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Totally Synthetic by Paul H. Docherty, 23 September 2008

Total Synthesis of Histrionicotoxin 285A


J. M. Macdonald, H. T. Horsley, J. H. Ryan, S. Saubern, A. B. Holmes, Org. Lett. 2008, 10, 4227-4229.

DOI: 10.1021/ol801604z

The target, histrionicotoxin 285A, was (like the rest of the family) isolated by blending poison-arrow frogs, and turns out to be a pretty potent inhibitor of the nicotinic acetylcholine receptor. Although there’s been loads of work on HTX 283A (including a synthesis by the group back in 2004, and even further back in 1999…), this is the first total synthesis of 285A, using a strategy familiar to the group - a nitrone dipolar cycloaddition:

The substrate took a few steps to make (mostly through acetylide additions / reduction), but this is a pretty nice way to construct a ring and two stereocenters. However, after a deprotection of the masked aldehyde and Wittig olefination, they open the ring and destroy the recently installed stereocenters… only to reinstall them again, using a second nitrone dipolar cycloaddition. This is because the reaction with styrene was only actually protecting the nitrone. Under the microwave conditions, the cycloaddition reverses, and the free nitrone is revealed to react again. This time, however, the reaction is intramolecular, building a more important carbocyclic ring found in the target.

Transformation of this intermediate into the natural product didn’t take too long; I have shown a partial retrosynthesis to illustrate it. What I did like was the allene addition; simply take one primary iodide, displace with lithiated allene, and enjoy the 99% yield.

Nice work, showing the most evolved example of the group’s method for making this family.