Methyl Lysergate Near-Total Synthesis

[PrimoPyro]

Do you think this would work?



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

(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

[PrimoPyro]

Not a whole lot of "theoretical bees" around are there? Guess not....oh well.

One possible problem I realized late last night, is one that might occur in the Wittig Reaction stage.

Look at the structure of the Wittig reagent, the a-cyano-b-bromopropionic acid, methyl ester compound. That tertiary carbon has two electron withdrawing groups off it. That proton has to be at least slightly acidic.

I don't recall the exact structure of the adduct between this bromide and the triphenylphosphine, but I am wondering if perhaps a strong base like KOtBu would not react properly with the ylide precursor.

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? That would suck.

I guess it all depends on which is easier to remove: The proton in this case, or HBr to form the ylide. Any comments or suggestions? This really bugs me, because I don't know what to analyze to get an answer to this issue.

PrimoPyro

[Cyrax]

I 've got a remark, concerning the benzoyl amine protection and the use of that polyphosphoric acid in the next step. 

The use of polyphosphoric acid in the synthesis of alpha-tetralone is well established, but the reaction conditions are pretty harsh ...:
Heat 120 g of polyphosphoric acid to 90 °C on a steam bad.
Liquefy 33 g of phenylbutanoic acid by heating to 70 °C and add this in one portion to the polyphosphoric acid with manual stirring.  Remove the beaker from the steam bath and continue stirring for 3 minutes; the temperature should remain at about 90 °C.  Then add 100 g more of polyphosphoric acid and warm on a steam bath for 4 minutes.
After workup, the yield is 79 %.

So, what's the problem?  Well, I fear that these reaction conditions could remove the benzoyl protection.  I bet the yield with the acyl chloride is higher & the reaction conditions aren't so harsh.

If I had to perform this synthesis, I'd use oxalyl chloride to generate the acid chloride, especially since the workup is so easy (all the side products are gasses, so you could perform the ring closure probably in the same pot).

By the way, what is the ref. for that Rabek synthesis - I 'm interested   .

I understand completely that you were a bit grumpy because no bee responded to your post.  In my eyes, that reaction scheme looks pretty cool.  Congratulations, PrymoPyro.  It really pisses me off that all the really nice posts almost get no attention.  This makes you start wondering: why the hell post all those fine procedures ..., since noone seems to appreciate them.


What we are looking at is good and evil, right and wrong.

[PrimoPyro]

Ok, I suppose you are likely right about that. I do know for certain that the acyl chloride variant works, because it is what is traditionally employed. The yields are not wonderful, but as was stated, this is not meant to be economical.

I would probably initially prepare the acyl chloride with known reagents, but then venture into new waters and try out trichloroisocyanuric acid as a chlorinating reagent.

Actually, Im not grumpy, just was a little disappointed. This cant be placed in the same category as someone being pissed after posting a new procedure. This is just fantasy, I havent actually performed any of these reactions before. I just wanted to shoot the shit about em, so to speak.

Now if I come back after my hiatus, having performed some or al of this shit, and I still get nothing, then you can sure as fuck expect a real bitch/complaint marathon, but until then you are safe.  

The ref for the Rebek synthesis of lysergic acid comes from the book, The Chemistry of Mind Altering Drugs ISBN: 0-8412-3253-9 in the LSD chapter. I think the book has additional refs listed in it, I will post them in a little bit once I wake up. (had to get that Hive fix in first thing in the morning, right after that first morning piss)  

The cyano-bromo carboxylate might be a true bitch to make. I'll start thinking about it now, but I fear it would be a true (bleeped out for the young'ns) to make.  

PrimoPyro

[lab_bitch]

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.

[PrimoPyro]

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

[pHarmacist]

Im not familliar with the pKa of NaOCH3 but I know for sure that it is a exceptionally strong base.
Never underestimate the power of retrosynthesis.

[Rhodium]

Exceptionally strong? I wouldn't say so, with a pKa of 15.5, it is on par with NaOH (pKa 15.7).

tert-Butoxide is more strongish at pKa 18, 200 times stronger than the above.

[pHarmacist]

Well exceptionally strong might be too much but it's strong.. , then agin it depends what you compare it with. H2SO4 is very strong acid but there are acids that are many times stronger, making H2SO4 weak compared to them.. anyways you are right, it's strong but not exceptionally strong...
Never underestimate the power of retrosynthesis.