Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. 2018, 20, 119−121
Total Synthesis of Huperzine R Toshimune Nomura, Satoshi Yokoshima,* and Tohru Fukuyama* Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan S Supporting Information *
ABSTRACT: A total synthesis of huperzine R was accomplished. Intramolecular cycloaddition of a nitrile oxide and reductive cleavage of the resulting isoxazoline induced sequential cleavage of the C−C and C−O bonds to form the characteristic bicyclic lactam core with an enone moiety. Construction of the butenolide moiety from the enone afforded huperzine R.
H
uperzine R (1), isolated from Lycopodium serratum by Zhu and co-workers in 2002, is characterized by a unique bicyclic lactam core (Figure 1).1 Although huperzine R can be
ring (Scheme 1). Although the resulting tertiary amine moiety in 7 could not be converted into the amide moiety, the Scheme 1. Synthetic Strategy toward Huperzine R
Figure 1. Fawcettimine-type Lycopodium alkaloids.
classified as a fawcettimine-type Lycopodium alkaloid on the basis of structural similarities, it lacks the C12−C13 bond.2 Phlegmariurine-A (3) is a related natural product that has the same bicyclic lactam moiety, and its biosynthetic pathway from lycoposerramine-C (4) has been proposed by Takayama and co-workers.3 The chemical transformation of lycoposerramineC into phlegmariurine-A has been reported, in which a vinylogous retro-aldol reaction was induced by treatment with sodium methoxide or potassium tert-butoxide.3,4 While these reports are the only successful synthetic approaches to this class of alkaloids to date, we now disclose a total synthesis of huperzine R. The lactam moiety in huperzine R contains two mediumsized rings whose transannular strains make it difficult to construct.5 For the construction of medium-sized rings, cleavage of a bond shared by two rings in a fused bicyclic system to form a larger ring system is a reasonable solution.6 In our previous synthetic studies toward huperzine R,7 we prepared ammonium salt 6 via six-membered ring formation from mesylate 5, and subsequent cleavage of the C−N bond shared by the rings produced 7 containing an 11-membered © 2017 American Chemical Society
successful formation of the requisite ring system motivated us to try the ring-enlargement strategy with other fused ring systems. Thus, the connection between C12 and C13 in huperzine R (1) led to hemiaminal 8 as a candidate for a fused ring system, which is similar to that of fawcettimine (2) or lycoposerramine-C (4). We envisioned that cleavage of the shared C12−C13 bond could be achieved using a suitable ketone (X = O) or imine (X = NR) through a retro-aldol-type reaction of the resulting β-hydroxy ketone or imine.8 The hemiaminal moiety in 8 could in turn be formed from an amino ketone via formation of the seven-membered ring. To simultaneously install X and Y in 8, we employed the 1,3dipolar cycloaddition of a nitrile oxide to form isoxazoline 9.9 Our synthesis commenced with the preparation of the precursor for the nitrile oxide (Scheme 2). Symmetrical alkyne 1010 was subjected to a hydrozirconation/iodination process to Received: November 16, 2017 Published: December 8, 2017 119
DOI: 10.1021/acs.orglett.7b03555 Org. Lett. 2018, 20, 119−121
Letter
Organic Letters Scheme 2. Preparation of Isoxazoline 18
Scheme 3. Construction of the Bicyclic Lactam Core
After construction of the bicyclic lactam core, the remaining task toward the synthesis of huperzine R was to construct the butenolide moiety (Scheme 4). Nucleophilic epoxidation Scheme 4. Completion of the Synthesis
give iodide 11. After removal of the TBS groups, the resulting diol was converted into bismesylate 12, which was then reacted with nosylamide and cesium carbonate to furnish a cyclic amine derivative.11 Replacement of the nosyl group with a Boc group afforded 13. Halogen/lithium exchange in 13 generated an alkenyllithium species, which upon addition of lactone 14 provided hydroxy ketone 15. Oxidation of 15 with Dess− Martin periodinane12 followed by condensation with hydroxylamine afforded oxime 16. Chlorination of the oxime with sodium hypochlorite and subsequent treatment with sodium hydroxide generated a nitrile oxide that underwent intramolecular cycloaddition with the olefin moiety to give isoxazoline 17 in a diastereomeric ratio of 3.7:1. The diastereomers could be separated after cleavage of the Boc group with TFA to afford hemiaminal 18 in 56% yield. With the requisite isoxazoline in hand, we next focused on the ring enlargement via cleavage of the C12−C13 bond (Scheme 3). Treatment of 18 with a base did not induce the C−C bond cleavage, resulting in recovery of the starting material. Hence, liberation of the ketone function from isoxazoline 18 was attempted by reduction with Raney nickel. While cleavage of the N−O bond proceeded to generate imine 19, undesired cleavage of the C4−C12 bond occurred to give β-amino-α,β-unsaturated ketone 20.13 After extensive investigation into the reductive conditions, much to our delight, Kulinkovich’s conditions14 effected the desired transformation. Thus, 18 was treated with a titanium(III) reagent, prepared by premixing Ti(OiPr)4 and EtMgBr,15 to give lactam 23. Under these conditions, upon reductive cleavage of the N−O bond, a retro-aldol-type reaction of 21 cleaved the C12−C13 bond to generate 22, from which an elimination reaction proceeded to afford 23.16
toward the enone moiety in 23 afforded epoxy ketone 24, which was subjected to a Wittig reaction with (methoxymethylene)(triphenyl)phosphorane to give, after acidic hydrolysis, hydroxyaldehyde 25. Oxidation with Jones reagent furnished ketocarboxylic acid 26, which was stereoselectively reduced with lithium borohydride to give huperzine R (1). In conclusion, we have accomplished a total synthesis of huperzine R (1). Our synthesis features intramolecular 1,3dipolar cycloaddition of a nitrile oxide and reductive cleavage of the resulting isoxazoline to induce a retro-aldol-type reaction, forming the bicyclic lactam core. Further transformations of the bicyclic lactam intermediate into natural and unnatural analogues are currently underway and will be reported in due course.
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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.7b03555. 120
DOI: 10.1021/acs.orglett.7b03555 Org. Lett. 2018, 20, 119−121
Letter
Organic Letters
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Experimental procedures, spectroscopic data, and 1H and 13 C NMR spectra (PDF)
Org. Chem. 2015, 2015, 5709. (f) Gros, G.; Hasserodt, J. Eur. J. Org. Chem. 2015, 2015, 183. (g) Prado, G.; Veiga, A. X.; Fernández-Nieto, F.; Paleo, M. R.; Sardina, F. J. Org. Lett. 2015, 17, 2054. (h) Tong, T. M. T.; Soeta, T.; Suga, T.; Kawamoto, K.; Hayashi, Y.; Ukaji, Y. J. Org. Chem. 2017, 82, 1969. (7) Kumazaki, H.; Nakajima, R.; Bessho, Y.; Yokoshima, S.; Fukuyama, T. Synlett 2015, 26, 2131. (8) For selected examples of the related cleavage via retro-aldol-type reaction, see: (a) Von Strandtmann, M.; Puchalski, C.; Shavel, J. J. J. Org. Chem. 1968, 33, 4010. (b) Ohnuma, T.; Nagasaki, M.; Tabe, M.; Ban, Y. Tetrahedron Lett. 1983, 24, 4253. (c) Crabb, T. A.; Roxburgh, C. J.; Newton, R. F. J. Chem. Soc., Perkin Trans. 1 1989, 2431. (d) Moon, B.; Han, S.; Yoon, Y.; Kwon, H. Org. Lett. 2005, 7, 1031. (e) Roxburgh, C. J.; Banting, L. Aust. J. Chem. 2006, 59, 59. (f) Yeom, H.-S.; Lee, Y.; Jeong, J.; So, E.; Hwang, S.; Lee, J.-E.; Lee, S. S.; Shin, S. Angew. Chem., Int. Ed. 2010, 49, 1611. (g) Kitsiou, C.; Hindes, J. J.; I’anson, P.; Jackson, P.; Wilson, T. C.; Daly, E. K.; Felstead, H. R.; Hearnshaw, P.; Unsworth, W. P. Angew. Chem., Int. Ed. 2015, 54, 15794. (9) (a) Curran, D. P. J. Am. Chem. Soc. 1982, 104, 4024. (b) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410. For recent examples, see: (c) Maehara, T.; Motoyama, K.; Toma, T.; Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed. 2017, 56, 1549. (d) Fischer, S.; Huwyler, N.; Wolfrum, S.; Carreira, E. M. Angew. Chem., Int. Ed. 2016, 55, 2555. (e) Hog, D. T.; Huber, F. M. E.; Jiménez-Osés, G.; Mayer, P.; Houk, K. N.; Trauner, D. Chem. - Eur. J. 2015, 21, 13646. (f) Xuan, J.; Pan, S.; Zhang, Y.; Ye, B.; Ding, H. Org. Biomol. Chem. 2015, 13, 1643. (g) Hartung, J.; Wright, B. J. D.; Danishefsky, S. J. Chem. - Eur. J. 2014, 20, 8731. (h) Enev, V. S.; Felzmann, W.; Gromov, A.; Marchart, S.; Mulzer, J. Chem. - Eur. J. 2012, 18, 9651. (10) Shimada, N.; Abe, Y.; Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed. 2012, 51, 11824. (11) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373. (b) Kan, T.; Kobayashi, H.; Fukuyama, T. Synlett 2002, 2002, 697. (c) Kan, T.; Fukuyama, T. Yuki Gosei Kagaku Kyokaishi 2001, 59, 779. (d) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353. (12) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (13) Upon reduction of 17 with Raney nickel, undesired cleavage of the C4−C12 bond also occurred. For details, see the Supporting Information. (14) Churykau, D. H.; Zinovich, V. G.; Kulinkovich, O. G. Synlett 2004, 2004, 1949. (15) Although the first trial of the reaction with aged Ti(Oi-Pr)4 produced 23 in good yield, distillation of Ti(Oi-Pr)4 prior to use lowered the yield of the reaction. We found that addition of 2propanol improved the reproducibility. (16) Under the protic solvent (ethanol) conditions of the Raney Ni reaction, the hemiaminal and ketone were present in equilibrium, and liberation of the ketone moiety could potentially facilitate the cleavage of the C4−C12 bond via a retro-aldol reaction. On the other hand, under Kulinkovich’s conditions, the hemiaminal moiety was present as the corresponding anion in an aprotic solvent (THF), which may have suppressed the cleavage of the C−N bond in the hemiaminal moiety.
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Satoshi Yokoshima: 0000-0003-4036-0062 Tohru Fukuyama: 0000-0001-9612-5665 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by JSPS KAKENHI (Grants 26713001, 16H01141, and 17H01523) and by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research; BINDS) from the Japan Agency for Medical Research and Development (AMED).
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REFERENCES
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DOI: 10.1021/acs.orglett.7b03555 Org. Lett. 2018, 20, 119−121
