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


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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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 | 26,814 views | 1 comment 1 Comment

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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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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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.


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