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



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!


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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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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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(-)-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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