Evans, Scheerer, Lawrence and Wang. JACS, 2007, ASAP. DOI: 10.1021/ja073590a.
The first JACS total synthesis I’ve seen in a while, this is a nice piece of work by the legend that is Dave Evans. The target certainly has a bit of a kick; I quote: “the most potent naturally occurring hallucinogen“. Interesting times for the students in that lab. I can see them now – being chased around the lab by malevolent HPLC machines… It’s apparently also the only non-alkaloidal psychoactive natural product, so certainly of quite some interest.
The start of the synthesis is distinctly Evans terratory, with a catalytic enantioselective ortho-ester alkylation using an interesting nickel complex. A bit of hindered base, LA and ortho-ester then returns the stereocenter in very good e.e. It’s also interesting to see the use of ortho-esters, which are of course just masked aldehydes… The reference for the methodology (it’s Evan’s own work from 2005) is here.
There’s a whole sequence of impressive transformations on this substrate – which I’m not reiterating here, but I’d love to hear your comments. However, there is another fragment to discuss – that of the furan. The stereochemistry on this fragment is derived from a simple CBS reduction, but the acetylene is in the wrong place, so it’s simply “zipped” down the chain using Charles Brown’s isomerisation. This is a reaction that my supervisor is quite enthusiastic about, and I agree – it engenders incredible synthetic utility, and seems so simple!
This terminal acetylene is then carbometalated and coupled to the more elaborate sidechain, with macrolactonisation giving the twelve-member ring. Then it’s time for the piece de resistance – an impressive bis-Michael transannular cyclisation, which they prefer to think of as stepwise. The alternative, an exo-Diels Alder is also possible, however.
The reaction efficiency is amazing, and seems very mild, so was well planned! This sets-up a further three stereocentres from the original three, and completes the carbocyclic skeleton. Elaboration to the natural product was quickly and efficiently completed from here. Excellent stuff.