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


Total Synthesis of (-)-Calyciphylline N

Long time no post! Other writing commitments—and the death of my laptop, containing two half-written posts—have conspired to keep me from getting any blogging done for the past couple of months, not to mention that being a postdoc in the US is somewhat more intense than it was in the UK. I’ll try and get back on some kind of semi-regular posting schedule again, even if it's just once or twice a month for the time being. Thanks for your patience! —BRSM


Total Synthesis of (−)-Calyciphylline N

A. B. Smith, III et al., J. Am. Chem. Soc., 2013, ASAP [PDF][SI][GROUP]

DOI: 10.1021/ja411539w


If you’ve read more than a couple of posts on this site, you’ll have probably noticed by now that I’ve got quite a soft spot for chemical history and syntheses of so-called 'classic' targets. Aside from the fun of comparing how the techniques for actually making molecules have evolved—and marvelling at some of the dangerous reactions people used to do—it’s great to examine targets that have been made a number of times and compare the routes that different chemists chose. If I had a bit more time, I’d write a lot more blog posts in this vein. Or a book.[1]

In fact, so similar is the structure of calyciphylline N—whose total synthesis was published by Amos Smith last week—to that of daphmanidin E, which Eric Carreira conquered back in 2011, that I immediately found myself wanting to look through my old blog post and compare the two approaches. I'm not going to write this blog post up as a head-to-head comparison of the two, mostly because they're both heroic endeavours in their own rights, and hence such a post would be quite unwieldy—and certainly not casual holiday reading—but I'd encourage you to take a look for yourself.

Filed under: Current Literature, Total Synthesis | 18,366 views | 8 comments Continue reading

And Now For Something Completely Different 9: Typographical Mistakes Of Yesteryear

Thanks to a co-worker, I recently became aware of a rather unique aside published within Thomas Tidewell's somewhat dated Tetrahedron Report on the Addition Reactions of Ketenes (Tetrahedron, 1986, 42, 2587–1613). Found spread over pages 2587–2588 is the following:


It turns out that this note originates from a satirical piece in Chemistry in Britain (Chem. Br., 1965, 1, 230) published some 20 years previously. As far as I can tell, the root cause was an unfortunate typo in a Chemical Abstracts entry (Chem. Abst., 1965, 62,1561d) report from Paris on the discovery of a new chemical species—namely "O-Silylated Vinyl Ketene Animals"—by K. Vijayakumaran. If only such errors were uncommon enough (and chemists good natured enough) for this kind of banter in the literature of today! Have a good weekend!

Filed under: ANFSCD, Fun, Literature | 21,677 views | 2 comments 2 Comments

Include Me Out: Mercury Azides

An interesting paper appeared in Angewandte Chemie yesterday detailing a re-investigation of a number of mercury azides that were—for reasons that will become apparent—not properly characterized when they were first reported in the literature back in the 1890s.[1] This publication is remarkable in a number of ways, not least that it has made today’s report on (trinitromethyl)borate synthesis seem rather boring and jejune in comparison.


"Always  look on the bright azide of life" —Image and pun from Angewandte Chemie, 2013, Early View

It turns out that Hg2(N3)2 and α-Hg(N3)2 are both easily prepared using reported methods and are display predictable instability/toxicity, but nothing to write home about. The most exciting part of this paper focuses on the alternative β- form of Hg(N3)2. The authors describe the procedure as follows:

“In analogy to the preparation of β-Pb(N3)2, a second metastable modification of mercury(II) azide, β-Hg(N3)2 can be obtained by slow diffusion of aqueous NaN3 into a solution of mercury(II) nitrate which is separated by a layer of aqueous NaNO3. Thereby, needle-like crystals of β-Hg(N3)2 start to form in the lower mercury(II) nitrate layer which is always accompanied by spontaneous explosions during crystal growth finally leading to a mixing of the layers and the fast precipitation of α-Hg(N3)… Slow crystallization during the preparation of α- or β-Hg(N3)2 leads to the formation of large crystals which are extraordinarily sensitive to all kinds of provocation (e.g. even detonate in solution) and therefore should be avoided by all means. Nevertheless, with extreme care, we were able to manually isolate some specimens of β-Hg(N3)2 under the microscope which allowed the characterization by vibrational spectroscopy, single-crystal X-ray diffraction, and the determination of the melting point.

Now, when people talk about metastability I think of things like diamond and Dewar benzene; substances that actually have an appreciable energy barrier to their decay. You know, the sort of thing where you can say “hey, check this out! It’s metastable!” without your statement being punctuated by detonations and the sound of breaking glass followed by screams. Seriously, how are you supposed to prepare a compound that detonates at random under its own weight during crystallisation?

That said, if you look at the detailed procedure for the synthesis of β- Hg(N3)2 in the paper’s supporting information and skip the line that cautions “during this period explosions frequently occur” (just keep calm and carry on), then once you’ve made and isolated the compound it does sound surprisingly stable. In fact, once dry and pure—and after some rather fraught measurements by one of the students—the group was able to determine that the compound was stable up to 180 ºC when it sublimed. One day, I would like to meet the kind of person that works on projects like this!


  1. Of course, charactization during  that period largely revolved around melting point, taste and combustion analysis, all of which are hugely inappropriate for explosive mercury compounds (although I don’t doubt that people tried; the Merck index includes information on the taste of pyridine, presumably obtained shortly after its isolation a few decades previously).
  2. Also, does this figure from the paper seem a bit strange to you?

Mercury azide owl

Alternative caption: Figure 2. Top: ORTEP drawing of Hg2(N3)2.

Thermal ellipsoids set at 50% probability at 173 K. Selected

structural data are summarized in Table 1. Symmetry code (i) x+2, y, z+1.

Bottom:  Owl in flight, seen during acid trip.

Filed under: ANFSCD, Current Literature, Fun | 18,100 views | 5 comments 5 Comments


Stereoselective Total Synthesis of Hainanolidol and Harringtonolide via Oxidopyrylium-Based [5 + 2] Cycloaddition

Weiping Tang et al., J. Am. Chem. Soc., 2013, ASAP; [PDF] [SI] [GROUP]

DOI: 10.1021/ja406255j


Everyone who's studies organic chemistry long enough has a favorite reaction or two, although unusually in my case I’ve never actually performed either of mine. One is the alkene–arene metaphotocycloaddition that I wrote about last year for Carmen’s IYC2011 Favourite Reaction Carnival, first discovered by Bryce-Smith (in Reading, UK, of all places) and sharpened into a useful synthetic tool by Wender, Mulzer and others. The second is probably the [5 + 2] oxidopyrylium cycloaddition, a handy way of making 7-membered rings with nary a metal in sight.[1] Neither is particularly common in total synthesis, so imagine my delight when I saw the latter featured in Tang’s recent synthesis of harringtonolide a couple of weeks back.

The target in question comes from the Cephalotaxus genus of plants, which—by means of the incredibly popular cephalotaxine and harringtonine alkaloids—has provided synthetic chemists with a great deal of entertainment over the past 50 years or so. It’s interesting to note that the Cephalotaxus genus itself belongs to the larger family Taxaceae, which also encompasses the yew tree Taxus baccata, well known to natural products chemists as the original source of the famous microtubule stabiliser and anti-cancer drug taxol. Well, it seems that humankind has again struck gold in the Taxaeae family as harringtonolide has recently been demonstrated to be a remarkable potent and selective anti-neoplastic agent. But enough on taxol and taxonomy—let’s talk synthesis!

The group’s plan relied on the use of the aforementioned [5 + 2] oxidopyrylium cycloaddition to construct the seven membered ring. This clever, central disconnection essentially reduces the rather intimidating carbon skeleton of harringtonolide to a comparatively simple problem in decalin synthesis and—although it's a rather strange looking species—the precursor to the oxidopyrylium required to pull it off is just a simple furan.


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US Here I Come!

Hi all,

Somewhat later than planned, I'm off to the US tomorrow to finally start my postdoc! I suspect I'm gonna be pretty busy finding a place to live and settling into my new group for the next couple of weeks, so things could be quite quiet around here for a little while. I hope to resume blogging when I've gotten into a new routine, and I'm looking forward to having lots of new experiences to write about. Thanks for your advice and patience!



P.s. Although this is a dedicated organic synthesis blog, lots of people have asked me about my move to the US, so I'll probably attempt to write a series like Nessa's Transatlantic Tales about my experiences and mix that in with the usual content when normal service resumes. What do you think?

Filed under: Ask the audience, Not Chemistry | 11,997 views | 3 comments 3 Comments

Woodward Wednesday 7: Steroids

R. B. Woodward et al., J. Am. Chem. Soc., 1952, 74, 4223 [PDF] (Full paper)

For preliminary communications see: JACS, 1951, 73, 3547 [PDF]; JACS, 1951, 73, 3548 [PDF]; JACS, 1951, 73, 4057 [PDF]; JACS, 1951, 73, 2403 [PDF]

Hundreds, if not thousands, of steroids have been characterised to date, isolated from a bewildering variety of organisms from across the animal, plant and fungal kingdoms. Their roles as hormones, drugs, and in cell membranes make them crucial to life as we know it, and are the reason that they’re one of the best studied classes of natural products. People have been interested in making steroids since the earliest days of total synthesis in the 1930s and 40s, and the field of steroid synthesis has made the careers of legendary chemists such as Russell Marker, George Rosenkranz, Arthur Birch and Carl Djerassi, as well as ensnaring and captivating many others. Indeed, some five Nobel Prizes have been awarded for steroid research, and the fruits of these labours have included many important drugs and much useful chemistry.

R. B. Woodward was also heavily involved in steroid chemistry during his early career, perhaps inspired by his PhD studies on ‘A Synthetic Attack on the Oestrone Problem’. As I wrote about in an earlier post, he also famously collaborated with Konrad Bloch to elucidate the details of steroid biosynthesis, work for which Bloch would receive the Nobel Prize in medicine the year before Woodward received his in chemistry. Woodward’s synthetic contributions to the field came in the form of a groundbreaking synthesis of methyl 3-keto-Δ4,9(11),16-etiocholatrienate, which he resolved and converted into a number of known compounds, achieving the formal total synthesis of some of the best known steroids.


This flexible intermediate contained enough latent functionality (largely in the form of unsaturation in the carbon skeleton) to enable the interception of previously reported compounds that could be converted into cortisone, testosterone, progesterone and cholesterol, the archetypal members of four of the most important steroid families.


Filed under: Literature, Total Synthesis, Woodward Wednesdays | 27,593 views | 16 comments Continue reading

Non-Thermal Microwave Effects: Probably Still Bollocks

Thanks to Brandon and Martyn for pointing out these publications. Be warned, this post turned out seriously long and wordy!


Almost since the dawn of microwave chemistry, which began in the 1980s with people simply putting Erlenmeyer flasks full of reactants in domestic microwaves, chemists have reported all kinds of improvements from heating in this fashion. To name a few of the more common ones, I've heard people claim higher yields, shorter reaction times, cleaner reactions, different selectivities, milder conditions and better overall energy efficiency. Microwave chemistry can be a good thing, and many of these effects are real, widely observed phenomena; the problem is that chemists disagree on their origins. However, comparison between microwave and conventionally heated reactions is fraught with difficulties. One obvious factor is that microwave reactions, at least in the organic chemistry labs that I’ve worked in, are inevitably conducted in sealed tubes, which makes direct comparison to the ‘open’ systems that are typically used in conventional reaction set-ups. Heck, even in open systems, superheating of solvents past their boiling points can occur if nucleation sites are lacking – even two reactions apparently refluxing in the same solvent can be at different temperatures! In fact, simply getting the temperature wrong is probably the major reason for the disparate results obtained when conventional reactions are compared to their microwave ‘equivalents’. This isn't helped by the fact that your average lab microwave only reads the reaction temperature by IR measurements of the surface of the reaction vessel; I’ve heard descriptions of this practice ranging from ‘optimistic’ to ‘demonstrably, hopelessly inaccurate’.


I'm reusing this photo of a microwave just to break up the text a bit!

Because of these (and various other) hard-to-pin-down factors, it’s actually pretty hard to compare conventional and microwave heated reactions, and not everyone has the kit required to do so properly. This has led to numerous claims of so called ‘non-thermal’ or ‘specific’ microwave effects in the literature. These generally explain the apparent benefits of microwave heating by claiming that the microwaves don’t just simply heat the reaction medium (hence ‘non-thermal’), but instead excite (or even stabilise!) particular bonds or intermediates directly, in a fashion distinct from simple macroscopic heating of the reaction mixture. Such claims have been debunked for over a decade, and physical chemists will tell you—at least in the liquid phase—that energy is redistributed amongst the molecules in the reaction vessel on a much shorter timescale than the period of the microwaves used to excite them, making specific heating of one species over another unlikely. Certainly, temperature gradients and macroscopic hotspots may well exist (particularly in viscous/high dielectric/inadequately stirred media), and are readily measured with a temperature probe, but I’ve yet to see credible evidence for the molecular-scale thermal aberrations that are continually reported. It seems that, when investigated in detail, with care to eliminate other factors, claims of non-thermal effects have yet to stand up to scrutiny. In fact, I'm a little baffled as to why we see the continued reporting of results predicated on this phenomenon, with few proper control experiments. I'm not saying that they don't exist, and I'll happily accept their existence when sufficient proof is presented, but I think a lot of rubbish is generally talked on the subject.

One of the most prominent chemists to voice their disbelief in so called ‘non-thermal microwave effects’ is Austrian Professor Oliver Kappe, who's been countering such claims in the literature for at least as long as I’ve been a chemist. He periodically publishes smack-downs of claims of chemistry of this type, most recently in an Angewandte Chemie Essay that appeared just before Christmas (that I blogged about at the time). One of the groups whose work he criticised was that of Gregory Dudley at Florida state university, and things escalated this week with the publication of Dudley's reply to Kappe’s attack, followed swiftly by a further rebuttal by Kappe. The last ‘literature boxing match’ of this type that I can recall was the citalopram back-and-forth in OPRD a couple of years back, covered at the time by Derek over at In The Pipeline, and while the claims made by either side here are not in the same league of dubiosity there’s plenty of thinly veiled frustration and strained civility to enjoy!

Filed under: BRSM Reviews, Current Literature, Serious | 17,010 views | 4 comments Continue reading

And Now For Something Completely Different 8: Summarising Blogs With Wordle

Reading blogs is fun, but find new ones that you'll enjoy can be time consuming. Fortunately, there's a really useful tool to simplify the process: Wordle.[1] Just give it a URL or a block of text, and you get out a 'word cloud' that helpfully illustrates the frequency with which words are used.[2] This can give a useful flavour of what a blog is about! For example, entering the URL of this blog give the following:

'Synthesis' and 'reaction' are the most abundant words, and I think this gives a pretty good idea of what you'll find here on a typical day.If we subject Chemjobber to the same treatment we get the following (you can changes the colours easily):


Clearly, Chemjobber mostly writes about chemicals and percentages! Finally, I thought I'd subject Just Like Cooking to the same, rigorous analysis:

See Arr OHI'm not sure sure what to make of this one; it appears that the most common word recently used by See Arr Oh on his blog is 'really'![3] I wonder how this thing would cope with actual papers?

1. I got this idea by reading this post from Chemically Cultured this morning.

2. Apparently really common words like 'the', 'and' and  'a' are omitted to make things more interesting!

3. I think the program works by just pulling your RSS feed, so it only 'analyses' the most recent posts on a blog.

Filed under: ANFSCD, Fun, Not Chemistry | 13,297 views | 3 comments 3 Comments

(-)-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.

Filed under: Current Literature, Literature, Total Synthesis | 20,035 views | 3 comments Continue reading

Guest Post: Pentacycloanammoxic Acid

Today's guest post is from Siddharth Yadav, an enthusiastic young chemist from somewhere in India. Enjoy!


I found B.R.S.M. when I was searching the web for the synthesis of cubane by Philip Eaton and was much delighted by the way the material was presented and interpreted, although a quick glance through B.R.S.M. showed me that this blog is not actually centred on compounds like cubane but rather on natural compounds (with their asymmetric carbons and stuff). So, I decided to write up a post on a compound that is much strained like the unnatural compounds but is indeed a naturally occurring chemical – pentacycloanammoxic acid.

Fig 1

It all started when a guy named Damste discovered some unique lipids in some rare bacteria known as ‘Anammox’ (derived from Anaerobic Ammonia Oxidation) bacteria. These tiny guys oxidize ammonia and nitrite ions to liberate nitrogen gas and water, but during this conversion they produce hydroxylamine and hydrazine; two very damaging and membrane permeable intermediates! So as an SOS, these guys have a lipid bi-layer made of pentacycloanammoxic acid, which is denser than average membranes (dense enough to keep hydroxylamine and hydrazine at bay; hence avoiding their diffusion into the cytoplasm and preventing cellular damage).

Now to the really interesting part – structural determination of this ‘unique’ lipid gave a rather odd looking architecture! In fact they found two such lipids with slightly different structures. Much to the delight of the synthetic community; E. J. Corey and Vincent Mascitti jumped on the challenge for a total synthesis for pentacycloanammoxic acid. Any guesses why Corey and Mascitti didn’t choose the other acid?

Filed under: Guest Post, Literature, Total Synthesis | 18,221 views | 1 comment Continue reading