B.R.S.M. All this happened, more or less.

13Feb/144

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.

B12

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30Aug/134

And Now For Something Completely Different 9: Typographical Mistakes Of Yesteryear

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:

Aminals

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!

Filed under: ANFSCD, Fun, Literature | 12,008 views | 4 comments 4 Comments
16Jul/1316

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.

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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.

1

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16Jun/133

(-)-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]

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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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13Jun/132

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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23May/133

I’m Unemployed And It’s Awesome

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.

Slide1

Yes, I did steal that image from Dave Evans' notes...

Here it is: Substrate Control in Acyclic Systems BRSM (2 mb)

Filed under: Literature, Not Chemistry | 8,070 views | 3 comments 3 Comments
2Dec/124

Mulvember 3: Lycoflexine

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.[1] 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.

 

 

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18Nov/125

Mulvember 2: Echinopines A and B

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.[1]

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5Nov/126

Mulvember 1: Introduction and Penifulvin A

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![1]

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20Oct/123

I’ll see your Diels-Alder and raise you one 1,3-dipolar cycloaddition

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.


Have a think and then read on for a possible answer!

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