When the synthesis is spaced over two papers, you know it’s a biggie; a true beast of a natural product, Norzoanthamine made the gloried pages of Science when it was first completed by Miyashita back in 2004. Bulging with interesting biological activity (the headline being prevention of decrease in bone weight in osteoporotic mice), med-chem work is apparently under way. Coupled with a lack of comments about ‘scarcity’ or ‘low isolation yield’, I’d guess that it’s relatively easy to get hold of (though perhaps not is kilo-quantities), but that shouldn’t stop work on it’s synthesis.
Kobayashi’s approach is surprisingly linear, starting with the now rather familiar Hajos-Parrish ketone (discussed here a few months back); the easily installed asymmetry in this starting material is used to control the bulk of the synthesis. However, it has to be said that elaboration of the 6,5-fused system took quite a bit of effort; eighteen steps took them to a tightly functionalised, but still small core. In a few more steps, though, this was to change, as a rather nice alkylation bolted on a diene (nice stereocontrol, but this centre is perhaps irrelevent). This allowed a powerful IMDA reaction to occur, creating a further pair of stereocenters, and completing the A,B,C fragment. A hard slog, but with nine stereocenters, it was never going to be easy.
Next up was the fragmentation of the original penanone moiety found in the SM, now revealed. This was intended to become the D ring, a lactone, and thus an oxidative fragmentation was intended. However, things didn’t go as planned (which I’m sure involved a Baeyer Villiger oxidation), but the job was done using a pretty interesting series of reactions. Formation of a silyl enol ether using base and silyl chloride went as expected, but treatment of the enol ether with oxone ozone didn’t result in cleavage as expected, but as a single diastereomer of the Î±-hydroxy ketone. When this was treated with lead acetate, cleavage of the carbon-carbon bond was this time evident, but again the result was not quite as expected – rather than delivering homolytic oxidation, it appears that the hydroxy center is the focus of the oxidation action. The group postulate a mechanism for this chemistry, including a 1,2-hydride shift of the intermediate lead complex – worth a look…
Formation of the desired D ring was simplicity itself – treatment of the SM with unbuffered TBAF resulted in selective deprotection of the C-ring TBS ether and cyclisation in the basic environment. The last of the carbon skeleton was appended using a Horner-Wadsworth-Emmons olefination, and the group were soon ready to build the distictive bicyclic O,N-acetal. This went in reasonable yield, generating the desired stereocenter; the group must have been confident on this success, though, through model studies.
The D-ring, which had only been in place for a few steps, was then broken apart to allow oxidation of the C-ring centre. Then a final cyclisation, building two rings, completed the synthesis by formation of the second N,O-acetal. This is certainly tidier than the end-game employed by Miyashita, but a similar strategy.
Hmm. There are certainly some nice reactions used in this synthesis, but I feel somewhat underwhelmed. Don’t get me wrong – a synthesis on this scale is an extraordinary acheivement – but I don’t think I learned a lot along the way. Tell me what I missed!