Disclaimer: This article is purely informative, and it does not contain information about how to actually perform the experimental procedure of synthesis of LSD or any drug, which should NOT be attempted at home.

Lysergic acid diethylamide, commonly known as LSD, and colloquially called acid is a psychedelic drug which was first synthesized on November 16th, 1938 by a chemist called Albert Hofmann.

Do you want to known everything about the discovery and total synthesis of LSD? Keep reading!

LSD was discovered in Switzerland, but it was not until 1943 that the special properties of the compound were found. Today we do not focus on chemistry concepts but rather on a historical landmark. You probably knew this, but also you probably don’t know much more about its discovery and synthesis. That’s what we are going to fix in this article, it is a very interesting story and of course a very remarkable synthesis! Keep reading:

When it was discovered by Sandoz Laboratories, its purpose was supposed to be obtaining a respiratory and circulatory stimulant, preparing and investigating organic compounds obtained from the fungus ergot and the medicinal plant squill.

LSD is well known for its psychological effects, which can give rise to closed and open eye visual hallucinations, alter the thinking process and the sense of time or, in a nutshell, induce abnormal psychic states, but as we have already told, all of these properties were found no less than five years after its discovery, by the same guy who first synthetized it, Albert Hofmann. He was the first person to ingest and experiment the effects of the drug. The Telegraph newspaper placed him on the first position in a list of the 100 greatest living geniuses. The discovery of its properties was a bit of a coincidence, since the Swiss chemistry accidentally absorbed a very small amount of the compound (the threshold dose is only about 20 micrograms) through his fingertips, finding the psychoactive effects by himself. He also described how he was felling:

“…affected by a remarkable restlessness, combined with a slight dizziness. At home I lay down and sank into a not unpleasant intoxicated-like condition, characterized by an extremely stimulated imagination. In a dreamlike state, with eyes closed (I found the daylight to be unpleasantly glaring), I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors. After about two hours this condition faded away”

But the synthetic route that Hofmann used to prepare LSD is quite simple; the structure of the drug was very similar to the compounds extracted from the ergot fungus. He used as starting material ergotamine and most of the structural work was already been done by nature, so we will focus in this article on the total synthesis of the drug, which means, a synthetic route that can be performed using reagents that are commercially available.

The new physiological properties of ergot fungus directed Arthur Stoll attention, and with his investigations played a really important role, he lead to the isolation of products like ergotamine, ergonovine (the simplest one) and so on.

Growing Interest on the Synthesis of Lysergic Acid

The interest on the synthesis of lysergic acid rose from the moment of the discovery of all of these compounds which had that part of the structure in common. The whole structure was not resolved and confirmed until 1949, however, it draw the attention of many organic and medical chemists anyway. Once the properties of LSD were found, this interest increased even more.

The first LSD synthesis was published on 1956, by one of the most (if not the most) greatest organic chemists of all times, Robert Burns Woodward, born in Boston, Massachusetts. He is considered to be the best organic chemist of the 20th century, in terms of experimental and theoretical studies of chemical organic reactions. He also received the Nobel Prize in chemistry in 1965 for his synthesis of complex organic molecules. One of these molecules was lysergic acid. We will review this synthetic route as it deserves to be done. Also, we will cover the LSD synthesis mechanism for each of the steps, so it can be of aid for organic chemistry students. The original publication can be found here.

The synthesis of lysergic acid presented an important problem: the high reactivity of its indole group. This heterocycle was considered so far incompatible with any long synthetic procedure. So, to avoid this problem, Woodward’s group decided to use dihydroindole compounds (just like indole, but with 2 more hydrogens, and one double bond less), like the starting material, which was β-carboxyethyldihydroindole, protected with a benzoyl group at the nitrogen.

Synthesis of LSD first step: Ring C Formation

The initial compound is treated with thionyl chloride (using ether as the solvent), converting it to the acid chloride. Then, the molecule undergoes an intramolecular Friedel-Crafts reaction after the addition of aluminum chloride. This last reaction was firstly performed with bad results with benzene as solvent. Using carbon disulfide, the reaction went perfectly to give the ketone shown in the picture above.

Second Step on the LSD Synthesis: The Nitrogen-Containing Ring

The most problematic part of the synthetic route was the formation of ring D of the compound. Since they needed to add a substituent to the α-carbon to ketone carbonyl, the following brominated derivative was an intermediate that should be obviously formed, treating the compound with acid media and then with bromine:

The last compound was obtained in a very good yield, but the first attempts to continue the synthesis from here failed. Many alkylations/aminations were tried, but as time passed by, those reactions seemed less promising.

However, after many unsuccessful reactions and some successful but in very poor yields (like those who took place through the use of epoxydation reactions), it was found that treating the brominated intermediate with methylaminoacetate ethylene ketal in a non-polar solvent, gave the desired alkylated intermediate in an excellent yield, which could be hydrolyzed using HCl to deprotect the acetal (releasing the ketone) and the benzoyl group that protected the first nitrogen atom.

Finishing The Tetracyclic Core for the LSD Synthesis

The obvious next step is the formation of the heteroring D, which was achieved effectively treating the last ketone intermediate with sodium methoxide, using pure ethanol as the reaction solvent.

The mechanism of this step consists on the kinetic enolate formation and then, its addition to the other ketone, closing the third and last ring of the molecule.

An elimination reaction also takes place spontaneously, giving the α-β- insaturated ketone.

The treatment of this compound with sodium borohydride and sodium anhydride (in any order), which selectively reduce the ketone group and protects the ring B amine nitrogen. The next step to be performed was the substitution of the alcohol group for a chlorine atom. The first attempt on doing this was treating the alcohol with liquid hydrogen cyanide catalyzed by boron fluoride ethearate, but this did not lead to the desired intermediate. After many tests, it was found that treating the alcohol with thionyl chloride in sulfur dioxide (liquid) gave the intermediate in a good yield.

The obtained chlorinated intermediate was found to be very susceptible to hydrolysis to yield once again the alcohol, so the next reaction had to be performed fast and in special conditions: Treatment of the compound with sodium cyanide (in excess) in anhydrous liquid hydrogen cyanide (pretty scary thing!). Anyway, Woodward’s group managed to make the reaction go well and the resulting intermediate was treated with methanol, to yield the methyl ester in a sulfuric acid catalyzed methanolysis. Also, the acetyl protecting group on the nitrogen of ring B was removed due to the acidic conditions.

After this the product was worked-up using acidic water to hydrolyze the ester to give the corresponding carboxylic acid.

Now the work was almost done! The only remaining task to obtain lysergic acid was the formation of the indole group selectively removing the two hydrogen atoms of the intermediate which would give the corresponding double bond. The first thing tried was the treatment of the compound with Raney nickel in boiling water, but this procedure also reduced the double bond in the ring D.

Subsequent trial and error easily solved this problem, when a similar experiment, when the last intermediate of the synthetic route was treated with previously heat-deactivated Raney nickel.

The final product, lysergic acid, was obtained as a racemic mixture (mixture of the two possible enantiomers on the D ring carbon that is holding the carboxylic acid group –carbon 8-), and the last step to obtain the pure enantiomer a chiral resolution was performed, giving the final product of the synthesis, D-lysergic acid. After resolution, it was successfully converted to the natural product ergonovine, what made the alkaloid preparation and identification complete.

Final Amidation of Lysergic Acid to Give LSD

However, this does not complete the synthesis of LSD, but the last step is just the formation of an amide bond between lysergic acid and diethylamine.

The following are the reaction conditions used by Shulgin to obtain LSD from lysergic acid:

Alexander “Sasha” Shulgin was an American chemist author of the famous book PiHKAL: A Chemical Love Story (Phenylethylamines I Have Known And Loved), and its continuation, TiHKAL (which stands for Tryptamines I Have Known And Loved), where he makes a detailed explanation and analysis of how he discovered, synthesized and personally bioassayed a huge variety of drugs, all by himself (with the assistance of his wife, Aten Shulgin). He died less than a year ago, June 2, 2014 (aged 88), and with this last reaction I intended to make a small tribute to this great medicinal chemist, biochemist and psychopharmacologist.

You can PiHKAL books through Amazon, I promise they are worth a read!

“LSD,” -writes the chemist Alexander Shulgin– “is an unusually fragile molecule… As a salt, in water, cold, and free from air and light exposure, it is stable indefinitely.”

But of course, this is not the end of the story… Organic chemistry and synthesis technics have advanced A LOT from those years to present, and way better methods have been published to prepare lysergic acid diethylamide in a more efficient and easier way, besides the Hofmann 1938 method that consisted on the hydrolysis of ergotamine, the above mentioned natural product derived from the ergot fungus.

Modern LSD Synthesis Routes

A very recent route for the total synthesis of LSD is that published by Tohru Fukuyama et al. from the Graduate School of Pharmaceutical Sciences, University of Tokyo, in 2013.

This LSD synthesis is based on the Evans aldol reaction, which allows a stereoselective construction of the needed chiral center followed by a sequential process, which includes a metathesis reaction that produces the ring-closure and finally a Heck reaction which finishes the construction of the rings C and D.

To finish this article, I would like to say that this is just an example of the discovery, isolation, preparation and development of a new kind of drug, and many others have been discovered over the years, which have saved and improved (and of course, still do) the life of humanity. The fact that LSD can be used as a recreational drug is not the topic of this review.

Organic synthesis and medicinal chemistry is a world that I enjoy a lot (it is part of my life, anyway, what I studied and what I work on every day), and I am pleased to write this kind of articles, so, if you share your thoughts, criticism, gratefulness, anger or whatever in the comments, it will be much appreciated, and will encourage me to keep publishing this kind of writings.

After all, organic chemistry can explain a great deal of things, such as why urine smells bad after eating asparagus, as we covered in another post.

Also, if you have any suggestion or idea for future posts, will be strongly valued too!