Choshi, T.; Fujimoto, H.; Sugino, E.; Hibino, S.Heterocycles 1996, 43, 1847–1854; (c) Choshi, T.; Sada, T.; Fujimoto,H.;Nagayama, C.; Sugino, E.; Hibino, S. J. Org. Chem. 1997, 62, 2535–2543; (d)Hagiwara, H.; Choshi, T.; Fujimoto, H.; Sugino, E.; Hibino, S. Chem. Pharm. Bull.1998, 46, 1948–1949; (e) Hagiwara, H.; Choshi, T.; Fujimoto, H.; Sugino, E.;Hibino, S. Tetrahedron 2000, 56, 5807–5811; (f) Hagiwara, H.; Choshi, T.;Nobuhiro, J.; Fujimoto, H.; Hibino, S. Chem. Pharm. Bull. 2001, 49, 881–886; (g)Hirayama, M.; Choshi, T.; Kumemura, T.; Tohyama, S.; Nobuhiro, T.; Hibino, S.Heterocycles 2004, 63, 1765–1770; (h) Tohyama, S.; Choshi, T.; Matsumoto, K.;Yamabuki, A.; Ikegata, K.; Nobuhiro, J.;Hibino, S. Tetrahedron Lett. 2005, 46,5263–5264; (i) Nobuhiro, J.; Hirayama, M.; Choshi, T.; Kamoshita, S.;Maruyama, Y.; Sukenaga, Y.; Ishizu, T.; Fujioka, H.; Hibino, S. Heterocycles2006, 70, 491–499;(j) Yamabuki, A.; Fujinawa, H.; Choshi, T.; Tohyama, S.;Matsumoto, K.; Ohmura, K.; Nobuhiro, J.; Hibino, S. Tetrahedron Lett. 2006, 47,5859–5861; (k) Tohyama, S.; Choshi, T.; Azuma, S.; Fujioka, H.; Hibino, S.Heterocycles 2009, 79, 955–965.8. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483; (b) Miyaura, N. Top.Curr. Chem. 2002, 219, 11–58.9. Suzuki, H.; Gyoutoku, H.; Yokoo, H.; Shinba,M.; Sato, Y.; Yamada, H.;Murakami, Y. Synlett 2000, 1196–1198.10. Condie, G. C.; Channon, M. F.; Ivory Kumar, A. J.; Kumar, N.; Black, D. S.Tetrahedron 2005, 61, 4989–5004.11. (a) van Horn, D. E.; Negishi, E. J. Am. Chem. Soc. 1978, 100, 2252–2254; (b)Negishi, E.; van Horn, D. E.; King, A. O.; Okukado, N. Synthesis 1979, 501; (c)Rand, C. L.; van Horn, D. E.; Moore, M. W.; Negishi, E. J. Org. Chem. 1981, 46,4097–4100; (d) van Horn, D. E.; Negishi, E.; Yoshida, T. J. Am. Chem. Soc. 1985,107, 6639–6647.12. (a) Oh-e, T.; Miyaura, N.; Suzuki, A. Synlett 1990, 221–223; (b) Miyaura, N.;Ishiyama, T.; Hayashi, H.; Ishikawa, M.; Satoh, M.; Suzuki, A. J. Am. Chem. Soc.1989, 111, 314–321.13. Kazankova, M. A.; Protsenko, N. P.; Lutsenko, I. F. Russ. J. Gen. Chem. 1968, 38,106–108.14. Wang, W.; Li, T.; Atturdo, G. J. Org. Chem. 1997, 62, 6598–6602.15. Leboff, A.; Carbonnelle, A.-C.; Alazard, J.-P.; Thal, C.; Kende, A. S. TetrahedronLett. 1987, 28, 4163–4164.16. Data of carbazomadurin A (1): mp 166.5–168.5 _C; IR (ATR) m: 3480, 3420, 16401580, 1430, 1370 cm_1. 1H NMR (300 MHz, acetone-d6) d: 8.56 (1H, br s), 8.37(1H, br s), 7.77 (1H, br s), 7.57 (1H, s), 6.90 (1H, d, J = 7.7 Hz), 6.71 (1H, d,J = 7.7 Hz), 6.41 (1H, s), 5.01 (2H, s), 3.90 (1H, br s), 2.33 (2H, t, J = 7.7 Hz), 2.26(3H, s), 1.64–1.73 (1H, m), 1.50–1.57 (5H, m), 0.99 (6H, d, J = 6.6 Hz). 13C NMR(75 MHz, acetone-d6) d: 149.9, 142.9, 142.7, 133.5, 130.3, 128.1, 123.4, 122.4,122.3, 121.3, 120.3, 118.8, 109.6, 106.8, 64.0, 38.0, 37.7, 29.0, 22.8 (2C), 17.9,13.5. MS m/z: 353 (M+). HR-MS (EI) m/z: 353.1975 (M+) (calcd for C22H27NO3:353.1991).