Lysergic Acid, and definitely not LSD.
Fujii, Ohno, Inuki and Oishi, Org. Lett., 2008, ASAP. DOI: 10.1021/ol8022648.
Fancy making your own LSD?Â You could do a lot worse that this prep from Kyoto University.Â Of course, they don’t actually make the lysergic acid diethylamide, but I’m sure there’s a way to form that amide… Anyway, we should probably stick to the actual paper, and leave the class-A for another time.Â I’m sure we’re all aware of the biological activity of some of the members of the ergot alkaloid family, but did you know about synthetic members with anti-Parkinsonâ€™s disease properties?Â Certainly gives them a more legitimate reason to work on the synthesis.
For me, it gets interesting with a gold-mediated Claisen rearrangement.Â Done on a propargyl alcohol, this generates an allene in cracking yield.Â This is quoted over two steps, as they did an in-situ reduction of the initially formed aldehyde.Â It took a little effort to find these conditions, as their initial attempts with just a bunsen-burner resulted in both a shoddy yield and d.r.Â Switching to microwave irradiation boosted the yield, but left the d.r. unimproved, whist a bit of the oxo-gold complex did the job nicely.
However, separation of the diastereoisomers was ‘difficult’, so the mixture (a few steps on) was dumped into an impressive palladium-mediated domino cyclisation.Â A variety of conditions were applied, also varying the protecting group on the pendant amine from nosyl to the more optimal tosyl, finally resolving in the conditions shown.Â The yield is pretty decent for what is an impressive transformation, and the d.r. also.
I might have taken those yields and moved on, but the group were considerably more thorough, and did a useful mechanistic study.Â For this, they separated the mixture of allenic starting materials, and repeated the reactions with diastereomerically pure starting materials.Â Using the purified, desired SM, a worse d.r. (but better yield) was obtained for the cyclisations; the group suggest that this could result from two competing pathways.
They suggest that the preferable pathway (on the right) is such because of the disfavoured, strained palladacycle present in the first step of the minor pathway.
Impressive as this is, I must admit that my attention wavered as the group went on to make the title compound, and a pair of diastereomeric compounds, lysergol and isolysergol. However, I was somewhat taken by the use of thioglycolic acid along with lithium hydroxide to remove the tosyl group.Â I knew I’d seen that stuff in a bottle back home, and I was right – my grandmother uses it to ‘perm’ her hair…
Oh, and if you’re started ordering reagents to follow the prep, can I dissuade you, and suggest reading (or watching) ‘Fear And Loathing In Las Vegas‘ as an alternative to a life time of freaky flash-backs.