B.R.S.M. The road to Tet. Lett. Is paved with good intentions


Maoecrystal V (Part 2: Zakarian/Davies)

Enantioselective Synthesis of (−)-Maoecrystal V by Enantiodetermining C−H Functionalization

Armen Zakarian, Huw M. L. Davies et al.J. Am. Chem. Soc. 2014, 136, 17738 [PDF] [SI] [AZ GROUP] [HMLD GROUP]

DOI: 10.1021/ja510573v

0 minus 1This is the second part of my coverage of the two recently published syntheses of (–)-maoecrystal V, dealing with the route completed jointly by the Davies and Zakarian groups (Part 1, featuring the Thomson group synthesis is here).

That's right, for the first time in three and a half years' blogging I find myself writing about that rarest of publications: the collaborative total synthesis. Also somewhat unusually, the two US-based groups involved in the collaboration are both headed up by professors who originally hail from outside the States.[1]

Sharp eyed readers will note that a large part of this synthesis is adapted from the Zakarian group's previously reported total synthesis of racemic maoecrystal V from back in 2013, and in fact it reuses the same intramolecular Diels–Alder key step to construct the fused furanobicyclo[2.2.2]octane ring system:

I'm reusing this scheme because it took me an extremely long time to draw.

I'm reusing this scheme because it took me an extremely long time to draw.

This well-planned cycloaddition enabled the execution of a concise and efficient diastereoselective route (24 steps @ 1.5% overall yield) that compared quite favorably with the others that had been reported at the time. The 2013 paper finished with the following paragraph (emphasis mine):

"The strategic focus on the central strained tetrahydrofuran ring resulted in an initial disassembly of the lactone ring to a polycyclic enol ether. The enol ether was constructed by an IMDA reaction of a tethered CH2=CH2 equivalent with a 2,4-cyclohexadienone fragment obtained by oxidative dearomatization of a dihydrobenzofuran intermediate. This intermediate, in turn, was prepared by an effective rhodium-catalyzed C−H functionalization reaction which can potentially be modified to access enantioenriched products using chiral rhodium catalysts."

Well it seems that Zakarian group decided to go back and realize this dream, enlisting the help of C–H activation and rhodium experts the Davies group.

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Maoecrystal V (Part 1: Thomson)

Enantioselective Total Synthesis of (−)-Maoecrystal V

Regan J. Thompson et al., J. Am. Chem. Soc. 2014, 136, 17750 [PDF] [SI] [GROUP]

DOI: 10.1021/ja5109694

0 minus 1Maoecrystal V—as the advanced nature of its final letter implies—is one of a great many unusual terpinoids from the Chinese flowing plant Isodon eriocalyx.[1] It possesses a rather intricate and complex structure, a fact illustrated by the two decades that passed between its (first) isolation in 1994 and the successful determination of its structure in 2004—a long period indeed with modern spectroscopic techniques. Its dense, cage-like structure proved a tough nut to crack and another 5 years passed before the deluge of synthetic publications for this target began in 2009. The first total synthesis, reported somewhat controversially by the Yang group the following year, has only seemingly intensified the attention that it has received.

0 - Structure

Maoecrystal V exhibits a heavily modified version of the more common ent-kaurene skeleton.

Interestingly, despite the hugely varied interests and specializations of the groups involved, all five of the successful total syntheses reported to date have constructed the molecule’s prominent bicyclo[2.2.2]octane ring system using the venerable Diels–Alder reaction (often in conjunction with the similarly tried-and-true tactic of oxidative dearomatization to establish the diene). That said, the number of Diels–Alder variants employed is impressive, and you could almost imagine giving a short lecture course on the reaction using nothing but examples from synthetic studies on maoecrystal V. I’ve tried to illustrate the variety below.

All 5 total syntheses to date have used a Diels–Alder reaction to form the molecule's fused bicyclo[2.2.2]octane ring system. The reaction has also featured prominently in approaches by Baran, Trauner, Nicolaou, Chen, Movin, Sorensen and others.[2]

All 5 total syntheses to date have used a Diels–Alder reaction to form the molecule's fused bicyclo[2.2.2]octane ring system. The reaction has also featured prominently in approaches by Baran, Trauner, Nicolaou, Chen, Movin, Sorensen and others.[2]

I’ve long wanted to write something about maocrystal V total synthesis, but I’ve always been too busy around the time that people have completed it to get a blog post out reasonably close to the event. Fortunately, two back-to-back syntheses from the Zakarian and Thomson groups were published in J. Am. Chem. Soc. earlier this month and I’ve now got plenty time to write about both of them, starting with that of the Thomson group in this post.

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Jiadifenolide (Part 2: Dalby/Paterson)

In the four months I spent not writing this post, the Paterson–Dalby synthesis of jiadifenolide was covered over at Synthetic Nature, but as I’d already put a few hours into it I decided to use the Christmas holidays to dust it off and finish it up. Enjoy! —BRSM


Total Synthesis of Jiadifenolide

I. Paterson et al., Angew. Chem. Int. Ed. 2014, 53, 7286–7289 [PDF] [SI] [Group]

DOI: 10.1002/anie.201404224

The second synthesis in this two part series on jiadifenolide comes from the lab of Ian Paterson at Cambridge University in the UK, although it seems that Steven Dalby (now at Merck, Rahway) had enough of an impact on the work to also be named as a corresponding author. Like Sorensen’s approach, the British team also chose an “A-ring first” approach to the target, but instead of dipping into the chiral pool they instead built it up from simple 3-methyl-2-cyclopentenone through some clever use of a couple of highly diastereoselective rearrangements.


No fancy starting materials here!

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Jiadifenolide (Part 1: Sorensen)

Wow, real life really kicked my ass there. I'll try and post a couple of things a month again from now on. Thanks for still reading! —BRSM


An Enantiospecific Synthesis of Jiadifenolide

E. Sorensen et al., Angew. Chem. Int. Ed. 2014, 53, 5332–5335 [PDF] [SI] [Group]

DOI: 10.1002/anie.201402335

Given the massive number of people affected worldwide by neurodegenerative diseases and nerve injuries, it's not surprising that a number of synthetic groups have chosen to focus their research programs on neurotrophic[1] natural products. Of course, it's probably coincidence that aside from their potential uses to society, a number of these compounds seem to also be structurally unique and strikingly intricate molecules.[2] One such example is jiadifenolide, whose dense, caged seco-prezizaane-type structure has already seen 3 total syntheses since its isolation five years ago.


Now, there’s a saying in the field that a synthesis should strive to either be the first, or be the best (or sometimes "last", because no-one else will be able to do a better job). At any rate, it's certainly true that when a target's been made more than a couple of times, those are certainly the ones that people are more likely to remember. In this case, the impressive first synthesis of the target was achieved by Theodorakis and coworkers at UC San Diego back in 2011, but at 25 steps and 1.5% overall yield, it appeared that some in the community felt that the title of "last" was still very much in contention. Indeed, with syntheses from the Sorensen and Dalby/Paterson groups in the last few months, it seems that interest in the jiadifenolide problem is still strong.

I'd initially planned to write about the most recent 2 (or possibly all 3) syntheses in an epic all-in-one comparison blog-post, but in the interests of keeping these musings short and somewhat readable I've decided to break things down a bit. This week's installment will cover Sorenson's awesome synthesis from back in April.

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I originally started writing this post before Christmas but then lost the near-completed version with the death of my laptop. However, I recently found some old backups and decided to finish it up and put it online for your enjoyment. Have fun!---BRSM.

Total Synthesis of (+)-Crotogoudin

S. Breitler and E. M. Carreira*, Angew. Chem., Int. Ed., 2013, 52, 11168; [PDF][SI][GROUP]



As the name implies, crotogoudin is another natural product from the goldmine of bioactive compounds that is the Croton genus of flowering trees. Seeds of these plants have been used for hundreds of years to produce the famous croton oil, a violent emetic and purgative used in early medicine across the globe before anyone realised just how bad it really was. Now, the notorious extract is mostly used as a source of various natural products, a reproducible way of inducing pain and/or irritation in animal experiments and a case in point that things described as 100% natural can still be extremely bad for you. It also serves as the major source of  the important natural product phorbol, and gave its name to crotonic and tiglic acid (and thus crotonaldehyde).[1] Along with a number of other natural products isolated from this genus, crotogoudin displays promising cytotoxic activity, which, coupled with the rare 3,4-seco atisane skeleton, was probably one of the reasons that the Carreira group recently embarked on its total synthesis.

The group envisaged the use of a radical cyclisation as the key step to form the final ring in the natural product, the required radical generated from the reductive opening of a cyclopropyl ester as shown below. The precursor to this reaction could be prepared from the simpler chiral β-hydroxyketone, a building block that could be easily obtained in enantiopure form by enzymatic desymmetrisation of the corresponding meso-diketone. Although the use of enzymes to produce chiral starting materials is by no means a recent development, it remains a fairly uncommon sight in total synthesis,[2] possibly because such reactions are limited to the preparation of a relatively small number of simple building blocks—desymmetrisation works best for diols, diesters and diketones, for example—and it’s not always easy to design efficient routes around these starting materials. Additionally, large amounts of substitution around these motifs is often not well tolerated as the enzyme’s active site is just not able to fit such unnatural substrates in; unlike new catalysts promising implausible substrate scope and generality, enzymes usually have evolved to be very fussy about what molecules they'll accept. Of course, with the advent of synthetic biology, it’s becoming increasingly possible to retool enzymes for our own purposes, and I think that this approach become a lot more popular over the next decade (especially in industry, where it’s more reasonable to spend huge sums of money to find a way of optimising a single step to perfection).[3] Anyway, that’s probably the subject of another blog post, and—at least in the case of this synthesis—Nature's capabilities are adequate, and the reaction is a good fit for the route!


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The Best Thing Ever?

This week’s group meeting’s talk on ‘Strategies in Synthetic Planning’ raised a number of interesting points for discussion, but I wanted to put just one to my readers and the online synthetic community: what’s your favourite total synthesis?

Strangely, the question actually put to the group was a bit less subjective—the word "best" was used, as if there's a single right answer—but I've found that whenever conversations along these lines occur, that there's a wide spectrum of answers. The history of total synthesis—while rather short compared to many branches of science—is still vast, and there’s a lot of great work out there that I'm not sure can (or should) be ranked on some absolute scale. One problem is that there are just too many criteria on which syntheses can be judged (length, creativity, yield, scalability...); although I’ve heard several people liken completing a total synthesis to running a marathon, there’s much more to it than just doing it fast! I remember Rob Stockman introducing Andrew Phillips while chairing a session at a conference a few years ago by comparing the styles of different synthetic chemists to those of different painters, and I think that the analogy is a good one.[1] Looking back across the body of work produced by the synthetic community it’s easy to identify the “old masters”, but few would be prepared to rank them in order of greatness; you’d just as well choose a "best" fruit or colour.[2] Sure, there are now a bunch of metrics for assessing synthesis on everything from atom economy to percentage ideality,[3] but I’m pretty sure that’s not how K. C. Nicolaou decided what to put in his Classics in Total Synthesis series and I think it’ll be a while before we see a really elegant route to a target designed by a computer.

Anyway, that’s probably enough pontification for one blog post, so here are a few of my favourite syntheses and a few that came up in recent conversations—please add yours and your thoughts in the comments!

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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.

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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.

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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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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!

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