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

Total Synthesis
17 Feb 202307:04
EducationalLearning
32 Likes 10 Comments

TLDRThis video script delves into the recent advancements in the synthesis of LSD, highlighting a new method that reduces the process to just six laboratory steps. It explores the scientific rationale behind creating LSD analogs for potential therapeutic uses, such as the treatment of neurological and metabolic disorders. The script also discusses the importance of eliminating hallucinogenic side effects while retaining the psychoplastic properties of these compounds. Furthermore, it explains how chemists measure a molecule's 'trippiness' and provides a step-by-step breakdown of the synthesis process, emphasizing the efficiency and potential for drug discovery.

Takeaways
  • 📚 The video is purely educational, discussing the synthesis of LSD without promoting the creation of illegal substances.
  • 👩‍🔬 A new, more efficient method for synthesizing LSD has been developed, reducing the process to only 6 laboratory steps.
  • 🧪 The synthesis involves an intramolecular Heck reaction, a key step in creating the vinyl bond present in LSD.
  • 💡 LSD derivatives have potential pharmacological uses, such as treating neurological and metabolic disorders.
  • 🧬 Recent studies show that psychedelic compounds can be modified to lose hallucinogenic effects while retaining psychoplastogenic properties.
  • 🐭 Mice's head twitching is a validated method to estimate the 'trippiness' of a molecule, used for 70 years.
  • 🔬 The new synthesis route starts with a commercially available indole containing an aldehyde and a bromo group.
  • 🛠️ The synthesis includes steps like magnesium-halogen exchange, reduction, protection/deprotection, and isomerization.
  • 🌟 The final product of the synthesis is a brown solid, not suitable for distribution but useful for studying LSD analogs.
  • 🔄 The synthetic route can be adapted to create different LSD analogs, aiding in the discovery of future therapeutic drugs.
Q & A

  • What was the main topic of the video?

    -The main topic of the video was the discussion of a new, more efficient synthesis method for LSD, which involves only six laboratory steps, and its potential applications in drug discovery and the study of LSD analogs.

  • What was the significance of the history and total syntheses of lysergic acid discussed in the video?

    -The history and total syntheses of lysergic acid were significant because they provided context for the development of the new, more efficient LSD synthesis method. The older methods were lengthy, involving more than a dozen chemical steps, which the new method aims to simplify.

  • Why would scientists investigate more chemical syntheses of LSD?

    -Scientists investigate more chemical syntheses of LSD because LSD derivatives can be pharmacologically useful for the treatment of neurological, metabolic, and other disorders. More efficient synthesis methods can aid in drug discovery and the development of new therapeutic agents.

  • How do chemists measure the psychoactive potency of a molecule?

    -Chemists can estimate the psychoactive potency of a molecule by observing how often mice violently shake their heads after administration of psychoactive drugs. This is a well-validated proxy for hallucinations and has been used for about 70 years.

  • What is the key bond disconnection in the new LSD synthesis method?

    -The key bond disconnection in the new LSD synthesis method is an intramolecular Heck reaction, which creates the key vinyl bond present in LSD.

  • What is the starting material for the new synthesis route?

    -The starting material for the new synthesis route is an indole containing an aldehyde, which already has the bromo group necessary for the Heck reaction and can be purchased commercially.

  • What is the significance of the isomerization step in the synthesis process?

    -The isomerization step is significant because it moves the olefin to the necessary carbon position to enable the key Heck coupling reaction. This is achieved using LiTMP as a strong base to create the isomerized anion, which can then be protonated in a diastereoselective manner.

  • How many different products were formed in the final step of the synthesis?

    -In the final step of the synthesis, three different products were formed. However, they were all combined and treated with potassium hydroxide to yield lysergic acid.

  • What was the yield of the final product in the synthesis?

    -The yield of the final product, lysergic acid, was around 50%.

  • How can the new synthetic route be useful for studying LSD analogs?

    -The new synthetic route can be useful for studying LSD analogs by allowing scientists to create different derivatives through functionalization of the aryl chloride group. This could potentially lead to the discovery of future drugs with differentiated therapeutic profiles based on LSD.

Outlines
00:00
📚 Introduction to LSD Synthesis and its Applications

This paragraph introduces the educational and theoretical nature of the video, emphasizing that it does not promote the creation of illegal substances. It revisits the history and synthesis of lysergic acid, the precursor to LSD, and highlights a recent development in synthesizing LSD in just six laboratory steps. The discussion delves into the reasons behind investigating LSD syntheses further, such as the pharmacological utility of LSD derivatives in treating various disorders. It also touches on a study that shows the potential of engineering psychedelic compounds to retain their beneficial properties while losing hallucinogenic side effects. The segment concludes with a mention of the video creator's membership options for supporting the channel.

05:05
🧪 Detailed Mechanism of the Efficient LSD Synthesis Route

This paragraph delves into the specifics of the newly developed synthesis route for LSD, which is based on an intramolecular Heck reaction. It outlines the key bond disconnection and the convenience of the starting material, which is commercially available and already contains the necessary bromo group for the reaction. The summary walks through each step of the synthesis, from the magnesium-halogen exchange to the final reduction and isomerization processes. It also discusses the challenges of stereochemistry and the various products formed, which are then converted into lysergic acid. The paragraph concludes by highlighting the potential of this synthetic route for exploring and studying LSD analogs, which could lead to the discovery of future drugs with therapeutic profiles based on LSD.

Mindmap
Keywords
💡LSD
LSD, or lysergic acid diethylamide, is a well-known psychoactive drug derived from lysergic acid. In the video, the focus is on the history and various methods of synthesizing LSD, including a new, more efficient synthesis process. The significance of LSD in the video is not only its cultural impact but also its potential for scientific research, such as in the development of new drugs for neurological and metabolic disorders.
💡Chemical synthesis
Chemical synthesis refers to the process of creating a new compound from simpler substances. In the context of the video, it is the method by which LSD and its analogs are produced. The video highlights a recent advancement in the synthesis of LSD that reduces the number of steps required, making the process more efficient and potentially more accessible for scientific research.
💡Psychoactive drugs
Psychoactive drugs are substances that affect the mind, emotions, and behavior. In the video, LSD is a prime example of a psychoactive drug, with its well-known effects on perception and cognition. The discussion of psychoactive drugs in the video is not only for their recreational use but also for their potential therapeutic applications, such as in the treatment of neurological disorders.
💡Structure-activity relationship
Structure-activity relationship (SAR) is a fundamental concept in pharmacology and toxicology that describes the relationship between the chemical structure of a molecule and its biological effects. In the video, a study on psychedelic compounds like DMT is mentioned, which shows how altering the structure can reduce hallucinogenic side effects while retaining beneficial properties. This concept is crucial for the development of new drugs with improved therapeutic profiles.
💡Head twitching
Head twitching is a behavioral response in mice that has been validated as a proxy for hallucinations caused by psychoactive drugs. In the video, this phenomenon is used to estimate the 'trippy-ness' or hallucinogenic potency of different molecules, such as 5-methoxy-DMT and its isomer. This method provides a way to assess the effects of psychoactive compounds in a controlled and ethical manner.
💡Heck reaction
The Heck reaction is a chemical reaction used in organic synthesis to form a carbon-carbon bond, typically between an aryl or vinyl halide and an alkene. In the video, the Heck reaction is a key step in the new, more efficient synthesis of LSD, where it is used to create the vinyl bond present in the LSD molecule. The use of the Heck reaction in this context demonstrates its importance in modern synthetic chemistry and drug development.
💡Indole
Indole is an organic compound that is a core structure in many biologically important molecules, including LSD and other alkaloids. In the video, the starting material for the synthesis of LSD contains an indole ring, which is a key structural component that is functionalized through various chemical reactions. The indole ring's presence and its subsequent transformations are central to the synthesis process described in the video.
💡Nucleophilic addition
Nucleophilic addition is a type of chemical reaction where a nucleophile, an electron-rich species, adds to an electrophile, an electron-poor species. In the video, the magnesium-halogen exchange creates a nucleophilic species that adds to the electrophilic carbon of a functionalized aldehyde, which is a critical step in the synthesis of LSD. This reaction is fundamental to the formation of new chemical bonds in organic synthesis.
💡Protecting groups
Protecting groups are temporary modifications made to certain functional groups in a molecule to prevent unwanted reactions during a synthesis. In the video, the N-Boc protecting group is removed and then reinstalled during the synthesis of LSD. The use of protecting groups is a strategic approach in organic synthesis to control the reactivity of specific sites in a molecule, allowing for selective reactions.
💡Methylation
Methylation is a chemical reaction where a methyl group (-CH3) is added to a molecule. In the video, after the pyridine nitrogen is protected, it becomes the most nucleophilic group and is methylated with methyl triflate. This process is part of the functionalization of the molecule, which is necessary for the synthesis of LSD and its analogs.
💡Isomerization
Isomerization is a chemical reaction that results in the rearrangement of atoms within a molecule, leading to the formation of isomers. In the video, an isomerization is achieved using LiTMP as a strong base, which allows for the olefin to be located at the desired carbon for the Heck coupling reaction. This step is critical for setting up the correct stereochemistry needed for the synthesis of LSD.
💡Deprotection
Deprotection is the chemical process of removing a protecting group from a molecule. In the video, after the synthesis is complete, a double-deprotection step is used to yield lysergic acid. This step is essential in revealing the final product of the synthesis and is part of the overall strategy to obtain the desired compound with the correct functional groups and stereochemistry.
Highlights

The video discusses a new synthesis method for LSD that only requires 6 laboratory steps, a significant reduction from previous methods.

The history and total syntheses of lysergic acid, the precursor of LSD, are reviewed in the video.

The importance of efficient LSD synthesis for drug discovery and treatment of neurological and metabolic disorders is emphasized.

A study in 2020 showed that psychedelic compounds can be engineered to lose hallucinogenic side effects while retaining useful properties.

The video explains how chemists measure the 'trippiness' of a molecule through a well-validated method involving mice.

The synthesis is based on an intramolecular Heck reaction, a key innovation in creating the vinyl bond present in LSD.

The starting material for the synthesis is commercially available and contains a bromo group for the Heck reaction.

The first step of the synthesis involves a magnesium-halogen exchange to create a heterocyclic nucleophile.

The intermediate product is efficiently traced back to an indole containing an aldehyde, which is advantageous for further reactions.

The synthesis includes a reduction step with triethylsilane to remove a hydroxyl group, followed by re-installation of the N-Boc protecting group.

Methylation of the pyridine nitrogen with methyl triflate is performed to create a pyridinium salt, which is then reduced.

The Heck reaction proceeds with the standard mechanism, creating the C-C bond crucial for LSD structure.

Two beta-hydrogens lead to two elimination pathways, with the preferred one forming a product with the ester on the same side as the existing hydrogen.

The final products are obtained through a double-deprotection and isomerization step, yielding lysergic acid.

The synthetic route is demonstrated to be useful for exploring and studying LSD analogs, potentially leading to future therapeutic drugs.

The video concludes by highlighting the potential of this research in creating LSD analogs with differentiated therapeutic profiles.

Transcripts

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