Theoretical LSD Synthesis in 7 Steps (Organic Chemistry)

A team of chemists recently reported a synthesis of LSD in only 6 laboratory steps! We will look at the chemistry behind it and uncover some other insights – for example, how do chemists measure how trippy a molecule is?

Rationale for LSD synthesis

So these scientists, are they a bunch of Breaking Bad wannabes or why would they investigate even more chemical syntheses of LSD? Well, LSD derivatives such as bromocryptine can be pharmacologically useful for treatment of neurological, metabolic and other disorders. This means we want to get more efficient at making LSD-like scaffolds for drug discovery.

In 2020, there was an interesting structure-activity relationship study. It showed for the first time that psychedelic compounds, such as derivatives of DMT, can be engineered lose hallucinogenic side effects while retaining their useful psychoplastogenic properties. The left-hand side 5-methoxy-DMT makes you trip. The isomer with the methoxy substituent shifted by just one carbon, does not. While this might be disappointing for some of you, it’s obviously better if patients are not hallucinating weird shit after taking their pills.

If you wondered – trippy-ness can be estimated by looking at how often mice violently shake their head after administration of psychoactive drugs. This is a well-validated proxy for hallucinations and was first established already 70 years ago! You can see that while 5-methoxy-DMT leads to head twitching, the 6-methoxy isomer has no significant hallucinogenic activity. There’s actually a nice concentration dependent relationship.

Six-Step Synthesis of Lysergic Acid

So how does this super-quick route look like? This synthesis builds on a key intramolecular Heck reaction which creates the key vinyl bond that is present in LSD. This Heck-approach is not an invention of the 2023 synthesis, as it had been used in previous, longer syntheses already. However, this route efficiently traced the intermediate back to this indole containing. This starting material can be bought commercially and conveniently has the bromo group for the Heck reaction. Obviously this makes a lot more sense than unnecessarily taking apart the indole ring. Let’s take a closer look at the specifics of this synthesis.

The first step was a magnesium-halogen exchange of this iodopyridine to create a heterocyclic nucleophile. This one is happy to attack the electrophilic carbon of the functionalized aldehyde, leaving a hydroxyl group in the product. As you might remember, there is no oxygen in LSD at this position. Thus, the next step simply removed this group by reduction with triethylsilane.

The acid used in this step removed the N-Boc protecting group, so they re-installed afterwards. After this protection, the most nucleophilic group is the pyridine nitrogen – so it was methylated with methyl triflate. This gave a pyridinium salt which was reduced by sodium borohydride. Two hydride equivalents attack the ring: The first one gives the reduced tertiary amine that is part of LSD. The second hydride reduces one of the double bonds, leaving the alpha-beta unsaturated ester. All of this happened in the same reaction vessel. But still, the authors were a bit sneaky to categorize this as just one single step.

But wait – to enable the key Heck coupling reaction, the olefin actually needs to be located at the other carbon. They achieved this by using LiTMP as a strong base. The resulting isomerized anion which can be protonated in a diastereoselective manner. The desired isomer has the ester on the same side as the existing hydrogen of the 6-membered ring. While the preference isn’t great, they formed it in slight excess over the undesired one. Conveniently, they found subjecting it to the same conditions recycled some of it to the desired product.

The Heck reaction proceeded with the standard mechanism. Oxidative addition of Pd(0) allowed for olefin insertion and creation of the C-C bond in blue. Now, given there are two beta-hydrogens available, there are two pathways towards elimination. There’s the orange hydride elimination, and the pink one, which is preferred in a rough 1 to 3 ratio. Note that the stereochemistry of the ester became wobbly again the orange product. This is because the reaction occurred at a 100 degrees with mild base with some isomerization taking place.

Even though we end up with three different products, it’s no big deal. They simply added potassium hydroxide to all, and heated things up to get to lysergic acid in around 50% yield. This is double-deprotection and isomerization. Natural products are usually stable isomers so it’s not surprising that the isomerization forms the configuration present in LSD preferentially. Unfortunately, their final product is not so satisfying as they only isolated a brown solid. I don’t suggest supplying this to the dangerous dealer in the neighborhood. I’ve seen some procedures getting nice white crystals but these folks didn’t care too much about ultra-pure product.

Lastly, they showed that this synthetic route could be useful to explore and study LSD analogs – remember the methoxy-substituted DMT structures at the start? The started with a chloro-substituted indole starting material and replicated the reactions – including the Heck reaction – to create a C12-cholor-lysergic acid derivative. Theoretically, you could create different LSD analogs now by functionalizing the aryl chloride – which might help scientists find future drugs based on LSD with differentiated therapeutic profiles. 

If you are interested in the synthesis of other psychedelics, check out the discussion of ibogaine, psilocybin, MDMA or THC-P.

LSD synthesis references

– Six-Step Synthesis of (±)-Lysergic Acid | J. Org. Chem. 2023, 88, 2158
– Identification of Psychoplastogenic N,N-Dimethylaminoisotryptamine (isoDMT) Analogues through Structure–Activity Relationship Studies | J. Med. Chem. 2020, 63, 1142