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.
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!
Reading blogs is fun, but find new ones that you'll enjoy can be time consuming. Fortunately, there's a really useful tool to simplify the process: Wordle. Just give it a URL or a block of text, and you get out a 'word cloud' that helpfully illustrates the frequency with which words are used. This can give a useful flavour of what a blog is about! For example, entering the URL of this blog give the following:
'Synthesis' and 'reaction' are the most abundant words, and I think this gives a pretty good idea of what you'll find here on a typical day.If we subject Chemjobber to the same treatment we get the following (you can changes the colours easily):
1. I got this idea by reading this post from Chemically Cultured this morning.
2. Apparently really common words like 'the', 'and' and 'a' are omitted to make things more interesting!
3. I think the program works by just pulling your RSS feed, so it only 'analyses' the most recent posts on a blog.
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'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
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. 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.
I had completely forgotten that today was my 2nd anniversary as a blogger until my girlfriend sent me this photo a bit earlier:
Apparently, as there were no number 2 candles (cf. last year), she instead made two cakes (possibly setting a dangerous precedent in the process!).
I can't believe that it's that time again – I've now been talking to the internet for two whole years! It's been really busy period for me in real life but in contrast a quieter one for BRSM. Although I've written 5 papers, I've only managed 44 blog posts in the past 12 months, which is unfortunately quite a bit short of the one-a-week target that I try to aim for. How people like Derek, CJ and See Arr Oh write so much decent stuff, I don't know!
I still think of this a total synthesis blog—after all, it began with me reading a Totally Synthetic post one day and thinking "I could do that!"–but it seems that the posts that get the most hits tend to be the ones based on random observations or conversations with friends. For example, here are my top posts of 2012-13 (In descending order of pageviews):
1. Where Did It All Go Wrong? – I probably wrote this in about 10 mins after glimpsing a ridiculously misassigned structure in J. Nat. Prod., but a link from Derek probably helped this to the top.
2. Drugs I Shan’t Be Taking This Week 1: 2,4-Dinitrophenol – I really have no idea why people keep reading this. It must be high on some Google search!
3. And Now For Something Completely Different 4: Wikipedia Fun – Based on the chance tea time observation that my PhD supervisor is outranked on Google by a number of golfers and DJs with the same name. I think that occasional commenter Martyn (of gyrofaunal fame) did most of the legwork for this one.
4. Superlatives 3: The Longest Polyene – A friend emailed me a photo (thanks, James!), which I posted.
5. A Birthday Surprise for K. C. Nicolaou – Inspired by a drunken conversation in a pub.
Not a single scheme in sight – I am constantly surprised by what you guys will read!
While I'm reminiscing, I'd like to thank this year's three guest authors: my long-time benefactor DrFreddy, who promised me a post 'about teenage love, the Greenwich Observatory and TNT' that he surprisingly was able to deliver; Brandon from ChemTips, who wrote about Hanessian's recent full paper on pactamycin; and Siddharth Yadav, whose post on pentacycloanammoxic acid will be up later in the week. Conversely, I also wrote my first ever guest post, which attempted to give some practical advice for the Birch reduction, over at ChemTips. I also contributed a little bit to Blog Syn, by mostly failing to reproduce other people's work. I hope that we'll find a way to get that site going again!
I'd also really like to thank everyone who has gave me advice for my imminent move to the US whether it was in person, on twitter, or via the recent mini-carnival that Jess and Freda organised. Hopefully I'll catch up with some of you one day!
Finally, thank you all for reading and commenting! I don't know what a couple of years in the US will do to my ability to spend hours messing around on the internet, but hopefully I'll keep this thing up for another year!
1. This claim would be a lot less impressive if I told you where we sent them...
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)
Update 03/04/2013: Chemjobber made a few!
Thanks to a recent xkcd comic I've just discovered a wonderfully concise new way to communicate – non-overlapping Venn Diagrams:
For example, here's a statement my boss made last week expounded thus:
I quite enjoy the contradiction between the visual simplicity of displaying information in this way and the fact that it's actually a lot more effort to construct these than write a sentence that conveys the same information, as well as their highly inefficient use of space. There's just something kind of amusing about them. Or I think so, anyway.
Give it a go, and share any good (chemistry related) ones you can think of in the comments. I've just put one in a talk I'm writing on acyclic stereocontrol for a group meeting; I'll let you know how that goes down next week!
Most of the credit for this one goes to occasional commenter Martyn!
Is it just me, or will green chemistry journals publish anything these days? For example, check out this paper published this morning in the Journal of Sustainable Agitation:
Unpowered Mechanical Stirring of Reaction Media Using Renewable Stirring Fish (RSFs). [PDF]
I couldn't make this stuff up!