Thanks to a co-worker, I recently became aware of a rather unique aside published within Thomas Tidewell's somewhat dated Tetrahedron Report on the Addition Reactions of Ketenes (Tetrahedron, 1986, 42, 2587–1613). Found spread over pages 2587–2588 is the following:
It turns out that this note originates from a satirical piece in Chemistry in Britain (Chem. Br., 1965, 1, 230) published some 20 years previously. As far as I can tell, the root cause was an unfortunate typo in a Chemical Abstracts entry (Chem. Abst., 1965, 62,1561d) report from Paris on the discovery of a new chemical species—namely "O-Silylated Vinyl Ketene Animals"—by K. Vijayakumaran. If only such errors were uncommon enough (and chemists good natured enough) for this kind of banter in the literature of today! Have a good weekend!
R. B. Woodward et al., J. Am. Chem. Soc., 1952, 74, 4223 [PDF] (Full paper)
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.
Total Synthesis of (–)-Nakadomarin A
At 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. It might be a little dated now:
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. 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.
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.
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?
I don't like to apologise too much for things I do (or more often don't do) on here, because, well... it's not like you pay me anything. That said, I am sorry things have been so quiet around here for the last couple of months. It's been a hectic end to my postdoc, but I'm able to kick back for a couple of weeks at least before I head over to the USA. I'll try and write a few posts before then. And after. In the meantime, here's a talk I wrote for a group meeting at the start of the month on the topic of Felkin Ahn selectivity. We've been revising 'basic' topics, and I was amazed how much I've forgotten Maybe this'll be useful to someone.
Yes, I did steal that image from Dave Evans' notes...
Here it is: Substrate Control in Acyclic Systems BRSM (2 mb)
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. 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.
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.
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!
On Monday, See Arr Oh over at Just Like Cooking posted on this non-obvious Diels-Alder reaction recently published by the Vanderwal group, suggesting that it'd make good problem session fodder. And I agree:
Fortunately, this tied in perfectly with my plans to run our group problem session next week on a pericyclic theme and so it was duly incorporated. If you're interested in what else featured, I also included a question on the origin of the metastability of Dewar Benzene (which I've blogged about before).
After a few easier questions I finished up by asking people to suggest a mechanism for this interesting sequence published a few years back.
Although it's been a while I do intend to do at least one full size Woodward Wednesday post this month. In the mean time here's a short (but important) synthesis that you may not know about.
Who do you think was the first person to publish the preparation of tert-Butyllithium? Some big shot organometallic or inorganic chemist? Not so much. As far as I can tell it was none other than legendary organic chemist R. B. Woodward (J. Am. Chem. Soc., 1941, 63, 3229)! Many before tried and failed, and indeed Woodward noted that the the reaction between lithium and tert-butyl chloride was quite slow, although he discovered that it was efficiently catalysed by a few mole percent of magnesium. Eventually, the reaction could be performed using just lithium, providing it was finely enough divided. This so-called 'lithium sand' was prepared using a classic piece of kit invented by a fellow Harvard chemist: the Hershberg Wire Stirrer. This allowed molten lithium (in mineral oil at 250 degrees) to be whipped up into fine pieces. The mixture could then be cooled, the oil washed off and the lithium quickly used before it had a chance to react with the nitrogen atmosphere used to exclude air. You might ask why Woodward spent time fiddling around with such a dangerous reagent that appeared to defy all attempts to force it into existence. As best as I can tell, the answer was sheer curiosity; not so much regarding the substance itself, but to see if it could be used to prepare the elusive tri-tert-butyl carbinol. Alas, the only reaction observed with hexamethylacetone was reduction. Still, despite recent bad press, tert-BuLi remains a very useful reagent, and has helped me out of a tight synthetic spot on a few occasions.
1. I'll probably do reserpine next, but I'm not too sure what to do after that. Please leave suggestions in the comments!
2. Although, by Woodward's own admission, a couple of papers by the father of organometallic chemistry Henry Gilman from the previous year do imply that tert-BuLi was successfully prepared and used.