The shortest route to strychnine

Mar 27, 2019
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Editor’s note: following on from their previous groundbreaking publication on this blog – in which they provided a comprehensive overview of chemical-free consumer products – Drs Goldberg and Chemjobber submitted another manuscript to Nature Chemistry. Despite being summarily rejected by the editor, many (many) months later – and in the wake of some poetic exchanges on Twitter – the manuscript (and cover letter) are now both posted here on the blog with the permission of the authors. In the spirit of the Christmas papers published by the BMJ, consider this (tongue-in-cheek?) comment on synthetic chemistry by Alex and CJ a holiday-season gift to our readers!

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An expeditious and parsimonious approach to strychnine
Alexander F. G. Goldberg and C.J. Chemjobber

Throughout and following its structural elucidation1-5 strychnine has captured the imagination of synthetic chemists. Beginning with Woodward’s landmark total synthesis, reported in 1954 (ref. 6), this storied molecule has enabled chemists to showcase the state-of-the-art7,8. Advances in the field of organic synthesis over the following decades have culminated in a synthesis as short as six linear steps from commercial materials9. Indeed, each subsequent publication on this strychnine has been a reflection of the leading concepts of the time.

In this vein, we sought in our approach to limit the use of harmful reagents — and harmless reagents — and maximize step economy, atom economy10, redox economy11, word economy12, time economy13, graduate student economy14 and economy15.

Our efforts were initiated and concluded by obtaining commercially available strychnine as a light yellow powder from Sigma-Aldrich. Gratifyingly, all spectral data matched those reported in the literature, and the purity was found, fortuitously, to be as indicated by the vendor.

In summary, we are delighted to have obtained multi-gram quantities of strychnine in the shortest synthetic sequence to date from commercial materials. Future work will likely not be directed toward similar approaches to brucine, cinchonine, and erythropoietin.

Author contributions

A.F.G.G. and C.J.C. contributed equally to the experimental work.

Acknowledgements

We thank Sigma-Aldrich in advance for their sense of humour; A.F.G.G thanks Christine Hansplant for her patience in waiting for this acknowledgement for her contribution to our previous publication.

Affiliations

Stan’s Exchange Secondhand Store, Edmonton, AB.

Competing Financial Interests

A.F.G.G. is handily in the pockets of Big Strychnine.

References

1. Leuchs, H. Über Strychnon und Pseudo-strychnon als Nebenprodukte der Darstellung des Pseudo-strychnins und über weitere Versuche in dessen Reihe. (Teilweise mit Fritz Räck.) (über Strychnos-Alkaloide, 110. Mitteil.) Chem. Ber. 73, 731–739 (1940). [LINK]

2. Briggs, L. H., Openshaw, H. T. & Robinson, R. Strychnine and brucine. Part XLII. Constitution of the neo-series of bases and their oxidation products. J. Chem. Soc. 903 (1946). [LINK]

3. Robinson, R. The constitution of strychnine. Experientia 2, 28–29 (1946). [LINK]

4. Woodward, R. B., Brehm, W. J. & Nelson, A. L. The structure of strychnine J. Am. Chem. Soc. 69, 2250 (1947). [LINK]

5. Woodward, R. B. & Brehm, W. J. The Structure of Strychnine. Formulation of the Neo Bases J. Am. Chem. Soc. 70, 2107–2115 (1948). [LINK]

6. Woodward, R. B., Cava, M. P., Ollis, W. D., Hunger, A., Daeniker, H. U. & Schenker, K. The Total Synthesis of Strychnine. J. Am. Chem. Soc. 76, 4749–4751 (1954). [LINK]

7. Bonjoch, J. & Solé, D. Synthesis of Strychnine. Chem. Rev. 100, 3455–3482 (2000). [LINK]

8. Cannon, J. S. & Overman, L. E. Is There No End to the Total Syntheses of Strychnine? Lessons Learned in Strategy and Tactics in Total Synthesis. Angew. Chem. Int. Ed. 51, 4288–4311 (2012). [LINK]

9. Martin, D. B. C. & Vanderwal, C. D. A synthesis of strychnine by a longest linear sequence of six steps. Chem. Sci. 2, 649–651 (2011). [LINK]

10. Trost, B. M. Atom Economy—A Challenge for Organic Synthesis: Homogeneous Catalysis Leads the Way. Angew. Chem. Int. Ed. 34, 259–281 (1995). [LINK]

11. Burns, N.Z., Baran, P. S. & Hoffmann, R. W. Redox Economy in Organic Synthesis. Angew. Chem. Int. Ed. 48, 2854–2867 (2009). [LINK]

12. Goldberg, A. F. G. & Chemjobber, C. J. A comprehensive overview of chemical-free consumer products. The Sceptical Chymist. [LINK]

13. Hayashi, Y. & Ogasawara, S. Time Economical Synthesis of (–)-Oseltamivir. Org. Lett. 18, 3426–3429 (2016). [LINK]

14. (a) Wang, P., Dong, S., Brailsford, J. A., Iyer, K., Townsend, S. D., Zhang, Q., Hendrickson, R. C., Shieh, J., Moore, M. A. S., Danishefsky, S. J. At Last: Erythropoietin as a Single Glycoform. Angew. Chem. Int. Ed. 51, 11576–11584 (2012) and references therein. [LINK] (b) Nicolaou, K. C., Heretsch, P., Nakamura, T., Rudo, A., Murata, M. Konoki, K. Synthesis and Biological Evaluation of QRSTUVWXYZA’ Domains of Maitotoxin. J. Am. Chem. Soc. 136, 16444–16451 (2014) and references therein. [LINK] (c) Aad, G. et al. (ATLAS Collaboration, CMS Collaboration) Phys. Rev. Lett. 114, 191803 (2015). [LINK]

15. Newhouse, T., Baran, P. S. & Hoffmann, R. W. The economies of synthesis. Chem. Soc. Rev. 38, 3010–3021 (2009). [LINK]

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Cover letter

Dear Stu,

Please find attached our latest manuscript for your consideration for publication in Tetrahedron Letters or whatever it’s called, entitled “An Expeditious and Parsimonious Approach to Strychnine.” This scalable approach features a broadly-applicable method for accessing complex bioactive natural products, and adheres closely to the principles of green chemistry. For instance, our approach to strychnine was solvent-free and atom-economical, and all raw materials were obtained from renewable sources, which were fully incorporated into the final product. We trust that you will find that traditional green chemistry metrics such as atom economy, effective mass yield and E-factor are second to none.

Furthermore, the future of funding for basic research remains uncertain and subject to the whims of oft closed minded and myopic politicians. Pressing, therefore, is the need for cost-effective methods for obtaining important natural products, especially for the purposes of the biological studies which we all say we’re going to get around to.

Indeed, our zero-step synthesis of strychnine from commercially-available materials is a superb model for efficiency in synthetic chemistry. We are confident that the application of this method to other commercially available natural products will accelerate discovery in our own field, as well as in the fields of chemical biology and analytical chemistry; as the 200th anniversary of strychnine’s isolation approaches, we consider this timely and unparalleled manuscript suitable for the broad scientific audience of your publication.

Thank you in advance for your consideration,
Alexander Goldberg & CJ Chemjobber


Stu Cantrill

Chief Editor, Nature Chemistry, Springer Nature

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