Complanadine A part I
Sarpong, Fischer. JACS, 2010, 132, 5926 DOI: 10.1021/ja101893b. 
It’s quite hard to explain the phenomenon of simultaneous publication to people outside of chemistry, ’cause it simply isn’t easy to rationalise. This is now twice in as many months, as Englerin A took my fancy in this month’s Chemistry World. I’ve never been in the situation of working on a target with rival groups bearing down on me, but it must be quite punishing (I took the slightly easier option of working on a target that 1. had been made >30 times and 2. had it’s first synthesis in the 1960s…). The Sarpong and Siegel groups made it to JACS within days of each other, but the ribbon goes to the Sarpong group, so I’m covering their efforts first. Both syntheses show some similarity – the dimeric nature of the target almost requires this – but this aside, the routes are rather different. Lets see how the hold-up together…
Sarpong starts with the good stuff; a pretty remarkable cascade, starting with perchloric acid (thanks for the correction!), which hydrolyses the enamine-type system to provide a ketone which reacts as its enol tautomer. They then add a protected cyclohexenone (6 step literature synthesis), which is deprotected in-situ, forming the corresponding imine which goes on to react with the enol. A further reaction with the imine follows, with the cascade finally terminating with an enamide formation, completing two rings and the bulk of the Complanidine monomer, N-desmethyl ?-obscurine.
The dimerisation of this molecule is rather neat. Treatment of the 3,4-dihydropyridinone with lead acetate results in an oxidation to the pyridinone; a new reaction to me, but not particularly surprising. I wonder if one could substituted that nasty lead for a bit of hypervalent iodine – perhaps a little BAIB could do that oxidation. Anyway, it gets them to the next step in good yield, ready for triflation of the amide. This provides a neat handle for palladium chemistry, but they need a partner for that reaction. This was done easily – by reducing half of their material to the pyridine, and borylating in the 3-position using a little iridium catalysis and boron pinicolate (67% over two steps).
Coupling of the two halves was no problem – including the final deprotection, the finished the synthesis in a 42% yield. Very well executed.
(No Ratings Yet)
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If you read the C&EN news article on these syntheses you’ll see that they weren’t published within a few days of each other but rather back to back. This was coordinated by the authors themselves….
http://pubs.acs.org/cen/news/88/i17/8817notw9.html?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+cen_latestnews+%28Chemical+%26+Engineering+News%3A+Latest+News%29
Good to see a new synthesis up. I was getting a tad worried =D
Okay, considering the author of this publication I posted a question online people might be interested in:
Check it out
admittedly it’s a short list but you can only fit 5 possible answers so if there’s anyone you think should be on there that isn’t you’ll have to just respond to this thread.
I’m not saying he is the best synthetic organic chemist under 40, but I think he should definitely be on the list:
Mohammad Movassaghi
I agree!
I agree too.
Can anyone provide a reasonable mechanism for the first step here?
The first reagent is perchloric acid, not bleach (sodium hypochlorite). I believe the perchloric acid is simply functioning as an aqueous acid, first protonating the C-C double bond. The tertiary carbocation is stabilized via resonance with the amide nitrogen lone pairs. Water can then attack this carbocation. Protonation of the amide and its displacement by the lone pairs of the hydroxyl group yield the product.
See enamine hydrolysis
So “cleaves the amide bond oxidatively” is pretty accurate, apart from the fact that it’s not the amide bond which is cleaved, and it’s not oxidative…
Yeah. Oops… I think I’m getting rusty – I should blog more often anyway!
Thanks, the hole oxidative clevage thing really confused me when in reality it was a simple hydrolisis.
Don’t know about lactams, but Nicolaou published work using IBX to make fully saturated carbonyls a,b-unsaturated.
Tot Syn, I am disappointed that you left out the other synthesis of Complanadine A and chose to blog Sarpong’s Synthesis. The whole synthesis is concise and executed well, but tell me where is the novelty? The cascade reaction in the first scheme has been reported by Schumann before leading to the same tricyclic intermediate in his Lycopodine synthesis. Sarpong just followed that prep to make that tricyclic intermediate (Carter has also made the same tricyclic intermediate but using a different route in his synthesis of Lycopodine). I agree, that the last 4 steps are are novel but if you happen to use scifinder you will get atleast 3-4 hits for making pyridine 3-boronic acid from pyridine. No surprises, authors chose to use one such prep.
No doubt, this is a very efficient synthesis. This is also the first time, I have seen someone copy earlier published chemistry to make 75% of their molecule and still get published in JACS.
P.S – I generally admire Sarpong’s research.
I quote myself: ‘…ribbon goes to the Sarpong group, so I’m covering their efforts first…’.
Calm down! I’ve read and drawn structures for the Siegel synthesis – I’ll have it online fairly soon (though I am best-manning a wedding this weekend, so I’m kinda busy).
I’ll beg to differ on your criticism of pyridine-3-boronic acids made via the relatively recent route of Ir-catalysed C-H borylation. This is something that I (and hopefully, some colleagues from ‘the community’ as well…) will consider a functionalized scaffold. Therefore, it is relevant for total synthesis people like Sarpong to claim its novelty, since it worked in more than decent yield (67% over 2 steps).
IBX doesn’t work with lactams. There is however one way you can concert a lactam to an a,b unsaturated lactam. In this protocol, lactam first converted to silyl amidate by treatment with TMSOTf and base followed by the oxidation step using an one electron oxidation like DDQ or phenyl diselenide.
Thanks Paul. I appreciate the effort you put in this blog.
This synthesis is amamzing, good work Paul. Bullet Bullet GUNSHOT!!!
All known chemistry methods and strategy.
this is excellent synthesis by Sarpong from strategy stanpoint. For good synthesis people, I think Baran first, Movassaghi, Sarpon, Zakarian, Vanderwall, for now in US. Europe has Gaunt and Daren Dixon. In US, Baran and Movasaghi started first, so I think Sarpon especially will catch them soon.what do you think?
I think this is the most cliche’d stupid argument we, as scientists, can have
WHO CARES!
This is not a “who cares about Total Synthesis as a field” point, but a “who cares about the PI’s “TMZ” status” in this field…what a strange conversation to have
Exactly. Second this
Tot. Synth. – in the header, structure on the right is incorrect (bipyridyl connectivity)
At the risk of being shot down…..has anyone else noticed that Ryan Shenvi is joining Scripps as an assistant professor? I’d expect big things from him in a few years.
Whilst not as some are suggesting an entirely novel approach I would suggest that the benefit of this communication is not the total synthesis but the potential for constructing analogues of the parent. The compound has potential application in alzheimers and a diverse set of analogues would be the first step in establishing a SAR.
Just saw that Shenvi took up that position!
That’s gotta be intense. I just wonder though, what’s he going to do that’s different?
Christ, let a kid even get ONE GRAD STUDENT, before we start “wondering what he is going to do that is different”
My gosh we are a cannibalistic lot aren’t we.
All I am saying is that I’d like to see how far the apple falls from the tree. No need to get defensive.
Calm down there, firecracker.
The guy was just wondering what the future has in store. If anyone’s making for a hostile environment here, it’s you.
For Christ Sake!
Does it really matter?
The old ‘the circle is complete’ favorite son of a favorite son talk is a bore no matter who brings it up!
Sarpong’s synthesis is very old-fashioned, even the regioselective borylation step. It’s been known from the work of Miyaura and M.R.Smith III that the borylation on the pyridine ring always occures regioselectivly at position 3. Therefore, there’s no novelty in here. However, the synthesis is short, and the credit should be given to him for a nice way toward these alkaloids. On the other hand, Siegel’s key step has also been known for a while, yet it a nice way to apply old and forgotten methods in the synthesis. Both are good and am looking forward to seeing the Siegel’s route!
Speaking of acetoxy iodobenzene (or PhIOTFA2), can anyone tell me or show me where to find the reduction potentials of these organic oxidants? I am looking around but have yet to find them published. Maybe I am just not looking in the right place…
Or you just found a great and useful research project.
check here for some potentials:
http://www3.interscience.wiley.com/journal/113384973/abstract
–1.53 V vs Fc/Fc+ (solvent?)
A negative redox potential for an oxidant? Color me skeptical …
(For instance, the standard redox potential for O2 is +1.21 V vs. NHE – or about +0.6 V vs. Fc/Fc+)
I see Andy Phillips is on the move
to Yale
http://www.chem.yale.edu
Nice! Good for them. That place is really looking strong now.
So how would you folks rank Yale Chemistry now compared with the likes of Harvard, Scripps, Stanford………
That guy is getting very known – good luck to him! He came from New Zeland and spent two years in the Wipf group in Pittsburgh. He’s doing a great move and hopefully the right one! Good luck Andy and have a nice move!
JS,
since the Fc/Fc+ was used as a standard, you don’t be scared of having negative value for the redox-potential! Do simple calculation and there you go.
@Matt’s Chair: Scripps best then Stanford, Yale, Harvard, MIT, CalTech are all pretty much equal.
@ S Cripps: Scripps is a good school, however, students are not better than at Harvard, MIT, Yale, Stanford, CalTech!