The Chiral Pool and Resolution Strategies Flashcards
Why do we require reliable and predictable methods for stereocontrolled synthesis
- n Stereocentres in a molecules means there are up to 2^n stereoisomers- bad when large amounts of stereocentres
- Poor stereocontrol in synthesis is inelegant and wasteful
- Absolute and relative structure determination by synthesis
- Each enantiomer of a chiral molecule frequently has a different biological activity - react with receptors differently
- Pharmaceutical companies required to develop chiral drugs as single enantiomers
Name 4 compounds where their enantiomer has different properties
- Carvone
- penicillamine
- Thalidomide
- Aspartame
Where are enantiopure starting materials found
- Commonly available enantiopure molecules which are often naturally-occurring are often referred to as the chiral pool
What are the 4 types of starting material found in the chiral pool
- Amino acids
- Sugars
- Terpenes
- Hydroxy acids
What does the term chiral pool synthesis mean
- Often used for synthetic endeavours that build up complex natural products form simple chiral pool building blocks
What are the pros of chiral pool synthesis
- Potentially cheap
- Good availability
- Sustainability
- Academic challenge
What are the cons of chiral pool synthesis
- Structural restrictions - sometimes starting material is not suited to the product
- Single enantiomer availability - amino acids only available in s form until recently
- Low yield
Describe amino acids use in chiral pool synthesis
- alpha-amino acids are useful for medicinal as contain N
- Historically only (S)-alpha-amino acids were readily available from nature in large amounts via hydrolysis of proteins
- Both enantiomers now available from bacterial fermentation processes- (R)-enantiomers are more expensive
Describe how sugars are used in chiral pool synthesis
- A range or pyranose carbohydrates from nature
- Exist as an equilibrium between open chain and closed ring form - hexose <–>pyranose form
- Ideal for consideration in polyoxygenated contexts
- Cost and availability is directly related to natural abundance
- Diastereomers
What is an issue with using sugars
- Very highly oxygenated
- Need to remove some hydroxyl groups as not useful
- But can make bio OH for fuel by chopping up
Give an example of how sugars are used in drug synthesis
- Na/glucose co-transported SGLT2 is mainly expressed in the kidneys which is responsible for 90% glucose reabsorption in humans
- SGLT1 inhibitors work by blocking the reabsorption of glucose in the kidneys preventing the build up of glucose in blood - allowing elimination in urine- good for diabetes
- Drug candidate AP1 was developed as an inhibitor of SGLT1
Describe synthetic process of producing AP1
- Start with pyranose and Bn groups protecting free OH except on anomeric carbon
- TEMPO/bleach, NaHCO3 used to oxidise anomeric OH to =O
- Br-R-Et, n-BuLi added to anomeric carbon at Br, reducing =O to OH
- Adds selectively to top face creating new stereocentre- controlled
- BF3.OEt2/ i-Pr3SiH used to reduce out OH group
- H2, Pd/C used to deprotect OHs
Describe how D-mannitol is used to form D-glyceraldehyde acetonide
- Generates two molecules for every one D-mannitol
- Selectively protect terminal Hydroxyl group to form a bis-keta, using MeO-R-OMe
- Then oxidise remaining OH to =O and cleave across C-C bond using NaIO3 and NaHCO3- periodate cleavage
What can D-glyceraldehyde acetonide be used for
- Synthesis of a wide range of complex natural products
- With its aldehyde and protected diol fragments employed as handles to introduce functional groups and control stereoselectivity
Describe how terpenes can be used in chiral pool synthesis
- Offer a wide range of commercial hydrocarbon-rich building blocks
- Terpene have a large level of structural variety
- Often both enantiomers are available
- Cost per unit mass or volume can be very low
- Most widely available are those from turpentine
What do terpenes usually look like
- Monocyclic
- 6-membered ring
- Isopropyl group at bottom
Describe production of (-)-carvone
- From (+)-limonene - cheaper monoterpene acts as chiral building block for carvone
- Add NOCl
- Add Base
- Add H3O+
- Produces (-)-carvone
When may you want to do resolution of a racemic compound
- It can be more efficient to do resolution by selective crystallisation of diastereomeric salts
- When its easier to make a racemic compound then separate into enantiomers
Why is selective crystallisation frequently possible
- Diastereomeric salts like diastereomers, have different physical properties including melting points and solubility
Can you separate enantiomers by themselves
- No - have identical physical properties
How can you separate enantiomers
- React a racemic mix of acids with an enantiopure molecule
- Enantiomers of starting product will be converted to diastereomers which can then be separated
- Can then transfer back to original enantiomers to obtain in pure form
What are 3 methods used to separate racemic compounds
- Selective crystallisation
- Chiral chromatography
3.
Describe how chiral chromatography is used
- Separate a mixture of compounds by chromatography on a chiral (non-racemic) column
If you had a mixture of diastereomers how would you carry out HPLC to separate
- Add mix of diastereomers (S,S) and (R,S) to a column with an achiral stationary phase e.g. SiO2 (Silica)
- Diastereomers have different affinity for stationary phase and flow through column at different rates resulting in separation- elute separately
What would happen if you put a mix of enantiomers in a column with an achiral stationary phase
- Enantiomers have same physical properties
- Same affinity for stationary phase and flow through column at same rates
- No separation results- would elute together
How would you separate a mix of enantiomers using HPLC
- Use a chiral stationary phase
- Silica with a chiral modifier
- Enantiomers flowing down the chiral column have diastereomeric interactions with the chiral stationary phase and hence flow through the column at different rates
- R and S elute separately
Describe laboratory scale chiral separations
- Chiral HPLC often used to determine enantiomeric excess and to separate enantiomers of drug candidates for biological testing
What are the pros of lab scale chiral HPLC
- Efficient
- Rapid access to enantiopure compound
What is con of lab scale chiral HPLC
- Difficult to scale up for large amounts
What method would you use if you want a large amount of a material
- Selective fractional crystallisation
- Derivatisation with a chiral reagent affords diastereomeric salts
If you had a chiral amine - enantiomer racemic how would you produce on a large scale
- Racemic amine + enantiopure acid
- Salt formation- pair of diastereomeric salts
- One more crystalline than the other- precipitates out so can be filtered
- Neutralise with NaOH to produce amine
What is advantages of using fractional recrystallisation
- Rapidly produce larger amount of chiral products for drug synthesis
What is a con of using fractional recrystallisation
- Screen significant number of chiral acids to identify diastereomers which will differentially precipitate
- Max yield is 50%- only 1 enantiomer and rest is waste
