5
In summary, we have completed the first asymmetric total
synthesis of the β–carboline alkaloid, haploscleridamine (1).
Critical to the success of this synthesis campaign was a ring-
closing metathesis reaction of an imidazole derivative to facilitate
construction of the key piperidinone. Subsequent application of
the Buchwald modification of the classical Fischer indole
synthesis provides the β–carboline framework. Reductive
removal of an N-tosyl group was accomplished by dissolving
metal reduction. The rotation of the synthetic material was
higher but same direction as the natural material indicating that
the chiral center possesses an S-configuration. Efforts to extend
this work to other members of this class of alkaloids are
underway and will be reported in due course.
Acknowledgements: This work has been supported in part by
the NIH (GM065503), the Robert A. Welch Foundation (Y-1362)
and by instrumentation grants from the NSF (CHE-0234811 and
CHE-0840509) for the purchase of the NMR spectrometers used
in this research. The authors acknowledge the Texas Advanced
Computing Center (TACC) at The University of Texas at Austin
for providing resources that have contributed to the research
results reported within this paper. URL:
y, we have begun to explore other sequencesved
Click here to remove instruction text...
19. (a) Garcias, V.; Gasiecki, A. F.; Djuric, S. W., Tetrahedron
Lett. 2005, 46, 9049-9052; (b) Gracias, V.; Gasiecki, A. F.;
Djuric, S. W., Org. Lett. 2005, 7, 3183-3186; (c) Perl, N. R.;
Leighton, J. L., Org. Lett. 2007, 9, 3699–3701; (d) Berge, E.
V. D.; Pospíšil, J.; Trieu‐Van, T.; Collard, L.; Robiette, R.,
Eur. J. Org. Chem. 2011, 6649-6655; (e) Halland, N.; Blum,
H.; Buning, C.; Kohlmann, M.; Lindenschmidt, A., ACS Med.
Chem. Lett. 2014, 5, 193-198; (f) Lafaye, K.; Nicolas, L.;
Guérinot, A.; Reymond, S.; Cossy, J., Org, Lett. 2014, 10,
4972-4975.
20. (a) Singh, P.; Manda, S. L. K.; Samanta, K.; Panda, G.,
Tetrahedron 2017, 73, 1911-2008; (b) Mukherjee, S.; Sivappa,
R.; Yousufuddin, M.; Lovely, C. J., Org. Lett. 2010, 12, 4940-
4943.
21. Schmir, G. L.; Jones, W. M.; Cohen, L. A., Biochemistry 1965,
4, 539-545.
22. An X-ray crystal structure of 16 (CCDC = 1891638) was
obtained confirming the location of the tosyl protecting groups
and N-allylation. For more infomation see supporting
information.
23. As best we could tell, the other alcohol diastereomer was not
observed in the crude reaction mixture by NMR spectroscopy.
However, it is important to note that other side products were
observed that may have obscured signals in NMR spectra of
the crude reaction mixtures.
References:
1.
(a) Dai, J.; Dan, W.; Schneider, U.; Wang, J., Eur. J. Med.
Chem. 2018, 157, 622-656; (b) Ashok, P.; Ganguly, S.;
Murugesan, S., Mini-Rev. Med. Chem. 2013, 13, 1778-1791;
(c) Dominguez, G.; Perez-Castells, J., Eur. J. Org. Chem.
2011, 7243-7253; (d) Grazul, R. M.; Kuehne, M. E., Nat. Prod.
Lett. 1994, 5, 187-195.
2.
3.
Blunt, J. W.; Carroll, A. R.; Copp, B. R.; Davis, R. A.;
Keyzers, R. A.; Prinsep, M. R., Nat. Prod. Rep. 2018, 35, 8-53.
(a) Lindel, T., Alkaloids 2017, 77, 117-219; (b) Zhong, J., Nat.
Prod. Rep. 2016, 33, 1268-1317; (c) Al-Mourabit, A.;
Zancanella, M. A.; Tilvi, S.; Romo, D., Nat. Prod. Rep. 2011,
28, 1229-1260.
4.
(a) Netz, N.; Opatz, T., Mar. Drugs 2015, 13, 4814-1914; (b)
Berlinck, R. G. S.; Bertonha, A. F.; Takaki, M.; Rodriguez, J.
P. G., Nat. Prod. Rep. 2017, 34, 1264-1301.
5.
6.
7.
Patil, A. D.; Freyer, A. J.; Carte, B.; Taylor, P. B.; Johnson, R.
K.; Faulkner, D. J., J. Nat. Prod. 2002, 65, 628-9.
Searle, P. A.; Molinski, T. F., J. Nat. Prod. 1994, 59, 6600-
6605.
Yamanokuchi, R.; Imada, K.; Miyazaki, M.; Kato, H.;
Watanabe, T.; Fujimuro, M.; Saeki, Y.; Yoshinaga, S.;
Terasawa, H.; Iwasaki, N.; Rotinsulu, H.; Losung, F.;
Mangindaan, R. E. P.; Namikoshi, M.; Voogd, N. J. d.;
Yokosawa, H.; Tsukamoto, S., Bioorg. Med. Chem. 2012, 20,
4437-4442.
24. Deposited in the Cambridge Crystallographic Data Center -
1891427
8.
9.
Espada, A.; Jiménez, C.; Debitus, C.; Riguera, R., Tetrahedron
Lett. 1993, 34, 7773-7776.
He, W.-F.; Xue, D.-Q.; Yao, L.-G.; Li, J.-Y.; Li, J.; Guo, Y.-
W., Mar. Drugs 2014, 12, 3982-3993.
25. Ahn, N. T.; Eisenstein, O., Tetrahedron Lett. 1976, 155-158.
26. Hoye, T. R.; Zhao, H., Org. Lett. 1999, 1, 1123-1125.
27. (a) Chen, Y.; Dias, H. V. R.; Lovely, C. J., Tetrahedron Lett.
2003, 44, 1379-1382; (b) Lovely, C. J.; Chen, Y.; Ekanayake,
E. V., Heterocycles 2007, 44, 873-894.
10. Iinuma, Y.; Kozawa, S.; Ishiyama, H.; Tsuda, M.; Fukushi, E.;
Kawabata, J.; Fromont, J.; Kobayashi, J. i., J. Nat. Prod. 2005,
68, 1109-1110.
11. Pedpradab, S.; Edrada, R.; Ebel, R.; Wray, V.; Proksch, P., J.
Nat. Prod. 2004, 67, 2113-2116.
12. (a) Du, H.; He, Y.; Rasapalli, S.; Lovely, C. J., Synlett 2006,
965-992; (b) Koswatta, P. B.; Lovely, C. J., Nat. Prod. Rep.
2011, 28, 511-528; (c) Lovely, C. J., Development of a
General Approach to the Leucetta Alkaloids. In Strategies and
Tactics in Organic Synthesis, Harmata, M., Ed. Academic
Press: 2012; Vol. 8, pp 199-224.
13. Dalpozzo, R., Molecules 2016, 21, 699-717.
14. Bonamore, A.; Calisti, L.; Calcaterra, A.; Ismail, O. H.;
Gargano, M.; D’Acquarica, I.; Botta, B.; Boffi, A.; Macone,
A., ChemistrySelect 2016, 1, 1525-1528.
28. The CIF was deposited at the Cambridge Crystallographic
Data Center (CCDC #1893399)
29. (a) Wagaw, S.; Yang, B. H.; Buchwald, S. L., J. Am. Chem.
Soc 1998, 120, 6621-6622; (b) Wagaw, S.; Yang, B. H.;
Buchwald, S. L., J. Am. Chem. Soc 1999, 121, 10251-10263.
30. Maia, H. L. S.; Monteiro, L. S.; Sebasiao, J., Eur. J. Org.
Chem. 2001, 1967-1970.
31. An attempt to hydrolyze the tosylamide with aqueous NaOH
resulted in the formation of the corresponing aromatized
product through elimation and then subsequent air oxidation.
32. We used slightly different work-up conditions HCl vs aqueous
NH4Cl.
33. We were unable to obtain an authentic sample and no copies of
the original spectra were available through supplementary
information or from the original authors.
15. Laine, A. E.; Lood, C.; Koskinen, A. M. P., Molecules 2014,
19, 1544-1567.
16. F.Taber, D.; K.Tirunahari, P., Tetrahedron 2011, 67, 7195-
7210.
17. Heravi, M. M.; Rohani, S.; Zadsirjan, V.; Zahedi, N., RSC Adv.
2017, 7, 52852-52887.
18. Deiters, A.; Martin, S. F., Chem. Rev. 2004, 114, 2199-2238.