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


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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DiRocco’s Electrochemical Series of Photocatalysts

So, if you've been reading the chemical literature much in the last 5 years or so, you've probably noticed the ongoing explosion of papers on the topic of Photoredox chemistry. It seems that organic chemists in the field have been borrowing increasingly bizarre transition metal complexes from the electroluminescence, photophysical and materials literature for some time now, and keeping track of them all is a real pain. I mean, how many people can draw from memory the structure of that Bernhard Ir(4',6'-dF-5-CF3-ppy)2(4,4'-dtbbpy)PF6 catalyst from the latest MacMillan group paper? Don't look at me like that—it's commercially available from Aldrich.[1] And you can remember its oxidation potential, right? Versus the Saturated Calomel Electrode? In the Ir(iii)* excited state and as Ir(iv) after reductive quenching?

Well, if this isn't your area of expertise, help is at hand. A friend recently emailed me this handy series of common photocatalysts apparently assembled by Daniel DiRocco at Merck,[2] which I thought it would be worth sharing more widely. Hopefully DiRocco won't mind – it's pretty darn useful and I've seen it a couple of places online already.

DiRocco Electrochemical Series

Electrochemical Series compiled by Daniel DiRocco of Merck. Click for large PNG image.*

*Alternatively, here's a better quality version as a PDF. I hear it looks nice printed to A3 if you can manage it.


1. You'll probably want to make it, though, as it's not far off $1/mg.

2. You probably saw him most recently as lead author on that awesome Merck photoredox-Minisci heterocycle alkylation paper in Angewandte earlier in the year: Daniel A. DiRocco et al.Angew. Chem. Int. Ed. 2014, 53, 4802 –4806.

Filed under: Literature | 9,027 views | 1 comment 1 Comment

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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And Now For Something Completely Different 10: Don’t Buy Your Undecacycloicosane From Sigma-Aldrich

A funny thing happened the other day: I went onto the Sigma-Aldrich website to order some undecacyclo[,11).0(3,6).0(4,9).0(5,8).0(7,10).0(13,16).0(14,19).0(15,18).0(17,20)]icosane, and was amused to notice a rather M. C. Escher-like rendering of the structure:


Looking for alternative suppliers on Chemspider, I noticed it too had depicted the molecule in quite a strange way (although interestingly their 3D view of the molecule is spot on):

4788435 I guess that both these structures were probably drawn by computers, so I decided to see how Chemdraw's name-to-structure function would deal with such a complicated case. I was certain that the name would either be rejected or that some kind of tortuous hydrocarbon Gordian knot would result, but to my surprise Chemdraw emerged as the clear winner in this bizarre and impromptu competition:

icosane 2

More serious posts soon!

Filed under: ANFSCD, Fun | 14,576 views | 6 comments 6 Comments

Those hard to find references

In a recent group meeting the old Woodward aphorism came out again: "the only model system worth using is the enantiomer", which led to a scrabble afterwards to find when and where he'd actually said it. To my annoyance, I knew I'd undertaken the same search at the start of my PhD—and had all but given up until someone on Twitter helped me out. However, as I'd unfortunately lost the reference with the death of my old laptop, I again spent a considerable amount of time tracking it down again, for at least the second or third time in my life. Thus, as a favor to my future self—and in case anyone else is interested—I'm documenting the origins of the phrase here.

The quote itself most likely comes from a remark made by Woodward during a lecture he gave in London in 1968 on his progress towards the synthesis of vitamin B12. I'm probably not going  to do a Woodward Wednesdays post on the B12 synthesis any time soon for reasons of time (as much as anything), but to give some context to the quote, a partial retrosynthesis is shown below. Woodward disconnected the molecule into eastern (B/C) and western domains (A/D), and set out to synthesise the western domain from the tricyclic indoline shown. Although B12 would be a daunting molecule to synthesis even diastereoselectively today, Woodward's aim was in fact to devise a route to the target in its natural,  enantioenriched form—which in the 1960s meant either a dip in the chiral pool, or a resolution. Although the group was able to develop a route to either enantiomer of the slightly later intermediate XXXVII, starting from (+)- or (-)-camphor, for the final sequence they found that it was in fact more efficient to instead use a resolution of the earlier indoline, accomplished by derivatisation with (S)-α-phenylethyl isocyanate and separation of the resulting diastereomers.


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Chemistry World: Organic Matter

Organic Matter_beige_300

Fantastic artwork from the RSC

Paul Dochety's blog at Totallysynthetic.com was a massive inspiration to me in my early days as a blogger, showing me that there was enough of a synthetic organic chemistry community online to make writing seemingly very esoteric posts on a small, specialised sub-field rewarding and worthwhile. A couple of years ago, Paul moved away from the online community, but continued his excellent monthly column for the RSC's Chemistry World (think British C&EN, if you're not familiar with it). However, his tenure there has recently also come to an end, and to try to fill the organic-shaped hole in its opinion pages the RSC has commisioned a new column – Organic Matter. As you've probably heard already, authorship will be shared between myself, Karl Collins (of A Retrosynthetic Life) and the legendary Chemjobber (anyone who needs a link to CJ should really rethink their blog-reading priorities). Karl was up first in the January issue, with this piece on some recent C-H oxidation chemistry, and I'm pleased to announce that my contribution to January's issue is now available online for free here. I'm super excited to be given this opportunity to be a part of the Chemistry World team and share authorship with two awesome chemists—and to see what Chemjobber gets up to in March!

Finally, I would like to wish Paul all the best; although unfortunately we've never made it past two degrees of separation, if I'd never read  Tot. Syn. I would not have started this blog, and would never have considered writing or publishing as possible career moves. Thanks, man!


Filed under: Total Synthesis | 26,139 views | 1 comment 1 Comment

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!

Filed under: Ask the audience, Current Literature | 55,147 views | 25 comments Continue reading