Total Synthesis of Lysergic Acid (LSD Precursor): Retrosynthesis & Mechanisms (Hofmann, Woodward)

Welcome to this channel on organic synthesis. This is not an experimental channel showcasing chemical experiments but rather will deal with theoretical discussions of syntheses of important chemicals and interesting natural products. If you are not familiar with organic chemistry, do not expect to understand everything I'm talking about. Please consult the literature, the myriad of youtube videos about basic chemistry or just Google.
In this first video, we will cover the history of lysergic acid, a LSD precursor, its first total synthesis and a modern approach (with increasing difficulty).
/ totalsynthesis
🚀 Thanks to all channel supporters!!!
/ totalsynthesis_official
👉 Follow me on Instagram to follow updates on other random chemistry research and interesting news!
total-synthesis.com
total-synthesis.com/lsd-synth...
00:00 Introduction about the significance of lysergic acid derivatives and importance of natural products
00:49 Overview
02:09 History preceding the synthesis of lysergic acid about the work of Albert Hofmann at Sandoz (first semisynthesis)
04:12 First total synthesis by chemists at Lilly & Nobel laureate Robert Burns Woodward. This synthesis employs reactions encountered at in the first two years at an undergrad level.
12:40 Modern approach by Prof. Ohno at Kyoto University. This contemporary synthesis relies on organometallic chemistry and more advanced retrosynthetic disconnections. This part contains a short discussion of reaction mechanism.
18:10 Closing comments
Disclaimer - This channel does not provide medical advice!
No information on this channel is intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of information on KZbin.
Some recommended books on organic synthesis:
- Clayden, Greeves, Warren; Organic Chemistry (basic organic chemistry knowledge)
- Wyatt, Warren; Organic Synthesis: The Disconnection Approach (excellent introduction to retrosynthesis)
- Kurti, Czako; Strategic Applications of Named Reactions in Organic Synthesis (extensive toolkit of reactions and applications thereof with common conditions)
- Nicolaou et al; Classics in Total Synthesis 1-3 (the ultimate total synthesis trilogy)
- Nicolaou; Molecules That Changed the World (the world's most important molecules and their impact on everyday life)
- Carreira, Kvaerno; Classics in Stereoselective Synthesis (compilation of the groundbreaking methods of stereoselective synthesis and application to synthesis of stereochemically complex structures)

[@totalsynthesis]

Feel free to check out my other videos in case you're interested in chemistry and science! I also plan on sharing smaller, bite-sized insights on instagram: instagram.com/totalsynthesis_official/

[@fukpoeslaw3613]

Would bromadol be easy enough to make?

[@brettmoore3194]

Why synthesize when nature makes it so easily, while sequesting carbon, extracting minerals while also making sugars,starches and cellulose. A inventor would be proud to have a product perform so well

[@fukpoeslaw3613]

@@brettmoore3194 men improves on nature's medical drugs by 10, 100, 1000 times.

[@brettmoore3194]

@@fukpoeslaw3613 sorry but you consider a product that doesn't cause unwanted effects from a product that say it does this but also has these adverse reactions .... How is that improved. Father of medicine said it best let food be the medicine.

[@brettmoore3194]

@@fukpoeslaw3613 sound kinda pompous to say man can improve on perfection

[@viktorprypoten5233]

man, chemistry really did peak in the 50s and 60s

[@kennethstreet7868]

@Joe Alexander Mandelbrot, no space

[@cvspvr]

sounds like something tom from explosions and fire would say

[@viktorprypoten5233]

@@cvspvr precisely the shitpost

[@Swagtildawn]

@Joe Alexander What about it? There have been textbooks written on the subject in length. Not that they explain everything, but what are you referring to exactly?

[@skm9420]

It's all gone yellow

[@lumpygasinavacuum8449]

the world needs mass amounts of bike day chemicals. humanity needs more chemists

[@bergenmatthew]

No we need the chemicals unregulated

[@bergenmatthew]

So much of thestuff to synthesize lsd is regulated

[@Yazyk]

@@bergenmatthew there are ways around this if you're are looking for ways. We need more people who take initiative.

[@bergenmatthew]

@@Yazyk growing ergot doesnt seem fun to me.

[@Greatwealthgentleman]

Yes we need both, too bad that organic chemistry is so complicated otherwise we would have more people making it

[@prostrongmanzack]

As a chemist in industry, this is fantastically interesting. I found the depth of explanation of each time period most interesting, it is fun to think about chemists not so concerned with PPE 🤣🙏

[@nana-rs8en]

Some still don't, I always hated being forced to use it when I was learning.

[@alexlabs4858]

Dealing with cyanide? Just have a smoke!

[@edwardarruda7215]

I'm a retired R&D chemist and find this a nice refresher.

[@SAVEmeFROMtheANTS]

Still looking for 'work'? ;)

[@Pillowpetlover]

heisenburg

[@AltarParssoy]

ohno process too far fetched to my eyes, don't you think?

[@jackmariner]

How would one go about isolating LSA from morning glory seeds, and then turn it into LSD? Not asking for me or a friend just curious

[@electronium6378]

say my name

[@trevortyleris]

Straight called out for watching this while tripping. You earned a like.

[@yourface13able]

"..Or some random bloke just tripping acid, I hope you enjoy this video" Me on acid watching this video: ¤_◇ I am chemical

[@ScheveSneeuwSchuifSchep]

@Jay Hamrz uhh where do you live? It's pretty easy to get here lol

[@ScheveSneeuwSchuifSchep]

@Jay Hamrz you can actually send your drugs to a test lab for free where I live to test if your dealer supplied you with what they said they sold you

[@ScheveSneeuwSchuifSchep]

@Jay Hamrz yes you can buy test kits on Amazon but I refuse to buy anything on Amazon. Also I'd rather have it tested by a certified lab chemist which is legal and free in my country. Piss off, just because you live in a different country with different supply it doesn't mean that your situation is true for the entire world.

[@borat1]

@@ScheveSneeuwSchuifSchep man what country do you live in? I want to try acid but I’m kinda scared of the fake stuff.

[@kmit9191]

@@borat1 In Austria for example his Situation could be true.

[@elit3chemist958]

keep up the good work buddy, honestly this is what i want to see on youtube , will support ur channel :)

[@totalsynthesis]

Thanks mate. I have no time at all to make a video this weekend and coming week but will try to make a new one by next Sunday.

[@BushyHairedStranger]

Total Synthesis Garbrecth synthesis video? It would be great to have the resource variety of different synthesis available on KZbin. Appreciate what you’ve provided here alone.

[@ThaFill]

I really like how you explain the history, give some anecdotes and cover the modern as well as the old approaches. This is something that fascinates me the most, in terms of green chemistry and upscaling! Thanks for the heads up on reddit and the amazing content! Keep going!

[@n.thatte7698]

I really enjoyed the clarity of explanation: the video engaged well with the philosophy of why certain steps are taken. Good job! I thought the difficulty level was spot-on too!

[@jedwalsh5308]

Me being an A level student who has only just done Friedel-Crafts reactions thinking I would have a chance to understand the mechanisms.

[@jg_5082]

Bro same 😂 still cool though

[@Bjarku]

Yeah I remember taking one look at this synthesis as an A level student and just being like ‘nope.’

[@jedwalsh5308]

@@Bjarku so much still to learn 😂

[@stochastic24]

Great video, I really appreciate the extensive description with timestamps and further information.

[@juanbisceglia8322]

Watching the 2011 synthesis I can't help stare in awe at our predecessors ingenuity. Beautiful video!

[@ronaldpeanut779]

Excellent. Wish I had a teacher like you when I started grad school in 1987.

[@abhijitha8150]

Enjoyed the video. I feel stereoselectivity is of paramount importance while discussing total synthesis in this day and age and maybe you can ask your viewers who find it difficult to skip to another point in the video. This is a very good initiative and I sincerely hope you will inspire many thousands of students to pursue Organic chemistry.

[@GamerBraga]

This is a perfect video, do not downgrade the difficulty of the synthesis, people need to study more. I would like you to explain more 'bout some more interesting and difficult mechanisms. A special thanks to the articles references! Please, keep updating us with more videos.

[@donbredorouso2787]

I took ochem to the 400 level, and after 8 years, I can recognize some of what you are saying. I understand the drawings. I dont know every or any of the reaction type or mechanisms behind them. It would be cool if you had the molecules move around and have arrows moving around to show the reaction. I like the history aspect, old, middle, new. I think it was great, I will watch more.

[@hugostiglitz6823]

So what you're saying after 8 years even attempting lsd synthesis is almost impossible to the layman 😄

[@donbredorouso2787]

@@hugostiglitz6823 but we all dream of doing it.... i thought about it today....

[@BrasilKid]

@@donbredorouso2787no way can it be impossible think PyBOP mechanics

[@TajwarC]

Came from reddit - found the retrosynthesis very well suited to my knowledge level as an undergraduate. I can see some of the sharper college students (17/18 year olds) keeping up too if the reactions or mechanisms are named during the forward synthesis. Keep it up!

[@Rayselddiaz]

Complicated and history driven videos are a delight.

[@lumiii_-]

Happy I found this. I want to study the effects of LSD analogs, specifically AL-LAD, and try to understand why differences and similarities may occur between them. Research so far has been...groovy ✌

[@TheChrisBeattie]

Really interesting video as a grad student in total synthesis who wants to do some wider reading in an enjoyable manner! History is always interesting to hear about. Clear explanation of why certain strategies were employed and the potential pitfalls in the synthesis is always great to listen to. Look forward to more!

[@idontknowwhatthisis1]

This is a brilliant project and I hope you have plenty more videos planned! I'd like to echo other's requests for more mechanistic detail. For me (an undergraduate), and I'm sure for many others, arrow pushing is the best way to really to get to the heart of the chemistry that's happening.

[@hellfirelordofevil]

This is very good overview of the subject! This sort of analysis of the synthesis is highly educational on how one aught to approach the retro-synthesis of complicated organic molecule.

[@chelseadekle3532]

I'm not a chemistry major, yet I seem to know what I've learned from this experience in viewing your video explanation. Thanks for the very thorough review of lysergic acid synthesization and the basic history of its origins.

[@TheBen9701]

I have no idea on half of the content of this video, but your voice is soothing and the history is interesting!

[@venkatrajnarayanan2785]

great video! As usual the history part gives better perspective for the why and how the synthesis was done! Enjoyed the chemistry mechanistic nuances...

[@readingisbelieving5248]

Just subscribed! It's great to see more chemistry youtubers!

[@dpjellema]

Great video! It was really interesting to watch and I really liked how you clearly explained the synthesis. Sometimes the video needed a bit more pace but that could just be my preference. Really looking forward to more videos!

[@foxtrot7506]

It is a very nice initiative buddy. This is the kind of content I look for on KZbin. I wish you all the success.

[@jimmysjamin1]

I love the idea of helping people displaying symptoms of Altzhimers and other challenging conditions very well done and easy to understand lecture.

[@slippyq5336]

I thoroughly enjoyed your video. Not too tough, it challenges me to investigate what I don’t understand. Looking forward to your next video!

[@koukouzee2923]

I find it fascinating synthesizing complex drugs like this

[@vanessaaitkensilva4279]

I just needed some fun synthesis content and this was just perfect for me, thank u!!!!

[@JustinKoenigSilica]

Thanks man, came from your PM from reddit. good shit!

[@ivanmassimo4769]

high quality video.. no music no bullshit... it's hard nowadays to find such seriousness in youtube.

[@GroovyPancake]

Liking the video. Subscribed and looking forward to see how this channel grows

[@grantkoppelberger102]

I loved this video! I'm an undergraduate, but could easily follow until toward the end of the third part, where I just took your word for it. I enjoyed the quick history before jumping into the chemistry! I know it may be boring to many people, but I would love to see a video going through the full mechanism for different synthesis.

[@seankauder9721]

Undergrad ChemE. This was well suited to my knowledge level, I was familiar with 90% of the old-school synthesis

[@jimpinkowski3394]

Please show more of mechanisms - that is the interesting stuff! Thanks for explaining why the mechanistic pathway was chosen.

[@shaunrempel9842]

I really enjoyed this. well put together. Good job. I would be interested in more videos like this

[@kaezaklimber3391]

4:25 "Back in those days, structural analysis was a master's craft" Very good content video. Make more videos please. Maybe also on old structural elucidation techniques... so cool

[@MrKrtek00]

Nice video! Generally, I phase out when reading papers (not an organic chemist), so it is very helpful to have such a discussion on strategies.

[@Bippah]

When I got your PM on reddit I really didn´t know what to expect... But this is amazing ! Keep up the great work! Also as an undergraduate student I´d love to see more of simpler synthesis; I really enjoyed the history parts aswell !

[@MrTVx99]

Nice video man. As someone who struggles with organic chemistry, the explanations help out

[@jonathansmith4634]

That was a great video. Thank you. I'm fairly new to Chemistry, so there is a lot that I have to learn.

[@seancady4570]

Random bloke part made smile. Thanks for the shout out

[@totalsynthesis]

I knew you would watch this after 6 years!

[@adam54859]

You are awesome man!!! Keep up the good work

[@HamzaAli-gg1jq]

Awesome content - keep it up!

[@Morl0ck77]

Thanks alot for this video, i loved watching it . I don't know most of the mechanisms of the 3rd part yet, but still had fun trying to make sense with the knowledge i have as of now. I like the format as it is, with the 2 different levels of expertise and the evolvement of chemical thinking over time. Looking forward to your next total synthesis!

As a grad student in natural product synthesis a channel like this is music to my ears. Very nice first video, might wanna speak up a bit and put the mic much farther away, should sound better. Keep it up.

[@apppples]

Dude, I have a new channel to subscribe to! Hell yeah. Please more modern chemistry and mentions of stereochemistry. I just finished my advanced ochem courses on modern techniques and love seeing uses of the stuff I learned!

[@totalsynthesis]

Awesome, very happy to hear that!

[@mathiaswesterlund292]

Very interesting! You kinda went through some of the maybe more complicated reactions a bit fast however. Would love to see more!

[@Richard_allrich]

Well that's some high level chemistry there. And this is giving me good inspiration for creating new research chemicals. Currently working on aryltrifluoroborates and aryltricyanoborates. They have potential as a catalizer for some cycloadditions.

[@LIVEMETRIX187]

any luck?

[@williamguthrie8507]

This video is kind of old now but as an undergrad chemistry student, this video was perfectly suited for my knowledge level, love the video.

[@totalsynthesis]

Thank you! I hope you enjoy the new ones as well

[@roedurham3499]

Thank you fir yhis video this was an absolutely really great balanced video between science and history. It was so detailed with the science and just informative enough with the history that this made me super excited to rewatch and learn more about chemistry i really want to fluidly understand your chemical processes so i can smoothly follow along. But whT i did understand it was just way better than a lot of videos. Thank you very much

[@totalsynthesis]

Thanks for the kind words! I'm very happy to hear this.

[@djinnmagik6867]

You gave a brilliant analysis 🙏🏽

[@whitehornwindchime6838]

Go advanced always that's what's needed for us thank you!!!

[@jacktennant6749]

This was really good! I liked this level of detail, but showing some electron-pushing mechs for each step would really help me see what’s going on!

[@augustus4682]

Hell yeah man make a video on Woodward .. we'll love to see the great rare content

[@shortchanged.]

Nice vid, very good research ..subbed. and I say do more of both simple and complex

[@danielcezar4599]

Thank you very much. Your scientific work is clear and motivating ...from an undergrad!

[@augustus4682]

Keep making such good stuff man..

[@BrickForSheep]

2nd year analytical chemistry student, I definitely should be able to follow & draw out these mechanisms as I've learned them within the last 8 months or so. My sign to go back and work on them a bit more lol

[@darkdevil905]

I have a degree in mathematical physics and all this organic chemistry stuff looks mental

[@moneymaker2109]

need u bro

[@NabilBreda]

I have a phd in chemistry but mathematics looks mental to me hahaha

[@Psilocybiant]

@@NabilBreda do your duty 😉

[@ethangormong7506]

My PhD advisor was a student of RBW! Such a brilliant mind

[@kalimsheikh2494]

Nice Video! Keep up the good Literature Research!!

[@dcaabd]

this was very nice, thx for sharing.

[@OsmioIridio-og8cn]

Great video.. thanks for sharing

[@cyberhops]

You're lecturing style is amazing. Love to listen

[@totalsynthesis]

Thanks!!

[@javanotmocha8795]

Really great content, I've only taken chem I so this was pretty fast-paced but awesome

[@piperna5786]

Wow! What a channel!

[@fergonsil1]

Good initiative! The history part was a really nice touch. I think that very often it gets neglected when studying a subject in chemistry and yet very interesting and helps in understanding how the knowledge was created. Answering your question, I think you should focus on easier approaches, for example not omitting some reaction mechanisms, that way you would captivate more public and would be easier to understand, just my personal opinion... I have a question also: is this a monthly series or will you be posting less or more frequently?

[@totalsynthesis]

Thanks Miguel! I'll try to make a new video every week!

[@npm1811]

Dude ur videos r great we need more similar content creators like u

[@erosionhead420]

It’s a fascinating history. God Bless Stanley Owsley. There’s a really great presentation he did before he died. It’s on the KZbin. Evidently,, he figured out the best method. I’m getting old and therefore,, only trip about one time a year now. 😊

[@omarvela3154]

i have a mere bachelors in chemistry but used to study this synthesis in my college days very nice presentation and very well suited to my knowledge level. I work in an environmental lab and the chemistry is no where near as complicated or fascinating

[@whatcher8151]

your studies professional or pleasure, both? i had my day of perceptions. Can only look back a the puzzling adventure of a candid mind looking for the combination to reveal the answer to the next gate.

[@espanadorada7962]

Great video! Got a little lost near the end lol but I loved it all. The only thing I would change is maybe spend just a little time on some of the less obvious mechanisms for the “easy” part. I know it would help out a lot of people just learning those reactions connect their learning to this video and maybe give a little refresher to those of us who haven’t done ochem in a bit (hehe).

[@TheShimming]

Very interesting. Thank you very much.

[@user-nh5tw3jh5d]

This is an A class KZbin content

[@zakirzak1494]

As a beginner and a novice to chemistry, I found it hard to digest .. I may need to watch it few more times to get an idea about it. Anyway your sincere work is appreciated... keep posting. Thanks

[@irinak8763]

Nice video, thank you!

[@thermotronica]

yes fine video, history is great

[@TheWarriorSage1357]

Amazing content

[@elnini415]

My recommendation; keep the videos advanced, this will influence more viewers to ponder off and do more research of the terms, and hopefully become more informed. Ps: great content (:

[@elnini415]

@@smartjared7203 nice marketing I used to own a spore company and do the same thing because I couldn’t run ads to a high risk business lol

[@jbsc6180]

This is JBSC314 from reddit. Hey thanks for the reply on reddit. I almost forgot about this channel until you replied back. GREAT GREAT PHENOMINAL VIDEO !!!!!!!!!!!!!!!!!!!!! I subscribed and liked this time so I do not loose your channel this time. IT IS TO VALUABLE !!!!!!!!!!!!! I am not as advanced as you but the main thing I would LOVE to do form your video is put a 2nd ring on a benzene ring and a freidel crafts acylation is easy. An intramolecular one should be even easier.

[@joncrabb5926]

Man, I'm only in first year of a level chemistry so I don't understand this but I so want to this was a great video

[@totalsynthesis]

Nice, keep at it! Btw I'm working on another similar video so stay tuned

[@livingintheukandting]

Contrasting the classic and modern approaches was a good approach. This level of detail is just about perfect for undergrads, but as other people are saying more sterochem would be good - that's the hardest part!

[@totalsynthesis]

More advanced videos will be out in due time!

[@TheChrisBeattie]

Have to agree with ralph that I love the contrast of the classical approach with a series of simple robust steps, contrasted with a modern approach where the emphasis is on coupling reactions and rapid assembly of acyclic substrates.

[@grinreaperoftrolls7528]

So I did really well in organic chemistry, and it’s my favorite class I’ve ever taken. The lilly-woodward synthesis was pretty simple. It is, however, absolutely terrifying 😂

[@blib3786]

Why is it terrifying?

[@shayneoneill1506]

Some people just click with it. A good friend of mine was a terrible student, and took nearly 6 years to finish his chemistry degree (partly because we spent so much time in the student union bar lol) but was an absolute genius with org chem from the outset. Meanwhile I know people who are brilliant physicists who can do navier stokes equasions in their sleep but had to take org chem twice due to flunking it first time. As a coder, we have our own equivelent, academic database theory. Some people like just intuitively get the relational calculus from day 1, some never get it and struggle with database theory all their lives. Somewhat Scandalously, one of the guys who wrote one of the more common SQL database textbooks admitted to me he still doesnt understand relational joins. Frankly his book should be withdrawn from circulation, but who am I to say, I'm just a lowly guy who has to clean up the mess left by the people misled by this idiots book.

[@arturwojciechowicz3124]

Very good initiative.If J can suggest, two types videos(easier and advanced one) would be great on your channel.

[@arturwojciechowicz3124]

J'm waiting with excitement for new video, all in metaloorganic structures, at last it reached into me, thanks.

[@matthewabbott588]

yep I saw the indole to indoline. prob with any acid synth I thought and why woodward used the indoline and then oxidized too indole after making the back bone of the molecule first. lovely descriptions thankyou.

[@smxnke]

I wish I learned organic chem like this. I really wish I had a teacher like you.

[@totalsynthesis]

Thank you - new video coming, stay tuned

[@smxnke]

I'm hooked

[@whatcher8151]

@@totalsynthesis and a red light. Then a broom to stick between my legs and jump over camp fires, ouch.

[@pragyayadav2311]

Please make video more mechanism oriented and detailed about reagents used .......however very informative and interesting 👍👍

[@christobalgonzalez3529]

Thanks for showing me how to make it. I was missing one small piece of info that was the HyP- 21∆° ¶π /33°×¥ Now it all makes sense

[@feedmewifi_477]

having passed orgo 2 in the US, i am proud to say i understand more or less all of this

[@psychedguitar2716]

great video man thank you for sharing with us. btw if you talk next to the mic and not into the mic you will get less of those pops and will pick up less of that saturation you dont really need to pull it too far away from your face, Im a little bit of a sound geek. hope you keep making great videos.

[@borat1]

Man I’m a high school chemistry student but I suck at it. This makes me want to learn so I can do some fun stuff like this.

[@marcochimio]

Wonderful description. One question, though: Can you explain why the last mechanism required a hydride shift? Couldn't that same hydrogen be released as a proton, leaving it's bonding electrons to form a double bond, pushing the position of the other two double bonds, resulting in the quenching of the indole N's positive charge and the formation of a Zn-enolate? Then that enolate could rearrange to the ketone? I assume that I'm missing something obvious, but what? Thanks (I'm not an organic chemist, but I have some understanding of all of the steps you showed.)

[@Swagtildawn]

Absolutely love seeing stuff like this in regards to LSD and recreational drug use and not just lazy, biased stoner shit. Great video!

[@randypullman1155]

Bravo! Fairly entertaining. I enjoy the subject more than nile reds subjects. I do however like the hands on approach nile red uses. Often the final solution does not actually synthesize...quite interesting.

[@elguero933]

Total Synthesis is a worldly treasure and must be protected at all costs.

[@juttahullkone2365]

Please add some sound adsorbing panels to your studio and some compression to your audio processing. Thank you for your understanding. Great video.