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Totally Synthetic by Paul H. Docherty, 1 July 2007

Total Synthesis of Salvinorin A


J. R. Scheerer, J. F. Lawrence, G. C. Wang, D. A. Evans, J. Am. Chem. Soc. 2007, 129, 8968-8969.

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 territory, 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 stereocenters from the original three, and completes the carbocyclic skeleton. Elaboration to the natural product was quickly and efficiently completed from here. Excellent stuff.