BE-43472B
Nicolaou, Lim, Becker. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200900058. 
Huh; you wait months for a Nicolaou synthesis, and then two come at once! This little beastie and sporolide B dropped in Angewandte on consecutive days, both represented by abstracts drawn in the now familiar crayon-o-vision styling of La Jolla’s most-prolific chemist and photoshop abuser. Seriously, check this stuff out – this is on his home page! The last time I saw anything like this I’d been over-doing both the ether and the geocities…
Of course, all this wouldn’t be half as ridiculous if the man wasn’t such an awesome chemist. Both these new syntheses show that he’s definitely still got it, with BE-43472B demonstrating impressive control of Diels-Alder chemistry. However, before we get into the synthesis, a quick look at the abstract:
…because aromatic rings are orange, obviously.
Anyway, the synthesis begins with a fairly pedestrian synthesis of the two coupling partners for the cycloaddition. The smaller, chiral fragment gains its asymmetry from the chiral pool, in this case lactic acid. As it happens, it’s the unnatural enantiomer that is required for this synthesis, but KC didn’t know this at the start, so actually did the synthesis first with the cheaper enantiomer, and then again with the more exotic. Nice to be sure… The synthesis of the aromatic fragment is actually quite sweet, but there’s nothing to get too excited about. I did like their installation of the aryl stannane, though – they used a fused cyclohexanone as SM, did a double α-bromination and then elimination to give the ortho bromo phenol (which was stannylated) in the end.
Taking both starting materials up in DCM, and heating to a rather toastie 85 °C in a sealed tube resulted in a highly controlled cycloaddition, which would appear to generate a single stereoisomer of the initial product. KC suggests that the control results from several parameters, including an intermolecular hydrogen bond, and 1,3-allylic strain. The γ-hydroxy ketone is then perfectly set to form the THF-hemiacetal, the initial terminus of this cascade sequence. A bit of NMR jiggery-pokery (a technical term like ROESY, but more diffuse) led them to believe that it is at this point that epimerisation of the α-keto position occurs. This is (probably) inconsequential, as this stereocenter is destroyed later in the synthesis, but it worries me a little, as this position could influence the synthesis later on.
It was then time to move to a higher-boiling solvent – toluene in this case. (I wonder what happened when they started out with toluene…) A tickle with the bunsen resulted in internal ketalisation (quite a strained system to the naked-eye, but not so after modelling). This process removes aromaticity from the system, so the expected resumption occurs via loss of methanol, and completion of the cascade. The yield quoted in the SI is 98%, with no qualifiers, but in the main text, Nicolaou states that the yield is based upon 5, or in other words upon the SM. Hrm… The product of this process is also easily epimerisable…
Completion of the synthesis didn’t tax the group at all; first up was installation of the tertiary alcohol by epoxidation of the silyl-enol-ether. Desilylation gave them the desired hydroxyl and an extraneous ketone which was removed by dithiane formation and reduction. A second epoxidation was used to install a further hydroxyl, rearranging this intermediate into the natural product using a mercury-lamp – a reaction I’ve not seen in a very long time, and a rather nice way to end an impressive synthesis.
(20 votes, average: 4.05 out of 5)
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I am the only person I know who actually wants to know how to draw like that. I love it.
I like those abstracts, too. The sense of humor involved in making these abstracts is admirable.
I thought the “based on 5″ line was just to inform the reader about which was the limiting reagent without having to dig into the SI (and this being Angewandte, there’s no guarantee the SI would provide this info anyway).
Hey Paul, thanks a lot for the add and your great discussion. Smitty is right, this is a cascade reaction building the central core of the beast stereoselectively in one operation in essentially quantitative yield (orange-yellow!!! spot to orange-yellow!!! spot, due to the aromatic rings). The 98% refer to the limiting dienophile because 2.0 equiv of the easily accesible diene were used, maybee you can correct that. About the epimerization of the ketone: As first seen in the old Woodward steroid syntheses (JACS 1952), this annualted decalin centers will allways epimerize if there is no termodynamically favored epimer. Therefore it will epimerize in each reaction till it is erased and therefore it makes no difference starting from a pure epimer or from a mixture, even if the epimers may behave different in the epoxidation reaction (as discussed in footnote 16). Do you agree?
Keep on with your great page, Paul. You are the rolling stone magazine for total synthesis!
I particularly like the 4-color scheme for CP molecules (top right in the graphic).
I’ll say it again, I am not a Nicolaou fan, his colour schemes included, but I do like this little synthesis. The problem with Nicolaou’s colour schemes are that he emphasizes everything, and as a result he emphasizes nothing. At least there wasn’t a mythical creature forcing the two Diels-Alder components together with its mind powers. Maybe he is chilling out with his old age!
Good to see azadirachtin in the bottom left, even KC could not make that bad boy. In steps Steve Ley
zzzzz
…yes, but azadirachtin was still a relay synthesis…
zzzzz
he still made the quaternary centre, nothing KC could ever do despite throwing 598 post docs at it. (and still is)
Intelligence >>>>>>>>>>> numbers
So Nicolaou isn’t intelligent now? TWYI, which professorships do you hold that puts you in the position to say? Can we get a CV with list of publications (presumably including a number of intelligent total syntheses of azadirachtin)?
u guys are so predictably relentless….why do we always get drawn into this every time?!
Hi!
Great synthesis and !
One short question: Can you upload your Chemdraw-file(s)?
Thanks a lot!
[...] But nevertheless here it is: the nice KCN approach to the relatively new class of Lomaiviticins A and B which structures reminds me somewhat of a class of compounds reviewed by Paul: http://totallysynthetic.com/blog/?p=1520 [...]
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