B.R.S.M. To strive, to seek, to find and not to give a yield


(-)-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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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?

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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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Woodward Wednesday 6: Reserpine (Part 2/2)

Okay, this second post is a lot later and a fair bit shorter than I had hoped it would be, but it's been a crazy and not entirely pleasant month. Enjoy! 


In the previous Woodward Wednesday post I showed you guys the first half of Woodward's epic total synthesis of the popular bioactive natural product reserpine. If you didn't catch that when it came out, go and check it out, because I'm just going to carry straight on where it left off. Here goes!

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Woodward Wednesdays 6: Reserpine (Part 1/2)

I'm going to do this one in two parts, in the hope that posting the first half now will force me to find time to write the second part at the weekend. Also, it'll hopefully make for shorter and more readable posts. Enjoy!


Reserpine is an indole alkaloid isolated in 1952 from the extract of Rauwolfia sepentina or ‘Indian snake root’, a popular plant in traditional Indian medicine used as a sedative and antipyretic, and reportedly taken by Mahatma Gandhi himself. It's also enjoyed some attention from Western doctors as an antihypertensive and antipsychotic, notably being the first ever drug to successfully demonstrate antidepressant properties in a randomized placebo-controlled trial (although it’s rarely used nowadays because of its numerous side effects, which are as varied as they are unpleasant). Its structure was solved in just 3 years (a remarkably short period for the pre-NMR era) and, when it was finally reported in the summer of 1955, Woodward immediately set to work. By the end of 1956, just a year later, he was able to report a  detailed series of studies culminating in the landmark first total synthesis of the natural product, again pushing forward the complexity limit at which synthetic chemists could operate. In the years that followed, reserpine became a classic target, worked on by some of the greatest chemists of the past 50 years.[1] In fact, it remains a popular molecule to this day, as indicated by a new total synthesis reported just a month or so ago by Jacobsen and co-workers, (Org. Lett., 2013, 3, 706).

Although Woodward’s synthesis of this target, supposedly his personal favourite of all those he masterminded, has been discussed in just about every book to be written on the history of total synthesis, I can’t resist the temptation of writing my own summary of it any longer, so here goes.

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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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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.

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Mulvember 3: Lycoflexine

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.[1] 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.



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Mulvember 2: Echinopines A and B

Although there have been a couple of interesting syntheses this week, I'm still very busy so I'm going to write about another Mulzer synthesis from my talk. See my previous post for the background to this tribute.


Since their fairly recent isolation in 2008 the echinopine sesquiterpenes have proved quite popular targets for total synthesis. In fact, four rather different total syntheses have been reported since their unusual and compact molecular architectures first graced the literature. The first of these was that of Johann Mulzer, published just a year after their isolation, in which both natural products were synthesised in near enantiopure form (starting from cyclooctadiene!) and their absolute configurations were confirmed for the first time.[1]

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Mulvember 1: Introduction and Penifulvin A

Like many research groups, the one I’m in does weekly literature talks so people get a bit of practice with powerpoint and public speaking. Because excessive freedom can be a bit daunting, although people are free to choose the topic of their own talk it has to fit in with a particular theme, which, at the moment, is living Germanic chemists. In this vein, last month I wrote and gave a talk on the life and work of Johann Mulzer. Now, as I've been a bit busy lately, and the literature has been a bit lacking in interesting total syntheses, I've decided to rehash my talk as a series of blog posts. On the upside, this should mean more posts for you guys and less hassle for me (as I've already drawn everything in ChemDraw). Also, although I didn't know this when I wrote the talk, it seems that Mulzer is finally winding down and I think he deserves a bit of send-off. I, for one, have learnt a lot from reading his papers over the past few years.

From a recent Angewandte paper.

Unfortunately, most of the syntheses that I covered in my talk are already pretty well known, and many of them have also already been covered on Totally Synthetic at one time or other. Still, if you missed somehow missed reading about them there or prefer my more rambling style then read on!

Incidentally, if you’re wondering what the German text on the slide is all about, it’s taken from the group website and is usually rendered (non-literally) in English as ‘no battle plan survives contact with the enemy’, something all chemists who have worked in total synthesis know well![1]

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