Do you think this would work?
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000373809-file_gnxy.gif)
The first step is known, it is the first step of the traditional Rebek total synthesis of lysergic acid. The next step is a minor modification of the Rebek TS, in which he performs an intramolacular Friedel-Crafts acylation to get the cyclic ketone. Rebek prepares the acyl chloride and then the FC acylation. I am specifying the use of polyphosphoric acid on the free acid to prepare the same product.
The next step is where the synthesis starts to veer off course from the traditional Rebek Synthesis. A Wittig reaction with (the albeit weird) compound a-cyano-b-bromopropionic acid, methyl ester, using triphenylphosphine and potassium t-butoxide as base, yields the next intermediate as shown on the bottom right.
The order of the next few reactions is somewhat open to debate. If the amines are deprotected, the indoline can be oxidized/dehydrogenated with DDQ back to the indole. This is also used in the Rebek Synthesis to restore the indole ring.
Now, the method outlined in Post 351772 (https://www.thevespiary.org/talk/index.php?topic=12580.msg35177200#msg35177200)
(Barium: "Nitriles to tertiary amines", Tryptamine Chemistry) and verified via OrgSyn is then used to couple the nitrile and secondary amine functions, and this is reduced with NaBH4 to racemic methyl lysergate.
All I want to know is, "Can this work?" Just curious as to your thoughts on the whole shebang. I know it is not economical. I don't plan on doing this, it's purely academic chemistry.
PrimoPyro
Instead of removing HBr from the molecule to form the ylide, would a side reaction occur as well, removing the proton at the tertiary carbon instead?
The oxaphosphetane is formed prior to the wittig rxn by reacting the organic bromide with triphenylphosphine. It is then deprotonated at the tertiary carbon with a base to form an ylid, which then adds to the ketone. Due to the high acidity of this proton, a weak base can be used. The ylid is extremely stable due to the conjugation formed by deprotonation and the strong electron withdrawing groups in the conjugated system that is formed.
a weak base can be used.
Would NaOMe be a 'weak' base, or still too strong? I don't understand why I see writings of KOtBu being used so often if a weak base will do the job. KOtBu is certainly a strong base. Im not discounting your statement, just saying I find this contrast curious.
PrimoPyro