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

Total Synthesis

12 Jun 201818:48

EducationalLearning

32 Likes 10 Comments

TLDRThis script explores the synthesis of lysergic acid, a precursor to LSD, with a focus on its legitimate medical uses. It delves into the history of LSD, the first total synthesis by Lillie and Woodward, and modern approaches including an asymmetric synthesis by Ono's team. The video aims to educate viewers on the evolution of synthetic strategies, the importance of retrosynthetic analysis, and the complexities of modern organic chemistry.

Takeaways

🚫 The video does not endorse the synthesis or use of illegal drugs, focusing instead on the legitimate medical uses of lysergic acid derivatives.
💊 Lysergic acid derivatives, such as bromocriptine and pergolide, are used in treating conditions like early-stage Parkinson's disease and type 2 diabetes.
📚 The video aims to educate viewers with varying levels of chemistry knowledge about the history and synthetic strategies of lysergic acid.
🧪 Swiss chemist Albert Hofmann first prepared LSD in 1938 at Sandoz Laboratories, modifying natural products from grain fungi.
📝 Hofmann's documentation of LSD's psychoactive effects is celebrated as 'Bicycle Day' by enthusiasts, highlighting his meticulous lab journaling.
🔍 The chemical structure of lysergic acid was determined in 1949, setting the stage for the first total synthesis reported in 1954.
🔬 The first total synthesis of lysergic acid was a collaborative effort between chemists at Lilly and Robert Burns Woodward, with Woodward consulting on the process.
🛠️ The synthesis process involved complex steps, including the use of Friedel-Crafts acylation, bromination, and aldol condensation reactions.
⚠️ The original synthesis used dangerous chemicals like hydrogen cyanide, highlighting the evolution of safer synthetic methods in modern chemistry.
🌐 A modern approach to lysergic acid synthesis, published in 2011, utilized asymmetric synthesis and transition metal-mediated coupling reactions for a more direct and efficient process.
🔬 The modern synthesis by Hiroki Ono and colleagues at Kyoto University demonstrated the importance of retrosynthetic analysis in planning complex chemical syntheses.

Q & A

What is lysergic acid and why is it significant?
-Lysergic acid is a precursor to the psychoactive drug LSD and is also used in the synthesis of medically significant drugs like bromocriptine, which treats Parkinson's disease and type 2 diabetes.
Who first synthesized LSD and when?
-Swiss chemist Albert Hofmann first synthesized LSD semi-synthetically in 1938 at Sandoz Laboratories.
What was the key discovery made by Albert Hofmann in 1943?
-In 1943, Albert Hofmann discovered the psychoactive properties of LSD through both accidental and intentional self-experiments.
What is the significance of 'Bicycle Day' in the context of LSD?
-'Bicycle Day' is celebrated by LSD enthusiasts to commemorate Albert Hofmann's first intentional LSD trip on April 19, 1943, when he rode his bicycle home while experiencing its effects.
Who were the key chemists involved in the first total synthesis of lysergic acid?
-The first total synthesis of lysergic acid was reported in 1954 by chemists at Eli Lilly and Company, including Robert Burns Woodward who served as a consultant.
Why did the Lilly-Woodward team use a dihydroindole system in their synthesis of lysergic acid?
-The dihydroindole system was used to decrease the reactivity of the indole system, preventing undesired side reactions and avoiding the isomerization to the more stable naphthalene system.
What was a major challenge in the Lilly-Woodward synthesis of lysergic acid?
-A major challenge was the high instability of intermediate compounds, such as the need to perform a cyanide substitution in liquid hydrogen cyanide (HCN), which is highly toxic.
How did the modern approach to synthesizing lysergic acid differ from the Lilly-Woodward method?
-The modern approach, such as the one published by Professor Hiroki Ono in 2011, employed more direct methods using transition metal-mediated coupling reactions and avoided hazardous conditions like using liquid HCN.
What was the purpose of the epoxide reduction step in the modern synthesis of lysergic acid?
-The epoxide reduction step aimed to regioselectively open the epoxide ring, setting up the necessary stereochemistry for further transformations.
What are some key considerations in the retrosynthetic analysis of lysergic acid?
-Key considerations include simplifying the target molecule step by step, selecting appropriate protecting groups to control reactivity, and anticipating possible side reactions and how to prevent them.

Outlines

00:00

🧪 Introduction to Lysergic Acid Synthesis

This paragraph introduces the topic of lysergic acid, a precursor to LSD, and clarifies that the video does not endorse illegal drug synthesis. It highlights the importance of natural product derivatives in medical treatments, such as bromocriptine for Parkinson's disease and metformin for type 2 diabetes. The script outlines the structure of the video, starting with the history of lysergic acid, moving on to the first total synthesis by Lillie and Woodward, and concluding with modern approaches to its synthesis. The video is aimed at a wide audience, from high school students to experts, and encourages viewers to stay for the parts they understand, with a promise of future videos on varying complexity.

05:03

🔬 Historical and Synthetic Strategies of Lysergic Acid

This paragraph delves into the history of lysergic acid synthesis, starting with its first preparation by Albert Hofmann in 1938. It discusses the semi-synthetic nature of early drug discovery and the accidental discovery of LSD's psychoactive properties. The paragraph then focuses on the first total synthesis of lysergic acid in 1954, clarifying that it was primarily the work of Lillie and Cornfeld, with Woodward as a consultant. The discussion includes the importance of retrosynthetic analysis in understanding the 'why' behind key synthetic steps and precautions, and the rationale behind choosing a dye hydro indole analog as a starting point to avoid side reactions and isomerization issues.

10:05

🛠️ The Lillie-Woodward Synthesis Process

This paragraph details the Lillie-Woodward synthesis of lysergic acid, starting from the partial hydrogenation of the starting material to the protection of the nitrogen as a benzoyl amide. It describes the Friedel-Crafts acylation, alpha bromination, and nucleophilic substitution to introduce the side chain. The synthesis includes an intramolecular aldol condensation, a series of functional group interconversions, and the use of dangerous chemicals like liquid HCN for the cyanide substitution. The paragraph highlights the expertise required to handle such reactive and hazardous materials and the challenges faced in the synthesis process.

15:05

🌟 Modern Approaches and Asymmetric Synthesis of Lysergic Acid

The final paragraph discusses modern approaches to lysergic acid synthesis, focusing on an asymmetric synthesis published by Hiroki Ono and colleagues in 2011. It contrasts the stepwise assembly of the Lillie-Woodward synthesis with a more direct approach that uses transition metal-mediated coupling reactions and a domino reaction to form two rings in one step. The paragraph explains the retrosynthetic analysis leading to the choice of starting materials and the key steps in the forward synthesis, including enantioselective epoxidation, the Mukaiyama coupling, and the Evans-Tishchenko reaction. It concludes with a discussion of the regioselective reduction of an epoxide and the unexpected formation of a ketone as a side product, emphasizing the unpredictability of chemical reactions and the importance of careful experimental design.

Mindmap

Keywords

💡Lysergic acid

Lysergic acid is a chemical compound and the precursor to the psychoactive drug LSD. It is significant in the video as it is the main subject of the synthesis discussion. The script explains that while it is known for its association with LSD, derivatives of lysergic acid are used in legitimate medical treatments, such as for Parkinson's disease and type 2 diabetes.

💡Semi-synthetic

Semi-synthetic refers to the process of modifying natural products to create new compounds, as mentioned in the context of bromocriptine, a derivative of lysergic acid used for medical purposes. The video discusses how semi-synthesis was crucial for accessing complex natural products and remains an important tool in drug discovery.

💡Total synthesis

Total synthesis is a chemical process where complex organic molecules are synthesized from simpler ones. The script outlines the historical context of lysergic acid's total synthesis, highlighting the work of chemists at Lilly and Robert Burns Woodward, which was a significant achievement in organic chemistry.

💡Retrosynthetic analysis

Retrosynthetic analysis is a method used by chemists to work backward from the target molecule to identify the precursors and reactions needed for its synthesis. The video emphasizes the importance of this approach in understanding the 'why' behind the key steps taken in the synthesis of lysergic acid.

💡Indole

Indole is an organic compound that contains a bicyclic structure with a benzene ring fused to a pyrrole. The script discusses the use of a dye hydro indole analog in the synthesis of lysergic acid, highlighting its reactivity and the challenges it presents in synthetic transformations.

💡Aldol condensation

The aldol condensation is a fundamental reaction in organic chemistry that involves the reaction of an enolate ion with a carbonyl compound to form a β-hydroxy aldehyde or ketone. The video describes this reaction as a key step in the synthesis of lysergic acid, allowing for the formation of one of the rings in the molecule.

💡Electrophilic aromatic substitution

Electrophilic aromatic substitution is a reaction where an electrophile reacts with an aromatic ring, substituting a hydrogen atom. The script uses this concept to explain the formation of the tricyclic system in the synthesis of lysergic acid, applying knowledge of this reaction to the synthetic strategy.

💡Protecting groups

Protecting groups are used in organic synthesis to 'disarm' or mask reactive functional groups, preventing unwanted side reactions. The video mentions the use of protecting groups to manage the high reactivity of the indole nitrogen during the synthesis process.

💡Asymmetric synthesis

Asymmetric synthesis refers to the creation of chiral molecules with a specific three-dimensional arrangement of atoms. The script discusses a modern approach to lysergic acid synthesis by Professor Hiroki Ono, which involves asymmetric synthesis techniques to create the desired stereochemistry.

💡Domino reaction

A domino reaction is a sequence of reactions where one reaction triggers another, leading to the formation of multiple chemical bonds in a single operation. The video describes a domino reaction in the modern synthesis of lysergic acid, where two rings are formed in one step, showcasing the evolution of synthetic methods.

💡Palladium-catalyzed coupling

Palladium-catalyzed coupling is a type of chemical reaction where palladium, a transition metal, is used as a catalyst to facilitate the formation of carbon-carbon bonds. The script mentions this type of reaction as a key step in the modern synthesis of lysergic acid, highlighting its utility in forming complex molecular structures.

Highlights

The video discusses the synthesis of lysergic acid, a precursor to LSD, and its legitimate medical uses, such as in treating early-stage Parkinson's disease and type 2 diabetes.

Lysergic acid derivatives, like bromocriptine and pergolide, have life-saving medical applications, highlighting the importance of natural product derivatives in total synthesis.

The video is structured to cover the history of lysergic acid, the first total synthesis by Lillie and Woodward, and a modern approach to its synthesis.

Albert Hofmann first prepared LSD in 1938 at Sandoz Laboratories, and its psychoactive properties were discovered in 1943, now celebrated as Bicycle Day.

The chemical structure of lysergic acid was determined in 1949, paving the way for the first total synthesis reported in 1954.

The Lillie-Woodward synthesis is often mistakenly attributed solely to Robert Woodward, when in fact, it was designed and executed by Lillie and Cornfeld, with Woodward as a consultant.

Retrosynthetic analysis is used to understand the reasoning behind the key steps and precautions in the Lillie-Woodward synthesis.

The synthesis involved protecting the lysergic acid nitrogen as a benzoyl amide and converting the acid to an acyl chloride for Friedel-Crafts acylation.

A key transformation in the synthesis was the intramolecular aldol condensation, which required careful deprotection and reintroduction of a protecting group.

The use of liquid hydrogen cyanide as a solvent for the cyanide substitution step highlights the expertise and risks taken by old-school chemists.

A modern approach to lysergic acid synthesis by Hiroki Ono and co-workers at Kyoto University in 2011 employed asymmetric synthesis and transition metal-mediated coupling reactions.

The modern synthesis featured a domino reaction to form two rings in one step, initiated by a palladium-catalyzed intramolecular aminopalladation.

The synthesis involved enantioselective epoxidation of alkenes and regioselective reduction of the epoxide, with unexpected side products observed.

The video emphasizes the unpredictability of real outcomes in chemistry and the importance of fine-tuning reaction conditions and rigorous lab analysis.

The video concludes by inviting feedback on the content structure, difficulty level, and suggestions for future videos on simpler or more complex syntheses.

Transcripts

Browse More Related Video

Síntesis de LSD (Dietilamida del ácido liségico)

Organic Chemistry - Retrosynthetic Analysis

Biginelli Reaction

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

Organic Synthesis by Retrosynthesis: Organic Chemistry PRACTICE PROBLEMS

Cannizzaro Reaction