Why don't people start working on trying to discover a new route to lysergic acid by way of tryptophan? Tryptophan is clearly one of the most economical and clandestinely appropriate precursors imaginable, and not that many atoms apart from lysergic acid, and if one desires an economic route, this is the precursor to shoot for.
If one person tries to work on this, he might fail, but if more people started working on it on the Hive, and shared information on their failures, other people could try out other things instead of working on what had already failed, and work might progress quicker.
This is the Hive. We like chemistry, not fungi. For the forseeable future, Claviceps paspali will be yielding about 2 grams max per liter, even under optimal conditions in huge, expensive biotech plants. To supply an annual demand of 200 million, 100 microgram doses, 20 kg of LSD tartrate is required. Using the POCl3 synthesis like Shulgin does, getting 52% like him, about 23 kg of lysergic acid monohydrate is required. Assuming as much as 2 grams yield of lysergic acid monohydrate per liter of culture broth extracted, about 12000 liters of broth are required. That's 12 cubic meters, or about 12 full-height refrigerators filled with culture broth. Claviceps grows slowly (about 20 days from preculture to extraction), which requires very high standards of sterility (i.e., this isn't exactly like brewing beer). This may be possible on a 1-5 liter scale, where you can put each container full of medium in an autoclave, and properly sterilize everything, but it's quite another thing to put a 100 liter "jug" into a pressure cooker, or even 20 five-liter jugs. And someone'd have to do that, oh, just 120 times per year to meet world demand.
In the future, with sexually bred Claviceps and maybe genetic engineering, it is likely there will be 10 g/L yielding strains, or even 20-30 g/L (or indeed 5000 g/L, why not?), and it is clear that no synthesis, even a miraculous 99% yielding one, using chemical reactions will ever be able to compete with that economy. However, in the present, even a 15% yielding synthesis from tryptophan, using relatively simple and inexpensive reagents, would begin to be competitive with current fermentation technique.
The most economical synthesis of lysergic acid thus far, as far as I can tell, is the one by Rebek from 1984 using L-tryptophan. The d-isomer is the sole product, but yield is still only about 4% to d-lysergic acid. The syntesis is elegant, but some reagents are expensive (though some cheaper could probably be found with a little effort), and a major loss of yield comes from the decision, as in all the
other reported syntheses of lysergic acid I have come across, to protect the indole structure in the form of an indoline, giving two low-yielding reactions at the beginning and the end.
The decision to use such protective measures is usually never defended to any greater extent than to cite some older article in which the same measure is used, but in which, funnily enough, there is also not provided any evidence except for references. And when you finally come to the "original" reference, you typically find it says no such thing.
To skip the indoline reduction/oxidation could potentially mean a sizeable gain in yield. There are many good indications that a tryptophan derivative could be intramolecularly cyclized predominantly the 4-position instead of the 2- by proper adjustment of experimental reagents and conditions, either as the acid chloride or an azlactone.
The only Friedel-Crafts catalyst reported for cyclization in these types of cases is aluminum chloride, a cheap but extremely reactive reagent, but this appears to be again due to the effect of reference-aping. I think there is at least a possibilty that something milder like ferric chloride could be used instead, or why not even some of the modern pillared clay-catalysts?
In any event, maybe without or maybe with N-protective agents, it should be possible to achieve the tricycle 4-amino-5-oxo-1,3,4,5-tetrahydrobenz[cd]indole, in presumably around 50% yield. This is just two or three steps from tryptophan. I.e., N-acylation, dehydration and condensation in the case of the azlactone method or chlorination and condensation in the case of the acid chloride method.
In a variation on Uhle in JACS 73, 2403-3 (1951), barring dialkylation, alkylation with an alpha-(halomethyl)succinic acid ester and subsequent intramolecular Knoevenagel condensation should afford 9-carboxynorlysergic acid. Decarboxylation might afford either norlysergic acid, ergolene, ergoline or 9-carboxyergolene, or even lead to the dreaded benz[cd]indoline-isomerization, with the former being the desirable outcome of course. Of course, given norlysergic acid, simple alkylation with alkyl halide will afford the active 6-alkyl analogues.
In any event, a succesful ergolene test after the Knoevenagel, even without successful decarboxylation, should prove the basic soundness of using the tricyclic aminoketone as a promising point for further synthetic operations.
