Snyder, Tang, Gupta. JACS, 2009, 131, 5744. DOI: 10.1021/ja9014716.
Okay, it’s taken me far too long to get around to this article – I actually wrote the Chemdraw back when this article was in ASAP… but other stuff got in the way, like a little Nature paper from Baran. However, it’s a damned nice paper, so it’s impossible for me not to go back and look at it properly. The target here is an halogenated natural product, isolated from Streptomyces bacteria – so it’s not too surprising that this family possess antibacterial activity. The headline, though, is in vivo activity against MRSA and VRSA strains – a guaranteed grant-winner! This brought quite a bit of attention, and a racemic synthesis by Tatsuta back in 2002. However, Snyder has set his sights a little higher, with an enantioselective synthesis in this paper.
The starting point for this post is a bit of chemistry on flaviolin; a prep published when flash chromatography was but a dream… This prep took eight steps to complete flaviolin, but Snyder managed to shorten it to only two – neat work. The first step I’m covering, and keeping the chemistry nice and flat, is a Knovenagel condensation (bear in mind the 1,3-diketone tautomer), followed by a sigmatropic electrocyclic rearrangement to give the the desired tricycle.
Now it was time to get asymmetric, doing a dichlorination using a bit of Lewis acid, chlorine gas (eeeeh…), and some BINOL-type axially-chiral ligand. The prep for this is quite interesting, as they had to use four equivalents of the BINOL-thing, stew it up with borane-THF and isolate the intermediate, which is presumably the chiral-borane adduct. Addition of the substrate at this point, and chelation of the borane is controlled by pi-stacking interaction, and allows selective trans- delivery of chlorine across the double bond. Neat, but that’s a lot of 9 in the pot – a point addressed by Snyder, who stated that firstly that the ligand could be recovered, and the excess was required to prevent chlorination of the aryl moieties.
They then selectively functionalised the allylic chloride by displacing with acetate, and with retention of stereochemistry by using potassium acetate and 18-c-6, which presumably presents a source of naked acetate. The acetate group was removed to free the hydroxyl, and the remaining phenol protected – setting them up for a Tot.Syn. favourite – a Johnson Claisen. This bad-boy does a fantastic job of rearranging the allylic alcohol into a hetero-quaternary center, and providing a methyl ester as a functional handle. The yield of product was unfortunately low, but if you consider the congested transition state here, it’s not too surprising; at least they were able to recover the SM.
I’ll stop about here, as completion of the target didn’t take much more effort. The ester was reduced and Wittiged, whilst the final stereocenter was imparted using base and NCS. Unfortunately this resulted in the enantiomer of the target, but that doesn’t matter a damn. Good stuff!