Letter pubs.acs.org/OrgLett
Asymmetric Total Synthesis of Pentacyclic Indole Alkaloid Andranginine and Absolute Configuration of Natural Product Isolated from Kopsia arborea Shino Tooriyama, Yuji Mimori, Yuqiu Wu, Noriyuki Kogure, Mariko Kitajima, and Hiromitsu Takayama* Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan S Supporting Information *
ABSTRACT: The first asymmetric total synthesis of andranginine (1) via an asymmetric Morita−Baylis−Hillman reaction and a diastereoselective intramolecular Diels−Alder reaction has revealed that natural andranginine (1) isolated from Kopsia arborea existed as a scalemic mixture and contained predominantly the (16R,21S) form rather than the (16S,21R) form.
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Scheme 1. Proposed Biogenesis of (±)-Andranginine (1)
he genus Kopsia, belonging to the family Apocynaceae, is an abundant source of monoterpenoid indole alkaloids possessing structural diversity and significant biological activities, 1 which have caught the eye of not only pharmaceutical researchers but also synthetic organic chemists.2 In our chemical studies on novel bioactive alkaloids,3 we have found andranginine (1) and several unique monoterpenoid indole alkaloids, such as kopsiyunnanines A−M, from Kopsia arborea native to Yunnan Province in China4 (Figure 1). Andranginine (1), a pentacyclic monoterpenoid indole alkaloid, was first isolated from Craspidospermum verticillatum
as a racemate by Potier’s group in 19745 (Figure 1). Biosynthetically, andranginine (1) is thought to be produced by a nonenzymatic Diels−Alder cycloaddition of a secodinetype precursor6 (Scheme 1), resulting in the formation of racemic andranginine (1). 7 On the other hand, our andranginine (1), which was obtained from K. arborea, exhibited optical activity [[α]D20 −24.3 (c 0.1, CHCl3)].8 In order to elucidate the absolute stereochemistry of andranginine (1) in K. arborea, we carried out the asymmetric total synthesis of this alkaloid, and this enabled us to conclude that andranginine (1) obtained from K. arborea contained Figure 1. Structures of representative monoterpenoid indole alkaloids isolated from Kopsia arborea. © XXXX American Chemical Society
Received: April 10, 2017
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DOI: 10.1021/acs.orglett.7b01076 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 2. Retrosynthetic Analysis for Asymmetric Total Synthesis of 1
Scheme 4. Diastereoselective IMDA of (R)-7
Scheme 3. Synthesis of IMDA Substrate 7
The retrosynthetic analysis of optically active andranginine (1) is shown in Scheme 2. Target molecule 1 would be prepared by the Fischer indole synthesis at the final stage of synthesis. The C/E rings of the tricyclic compound would in turn be constructed by the intramolecular Diels−Alder reaction (IMDA) in which the diastereoselective IMDA would be achieved by installing a bulky substituent at the asymmetric center in 7. The chiral center in 7 would be constructed by the asymmetric Morita−Baylis−Hillman reaction of 9 using cinchona alkaloid as the catalyst.9 First, we prepared aldehyde 9 from 5-vinyl-2-pyridone (10)10 via a two-step operation that included the N-selective alkylation with 4-chloro-1,1-dimethoxybutane (11)11 and the deprotection of dimethyl acetal (Scheme 3). The asymmetric Morita− Baylis−Hillman reaction of aldehyde 9 with 1,1,1,3,3,3hexafluoroisopropyl acrylate (HFIPA) (13) was performed using β-isocupreidine (β-ICD) as the catalyst.9 The methanolysis of resultant ester 14 followed by the conversion into pnitrobenzoate gave chiral IMDA precursor 7 with 98% ee. The enantiomeric excess of 7 was increased to >99% ee by recrystallization from CH2Cl2/n-hexane. The absolute configuration of the stereocenter of 7 was determined as R at a later stage (see compound 15). We next examined the diastereoselective IMDA of (R)-7. Under the optimum reaction conditions (heating in toluene at
predominantly the (16R,21S) form rather than the (16S,21R) form. B
DOI: 10.1021/acs.orglett.7b01076 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
substrate for the Fischer indole synthesis in 87% yield. On treating 20 (99% ee) with ZnCl2 in AcOH under refluxing conditions,14 the [3.3] sigmatropic rearrangement proceeded to give Na-Bn andranginine 21 in 76% yield with 97% ee. Finally, deprotection of the Na-Bn group by treatment with AlCl3 in anisole15 afforded andranginine (1) [[α]D19 +96.1 (c 0.15, CHCl3)] in 71% yield with 97% ee. The chromatographic behavior and the UV, 1H NMR, 13C NMR, and mass spectra of synthetic 1 were identical with those of the natural compound obtained from K. arborea. The optical rotation of synthetic 1 having the 16S,21R configuration was dextrorotatory [[α]D19 +96.1 (c 0.15, CHCl3)],16 which was opposite to that of natural 1 [[α]D20 −24.3 (c 0.1, CHCl3)], and their absolute values of specific rotation were very different. Therefore, natural andranginine (1) isolated from K. arborea contained predominantly the (−)-enantiomer and existed as a scalemic mixture17 [(16R,21S)/(16S,21R) = approximately 62:38].18 The reason why 1 in K. arborea occurs as a scalemic mixture is probably because of the defective facial selectivity within the presumed Diels−Alderase enzyme catalyzing IMDA of hypothetical biogenetic intermediate 3. In conclusion, we have succeeded in the first asymmetric total synthesis of andranginine (1) via an asymmetric Morita− Baylis−Hillman reaction and a diastereoselective intramolecular Diels−Alder reaction. Our efforts have revealed that natural andranginine (1) isolated from Kopsia arborea existed as a scalemic mixture.
Scheme 5. Completion of Total Synthesis of (+)-Andranginine (1)
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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.7b01076. Experimental procedures for the isolation of andranginine (1) and the preparation of compounds 4−9, 12, 14, 15, 18−21, and synthetic 1; NMR spectral data for compounds 4−9, 12, 14, 15, 18−21, and natural and synthetic 1 (PDF) X-ray data for compound 15 (CIF) X-ray data for compound 18 (CIF)
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140 °C in a sealed tube in the presence of 1 equiv of dibutylhydroxytoluene), tricyclic endo adducts 6 and 15 were obtained in 62% and 16% yields, respectively (Scheme 4). The stereochemistry of 6 was assigned on the basis of its NOE correlation from the proton at C-2 to the proton at C-21, and the absolute configuration of diastereomer 15 was confirmed by X-ray crystallographic analysis. The diastereoselectivity in IMDA using (R)-7 could be explained as follows. The steric repulsion between the atomic bulky groups on C-2 and a proton on C-5 caused the equilibrium to shift toward transition state 1, resulting in the predominant formation of adduct 6. The removal of p-nitrobenzoate in 6 by treating with K2CO3 in MeOH gave alcohol 5 in a quantitative yield, which was then oxidized by AZADOL and iodobenzene diacetate (PIDA) to afford ketone 4 in 85% yield (Scheme 5).12 The condensation reaction of ketone 4 and phenylhydrazine (16) catalyzed by cyanuric chloride (17)13 afforded hydrazone amide 18 in 88% yield. At this stage, the 16S,21R configuration of 18 was again confirmed by X-ray crystallographic analysis. After the amideselective reduction of 18 using alane, the secondary amine was protected with a benzyl group in order to prevent its reaction with ester group in the acidic condition, thus forming a
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Hiromitsu Takayama: 0000-0003-3155-2214 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by JSPS KAKENHI Grant Nos. 26293023, 16H05094, and 17H03993 and The Uehara Memorial Foundation.
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REFERENCES
(1) (a) For a review, see: Kam, T.; Lim, K. Alkaloids of Kopsia. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, 2008; Vol. 66, pp 1−111. (b) Zeng, T.; Wu, W.-Y.; Yang, S.-X.; Lai, W.-C.; Shi, S.-D.; Zou, Q.; Liu, Y.; Li, L.-M. J. Nat. Prod. 2017, 80, 864. (c) Wong, S.; Chong, K.; Lim, K.; Lim, S.; Low, Y.; Kam, T. Org. Lett. 2016, 18, 1618−1621. (d) Yap, W.; Gan, C.; Sim, K.; Lim, S.; Low, Y.;
C
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Organic Letters Kam, T. J. Nat. Prod. 2016, 79, 230−239. (e) Wong, S.; Gan, C.; Lim, K.; Ting, K.; Low, Y.; Kam, T. Org. Lett. 2015, 17, 3628−3631. (f) Cheenpracha, S.; Raksat, A.; Ritthiwigrom, T.; Laphookhieo, S. Nat. Prod. Commun. 2014, 9, 1441−1443. (g) Morita, H.; Ahmad, K.; Hirasawa, Y.; Nugroho, A. E.; Hadi, A. H. A. Heterocycles 2012, 86, 1611−1619. (h) Yang, Y.; Zuo, W.; Zhao, Y.; Dong, W.; Mei, W.; Dai, H. Planta Med. 2012, 78, 1881−1884. (i) Chen, J.; Li, X.; Li, N.; Lu, J.; Xu, X.; Duan, H.; Qin, L. Chem. Nat. Compd. 2012, 48, 834−835. (j) Tan, M.; Yin, C.; Tang, C.; Ke, C.; Lin, G.; Ye, Y. Planta Med. 2011, 77, 939−944. (k) Chen, J.; Chen, J.-J.; Yao, X.; Gao, K. Org. Biomol. Chem. 2011, 9, 5334−5336. (l) Yap, W.; Gan, C.; Low, Y.; Choo, Y.; Etoh, T.; Hayashi, M.; Komiyama, K.; Kam, T. J. Nat. Prod. 2011, 74, 1309−1312. (2) (a) Wang, C.; Wang, Z.; Xie, X.; Yao, X.; Li, G.; Zu, L. Org. Lett. 2017, 19, 1828−1830. (b) Leng, L.; Zhou, X.; Liao, Q.; Wang, F.; Song, H.; Zhang, D.; Liu, X.-Y.; Qin, Y. Angew. Chem., Int. Ed. 2017, 56, 3703−3707. (c) Kirillova, M. S.; Muratore, M. E.; Dorel, R.; Echavarren, A. M. J. Am. Chem. Soc. 2016, 138, 3671−3674. (d) Nakajima, M.; Arai, S.; Nishida, A. Angew. Chem., Int. Ed. 2016, 55, 3473−3476. (e) Xu, Z.; Wang, Q.; Zhu, J. J. Am. Chem. Soc. 2015, 137, 6712−6724. (f) Wagnières, O.; Xu, Z.; Wang, Q.; Zhu, J. J. Am. Chem. Soc. 2014, 136, 15102−15108. (g) Lee, K.; Boger, D. L. J. Am. Chem. Soc. 2014, 136, 3312−3317. (h) Arai, S.; Nakajima, M.; Nishida, A. Angew. Chem., Int. Ed. 2014, 53, 5569−5572. (i) Xu, Z.; Wang, Q.; Zhu, J. J. Am. Chem. Soc. 2013, 135, 19127−19130. (j) Sui, X.; Zhu, R.; Li, G.; Ma, X.; Gu, Z. J. Am. Chem. Soc. 2013, 135, 9318−9321. (k) Laforteza, B. N.; Pickworth, M.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2013, 52, 11269−11272. (l) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442−6445. (m) Li, Z.; Zhang, S.; Wu, S.; Shen, X.; Zou, L.; Wang, F.; Li, X.; Peng, F.; Zhang, H.; Shao, Z. Angew. Chem., Int. Ed. 2013, 52, 4117−4121. (n) Gartshore, C. J.; Lupton, D. W. Angew. Chem., Int. Ed. 2013, 52, 4113−4116. (o) Wei, Y.; Zhao, D.; Ma, D. Angew. Chem., Int. Ed. 2013, 52, 12988−12991. (p) Iwama, Y.; Okano, K.; Sugimoto, K.; Tokuyama, H. Org. Lett. 2012, 14, 2320−2322. (q) Nakajima, R.; Ogino, T.; Yokoshima, S.; Fukuyama, T. J. Am. Chem. Soc. 2010, 132, 1236−1237. (r) See ref 1a and references cited therein (3) (a) Hirama, T.; Umemura, T.; Kogure, N.; Kitajima, M.; Takayama, H. Tetrahedron Lett. 2017, 58, 223−226. (b) Kitajima, M.; Watanabe, K.; Maeda, H.; Kogure, N.; Takayama, H. Org. Lett. 2016, 18, 1912−1915. (c) Takanashi, N.; Suzuki, K.; Kitajima, M.; Takayama, H. Tetrahedron Lett. 2016, 57, 375−378. (d) Ishida, H.; Kimura, S.; Kogure, N.; Kitajima, M.; Takayama, H. Org. Biomol. Chem. 2015, 13, 7762−7771. (e) Ishida, H.; Kimura, S.; Kogure, N.; Kitajima, M.; Takayama, H. Tetrahedron 2015, 71, 51−56. (f) Azuma, M.; Yoshikawa, T.; Kogure, N.; Kitajima, M.; Takayama, H. J. Am. Chem. Soc. 2014, 136, 11618−11621. (g) Terada, Y.; Kitajima, M.; Taguchi, F.; Takayama, H.; Horie, S.; Watanabe, T. J. Nat. Prod. 2014, 77, 1831−1838. (h) Harada, M.; Asaba, K.; Iwai, M.; Kogure, N.; Kitajima, M.; Takayama, H. Org. Lett. 2012, 14, 5800−5803. (4) (a) Kitajima, M.; Nakazawa, M.; Wu, Y.; Kogure, N.; Zhang, R.P.; Takayama, H. Tetrahedron 2016, 72, 6692−6696. (b) Tokuda, R.; Okamoto, Y.; Koyama, T.; Kogure, N.; Kitajima, M.; Takayama, H. Org. Lett. 2016, 18, 3490−3493. (c) Kitajima, M.; Koyama, T.; Wu, Y.; Kogure, N.; Zhang, R.; Takayama, H. Nat. Prod. Commun. 2015, 10, 49−51. (d) Kitajima, M.; Murakami, Y.; Takahashi, N.; Wu, Y.; Kogure, N.; Zhang, R.; Takayama, H. Org. Lett. 2014, 16, 5000−5003. (e) Kogure, N.; Suzuki, Y.; Wu, Y.; Kitajima, M.; Zhang, R.; Takayama, H. Tetrahedron Lett. 2012, 53, 6523−6526. (f) Wu, Y.; Kitajima, M.; Kogure, N.; Wang, Y.; Zhang, R.; Takayama, H. Chem. Pharm. Bull. 2010, 58, 961−963. (g) Wu, Y.; Suehiro, M.; Kitajima, M.; Matsuzaki, T.; Hashimoto, S.; Nagaoka, M.; Zhang, R.; Takayama, H. J. Nat. Prod. 2009, 72, 204−209. (h) Wu, Y.; Kitajima, M.; Kogure, N.; Wang, Y.; Zhang, R.; Takayama, H. J. Nat. Med. 2009, 63, 283−289. (i) Wu, Y.; Kitajima, M.; Kogure, N.; Zhang, R.; Takayama, H. Tetrahedron Lett. 2008, 49, 5935−5938 and 6596. (5) Kan-Fan, C.; Massiot, G.; Ahond, A.; Das, B. C.; Husson, H.-P.; Potier, P.; Scott, A. I.; Wei, C.-C. J. Chem. Soc., Chem. Commun. 1974, 164−165.
(6) Scott, A. I. Bioorg. Chem. 1974, 3, 398−429. (7) Syntheses of racemic andranginine were reported. (a) Reference 5. (b) Andriamialisoa, R. Z.; Diatta, L.; Rasoanaivo, P.; Langlois, N.; Potier, P. Tetrahedron 1975, 31, 2347−2348. (c) Mizoguchi, H.; Oikawa, H.; Oguri, H. Nat. Chem. 2013, 6, 57−64. (8) Similar examples on andrangine-related natural products have been reported. Andransinine, a congener of andranginine, was isolated as a racemate from Alstonia angustiloba (a) and Kopsia paucif lora (b). (a) Ku, W.-F.; Tan, S.-J.; Low, Y.-Y.; Komiyama, K.; Kam, T.-S. Phytochemistry 2011, 72, 2212−2218. (b) Low, Y.-Y.; Gan, C.-Y.; Kam, T.-S. J. Nat. Prod. 2014, 77, 1532−1535. Andransinine A, a methoxy derivative of andransinine, was isolated as a racemate from Melodinus yunnanensis (c and Kopsia paucif lora (c). (c) Cai, X.-H.; Li, Y.; Liu, Y.P.; Li, X.-N.; Bao, M.-F.; Luo, X.-D. Phytochemistry 2012, 83, 116−124. Melokhanine I, a carboxylic acid derivative of andransinine A, was isolated in an optically active form from Melodinus khasianusd). (d) Cheng, G.-G.; Li, D.; Hou, B.; Li, X.-N.; Liu, L.; Chen, Y.-Y.; Lunga, P.-K.; Khan, A.; Liu, Y.-P.; Zuo, Z.-L.; Luo, X.-D. J. Nat. Prod. 2016, 79, 2158−2166. (9) (a) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219−10220. (b) Hatakeyama, S. Yuki Gosei Kagaku Kyokaishi 2006, 64, 1132−1138. (10) Singh, B. K.; Cavalluzzo, C.; De Maeyer, M.; Debyser, Z.; Parmar, V.; van der Eycken, E. Eur. J. Org. Chem. 2009, 2009, 4589− 4592. (11) Sieburth, S. M.; Lin, C.-H.; Rucando, D. J. Org. Chem. 1999, 64, 950−953. (12) (a) Iwabuchi, Y. Chem. Pharm. Bull. 2013, 61, 1197−1213. (b) Shibuya, M.; Sasano, Y.; Tomizawa, M.; Hamada, T.; Kozawa, M.; Nagahama, N.; Iwabuchi, Y. Synthesis 2011, 2011, 3418−3425. (c) Iwabuchi, Y. Yuki Gosei Kagaku Kyokaishi 2008, 66, 1076−1084. (13) Siddalingamurthy, E.; Mahadevan, K. M.; Masagalli, J. N.; Harishkumar, H. N. Tetrahedron Lett. 2013, 54, 5591−5596. (14) Before use, ZnCl2 was dried by heating with a heat gun in vacuo. Otherwise, the yield and the enantiomeric excess of the product would be decreased. Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1996, 37, 4869−4872. (15) (a) Murakami, Y.; Watanabe, T.; Kobayashi, A.; Yokoyama, Y. Synthesis 1984, 1984, 738−740. (b) Watanabe, T.; Kobayashi, A.; Nishiura, M.; Takahashi, H.; Usui, T.; Kamiyama, I.; Mochizuki, N.; Noritake, K.; Yokoyama, Y.; Murakami, Y. Chem. Pharm. Bull. 1991, 39, 1152−1156. (16) We have verified that the enantiomeric excess of the product was not decreased in the following treatments: (a) refluxing in MeOH or CHCl3 for more than 10 h; (b) leaving the MeOH solution in the presence of SiO2 or the CDCl3 solution to stand for 1 week; and (c) refluxing in MeOH in the presence of 0.01 M citric acid for 14 h. Therefore, racemization via a retro-Diels−Alder reaction or retroMannich/Mannich reaction did not occur under the above conditions, and some of those treatments were used during the extraction and separation of the natural products. (17) For a review, see: Finefield, J.; Sherman, D. H.; Kreitman, M.; Williams, R. M. Angew. Chem., Int. Ed. 2012, 51, 4802−4836. (18) The enantiomeric ratio of natural product was calculated by comparison of the optical rotations between the synthetic and natural samples.
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DOI: 10.1021/acs.orglett.7b01076 Org. Lett. XXXX, XXX, XXX−XXX
