LSD Synthesis in 7 Steps (Educational) | Lysergic acid, organic chemistry, reaction mechanisms

This video does not explain or suggest how to make illegal substances, and is purely educational and theoretical. In my very first video we looked at the history and total syntheses of lysergic acid, the precursor of the psychoactive drug LSD. These oldschool and new-school syntheses were quite cool but they are quite lengthy, consisting of more than a dozen individual chemical steps.

Well, 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? So these scientists, are they a bunch of Breaking Bad wannabes or why would they investigate even more chemical syntheses of LSD?

Well, as we already established in my first video, 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 that 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 – whereas 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 – actually in a nice concentration dependent manner – the 6-methoxy isomer has no significant hallucinogenic activity. Before we continue - I opened a channel membership option on youtube and patreon.

Check it out if you would like to support. Appreciate any support to improve my ten cent hourly salary I get in return for spending so much time on these videos! So how does this super-quick route look like?

The key bond disconnection that this synthesis is based on is an intramolecular Heck reaction which creates the key vinyl bond that is present in LSD. This Heck-approach towards LSD is actually not an invention of 2023 synthesis as it had been used in previous, more lengthy syntheses already. However, the route we are discussing efficienctly traced the intermediate back to this indole containing an aldehyde, which lends itself to nucleophilic addition and other functionalizations.

This starting material is very convenient as it already has the bromo group for the Heck reaction later on and can be bought commercially. 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 so 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 are accepted by the ring – the first one gives the reduced tertiary amine that is part of LSD, and 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 which needs an isomerization. They achieved this by using LiTMP as a strong base – giving the isomerized anion which can be protonated in a diastereoselective manner.

The desired isomer is the one where the ester is on the same side as the existing hydrogen of the 6-membered ring – and while the preference isn’t great, it’s formed in slight excess over the undesired one. Conventienly, it can be recycled by subjecting it to the same conditions to convert 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 as this reaction was performed 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 threw them all together with some potassium hydroxide and heated things up to get to lysergic acid in around 50% yield. This is double-deprotection and isomerization.

Natural products usually correspond to 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 – so 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.

I hope all of you were able to take away some nice learnings from this video. If you liked it, please subscribe, leave a comment, activate notifications – and consider becoming a channel member! Thank you and until next time.