Strychnine: From Isolation to Total Synthesis – Part 3

  • ChemPubSoc Europe Logo
  • DOI: 10.1002/chemv.201500053
  • Author: Klaus Roth
  • Published Date: 07 July 2015
  • Source / Publisher: Chemie in unserer Zeit/Wiley-VCH
  • Copyright: Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
thumbnail image: Strychnine: From Isolation to Total Synthesis – Part 3

What is it that compels organic chemists to try, over and over again, to synthesize strychnine in a new way? Especially since the compound can easily be isolated directly in hundred-gram quantities, from seeds of the poison nut tree. The allure must be particularly great, since nearly 20 total syntheses have so far been published [45, 46], all of them unique (Table 2).


The personal motivation associated with one of the latest syntheses is elucidated in an interview with the two scientists, Christine Beemelmanns and Hans-Ulrich Reissig from Berlin, Germany, who were directly involved.

 

Table 2. Formal total syntheses of strychnine published until 2010.


No. Author Year Enantiomer Steps Yield Rings Synthesized
1 Woodward 1954 (–) 29 <0.1 A→B→C→G→E→D→F
2 Magnus 1992 (–) 30 <0.1 AB→D→CE→F→G
3 Overman 1993
1995
(–)
(+)
27
24

3.0

A→D→CE→B→F→G
4 Kuehne 1993 (rac) 20 1.0 AB→CE→D→G→F
5 Stork 1992 (rac) 19 n.d. AB→CE→D→F→G
6 Rawal 1994 (rac) 22 1.0 A→C→E→G→D→F
7 Kuehne 1998 (–) 22 3.5 AB→CE→D→F→G
8 Bonjoch 1999 (–) 22 0.2 AE→C→D→B→F→G
9 Martin 1999 (rac) 17 1.0 AB→D→CE→F→G
10 Vollhardt 2000 (rac) 19 0.1 AB→EG→C→D→F
11 Bodwell* 2002 (rac) 17 2.5 AB→CEG→D→F
12 Shibasaki 2002 (–) 30 1.0 E→A→BD→C→F→G
13 Mori 2002 (–) 27 0.1 E→A→B→C→G→D→F
14 Fukuyama 2004 (–) 29 1.0 A→B→D→CE→F→G
15 Padwa 2007 (rac) 22 0.5 AB→CE→D→F→G
16 Andrade 2010 (rac) 18 1.5 AB→CE→D→F→G
17 Beemelmanns & Reissig 2010 (rac) 16 1.0 AB→EG→C→D→F

*turned out to be incorrect, see below

 

Table 3. Recent formal total syntheses of strychnine [50,52–53].

No. Author Year
18 Vanderwal 2011
19 MacMillan 2011
20 Canesi 2015

 




5. Strychnine Total Synthesis of Beemelmanns & Reissig, 2010

This synthesis starts with two commercially available laboratory compounds: indole-3-acetonitrile (10, € 160/25 g) and oxopimelic acid diethylester (11, € 120/25 g). First, diester 11 is converted into the monoester, which itself is also available, but more expensive. Reaction of the latter with 10 gives indole derivative 12 (Fig. 10). This is followed by what is actually the key step in the synthesis: a double cyclization to tetracyclic compound 13.

 

Figure 10. The key reaction in strychnine synthesis of Beemelmanns & Reissig, 2010 [47].

 

Here we see, all at once, the creation of two six-membered rings with three adjacent stereocenters, all in the required configuration for conversion into strychnine. The basis for this complex series of reactions is the powerful reducing agent samarium diiodide (SmI2, the Kagan reagent). The preparative potential of this reagent has long been exploited in Reissig’s research group in Berlin, Germany, and its range of application extended. In this case, a molecule of samarium diiodide attacks the carbonyl group, transferring one electron, to produce a ketyl radical [48]. This radical center in turn attacks the 2-position of the indole, creating the first six-membered ring.


A second molecule of samarium diiodide then transfers another electron to the indole's 3-position, transforming a radical into a carbanion, which in turn undertakes an intramolecular nucleophilic attack on the carbonyl carbon atom of the ester group, closing a second ring. As a consequence of the two sequential ring closures, this can be characterized as a cascade reaction, which despite the mechanistically complex course of events results in a 77% yield of tetracyclic product 13.

This tetracyclic system (13) with its –CH2–CN sidechain at the 3-position of the indole unit already includes all the atoms necessary for completing the next ring. The subsequent third ring closure proceeded smoothly, so that starting from indole 10, three steps achieved pentacyclic system 14/15, for which Bodwell had required 13 steps (see Plan A in Fig. 11). Bodwell had already described the transformation of 14/15 into strychnine precursor 16 (the preparation of which in 18 steps had also been reported by Rawal [49]), so it appeared that a 17th formal total synthesis of strychnine had been successfully accomplished.




6. Was this the "Happy End"?

With a "formal" total synthesis, a complete new natural product synthesis has not been accomplished, only one up to a precursor, which at an earlier date has already been transformed into the true target molecule.

 

Figure 11. Total synthesis of strychnine of Beemelmanns & Reissig, 2010 – Plan A and Plan B.

 

A tedious set of NMR analyses showed, however, that the product was in fact not the desired compound 14, with its cis-connected five-membered ring (blue), but rather stereoisomer 15, with a trans-relationship (red) instead. The intended total synthesis had thus failed, as had Bodwell's. A new "Plan B" was therefore quickly developed, permitting compound 13 to indeed be transformed into the desired pentacyclic system 14 in the course of just three steps. Given the previous unhappy experience, and for safety's sake, 14 as obtained was nevertheless further converted into 16, which was shown to be identical to Rawal's intermediate.


The structural assignment of the tetracyclic system as published by Bodwell turned out to be incorrect, and Reissig discovered that the prepared tetracycle was not a synthetic precursor of 16, but rather of 15, which cannot be transformed into strychnine. Thus, this synthesis was in fact a failure, and the Bodwell strychnine synthesis was no longer tenable!


This marked the beginning of a drama, of which the two researchers themselves have spoken quite directly in their interview. It turns out that total syntheses may consist of more than just reaction schemes with their many straight and curved arrows, coupled with much hard work in the laboratory. The surroundings, the circumstances, and, of course, emotions – ranging from triumph to frustration – also play a major role, as may, of course, the luck of those who deserve it.


In this particular case, the participants were very fortunate. Thanks to a rapidly developed Plan B they were able to circumnavigate the suddenly encountered shoals without even increasing the length of the synthesis. By early May 2010, they had succeeded and were able to wrap up their strychnine total synthesis: the corresponding manuscript was quickly prepared and accepted, and in October 2010 it appeared in print. Hats off!


After this article was finished, Strychnine total synthesis No. 18 was published in February 2011, distinguished by fewer reaction steps and a very original double ring closure, though the latter was unfortunately limited to a yield of only 5–10 % [50]. In 2015, Beemelmanns and Reissig developed another short route to strychnine using a samarium-diiodide-induced cascade cyclization as a key step. [51].




Acknowledgements

I am especially grateful to Dr. C. Beemelmanns and Professor Hans-Ullrich Reissig, Free University Berlin, Germany, for their technical support in my foray into this challenging field, and for their willingness to speak so very openly regarding their research.


I wish further to thank Dr. C. Czekelius, also of the Free University Berlin, for raised eyebrows in conjunction with my request for a pinch of strychnine; Professor David W. Thomson, College of William and Mary, Williamsburg, Virginia, USA, for the loaned teaching materials; Sabine Rinberger, Director of the Valentin-Museum, Munich, Germany, for her help in research regarding Karl Valentin; Professor E. Vaupel, Deutsches Museum, Munich, Germany, for help in background research; Prof.essor Helmut Vorbrüggen, Free University of Berlin, for reports of his personal recollections of R. B. Woodward; and Dr. S. Streller and Dr. P. Winchester, Free University of Berlin, for valuable help with the manuscript.




References

[45] J. Bonjoch, D. Solé, Chem. Rev. 2000, 100, 3455. DOI: 10.1021/cr9902547

[46] M. Mori, Heterocycles 2010, 81, 259. DOI: 10.3987/rev-09-661

[47] C. Beemelmanns, Ph.D. Thesis 2010, Freie Universität Berlin, Germany.

[48] C. Beemelmanns, H.-U. Reissig, Pure Appl. Chem. 2011, 83, 507. DOI: 10.1351/pac-con-10-09-06

[49] G. J. Bodwell, J. Li, Angew. Chem. Int. Ed. 2002, 17, 3261.
DOI: 10.1002/1521-3773(20020902)41:17<3261::AID-ANIE3261>3.0.CO;2-K

[50] D. B. C. Martin, C. D. Vanderwal, Chem Sci. 2011, 2, 649. DOI: 10.1039/c1sc00009h

[51] C. Beemelmanns, H.-U. Reissig, Chem. Eur. J. 2015, 21, 8416. DOI: 10.1002/chem.201500094

[52] D. W. C. MacMillan et al., Nature 2011, 475, 183–188. DOI: 10.1038/nature10232

[53] S. Canesi et al., Chem. Eur. J. 2015, 21, 7713–7715. DOI: 10.1002/chem.201500185


The article has been published in German as:

and was translated by W. E. Russey.


Strychnine: From Isolation to Total Synthesis – Part 1

Just how toxic is strychnine, and why?


Strychnine: From Isolation to Total Synthesis – Part 2

Why did it take 130 years to determine the structure of strychnine?


Strychnine: From Isolation to Total Synthesis – Part 3

What can we learn from the total synthesis of strychnine?


Strychnine: From Isolation to Total Synthesis – Interview

Christine Beemelmanns and Hans-Ulrich Reissig explain why they developed the 17th total synthesis of strychnine


See all articles by Klaus Roth published in ChemViews Magazine


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