18 Questions
What type of reaction partners are involved in the disconnection approach?
Homolytic and heterolytic
Which software was used for the retrosynthesis of cocaine in the text?
Organic Synthesis Exploration Tool (OSET)
What is the first step in the retrosynthetic analysis of cocaine synthesis?
Mannich reaction
What is the goal of retrosynthetic approaches in organic chemistry?
To find readily obtainable starting materials
Which type of reaction is a Mannich reaction?
Multicomponent condensation
What is the main purpose of using structure-based disconnection approaches in drug synthesis?
Trace back a drug to simple starting materials
What is the preferred intermediate ylide in the Wittig reaction to form a Z-isomer?
Non-stabilized intermediate ylide
What type of reaction is typically used for the alkylation of the primary amine in retrosynthesis?
SN2 reaction
Why do various barriers need to be considered in drug development?
To ensure drug reaches the target receptor or enzyme
What is a crucial consideration in drug development from the very beginning?
Delivery of drug to the intended target
Why is metabolic stability an important consideration in drug development?
To keep the drug around and prevent rapid elimination
What is the last step in the retrosynthesis mentioned in the text?
Alkylation of primary amine
What is the advantage of the Mannich reaction?
High product yield
What type of reaction is the condensation in the retrosynthesis?
Esterification
What does Aldol stand for?
Aldehyde and Alcohol
What is the next retrosynthetic step after the Aldol addition according to OTEC?
Aldol condensation
What is required after the reduction with zinc and hydrogen step?
Clean-up from by-products
How are the two aldehydes retrieved from a cyclohexene double-bond?
Selective ozonolysis
Study Notes
Wittig Reaction
- Allows for positioning of the double bond based on the use of the respective base and the halide
- Non-stabilized intermediate ylide of the phosphonium salt is preferred to form a Z-isomer
- Fast reaction with good yields of the product
- Phosphonium salt can be recycled in good amounts
- Clean-up required after this step
Alkylation of Primary Amine
- Occurs through a simple SN2 reaction
- Last step in the retrosynthesis
Drug Development
- Getting the drug to the intended target is a major consideration
- Various barriers need to be considered: intestinal barrier, blood-brain barrier, and metabolic stability
- These considerations often start early when a structure is considered for development
Mannich Reaction
- Intramolecular reaction leading to a bicyclic ring formation
- Occurs under acidic conditions to allow for loss of water
- Advantage: high product yield
Ester Formation
- Between the aromatic ring system and the acyclic system
- OSET illustrates this by using benzoic acid as the reactant
- Yield of the product and overall reaction conditions are more favorable if the substrate is an acid halide
Aldol Addition
- Actually an Aldol addition, not condensation, as no water is abstracted
- Occurs under basic conditions, where methyl hydrogen atoms adjacent to the aldehyde are acidic and can be abstracted
Selective Ozonolysis
- Creates a transition state of a peroxide and an ether
- Followed by reduction with zinc and elemental hydrogen to retrieve primarily aldehydes
- Clean-up required after this step
Disconnection Approach/Retrosynthesis
- A common approach in synthesizing complex molecules
- Involves disconnecting bonds via homolytic or heterolytic reactions
- Goal: find starting materials, solvents, and intermediates that are readily obtainable, cost-effective, and environmentally friendly
Explore the concept of retrosynthesis in organic chemistry, where bonds are disconnected via various reactions such as homolytic, heterolytic, and pericyclic reactions. Learn how functional groups are disconnected from the core molecule to achieve synthesis goals.
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