Strychnofoline
Carreira and Lerchner. Chem. Eur. J., 2006, 12, 32, 8208-8219. DOI: 10.1002/chem.200600957
I must admit that I don’t often read Chemistry – A European Journal, but this months issue has a fantastic total synthesis of Strychnofoline by Eric Erick Carreira. This family of alkaloids have been made by a number of research groups, each with a new approach in the interesting 5,5-spiro subunit, and the Carreira group weigh in with their own methodology for this synthesis.
Their work concerns the formal ring expansion of the cyclopropane shown above using a nucleophilic opening with magnesium iodide to form the Mg-enolate and alkyl iodide. This is then displaced by the imine, allowing a Mannich reaction to compete the cyclisation. The methodology section explains that they can do this in good yield and excellent diastereoselectivity, so they pushed on for the total synthesis.
The synthesis of the three main fragments is very competent but reasonably well known chemistry that I won’t discuss, save for one particularly nice BOC deprotection (deBOCed for the benefit of “ddd“) using mild conditions, and as they state in the paper, byproducts that are volatile:
With this fragment complete, along with the cyclisation partner, the annulation could be completed – and in good yield, receiving the desired product as a single diastereomer in 55% over two steps – quite impressive. They also noted that the loading of MgI2 could be dropped to 0.5 mol without dropping the yield at all.
The impressive diastereoselectivity was reasoned by monitoring the change in d.r. versus pH. In acidic media, the protonated tertiary amine could coordinate the amide, whereas in non-acidic media, there was a converse electrostatic repulsion from the lone pairs.
All in, a really nice synthesis – perhaps I should read CAEJ more often!
(3 votes, average: 3.67 out of 5)
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All in all a rather elegant construction of the core structure. It is impressive to see a single diastereomer formed in the annulation of such a complicated molecule. It’s just a pity that the final Pictet-Spengler proceeds in modest yield (
What with JOC rapidly going down the tubes, Chem. Eur. J. is now getting a large number of good full papers, in the same way that Org. Lett. is getting a lot of the good comms that would previously have gone into JOC.
For a few personal CEJ favourites (methodology rather than total synthesis) from recent years, take a look at:
http://dx.doi.org/10.1002/chem.200401065 (Trost)
http://dx.doi.rg/10.1002/chem.200600174 (Echavarren)
http://dx.doi.org/10.1002/chem.200600034 (Denmark)
I just wish the journal title wasn’t quite so cumbersome…
A beautiful synthesis.! Just a little pity to see that they only get racemic. I suspect that there is maybe an entioselective version of MgI2-mediate ring expansion. The newly-generated chiral centers might be controlled by pre-installed chiral centers on imine parts. It will make synthesis more fascinating. At least it will be interesting to try to see what gonna happen.
dtb: why do you think JOC is going down the tubes? I have my own ideas, but I’d be interested in hearing yours.
Not to be a pain, but I hate it when people don’t spell my name correctly so I’m sure Carreira would prefer Erick, and not Eric. I also don’t think that we will see an enantioselective version of this reaction anytime soon. The reaction is at 80 degrees in THF- high temperature and a coordinating solvent- not the best conditions for keeping a ligand on Mg, or anything else, for that matter.
I’ve truly had an epiphany today… reading Chem: Eur J. all day, and I’ve just been astonished on the work I’ve missed!! I think I need to put more syntheses up from there this week/next week, and try to catch up a little! I’ll have a great paper by Ulrich Koert on the total synthesis of Apoptolidinone tomorrow…
DTB, you are absolutely right with your summary of JOC versus Chem. Eur J. – it’s amazing what’s getting into JOC just now… though I still think that Org Lett is my favourite journal (for now).
Why has everyone had the assumption that the only decent journals have to be ACS?
Well, probably because Wiley does not ask for serious Supp info…
angewanste supp material is a joke…I am not even sure where to find it…Secondly ACS journal a decent b/c tons of research labs are being opened in USA, and guess about UK? They close their chemistry departments…I do not remember exact reference but there were some articles in CEN news…
Does asking for Supporting Info really mean that the journal is “serious”?! LOL Are you aware of the problems with the LaClair paper? Do you know how easy it is to fake data with the panoply of sophisticated programs available?
The ACS journals are simply “fashionable” for the time being. I should recall that Org Lett started out (in 1999) as a fairly average journal and ended up beating the crap out of Tet Lett simply because people started sending their stuff there. The thing with JOC, IMHO, is that surprisingly the journal has lowered its standards. If you browse through the 1980′s JOC numbers, you’ll be astonished at how much good chemistry is in there.
CEJ remains fairly demanding in terms of quality and will not publish Organic stuff unless it’s really good (that’s why so many issues have “nothing of much interest to us”). Same applies to Chem Comm although it seems that nobody reads RSC journals nowadays. It’s all just a big trend…
Back to topic: has anyone read the paper? what about those 25% in the Pictet-Spengler, giving mainly the undesired diastereomer, a few steps from the end of the synthesis? Any thoughts?…..
[...] Strychnofoline [...]
JOC had high standards when Heathcock was editor
“angewanste supp material is a joke…”
?!?
Look up the synthesis of elatenyne (blogged here earlier in the month). Look at the supp. info which is downloadable from the abstract webpage – there is no way anyone can argue that it is not a rigorous piece of work.
Surely anyone (I hope?) that reads the literature on a regular basis takes in Elsevier and RSC journals too? It is a tad narrow minded to only read ASC journals and Angewandte as a means of keeping up to date with the subject.
You only have to look at the names that regularly publish in Tett. Lett for example (Danishefsky/Corey/Barrett in last months issue alone).
TWYI: I doubt it that more than 40% of grad students and post-docs read RSC and Elsevier Journals. I’d even risk putting forth the possibility that, in the US, the number drops further (below 20% IMO).
The proof: our group published 2 papers on the same project this year. One of them was highlighted as a hot paper in Chem Comm (which I think is exceptional since it’s purely synthetic work AND we’re not British LOL). The second one was an Org Lett communication. The Org Lett was already cited twice since it’s out, but people seem to ignore the Chem Comm one although in theory both should be cited in any of the cases mentioned…. rather impressive.
I would challenge Tot. Syn. to post on synthetic work published in Tet Lett and/or RSC journals (OBC seems to be growing to a respectable level, I think). hehe
tet lett should be demolished! How can you publish a scientific work without experimental part? When I browse through the Belstein I never even look at Tett lett ref, since they do not even have a supp part…This is stupid…Also mainly tet lett publications look more like “one page publication from my notebook”. I have to admit that 30 years ago they were better, but not now…
Tett. Lett is good enough for Nobel Laureates in todays day and age but not enough for ddd.
Nice synthesis. You should check the synthesis of surugatoxin by Inoue (tetrahedron vol. 50, no. 9, 2729-2752, 1994).
[...] was an example of this type of chemistry in synthesis, with the completion of Strychnofoline. We covered this beastie back in 2006 – the early days of this [...]
Guys, please! Anyone that has been in the synthesis business for a while can spot the smart work as easily in TL (and there’s plenty there) as in OL, Angew or JACS. Also, key procedures, compound data and even X-ray structures are included in most TL papers.
As for JOC, remember that its hottest section (communications) has gone post-1998, mostly to OL.