ARTICLE RESEARCH
Table 1
|
Enantioselective synthesis of six well-known indole
member of the Strychnos alkaloid family. We hope to describe the
value of this approach in terms of other natural product and medicinal
agent families in the near future.
alkaloids
O
NBoc
Enantioselective syntheses
of Strychnos, Aspidosperma
and Kopsia alkaloids
METHODS SUMMARY
Synthetic
elaboration
≤8 steps
N
P
All reactions were performed under an inert atmosphere using dry solvents in
anhydrous conditions, unless otherwise noted. Full experimental details and
characterization data for all new compounds are included in Supplementary
Information.
Common intermediate (1)
Compound
No. steps
here*
Overall
PSAC
steps
PSCA
steps
yield (%)
Received 4 February; accepted 26 May 2011.
N
H
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12
6.4
25 (refs 19, 20) 16 (ref. 21)
N
2. Va, P., Campbell, E. L., Robertson, W. M. & Boger, D. L. Total synthesis and
evaluation of a key series of C5-substituted vinblastine derivatives. J. Am. Chem.
Soc. 132, 8489–8495 (2010).
H
H
O
O
H
(2)-strychnine
3. Huang, Y., Walji, A. M., Larsen, C. H. & MacMillan, D. W. C. Enantioselective organo-
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(2009).
N
9
9
24
14
13 (ref. 30)
11 (ref. 29)
19 (ref. 32)
N
Me
H
H
5. Dewick, P. M. Medicinal Natural Products: A Biosynthetic Approach 3rd edn (Wiley,
(1)-aspidospermidine
2008).
N
6. Corey, E. J., Imai, N. & Pikul, S. Catalytic enantioselective synthesis of a key
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(1991).
NA
N
H
7. Kuehne, M. E., Wang, T. & Seraphin, D. The total synthesis of (6)-mossambine.
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CO2Me
8. Bandarage, U. K., Kuehne, M. E. & Glick, S. D. Total syntheses of racemic
albifloranine and its anti-addictive congeners, including 18-methoxycoronaridine.
Tetrahedron 55, 9405–9424 (1999).
(2)-kopsinine
N
9. Grondal, C., Jeanty, M. & Enders,D. Organocatalyticcascadereactionsasa newtool
in total synthesis. Nature Chem. 2, 167–178 (2010).
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syntheses of (6)-strychnine and (6)-akuammicine. J. Org. Chem. 75, 3529–3532
(2010).
10
11
10
NA
NA
NA
N
Me
H
H
CO2Me
(2)-akuammicine
N
12. Hudlicky, T. & Reed, J. W. The Way of Synthesis: Evolution of Design and Methods for
Natural Products (Wiley-VCH, 2007).
8.9
10 (ref. 31)
13. Jones, S. B., Simmons, B. & MacMillan, D. W. C. Nine-step enantioselective total
synthesis of (1)-minfiensine. J. Am. Chem. Soc. 131, 13606–13607 (2009).
14. Thomas, P. J. & Stirling, C. J. M. Elimination and addition reactions. Part 34. The
effect of activating group and medium on leaving group rank in elimination from
carbanions. J. Chem. Soc. Perkin Trans. II 11, 1130–1134 (1978).
15. Gatta, F. & Misiti, D. Selenium dioxide oxidation of tetrahydro-b-carboline
derivatives. J. Heterocycl. Chem. 24, 1183–1187 (1987).
N
H
Me
CO2Me
(1)-vincadifformine
O
N
11
10
NA
NA
16. Prashad, M., Lavecchia, L., Prasad, K. & Repic, O. A convenient synthesis of
3-substituted 1H-indoles. Synth. Commun. 25, 95–100 (1995).
17. Oestreich, M. Ed. The Mizoroki–Heck Reaction (Wiley, 2009).
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19. Knight, S. D. & Overman, L. E. Enantioselective total synthesis of (2)-strychnine.
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pathway to Strychnos indole alkaloids: total syntheses of (2)-tubifoline, (2)-
dehydrotubifoline, and (2)-strychnine using palladium-catalyzed asymmetric
allylic substitution. J. Am. Chem. Soc. 125, 9801–9807 (2003).
21. Sole, D. et al. Total synthesis of (2)-strychnine via the Wieland–Gumlich aldehyde.
Angew. Chem. Int. Ed. 38, 395–397 (1999).
N
H
(2)-kopsanone
Step counts represent the longest linear sequence from commercially available 9. NA, not applicable.
PSAC, previous shortest asymmetric catalytic synthesis; PSCA, previous shortest chiral auxiliary or
chiral pool synthesis.
* See Supplementary Information for details of these syntheses.
convert (2)-kopsinine to (2)-kopsanone thermally according to the
method of ref. 33 were unsuccessful. However, simple acid-mediated
hydrolysis to give kopsinic acid (29), and subsequent heating of this
material without solvent37, furnished (2)-kopsanone in only 11
chemical steps.
As anticipated, application of collective total synthesis to each of
the target compounds—strychnine, akuammicine, aspidospermidine,
vincadifformine, kopsinine and kopsanone—was readily accomp-
lished with unprecedented levels of efficiency (Table 1). Perhaps most
notably, these collective asymmetric syntheses took a total of 34 steps
for the six natural products described (in comparison with 76 total
steps in previous studies).
22. Martin, D. B. & Vanderwal, C. D. A synthesis of strychnine by a longest linear
sequence of six steps. Chem. Sci. 2, 649–651 (2011).
23. Sole, D., Diaba, F. & Bonjoch, J. Nitrogen heterocycles by palladium-catalyzed
cyclization of amino-tethered vinyl halides and ketone enolates. J. Org. Chem. 68,
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Tetrahedron 52, 10113–10130 (1996).
25. Marino, J. P., Rubio, M. B., Cao, G. F. & de Dios, A. Total synthesis of (1)-
aspidospermidine: a new strategy for the enantiospecific synthesis of
Aspidosperma alkaloids. J. Am. Chem. Soc. 124, 13398–13399 (2002).
26. Kobayashi, S., Peng, G. & Fukuyama, T. Efficient total syntheses of (6)-
vincadifformine and (2)-tabersonine. Tetrahedr. Lett. 40, 1519–1522 (1999).
27. Hajicek, J. A review on recent developments in syntheses of the post-secodine
indole alkaloids. Part I: The primary alkaloid types. Collect. Czech. Chem. Commun.
69, 1681–1767 (2004).
28. Cho, H.-K., Tam, N. T. & Cho, C. G. Total synthesis of (6) aspidospermidine starting
from 3-ethyl-5-bromo-2-pyrone. Bull. Korean Chem. Soc. 31, 3382–3384 (2010).
29. Gnecco, D. et al. Synthesisofanaspidospermaalkaloidprecursor: synthesis of(1)-
aspidospermidine. Arkivoc 2003 (xi), 185–192 (2003).
Conclusion
We have demonstrated the capabilities of collective total synthesis in
combination with organocascade catalysis, a synthetic strategy that
provides researchers with the tools to gain ready access to large col-
lections of complex molecular architectures. In particular, we describe
the shortest asymmetric synthesis of (2)-strychnine, the best-known
30. Kozmin, S. A., Iwama, T., Huang, Y. & Rawal, V. H. An efficient approach to
Aspidosperma alkaloids via [41 2] cycloadditions of aminosiloxydienes:
Stereocontrolled total synthesis of (6)-tabersonine. Gram-scale catalytic
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