The Chiral Pool and Resolution Strategies

Question 1

Why do we require reliable and predictable methods for stereocontrolled synthesis

Answer 1

1. n Stereocentres in a molecules means there are up to 2^n stereoisomers- bad when large amounts of stereocentres
2. Poor stereocontrol in synthesis is inelegant and wasteful
3. Absolute and relative structure determination by synthesis
4. Each enantiomer of a chiral molecule frequently has a different biological activity - react with receptors differently
5. Pharmaceutical companies required to develop chiral drugs as single enantiomers

Question 2

Name 4 compounds where their enantiomer has different properties

Answer 2

1. Carvone
2. penicillamine
3. Thalidomide
4. Aspartame

Question 3

Where are enantiopure starting materials found

Answer 3

1. Commonly available enantiopure molecules which are often naturally-occurring are often referred to as the chiral pool

Question 4

What are the 4 types of starting material found in the chiral pool

Answer 4

1. Amino acids
2. Sugars
3. Terpenes
4. Hydroxy acids

Question 5

What does the term chiral pool synthesis mean

Answer 5

1. Often used for synthetic endeavours that build up complex natural products form simple chiral pool building blocks

Question 6

What are the pros of chiral pool synthesis

Answer 6

1. Potentially cheap
2. Good availability
3. Sustainability
4. Academic challenge

Question 7

What are the cons of chiral pool synthesis

Answer 7

1. Structural restrictions - sometimes starting material is not suited to the product
2. Single enantiomer availability - amino acids only available in s form until recently
3. Low yield

Question 8

Describe amino acids use in chiral pool synthesis

Answer 8

1. alpha-amino acids are useful for medicinal as contain N
2. Historically only (S)-alpha-amino acids were readily available from nature in large amounts via hydrolysis of proteins
3. Both enantiomers now available from bacterial fermentation processes- (R)-enantiomers are more expensive

Question 9

Describe how sugars are used in chiral pool synthesis

Answer 9

1. A range or pyranose carbohydrates from nature
2. Exist as an equilibrium between open chain and closed ring form - hexose <–>pyranose form
3. Ideal for consideration in polyoxygenated contexts
4. Cost and availability is directly related to natural abundance
5. Diastereomers

Question 10

What is an issue with using sugars

Answer 10

1. Very highly oxygenated
2. Need to remove some hydroxyl groups as not useful
3. But can make bio OH for fuel by chopping up

Question 11

Give an example of how sugars are used in drug synthesis

Answer 11

1. Na/glucose co-transported SGLT2 is mainly expressed in the kidneys which is responsible for 90% glucose reabsorption in humans
2. 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
3. Drug candidate AP1 was developed as an inhibitor of SGLT1

Question 12

Describe synthetic process of producing AP1

Answer 12

1. Start with pyranose and Bn groups protecting free OH except on anomeric carbon
2. TEMPO/bleach, NaHCO3 used to oxidise anomeric OH to =O
3. Br-R-Et, n-BuLi added to anomeric carbon at Br, reducing =O to OH
4. Adds selectively to top face creating new stereocentre- controlled
5. BF3.OEt2/ i-Pr3SiH used to reduce out OH group
6. H2, Pd/C used to deprotect OHs

Question 13

Describe how D-mannitol is used to form D-glyceraldehyde acetonide

Answer 13

1. Generates two molecules for every one D-mannitol
2. Selectively protect terminal Hydroxyl group to form a bis-keta, using MeO-R-OMe
3. Then oxidise remaining OH to =O and cleave across C-C bond using NaIO3 and NaHCO3- periodate cleavage

Question 14

What can D-glyceraldehyde acetonide be used for

Answer 14

1. Synthesis of a wide range of complex natural products
2. With its aldehyde and protected diol fragments employed as handles to introduce functional groups and control stereoselectivity

Question 15

Describe how terpenes can be used in chiral pool synthesis

Answer 15

1. Offer a wide range of commercial hydrocarbon-rich building blocks
2. Terpene have a large level of structural variety
3. Often both enantiomers are available
4. Cost per unit mass or volume can be very low
5. Most widely available are those from turpentine

Question 16

What do terpenes usually look like

Answer 16

1. Monocyclic
2. 6-membered ring
3. Isopropyl group at bottom

Question 17

Describe production of (-)-carvone

Answer 17

1. From (+)-limonene - cheaper monoterpene acts as chiral building block for carvone
2. Add NOCl
3. Add Base
4. Add H3O+
5. Produces (-)-carvone

Question 18

When may you want to do resolution of a racemic compound

Answer 18

1. It can be more efficient to do resolution by selective crystallisation of diastereomeric salts
2. When its easier to make a racemic compound then separate into enantiomers

Question 19

Why is selective crystallisation frequently possible

Answer 19

1. Diastereomeric salts like diastereomers, have different physical properties including melting points and solubility

Question 20

Can you separate enantiomers by themselves

Answer 20

1. No - have identical physical properties

Question 21

How can you separate enantiomers

Answer 21

1. React a racemic mix of acids with an enantiopure molecule
2. Enantiomers of starting product will be converted to diastereomers which can then be separated
3. Can then transfer back to original enantiomers to obtain in pure form

Question 22

What are 3 methods used to separate racemic compounds

Answer 22

1. Selective crystallisation
2. Chiral chromatography
   3.

Question 23

Describe how chiral chromatography is used

Answer 23

1. Separate a mixture of compounds by chromatography on a chiral (non-racemic) column

Question 24

If you had a mixture of diastereomers how would you carry out HPLC to separate

Answer 24

1. Add mix of diastereomers (S,S) and (R,S) to a column with an achiral stationary phase e.g. SiO2 (Silica)
2. Diastereomers have different affinity for stationary phase and flow through column at different rates resulting in separation- elute separately

Question 25

What would happen if you put a mix of enantiomers in a column with an achiral stationary phase

Answer 25

1. Enantiomers have same physical properties
2. Same affinity for stationary phase and flow through column at same rates
3. No separation results- would elute together

Question 26

How would you separate a mix of enantiomers using HPLC

Answer 26

1. Use a chiral stationary phase
2. Silica with a chiral modifier
3. Enantiomers flowing down the chiral column have diastereomeric interactions with the chiral stationary phase and hence flow through the column at different rates
4. R and S elute separately

Question 27

Describe laboratory scale chiral separations

Answer 27

1. Chiral HPLC often used to determine enantiomeric excess and to separate enantiomers of drug candidates for biological testing

Question 28

What are the pros of lab scale chiral HPLC

Answer 28

1. Efficient
2. Rapid access to enantiopure compound

Question 29

What is con of lab scale chiral HPLC

Answer 29

1. Difficult to scale up for large amounts

Question 30

What method would you use if you want a large amount of a material

Answer 30

1. Selective fractional crystallisation
2. Derivatisation with a chiral reagent affords diastereomeric salts

Question 31

If you had a chiral amine - enantiomer racemic how would you produce on a large scale

Answer 31

1. Racemic amine + enantiopure acid
2. Salt formation- pair of diastereomeric salts
3. One more crystalline than the other- precipitates out so can be filtered
4. Neutralise with NaOH to produce amine

Question 32

What is advantages of using fractional recrystallisation

Answer 32

1. Rapidly produce larger amount of chiral products for drug synthesis

Question 33

What is a con of using fractional recrystallisation

Answer 33

1. Screen significant number of chiral acids to identify diastereomers which will differentially precipitate
2. Max yield is 50%- only 1 enantiomer and rest is waste