Totally Synthetic by Paul H. Docherty, 2 November 2008
Total Synthesis of Lysergic Acid
S. Inuki, S. Oishi, N. Fuji, H. Ohno, Org. Lett. 2008, 10, 5239-5242.
They don’t actually make the lysergic acid diethylamide, but I’m sure there’s a way to form that amide… And 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-Parkinson's disease properties? This certainly gives a more legitimate reason to work on the synthesis.
For me, it gets interesting with a gold-mediated
of a propargyl alcohol generating an allene in high yield. This is
quoted over two steps, as they did an in situ reduction of the initially formed
aldehyde. It took a little effort to find these conditions: switching to microwave irradiation boosted the yield, but left the d.r.
unimproved, whilst a bit of the oxo-gold complex did the job nicely.
However, separation of the diastereoisomers was ‘difficult’, so the mixture was used in an impressive palladium mediated domino cyclisation. 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. 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. For this, they separated the mixture of allenic starting materials, and repeated the reactions with diastereomerically pure starting materials. Using the purified, desired starting material, 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 pathway on the right is preferred, because of the disfavoured, strained palladacycle present in the first step of the minor pathway.
The group then went on to make the title compound, and a pair of diastereomeric compounds, lysergol and isolysergol.