10.1002/chem.201605362
Chemistry - A European Journal
FULL PAPER
Acknowledgements
This work was funded by the DFG - Deutsche Forschungs-
gemeinschaft (TI 831/2-1). Further support was provided by the
TUM Junior Fellow Fund. We thank Prof. R. A. Shenvi for
providing a sample of synthetic (–)-Jiadifenolide. Furthermore, the
support of Prof. Thorsten Bach and his group (TUM) is
acknowledged.
Keywords: Natural Products • Neurotrophic • Biological Activity
• Synthesis • Sesquiterpenes
CCDC contains the supplementary crystallographic data for this
paper (compounds 13, 21, 25, 29 and 33). These data can be
obtained free of charge from The Cambridge Crystallographic
Figure 3. Representative images of N2a-cells after cell differentiation and
neurite outgrowth.
compound 15; d compound 30 (all at 1000 n
a
DMSO (control);
b
M
(–)-Jiadifenolide (reference);
concentration).
c
References
the structure shows a high degree of similarity to the Anislactone
structure, especially in light of the position of the -lactone moiety.
Although it has been shown that Merrilactone A can be readily
converted to the related natural product,[5a] to the best of our
knowledge the biological activity of Anislactone A/B has not yet
been validated. The results presented confirm that the natural
product Merrilactone A can be structurally simplified while
retaining biological activity. The most active derivatives (15, 23,
30) are accessible in 6–8 synthetic steps with high yields from
commercial starting materials. This compares favorably to the 17–
26 steps required for the total syntheses of ()-Merrilactone A
reported.
[1]
[2]
[3]
[4]
[5]
E. A. Crane, K. Gademann, Angew. Chem. Int. Ed. 2016, 55, 3882–3902;
Angew. Chem. 2016, 128, 3948–3970.
J. Huang, R. Yokoyama, C. Yang, Y. Fukuyama, Tetrahedron Lett. 2000,
41, 6111–6114.
I. Kouno, K. Mori, N. Kawano, S. Sato, Tetrahedron Lett. 1989, 30, 7451–
7452.
M. Kubo, C. Okada, J. M. Huang, K. Harada, H. Hioki, Y. Fukuyama, Org.
Lett. 2009, 11, 5190–5193.
a) J.-M. Huang, C.-S. Yang, M. Tanaka, Y. Fukuyama, Tetrahedron 2001,
57, 4691–4698; b) V. B. Birman, S. J. Danishefsky, J. Am. Chem. Soc.
2002, 124, 2080–2081; c) M. Inoue, T. Sato, M. Hirama, J. Am. Chem.
Soc. 2003, 125, 10772–10773; d) K. Harada, H. Kato, Y. Fukuyama,
Tetrahedron Lett. 2005, 46, 7407–7410; e) J. Iriondo-Alberdi, J. E.
Perea-Buceta, M. F. Greaney, Org. Lett. 2005, 7, 3969–3971; f) G. Mehta,
S. R. Singh, Tetrahedron Lett. 2005, 46, 2079–2082; g) Z. Meng, S. J.
Danishefsky, Angew. Chem. Int. Ed. 2005, 44, 1511–1513; Angew.
Chem. 2005, 117, 1535–1537; h) M. Inoue, T. Sato, M. Hirama, Angew.
Chem. Int. Ed. 2006, 45, 4843–4848; Angew. Chem. 2006, 118, 4961–
4966; i) G. Mehta, S. R. Singh, Angew. Chem. Int. Ed. 2006, 45, 953–
955; Angew. Chem. 2006, 118, 967–969; j) K. Harada, H. Ito, H. Hioki,
Y. Fukuyama, Tetrahedron Lett. 2007, 48, 6105–6108; k) W. He, J.
Huang, X. Sun, A. J. Frontier, J. Am. Chem. Soc. 2007, 129, 498–499; l)
M. Inoue, N. Lee, S. Kasuya, T. Sato, M. Hirama, M. Moriyama, Y.
Fukuyama, J. Org. Chem. 2007, 3065–3075; m) W. He, J. Huang, X. Sun,
A. J. Frontier, J. Am. Chem. Soc. 2008, 130, 300–308; n) L. Shi, K. Meyer,
M. F. Greaney, Angew. Chem. Int. Ed. 2010, 49, 9250–9253; Angew.
Chem. 2010, 122, 9436–9439; o) J. Xu, L. Trzoss, W. K. Chang, E. A.
Theodorakis, Angew. Chem. Int. Ed. 2011, 50, 3672–3676; Angew.
Chem. 2011, 123, 3756–3760; p) N. Nazef, R. D. Davies, M. F. Greaney,
Org. Lett. 2012, 14, 3720–3723; q) J. Chen, P. Gao, F. Yu, Y. Yang, S.
Zhu, H. Zhai, Angew. Chem. Int. Ed. 2012, 51, 5897–5899; Angew.
Chem. 2012, 124, 5999–6001; r) L. Trzoss, J. Xu, M. H. Lacoske, E. A.
Theodorakis, Beilstein J. Org. Chem. 2013, 9, 1135–1140; s) D. A. Siler,
J. D. Mighion, E. J. Sorensen, Angew. Chem. Int. Ed. 2014, 53, 5332–
5335; Angew. Chem. 2014, 126, 5436–5439; t) I. Paterson, M. Xuan, S.
M. Dalby, Angew. Chem. Int. Ed. 2014, 53, 7286–7289; Angew. Chem.
2014, 126, 7414–7417; u) Y. Shen, L. Li, Z. Pan, Y. Wang, J. Li, K. Wang,
X. Wang, Y. Zhang, T. Hu, Y. Zhang, Org. Lett. 2015, 17, 5480–5483; v)
H. H. Lu, M. D. Martinez, R. A. Shenvi, Nat. Chem. 2015, 7, 604–607; w)
J. Gomes, C. Daeppen, R. Liffert, J. Roesslein, E. Kaufmann, A.
Conclusions
In conclusion, a series of structural analogs derived from the
neurotrophic
illicium
sesquiterpene
natural
products
()-Merrilactone A and ()-Anislactone A/B has been synthesized.
The concise synthetic route relies on the rapid construction of the
carbon skeleton and enables the gram-scale preparation of the
diastereomerically pure framework structure. Therefore, access is
provided to further modified and functionalized analogs. In total, a
library of 15 framework derivatives has been prepared, enabling
the analysis of the structure-activity relationship. Our study
identifies promising structural derivatives, i.e. simplified natural
product analogs, which are accessible in only 6–8 synthetic steps
and still promote neurite outgrowth (138% compared to control).
These results will aid biochemical studies aimed towards
elucidating the molecular mechanism and relevant targets
underlying the neurotrophic activity of the illicium sesquiterpenes
and analogs thereof. The simplified compounds could also
facilitate the development of new pharmaceuticals for the
treatment of neurodegenerative diseases.
This article is protected by copyright. All rights reserved.