The total synthesis of huperzine Q was accomplished. The synthesis features the construction of the cis-hydrindane skeleton via a Diels–Alder reaction and a ring contraction reaction of an epoxyketone.journal articl

73625

73626

73627

Fukuyama, Tohru

Tanimura, Shun

Yokoshima, Satoshi

Organic Letters

English

Shun Tanimura

Satoshi Yokoshima

Tohru Fukuyama

Crossref

Total Synthesis of Huperzine Q

Nagoya Repository

Total Synthesis of Huperzine Q Shun Tanimura,†,‡ Satoshi Yokoshima,†,* Tohru Fukuyama†,* †Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan ‡Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan  Supporting Information Placeholder ABSTRACT: The total synthesis of huperzine Q was accomplished. The synthesis features the construction of the cis-hydrindane skeleton via a Diels–Alder reaction and a ring contraction reaction of an epoxyketone. Huperzine Q (1, Figure 1) is an alkaloid isolated from Lyco-podium serratum by Zhu and coworkers in 2002.1,2 It is classi-fied as a fawcettimine-type Lycopodium alkaloid. Although the core structure, cis-hydrindane, is identical to that of faw-cettimine (2), the presence of an additional N,O-acetal moiety at C13 distinguished itself from 2. The formation of the N,O-acetal moiety in huperzine Q was first achieved by Takayama and coworkers in 2011 via dehydration of the corresponding hemiaminal by treatment with CSA in refluxing toluene, lead-ing to the total synthesis of huperzine Q.3 Lei and coworkers reported the formation of the N,O-acetal moiety via bromina-tion of an enamine in their synthesis of huperzine Q.4  Figure 1. Structures of huperzine Q and fawcettimine. The construction of the cis-hydrindane core of the Lycopo-dium alkaloids, which contains a quaternary carbon, has re-ceived significant attention, and a variety of synthetic strate-gies have been explored.2i-m A Diels–Alder reaction was em-ployed to construct the cis-fused bicyclic system in one such strategy. Diels–Alder reactions between a diene and cyclopen-tene derivative 3 can directly provide cis-hydrindane 4 (Scheme 1).5 Inubushi and coworkers carried out a Diels–Alder reaction of cyclohexenone 5 with 1,3-butadiene to pro-duce a cis-decaline 6, which was converted the cis-hydrindane skeleton 8 via oxidative cleavage of the cyclohexene moiety in a later step, followed by the intramolecular aldol condensation of the resulting dialdehyde 7.6 Although Inubushi’s strategy required a subsequent ring contraction to form the cis-hydrindane skeleton, the carbonyl group at C13 and the stere-ogenic center at C15, both of which originated from the cyclo-hexenone, could be directly used for the synthesis of faw-cettimine and related molecules. We envisioned that the side chain on the cis-hydrindane core might be installed as a part of the diene unit.7 Herein, we disclose our total synthesis of hu-perzine Q by means of a Diels–Alder reaction between 9 and 10 and a subsequent ring contraction reaction.  Scheme 1. Construction of the cis-Hydrindane Core via a Diels–Alder Reaction    Our synthesis commenced with the benzylation of the known hydroxyketone 138 according to Dudley’s protocol by using the reagent A (Scheme 2).9 α-Iodination, followed by Suzuki–Miyaura coupling10 with alkylborane B, afforded the coupling product 16. The crucial Diels–Alder reaction of 16 with diene C11 in the presence of zinc chloride occurred at the opposite side of the benzyloxymethyl group on the cyclohex-enone ring to furnish cis-decaline 17 as an inseparable mixture of the endo- and exo-isomers (dr = 1.5:1).12,13  Having constructed the cis-decaline system, we next fo-cused on the conversion into the cis-hydrindane core. We found that a ring contraction reaction of an epoxyketone was effective for this purpose.14 The silyl enolate moiety in 17 was oxidized with DDQ to afford enone 18.15 Sequential cleavage of the Boc and TBDPS groups gave hydroxy nosylamide 19, which, upon subjection to the Mitsunobu reaction conditions16 with di(2-methoxyethyl) azodicarboxylate (DMEAD),17 un-derwent cyclization to produce the tricyclic compound 20.18 Nucleophilic epoxidation of the enone moiety in 20 afforded epoxyketone 21 under standard conditions.14a,19 Upon treat-ment with TMSOTf in dichloromethane at –78°C, 21 under-went a selective cleavage of the epoxide, followed by a 1,2-shift of the carbonyl group, to give a ring-contracted product 23 in 91% yield.  Transformation of ketoaldehyde 23 into huperzine Q (1) proceeded uneventfully. Under the conditions for removal of the nosyl group, cleavage of the formyl group occurred con-comitantly by the addition of methanol to afford hemiaminal 24. The stereochemistry at C4 was thermodynamically con-trolled during the formation of the hemiaminal moiety.20 Cleavage of the benzyl group and the stereoselective reduction of the ketone moiety in 24 were simultaneously achieved via the Birch reduction, leaving the hemiaminal moiety intact. Finally, the formation of the N,O-acetal moiety was carried out according to Takayama’s procedure to furnish huperzine Q (1).3a             In summary, we have achieved a total synthesis of huper-zine Q in the racemic form. The Diels–Alder reaction con-structed the cis-decaline system, which was converted into the cis-hydrindane core of the natural product via a ring contrac-tion reaction of the epoxyketone.      Scheme 2. Total Synthesis of Huperzine Q    ASSOCIATED CONTENT  Supporting Information The Supporting Information is available free of charge on the ACS Publications website.  Experimental procedures, spectroscopic data, and 1H and 13C NMR spectra (PDF) AUTHOR INFORMATION  Corresponding Author *E-mail: yokosima@ps.nagoya-u.ac.jp *E-mail: fukuyama@ps.nagoya-u.ac.jp ACKNOWLEDGMENTS This work was financially supported by JSPS KAKENHI (Grant Numbers 25221301, 26713001, and 16H01141) and by the Plat-form Project for Supporting Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Struc-tural Life Science) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) and the Japan Agency for Medical Research and Development (AMED).  REFERENCES (1) Tan, C.-H.; Ma, X.-Q.; Chen, G.-F.; Zhu, D.-Y. Helv. Chim. Acta 2002, 85, 1058. (2) For reviews of the Lycopodium alkaloids, see: (a) MacLean, D. B. The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1968; Vol. 10, pp 305−382. (b) MacLean, D. B. The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1973; Vol. 14, pp 348−405. (c) MacLean, D. B. The Alkaloids; Brossi, A., Ed.; Aca-demic Press: Orlando, 1986; Vol. 26, pp 241−298. (d) Ayer, W. A.; Trifonov, L. S. The Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, 1994; Vol. 45, pp 233−266. (e) Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752. (f) Kobayashi, J.; Morita, H. The Alkaloids, Vol. 61; Cordell, G. A., Ed.; Academic Press: San Diego, 2005; pp 1−57. (g) Morita, H.; Hirasawa, Y.; Kobayashi, J. Heterocycles 2009, 77, 679. (h) Kitajima, M.; Takayama, H. Top. Curr. Chem. 2011, 309, 1. (i) Nakayama, A.; Kitajima, M.; Takayama, H. Synlett 2012, 23, 2014. (j) Siengalewicz, P.; Mulzer, J.; Rinner, U. The Alkaloids; Knölker, H.-J., Ed.; Academic Press: San Diego, 2013; Vol. 72, pp 1−151. (k) Wang, X.; Li, H.; Lei, X. Synlett 2013, 24, 1032. (l) Mur-phy, R. A.; Sarpong, R. Chem. Eur. J. 2014, 20, 42. (m) Takayama, H. J. Syn. Org. Chem. Jpn. 2015, 73, 1072.   (3)  (a) Nakayama, A.; Kogure, N.; Kitajima, M.; Takayama, H. Angew. Chem. Int. Ed. 2011, 50, 8025. Zhao and coworkers also con-structed the N,O-acetal moiety according to Takayama’s protocol, leading to the total synthesis of huperzine Q. (b) Zeng, C.; Zhao, J.; Zhao, G. Tetrahedron 2015, 71, 64. (4) Hong, B.; Li, H.; Wu, J.; Zhang, J.; Lei, X. Angew. Chem. Int. Ed. 2015, 54, 1011. (5)  (a) Boonsompat, J.; Padwa, A. J. Org. Chem. 2011, 76, 2753. (b) Pan, G.; Williams, R. M. J. Org. Chem. 2012, 77, 4801. (c) Zaimoku, H.; Nishide, H.; Nishibata, A.; Goto, N.; Taniguchi, T.; Ishibashi, H. Org. Lett. 2013, 15, 2140. (d) Zaimoku, H.; Taniguchi, T. Chem. Eur. J. 2014, 20, 9613. (e) Ishida, H.; Kimura, S.; Kogure, N.; Kitajima, M.; Takayama, H. Tetrahedron 2015, 71, 51. (6) Harayama, T.; Takatani, M.; Inubushi, Y. Tetrahedron Lett. 1979, 20, 4307. (7) For examples of the Diels–Alder reaction between a 2-substituted cyclohexenone and a 4-alkyl-2-siloxy-1,3-butadiene, see: (a) Usui, K.; Kanbe, M.; Nakada, A. M. Org. Lett. 2014, 16, 4734. (b) Berkes, B.; Ozsváth, K.; Molnár, L.; Gáti, T.; Holczbauer, T.; Kardos, G.; Soós, T. Chem. Eur. J. 2016, 22, 18101. (8) Kuwahara, S.; Mori, K. Tetrahedron 1990, 46, 8075. (9) Poon, K. W.; House, S. E.; Dudley, G. B. Synlett 2005, 2005, 3142. (10) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (11) Diene C was prepared from N-Boc-N-(4-penten-1-yl)-nosylamide in 3 steps. For details, see Supporting Information. (12) The dienophile face selectivity in the Diels-Alder reaction was deduced based on the literature, and could be confirmed by con-version into huperzine Q (1). Angeles, A. R.; Waters, S. P.; Danishef-sky, S. J. J. Am. Chem. Soc. 2008, 130, 13765. (13) When the Diels–Alder reaction time was extended from 2 to 24 hours, the mixture of 17 converged to a single isomer perhaps via either Lewis-acid-mediated cleavage of the C–C bond between the α-position of the ketone and the allylic position of the silyl enolate or retro Diels-Alder reaction. (14)  (a) House, H. O.; Wasson, R. L. J. Am. Chem. Soc. 1957, 79, 1488. (b) Ryerson, G. D.; Wasson, R. L.; House, H. O. Org. Synth. 1959, 39, 70. For recent examples, see: (c) Guerrab, Z.; Daou, B.; Fkih-Tetouani, S.; Ahmar, M.; Cazes, B. Tetrahedron Lett. 2003, 44, 5727. (d) Guerrab, Z.; Daou, B.; Fkih-Tetouani, S.; Ahmar, M.; Cazes, B. Tetrahedron 2007, 63, 3367. (e) Grishko, V. V.; Tolmacheva, I. A.; Pereslavtseva, A. V. Chem. Nat. Prod. 2015, 51, 1. (f) Biktagirov, I. M.; Faizullina, L. K.; Salikhov, S. M.; Valeev, F. A. Russ. J. Org. Chem. 2016, 52, 1468. (15)  (a) Ryu, I.; Murai, S.; Hatayama, Y.; Sonoda, N. Tetrahe-dron Lett. 1978, 19, 3455. For recent examples, see: (b) Siewert, J.; Textor, A.; Grond, S.; Von Zezschwitz, P. Chem. Eur. J. 2007, 13, 7424. (c) Zhang, H.; Sridhar Reddy, M.; Phoenix, S.; Deslongchamps, P. Angew. Chem. Int. Ed. 2008, 47, 1272. (d) Reddy, M. S.; Zhang, H.; Phoenix, S.; Deslongchamps, P. Chem. Asian J. 2009, 4, 725. (e) Zhu, J.-L.; Huang, P.-W.; You, R.-Y.; Lee, F.-Y.; Tsao, S.-W.; Chen, I.-C. Synthesis 2011, 2011, 715. (f) Peng, F.; Dai, M.; Angeles, A. R.; Danishefsky, S. J. Chem. Sci. 2012, 3, 3076. (g) Moussa, V. N.; Skel-ton, B. W.; Payne, A. D. Tetrahedron 2016, 72, 7470. (16) Mitsunobu, O. Synthesis 1981, 1. (17) Hagiya, K.; Muramoto, N.; Misaki, T.; Sugimura, T. Tetra-hedron 2009, 65, 6109. (18)  (a) Fukuyama, T.; Jow, C.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373. (b) Kan, T.; Fukuyama, T. J. Syn. Org. Chem. Jpn. 2001, 59, 779. (c) Kan, T.; Kobayashi, H.; Fukuyama, T. Synlett 2002, 697. (d) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353. (19) The epoxidation proceeded stereoselectively. Attempted confirmation of the stereochemistry using NOE techniques was un-successful due to the overlapping of the peaks in the 1H NMR spec-trum. (20)  (a) Heathcock, C. H.; Smith, K. M.; Blumenkopf, T. A. J. Am. Chem. Soc. 1986, 108, 5022. (b) Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. M. J. Org. Chem. 1989, 54, 1548.        

https://nagoya.repo.nii.ac.jp/record/24771/files/20170530_tanimura_rev.pdf

Total Synthesis of Huperzine Q

Abstract

Similar works

Full text

Available Versions

Crossref

Nagoya Repository