B.R.S.M. Help! I'm trapped in a molecule factory!


A Bank Holiday Treat

Update: Just noticed that the PDF isn't looking so great in places, so I've taken it down until I can fix it. In the mean time, please enjoy the DOC file.

I'm off for a long weekend of sea cliff climbing in beautiful southwest England, which means I may not be doing so much blogging this weekend. More things next week, but in the meantime - a special treat!

A few weeks ago I suggested to a wise coworker of mine that he should write something for this site and I'd put it up as a guest blog post. Well, I received an email yesterday from him yesterday and, breathless with excitement, opened the attached file. I'd expected an insightful piece on the future directions of organic synthesis, something in the vein of Dieter Seebach's famous Angew. Chem. article (although with fewer than 500 references), but what I'd been sent was even more exciting. Named Reaction Top Trumps!

Named Reaction Top Trumps 1.0 (56 cards) [PDF][DOC]

Man, I can think of so many uses for these... revision, confusing other commuters on train journeys, maintaining the illusion of thinking about chemistry at tea breaks etc. I think this is an awesome idea (and I can say that, because it wasn't mine in any way, shape or form), and I'm sure people will have as much fun printing them out and passing them round the lab as I have. This is only version 1.0 so the numbers probably need a bit of tweaking and there may be a few mistakes but here you go, world. As far as I can tell, this hasn't been done yet. And remember, you saw it here first!

I'd love to know what people think - corrections, suggestions for new catagories or reactions etc.


Filed under: Fun, Named reactions | 12,155 views | 7 comments 7 Comments

Woodward Wednesdays 1: (+)-cephalosporin C (1966)

This inaugural Woodward Wednesdays post will discuss the  subject of Woodward's 1965 chemistry Nobel Prize lecture - work culminating in the synthesis of (+)-cephalosporin C.[1] It was difficult to choose a synthesis to open the series with, as a lot of Woodward's papers are, quite rightly, considered classics and have been dissected elsewhere. Woodward's synthesis of strychnine, for example, crops up in a number of reviews, has a wikipedia page and is discussed at length in Nicolaou's Classics in Total Synthesis (Chapter 2) as well as T. Hud's Way of Synthesis (pages 803-808) and probably many other places besides; I'm not sure I can add much there that hasn't already been said! Woodward's reserpine synthesis, one of my top five syntheses of all time, is (unfortunately?) also covered in a similarly comprehensive fashion.[2] Strangely, the cephalosporin synthesis remains much less well known, despite containing some excellent chemistry and a few 'Woodwardian' steps.

"Having here this morning the responsibility of delivering a lecture on a topic related to the work - for which the Prize was awarded, I have chosen to present an account of an entirely new and hitherto unreported investigation which, I hope, will illuminate many facets of the spirit of contemporary work in chemical synthesis" - R. B. Woodward, Nobel Prize Lecture, 11 December 1965

So began Woodward's Nobel lecture - in a departure from tradition, for he spoke for the entirety of his lecture solely on his thus far undisclosed work on the synthesis of (+)-cephalosporin C, unpublished until the following year (J. Am. Chem. Soc., 1966, 88, 852), in his characteristically intelligent and articulate manner.

Filed under: Literature, Total Synthesis, Woodward Wednesdays | 60,327 views | 11 comments Continue reading

Projects I’m glad I didn’t work on

Obviously this style of post is borrowed from Derek Lowe's Things I Won't Work With. I'm not the most original person, and this certainly isn't the most original blog.

Hopefully many of you will have now read Baran's axinellamine paper (my take here) - it's an impressive piece of work and worth a few minutes of your time. I've noticed that I keep having the same conversation about it with different people over the last day or two:

BRSM: Have you seen Baran's new axinellamine paper? It's the shit!

Chemist: Yeah, it's pretty cool, but you couldn't pay me to work on that project. Those guys must have spent a lot of time staring off the roof of the Scripps chemistry building.

BRSM: But he's so sexy!

Chemist: I have to go now, I, uh, have a TLC running...

Or variations on that theme. Anyway, I realised that actually: 1. I'm probably inclined to agree, and 2. I find myself thinking this quite a lot. As I told commenter gippgig yesterday, I saw Baran give a talk about this work back in 2009. I remember him describing the silver(ii) picolinate oxidation and saying they had to screen a massive number of oxidants to find this successful reagent. I think he described one of his students as having a 'black tar phase' of 6 months or so, where everything presumably kept degrading when they attempted to install that troublesome hydroxyl. Silver(ii) picolinate obviously wasn't high on the list  of things to try as they had to make it specially, and none of the references they give for its use are later than the early 1970s. Periods of faliure come to everyone who practises chemistry long enough, but when you're pushing the boundaries of what's known, as Baran was here, you can spend months in the lab going nowhere at all.

A couple of other syntheses from this year with similar heroic efforts at optimisation come to mind. I should say now that I think they're both fantastic, but I'm not sure I would have had the dedication and mental fortitude to see them through.

Filed under: Ask the audience, Current Literature, Fun | 46,986 views | 19 comments Continue reading

(+/-)-axinellamines A and B

Update 20/08/11 - Tot. Syn. covers the same paper. Also, check out Tot. Syn. coverage of Baran's original route.

Scalable, Stereocontrolled Total Syntheses of (±)-Axinellamines A and B

Baran et al., J. Am. Chem. Soc., 2011, ASAP; [PDF][SI][GROUP]

DOI: 10.1021/ja206191g

Okay, so this isn't a new synthesis per se as Baran finished his impressive first generation synthesis of these two natural products back in 2008. At the time, this was a real tour de force as they hadn't been made, and are a total pain to draw and handle, let alone actually synthesise. However, as in his cortistatin work, Phil wasn't content to stop at just a first total synthesis, and has apparently spent some time since cleaning up and optimising the route to allow production of decent amounts of material for biological testing. And what a job the group has done! Shown below is the key intermediate used for the axinellamines (as well as previous Baran syntheses of the massadines and palau'amine), which, being a cyclopentane bearing 5 contiguous stereocentres, previously took them 20 steps to make. This paper reports a new pared down route of just 8 steps, all which can be performed on gram scale, which is an amazing achievement for a fragment of this complexity, and presumably will also allow access to larger quantities of the other natural products as well.

Some of the optimised conditions used are fantastically original, betokening the amount of work put into trimming down the route; Zinc mediated Barbier coupling low yielding? Just chuck in some indium! Tricky Pauson-Khand? Add ethylene glycol! Capricious chlorination? Needs more TfNH2! Read on to see how they came up with some of this stuff...

Filed under: Current Literature, Total Synthesis | 44,657 views | 11 comments Continue reading

Announcing: Woodward Wednesdays

It's been suggested that I need a few more (semi-) regular features, and a number of people seem to have enjoyed some of the work from the older literature I've highlighted (my posts on Eaton's synthesis of cubane and Hoffmann's use of TNT are among the most popular I've written). I considered a few possible ways of combining these two and, after chatting to a wise coworker, I have decided to launch Woodward Wednesdays. Basically, I'll post something about work done by R. B. Woodward on roughly one Wednesday a month until you or I get bored. I'm not going to write a long justification of this - the man was a genius and hopefully we can learn something from him.

The inspiration for this series was probably the recent appearance of Woodward's notes on organic superconductors being published in the current issue of tetrahedron (Tet., 2011, 67, 6771-6797) with a wonderful accompanying article in C&En, which just reminded me what a remarkable individual he was, with an enviable breadth of research interests far beyond organic synthesis. Bits of the tetrahedron article are way over my head, but the C&En article is a very enjoyable read. The latter contains a number of recollections from Woodward's son, including this one from his teenage years:

“My father arrived punctually at home at 6:25 every night for dinner. One night we sat down and he said, ‘I’ve had an inspiration. I think I can make a room-temperature superconductor.’ He described how that would be a material that loses no energy as it conducts electricity over large distances and how that would change the world,” Eric remembers. “He rarely would say anything about chemistry, but this day he was particularly inspired.”

Wow, nothing like setting your sights high! From talking to a few physicists I know, I get the impression we're still nowhere near this goal 40 years later. But Woodward gave it serious thought, producing 699 pages (or around 8") of notes on everything from scraps of paper to hotel stationary and napkins, all bearing his characteristic beautiful hand drawn structures.

Another piece on Woodward's involvement with the Woodward Research Institute in Basel, Switzerland and the work done there appeared in Helvetica Chemica Acta back in June, further illustrating the continued interest in the life and work of this amazing chemist (HCA, 2011, 94, 923-946). So, I'm getting on the Woodward bandwagon. First post next Wednesday. Look forward to it!


Filed under: Literature, Woodward Wednesdays | 11,645 views | 4 comments 4 Comments

(–)-N-Methylwelwitindolinone C Isothiocyanate

Update: 13/09/11. I have reworded the introduction considerably as the original version of this paragraph described work by Rawal and coworkers in this area unfairly. Having reread the papers and what I'd written I couldn't leave things as they were. The original text can be found in [5] at the end of the article.

Sorry things have been so quiet around here lately - moving out of the flat I've lived in for the past three years, having no internet and applying for conferences have made blogging tricky. I was a bit worried that someone'd beat me to this as it's such a nice bit of work, and Tot. Syn. did on Sunday, but I'd mostly finished this by then, so here's my take anyway.

Total Synthesis of (–)-N-Methylwelwitindolinone C Isothiocyanate

Garg et al., J. Am. Chem. Soc., 2011, ASAP; [PDF][SI][GROUP]

DOI: 10.1021/ja206538k

There's been a lot of interest in these unusual looking natural products in the past decade with publications from Wood, Trost, Baran, Simpkins, Martin and Rawal all appearing in the literature. Credit for the first total synthesis of a member of this family goes to Rawal and coworkers, who reported a neat route to racemic N-methylwelwitindolinone D isonitrile back in March of this year, unfortunately before I'd started this blog.[1,2] This paper by Garg describes the first synthesis of N-methylwelwitindolinone C isothiocyanate to date, using a chiral pool based approach from (S)-carvone, and also contains lots of interesting chemistry.

Filed under: Current Literature, Total Synthesis | 12,161 views | 3 comments Continue reading

This week in alkaloids part 1: (-)-Leuconicine A and B

Two nice alkaloid syntheses published last week; I'm not sure which I like more, so I'll cover them both. Look out for the second one in part two in a day or so. Also, I don't have any internet access at home for the next three weeks, so posts this month may be less well referenced, or just less existent.


Total Synthesis of (-)-Leuconicine A and B

Andrade et al., Org. Lett., 2011, ASAP; [PDF] [SI] [GROUP]

DOI: 10.1021/ol202056w

The leuconicines, like their more popular brethren strychnine and akuammicine, are members of the family of Strychnos alkaloids, and bear a strong resemblance to these natural products. They've got two fewer stereocentres and one less ring than strychnine itself, but they still look pretty formidable to me. The Andrade group accomplished syntheses of (±)-strychnine and (±)-akuammicine last year using a neat one pot spirocyclisation-Baylis-Hillman sequence to add the C and E rings to the indole core, but this paper is the first report of the use of their methodology to access enantioenriched targets.[1]

Filed under: Current Literature, Total Synthesis | 19,808 views | 9 comments Continue reading

Top 5 Syntheses of July 2011

I'm going to try and make this a regular thing. Top 5 for May/June can be found here. Please stop by in the comments and point out any good ones I've missed (or rubbish the ones I've picked). As before, these aren't in any particular order, because that would be silly.

Total Synthesis of (-)-Histrionicotoxin

Fukuyama et al., Org. Lett., 2011, ASAP; [PDF] [SI] [GROUP]

DOI: 10.1021/ol2018032

Like the erythromycins from the previous post, the histrionicotoxin alkaloids have a rich and storied synthetic history (which you can get a flavour of in Rob Stockman's review in Nat. Prod. Rep., 2007, 24, 298-326). I'm often left a little unenthused by Fukuyama syntheses (a friend of mine described his tactics as 'the world war one approach to synthesis') but there's some interesting chemistry in this paper. The way in which chiral information is moved about the molecule is quite cool: asymmetry is first introduced by preparation of a chiral propargylic alcohol using the Noyori reduction, then transferred to a chiral silyl allene. This is then finally alkylated to generate an all carbon quaternary centre that allows a long sequence of reactions to be carried out under substrate control. There's also a retro-Brook rearrangement, an asymmetric propargylation and some dienyne metathesis to keep things interesting.

Filed under: Current Literature, Top 5 | 15,773 views | 4 comments Continue reading