B.R.S.M. Pain is temporary, publications are eternal


(-)-Nakadomarin A

Total Synthesis of (–)-Nakadomarin A

David A. Evans et. al., J. Am. Chem. Soc., 2013, Just Accepted  [PDF] [SI] [GROUP]

DOI: 10.1021/ja404673s

0At first glance I didn't think that the appearance of another nakadomarin A synthesis in JACS a couple of days ago was too remarkable, but when I saw Dave Evans' name on it I have admit that I did raise an eyebrow. Although Dave is a living legend within the organic chemistry community, I had believed that his group had wound down to almost nothing, and I certainly wasn't expecting to see any new total syntheses from his group any time soon. And without an oxazolidinone in sight.

Of course, I’m not too surprised that people are still interested in making nakadomarin A; along with the rest of the manzamine alkaloids it's  been pretty popular over the last decade and I think that the field is still waiting for a 'final' synthesis. With potent cytotoxic, antibacterial and anti-microbial activity nakadomarin might be a little more exciting that the average natural product in terms of biological profile, but I suspect it’s the alluring structure and that unusual juxtaposition of small, medium and large rings that keeps synthetic chemists coming back for more. Certainly enough well-known groups have spent published work relating its synthesis. The double bonds in the two largest rings are just begging for an RCM-based approached, but it turns out (as with manzamine A), that this strategy is not as easy as it looks on paper. In fact, back in 2011 when I was considering a blog post on the (then) latest synthesis by Zhai, I made this graphic to illustrate the flaws with disconnection.[1] It might be a little dated now:[2]


Evans decided to avoid opening that particular Pandora’s box and instead make both these potentially troubling rings as early as possible, breaking the molecule into two fragments with one larger ring in each. The two components were then to be united in a Lewis-acid mediated formal [4 + 2] reaction as shown below.[2] The group was pretty sure that the one existing stereocentre on the azocine ring junction would limit the approach of this pseudo-dienophilic component to one of two possible trajectories. It was hoped that the tendency of carbonyl dipoles to oppose one another—like in the famous Evans Aldol reaction—would cause the desired (bottom) approach to be somewhat more favoured.

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I've not written all that many total synthesis posts this year, not for a dearth of interesting work, but more a lack of free time. I started writing this one about six months ago (!), and I guess most of you have probably seen this paper already, but I think it’s pretty cool so I decided it’d be worth finishing. Now featuring my new favourite piece of punctuation, the em dash!

Synthesis of (−)-Neothiobinupharidine

Ryan A. Shenvi et al., J. Am. Chem. Soc., 2013, 135, 1209 [PDF][SI][GROUP]

DOI: 10.1021/ja310778t


The first of the rather wacky looking nuphar alkaloids were actually isolated back in the 60s by Achmatowicz (of Achmatowicz reaction 'fame'), the family has now grown to a fair size, as you can see from the borrowed figure below. No-one paid them much attention for a while, as they weren't very bioactive, looked quite intimidating, and everyone was probably too busy psyching themselves up to make vernolepin anyway.[1] However, a recent report that they selectively kill off melanoma cells (via a mechanism that no-one’s worked out yet), combined with a pretty cool biosynthetic proposal by LaLonde, was enough for Shenvi to spend a little time working out a synthesis.

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And Now For Something Completely Different 6: Green Chemistry

Most of the credit for this one goes to occasional commenter Martyn!

Is it just me, or will green chemistry journals publish anything these days? For example, check out this paper published this morning in the Journal of Sustainable Agitation:


Unpowered Mechanical Stirring of Reaction Media Using Renewable Stirring Fish (RSFs). [PDF]


I couldn't make this stuff up!



Filed under: ANFSCD, Current Literature, Fun | 14,756 views | 6 comments 6 Comments

From Pasta to Superconductor In Four Easy Steps


From Chem. Commun., 2013, ASAP (DOI: 10.1039/C3CC38271K)

Seriously. From the abstract:

"Self-supporting superconducting replicas of pasta shapes are reported, yielding products of differing 3D architectures. Functioning high-temperature superconductor wires are developed and refined from replicas of spaghetti, demonstrating a unique sol–gel processing technique for the design and synthesis of novel macroscopic morphologies of complex functional materials."

Huh? And it gets better in the 'General Experimental' section:

"Spaghetti (own-brand durum wheat dried pasta) was purchased from The Co-operative Food (Co-operative Group Limited, UK), penne and fusilli (own-brand durum wheat dried pasta) were purchased from Sainsbury’s (J. Sainsbury’s plc, UK) and HonigTM Samen “Piraten Pasta” was a gift from Jamie Shenston (University of Bristol, UK) and Caroline Walker (Heinz)... Unless stated otherwise, all materials were used as received, and with no further purification."

The pasta is then soaked in a delicious blend of yttrium, barium, copper and silver (until green), oven baked at 920 ºC (gas mark 36, if you're trying this in your oven at home), sintered and annealed to taste then served in liquid helium. Yum!

Thanks to occasional commenter Martyn for pointing this out!

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(+)-Hyperforin (Shair, 2012)

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

J. Am. Chem. Soc., 2013, 135, 644 | [PDF][SI][GROUP]

B. A. Sparling, D. C. Moebius, and Matthew D. Shair,

DOI: 10.1021/ja312150d



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.[1] The Shair group saw a better way, disconnecting the molecule back to 6 key building blocks:


Credit: J. Am. Chem. Soc., 2013, 135, 644

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Who Ya Gonna Call? Blog Syn!

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.[1] 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

Filed under: Ask the audience, Current Literature, Fun | 10,083 views | 6 comments 6 Comments

Synthetic Biology versus Total Synthesis

From a series of paintings by David Cordes at Pacific University, Oregon.

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.[1] 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.

Reaction Vessels

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.

Filed under: Current Literature, Total Synthesis | 18,624 views | 8 comments 8 Comments

What’s Wrong With This Picture 2: An Intriguing Biosynthetic Proposal

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?

Filed under: Ask the audience, Current Literature, WWWTP | 10,718 views | 3 comments 3 Comments

Non-Thermal Microwave Effects: Probably Bollocks

Update 1900: This was blogged earlier today by Tom Phillips over at A Chemical Education. Whoops!

Update July, 2013: Part two! Because sometimes you just wanna flog that dead horse a bit longer, you know, to be safe.

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:[1]

From Angew. Chem. Int. Ed. 2012, 51, 2.

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Superlatives 2: The Gassiest Reaction of Them All?

Perhaps Organic and Biomolecular Chemistry isn't a journal well known for its reviews, however I recently enjoyed reading this rather unusual perspective by Jason Chen on "Gas Extrusion in Natural Products Total Synthesis". All the classics are there: the retro [4 + 1] cycloaddition of sulfolanes to generate dienes (and the related Ramberg–Bäcklund reaction), the Boger-style 1,2,4,5-tetrazine [4 + 2]-retro-[4 + 2] method for the synthesis of aromatic rings and many more unusual ways to lose nitrogen besides. There are also some much rarer reactions, including an example from Padwa's synthesis of stempeliopine where addition of carbon suboxide (O=C=C=C=O) to a thioamide is followed by a cascade that eventually spits out carbonyl sulfide (OCS). I bet that's a synthesis that makes you unpopular in the lab[1]

Probably the winner for the gassiest sequence described is from a Movassaghi paper that I remember from last year. Although the reaction hasn't actually been used to make a natural product yet, it looks like a useful way to access  hetero cyclotryptamine natural products, of which there are many. The idea is to synthesise an unsymmetrical sulfamide, where the two amines are connected to the two units to be linked. Oxidation of this with NCS then generated a thiadiaziridine dioxide in some bizarre Aza-Myers-Ramberg-Bäcklund-type reaction. This then lost sulfur dioxide as expected to give a diazene that was decomposed photolytically with loss of nitrogen to give a pair of radicals that recombined quickly. Amazingly this recombination occurred sufficiently to prevent the formation of homodimeric products. Neat reaction - I love the fact that the linker is completely traceless!

Gas extruding reactions are more important that might be imagined at first (especially for the construction of strained systems), and it's nice to see a review dedicated to them.



1. Carbon suboxide apparently smells (surprisingly?) awful . From an early review on its chemistry:

"The physical properties of carbon suboxide are of considerable interest.  It is a  gas  under ordinary conditions,  having  an unbearable odor like acrolein and mustard oil.  In  small amounts  it  acts as  a  lachrymator; in  high concentrations it attacks the eyes, nose  and breathing  organs, giving a  feeling of suffocation."

There are lots of ways to make it, some of which are more appealing than others. Padwa generates it from dibromomalonoyl dichloride and zinc in ether at room temperature, which sounds quite sensible. Unfortunately, the OCS by-product also smells pretty bad. It's a little known fact that pure carbon disulfide has a pleasant smell redolent of diethyl ether (according to the Merck index; I used to have a CS2 still and I never experienced this). The reason it's so unpleasant to work with are traces of OCS (and thiols) from its manufacture. According to Wolf and Amarego these can be removed by washing with aqueous KMnO4 solution, followed by mercury. Or not.


Filed under: Current Literature, Named reactions, Serious | 19,470 views | 5 comments 5 Comments