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A Short Synthesis of Strychnine from Pyridine

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Abstract

The synthesis of complex natural products serves as a source of great inspiration and challenge for organic chemists. The synthesis of strychnine is no exception. With six contiguous stereocenters, five of which adorn the central cyclohexane ring, a stereodefined trisubstituted olefin, and seven rings, strychnine (1, Fig. 4.1) presents a significant challenge for synthesis.

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Notes

  1. 1.

    A synthesis of strychnine by the Stork group was apparently disclosed in lecture form, and some of the details are provided in the review by Bonjoch and Solé from 2000 [15a]. While we prefer not to cite a synthesis that is not available in the primary literature, based on the account provided in [15a], the Stork group utilized a vinyl carbanionic D-ring-closure by C15–C20 bond formation that presumably proceeded via conjugate addition onto an α,β-unsaturated ester.

  2. 2.

    Although bromide 87, could also be suitable, we spent most of our efforts on accessing iodide 88, which would presumably be more reactive in the final Heck cyclization.

  3. 3.

    Our efforts to concretely determine the relative stereochemistry of this dimer have been met by failure. We have made attempts to resolve several of the monomeric tetracyclic aminoaldehydes of type 100 by HPLC using chiral stationary phase, in order to know for sure the structure of the homodimer. The poor solubility of these compounds in typical HPLC solvents hampered these efforts to access enantiopure monomer. A few attempts at diastereomeric salt formation from compounds of type 101 using chiral carboxylic acids were also unsuccessful. Computational analysis corroborates the assumption that the homodimer should be formed preferentially.

  4. 4.

    (a) For a relevant discussion of the difficulty of C15–C20 bond construction, see [10i] and [65a]. (b) For a discussion of D-ring formation in related pyrroloindoline natural products, see [20d].

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Acknowledgment

We dedicate this account to the memory of David Gin, a wonderful person and truly inspiring scientist. We thank the NSF (CAREER Award CHE-0847061) for support of our work. This project also benefited from support through graduate fellowships to D.B.C.M. from Eli Lilly, the NSERC of Canada, and Bristol–Myers Squibb, as well as an Amgen Young Investigator Award, an AstraZeneca Award for Excellence in Chemistry, and an Eli Lilly Grantee Award to C.D.V. D.B.C.M is a recipient of a Roche Excellence in Chemistry Award, and C.D.V. is a fellow of the A.P. Sloan Foundation and is a University of California, Irvine Chancellor’s Faculty Fellow.

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  1. Department of Chemistry, University of California, Irvine, CA, 92697, USA

    David B. C. Martin & Christopher D. Vanderwal

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  1. David B. C. Martin
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  1. Firestone Court 3, Skillman, 08558, New Jersey, USA

    Jie Jack Li

  2. , Dept. of Chemistry and Chemical Biology, Harvard University, Oxford Street 12, Cambridge, 02138, USA

    E.J. Corey

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Martin, D.B.C., Vanderwal, C.D. (2012). A Short Synthesis of Strychnine from Pyridine. In: Li, J., Corey, E. (eds) Total Synthesis of Natural Products. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-34065-9_4

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