Histrionicotoxin 285A… and some history…
Holmes, Macdonald,Â Horsley,Â Ryan and Saubern. Org Lett, 2008, ASAP. DOI: 10.1021/ol801604z.
I’m thoroughly glad I took a little more time to dig through ASAPs I’d missed, as I’d somehow neglected this Org Lett published by Andy Holmes.Â Y’see, some of the work towards the natural product was conducted in the lab I started my PhD in, back in 2004 in Cambridge.1 However, I’ll leave the reminicing for later in this post.
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.Â 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 synthesis of 285A, using a strategy familiar to the group.Â This utilises a key nitrone dipolar cycloaddition:
The substrate took a fair-few steps to make (mostly through acetylide additions / reduction), but this is a pretty nice was to construct a ring and two stereocentrers.Â 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.Â This is because the reaction with styrene was only actually protecting the nitrone.Â Under the microwave conditions, the cycloaddition reverses, and the free nitrone is revealed to react again.Â 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’ve shown a partial retrosynthesis to illustrate it.Â What I did like was the allene addition; simply take one primary iodide, displace with lithiated allene, and enjoy the 99% yield.Â I dunno why I was so taken with this, but I’d never have though it would have been so high yielding!
Nice work, showing the most evolved example of the group’s method for making this family.
1.Â Chemistry over; time for a bit of my life!Â I started my PhD studies with Jon Burton back in 2004, working in lab 287 at Cambridge University.Â This is where I met one Helen Horsely, one of the authors of this paper, as the Burton groups shared 287 with the Holmes group (Jon Phd’d and post-docd with Andy Holmes).Â It was a cracking lab, but a little dated (circa. 1950 I think!); everything was made from teak.Â However, at the end of my first year, Holmes moved to his current position in Australia, and the Burton group got it’s own (more modern) lab.Â 287 was emptied (by us students), and the lab transformed into some chemical-biology suite.Â Emptying that old lab was an experience in itself; we found several flasks with the initials “IF” on the side – Ian Fleming!Â We also found a half-case of champagne, a half-kilo of brucine and a bottle of hexamethylditin that was built into the framework of the teak benches… Nice!
However, of late I’ve felt a bit of nostalgia for the old-days, so here’s a couple of photos of the old lab.Â Mmm, I can almost smell the silica in the air, and DCM on the varnish.Â If you squint a bit, you can see the column I was running in the first photo, with the yellow netting on the outside.Â I only had one accident during my PhD, and it was with that column; twisting the gas-quick-fit adaptor on the top resulted in a sliced thumb, and a few stitches.Â I’ve got to thank Helen for her first-aid skills that day!
The fume-hood on the left in the second photo had a THF still in it; but it wasn’t over sodium.Â No, sodium was for wimps – we ran ours over potassium.Â Cards-on-the-table – I was terrified of that thing, and I was extremely glad it was decommissioned before it became my responsibility!Â However, that THF was dry.
Working in a huge lab like that, with loads of students and post-docs was a fantastic experience; I learnt loads in that lab just by walking past other students working.Â I don’t think that more modern labs (often smaller), with their individual bays, offer the same experience.Â But the health & saftey does count for something…!
It’s a bit of shame that 287 isn’t a synthetic lab anymore, but times move on and I guess teak isn’t where it’s at anymore…