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.