Okay, I've finally got round to a full post on this synthesis. I started writing this almost two weeks ago! More things soon. Enjoy!
Enantioselective Total Synthesis of Hyperforin
B. A. Sparling, D. C. Moebius, and Matthew D. Shair,
It's a little surprising how few people have made hyperforin, considering that it's been known for over four decades. Indeed, the list of groups with partial solutions and 'studies towards' is an august company indeed: Nicolaou, Chen, Nguyen, Mehta, Jacobsen and several others have all fallen at various hurdles along the way. The compound itself was first isolated in the early seventies from Saint John's Wort (Hypericum perforatum), and is believed to be responsible for the well-documented antidepressent activity of the plant and its extracts, which are popular herbal supplements. No-one's quite sure exactly how it works (although as I understand it that's pretty normal for anti-depressants), and its undesirable physical properties make it an unlikely drug, but perhaps if the right analogue could be made then it could be the next big thing for tormented grad students. Surprising, then, that the only reported synthesis of the molecule before Shair graced the scene was published by Shibasaki in 2010 and although that contained some tasty chemistry (the Fe catalysed asymmetric Diels-Alder and vinylogous Pummerer were my personal highlights), at 51 steps it was perhaps a bit long to do much medicinal chemistry with. The Shair group saw a better way, disconnecting the molecule back to 6 key building blocks:
Credit: J. Am. Chem. Soc., 2013, 135, 644
Ever see a reaction in the literature and think, "that seems a little too good to be true..."? Retro Baeyer-Villiger reaction? Quantitative cleavage of methyl ethers with Amberlyst-15? Catalytic reduction of alcohols to hydrocarbons with Dess-Martin? Bring it on! Ever struggle with a sensitive or fiddly reaction and wonder, "is it just me? Should this work?"? Well, now you don't have to! Thanks to a collaborative new website brought to you by See Arr Oh, with a little help from Organometallica, Mat Katcher and Myself. Now, if you find a reaction you can't reproduce or don't believe, simply head over to Blog Syn, and let us know. Alternatively, if you think you'd like to be part of helping to make the literature a little bit more reproducible, pay us a visit and see what needs checking! If we all just run a few extra reactions a year we should be able to save chemists around the world many wasted hours and much frustration. You might even have some fun, make some new friends, and perhaps even learn some chemistry besides!
1. Or email See Arr Oh or myself
Full post on this synthesis to come when I get back from holiday at the weekend and can use ChemDraw! Sorry for the hand-drawn stuctures - I've still not found a good way to draw stuctures on my iPad, which is all I have with me.
I've never been particularly excited by phloroglucinol-derived natural products, but I really enjoyed Shair's recent synthesis of the polyprenylation acylphloroglucinol (+)-hyperforin (it's a PPAP!), which appeared in the JACS ASAPs a few days ago.
I'll hopefully get round to a more detailed discussion of the route in the next week, but the first step immediately caught my attention. The chemistry's simple enough - a good old-fashioned deprotonation step with t-BuLi, followed by treatment with barium(ii) iodide and prenyl chloride. I remembered (after looking it up) that the prenylation is done via the organobarium to improve the regioselectivity of the reaction, a trick developed a couple of decades back by the Yamamoto group (J. Am. Chem. Soc., 1994, 116, 6130).
Still, I was curious about how the group carried out the reaction, and on what scale, so I delved into the SI (which, by the way, is excellent). There I found a slightly unusual tip for how to get the small barium pieces necessary to freshly prepare the BaI2:
"Using a hand drill hammer, a chisel, and a lead brick positioned on the laboratory floor, mineral oil-coated barium rod was portioned into approximately 25 mm segments... If a hand drill hammer and chisel are unavailable, a standard claw hammer and an appropriately-shaped shelving bracket may be employed in this step."
I'm not sure why, but seeing that in a JACS paper made me smile.
Happy Christmas from all of us* at BRSM! Thanks for reading and all your comments and help over the past year!
*it's actually just me.
I think most would agree that synthetic chemists can now make just about any non-protein/non-polysaccharide natural product if enough time, resources and manpower are brought to bear. But that's not to say that the field is yet mature, or stagnating, as there still remain so many challenges to make our science more efficient, practical, and free from its current over-dependence on rare metals and petrochemical feedstocks. Recently, synthetic biology has started to emerge as a serious alternative to total synthesis when large amounts of complex natural products are required. Just think how many total synthesis papers start with a desultory line about 'the dearth of natural material', before recounting an arduous one- or two-yearlong quest to make a few more milligrams of the compound in question. Perhaps it sometimes makes more sense to try a different approach and ask 'can't we just improve the natural source?'. We synthetic chemists like to think we're special because we have the ability to make new compounds never seen in Nature, but with an increasing understanding of enzymes and the genes that encode for them, organisms can now be coaxed into producing compounds that have never been seen before. If you're interested in reading further debate over the future of the two fields then you should definitely read this short piece in Nature, in which champions of synthetic chemistry Phil Baran and Abraham Mendoza duke it out with Jay D. Keasling, a strong proponent of synthetic biology.
From Nature, 492, 188.
1. Of course, there still exists the question of 'should we?'. Aside from the importance of total synthesis in structural determination, and ignoring for the moment the oft quoted reason of solving supply problems, the other main justification offered by the practitioners of the art is the development of new methodology. I'd love to find a way to test this claim, but my feeling is that few generally useful reactions are discovered in long synthetic campaigns. Let me know in the comments if I'm wrong about this.
As a synthetic chemist I'm always on the hunt for interesting molecules to disconnect/speculate about, and a couple of natural products published at the start of this month (Organic Letters ASAP; DOI: 10.1021/ol3028303) immediately caught my eye:
So far so good! Don't start looking for mistakes yet! The problems start when the authors go on to suggest what I'm going to politely call a most intriguing biosynthetic proposal:
It's not too bad at the start, borrowing heavily from Baldwin and Whitehead's hypothesis for manzamine and related alkaloids. The problems come one the authors need to go from the pyridinium dimer to the natural product itself. How the C4-C5 bond is supposed to form on the middle line is beyond me, and the arrows in the cyclopropane opening seem to go in entirely the wrong direction, but all that stuff seems entirely sensible compared to the madness on the top line. I know that people often play a bit fast and loose with steps in proposed biosyntheses; it's easy to shrug and go "there's probably an enzyme that does that", but this just shows no understanding whatsoever of arrow pushing. I can't believe this got into an ACS journal, or am I missing something?
I've got a few emails lately pointing me in the direction of good resources such as the much discussed How To Chemdraw video and the beautiful new name-reaction.com. I've also just recently become aware of great new(ish) blogs like Not The Lab, Doctor Galactic, The Chemistry Cascade, Chemistry Tips and Techniques, and The Organic Solution. However, I am sure that for every useful resource (blog, tutorial, reference...) that I've read, I've missed many more! Below are the links on my resource page at present, and you can see my blogroll on the right. I've just noticed that the former hasn't been updated in over a year. So, what should I be reading or linking to? Drop me a comment or email (N.B. new address on about page)!
Incidentally, if your bookmark/RSS feed to this site points to my old eristocracy.co.uk domain, you should change it as I'm losing that tomorrow.
Update 1900: This was blogged earlier today by Tom Phillips over at A Chemical Education. Whoops!
For a related post on things to check before publishing your controversial results to avoid potential humiliation, see my old piece on 'metal-free' reactions.
From Angew. Chem. Int. Ed. 2012, 51, 2.
It seems to me that people still talk a great deal about so-called 'non-thermal' effects in microwave reactions; i.e. some kind of mysterious rate acceleration that occurs from excitation (or even stabilisation) of particular bonds or intermediates directly, in a fashion distinct from simple macroscopic heating of the reaction mixture. One of the most prominent critics of those who claim to observe these phenomena is Austrian chemist Oliver Kappe, who's been debunking claims of non-thermal effects for at least a decade and he's just written an excellent Essay in Angewandte Chemie on the subject. Now, few people would argue that a lot of reactions work better in the microwave, but this can often be explained by rapid internal heating or increased pressure; that is, by thermal effects, however dramatic. An example from Kappe's essay illustrates the incredible magnitude of rate improvement that's sometimes observed:
From Angew. Chem. Int. Ed. 2012, 51, 2.
I'd originally planned to do four of these posts, but it looks like I've run out of time so I'll be getting back to more cutting edge work (as soon as something exciting is published). Maybe I'll post the last one in
March Mulch. Check out Mulvember 1: Penfulvin A and Mulvember 2: Echinopines A and B!
Okay, I suppose I should start off by acknowledging that Mulzer isn't the corresponding author on this one (instead it's Mulzer group postdoc Jürgen Ramharter), but it's still a nice piece of work so I'm including it anyway. The target itself is one of the perennially popular lycopodium alkaloids whose first member - lycopodium itself - was isolated way back in 1881. A number of classic syntheses of members of this family in the 1970s and 80s by famous alkaloid chemists such as Stork, Heathcock, Wiesner and Wenkert have set the bar pretty high, but work towards these targets continues to this day. Particularly, the fawcettimine-type members of this family, to which lycoflexine belongs, have proved very popular in recent years with a new synthesis seemingly out every few months.
Update 02-12-12: If anyone wants/needs a copy of the original image without the text and arrow added, you can find it here.
Some of you may remember this synthesis of the world's longest polyene from a few months ago, covered by See Arr Oh here. I'm not going to say much about the the chemistry of this synthesis (Wittigs. Shedloads of 'em), or its significance, but I'd like to post a little addendum to the work here.
I just got an email from a friend of mine who, upon reading the paper, asked the obvious question 'but what colour is it?'. Lycopene, of course, is famously red:
Unable to find a answer to the question in the paper itself, or the Supporting Information he contacted the authors. After a few days, they sent a short reply and a beautiful image:
Now, how often do organic chemists get colours like that?