Asymmetric synthesis

Question 1

What is the definition of asymmetric synthesis?

Answer 1

A reaction that selectively creates a configuration of one or more new stereogenic (chiral) centres by the action of a chiral auxillary or chiral catalyst on a substrate (ie the synthesis of single enantiomers of chiral molecules).

Question 2

How do you calculate enantiomeric excess (% ee)?

Answer 2

% ee = %(major) - %(minor)

Question 3

Why do we need asymmetric synthesis?

Answer 3

The biological effect of the 2 enantiomers of chiral drugs/pharmaceuticals can be very different in the body because the receptors they bind to are composed of chiral proteins. Therefore one enantiomer can fit perfectly in the receptor and trigger a particular response, but the other enantiomer will not fit the same way which can cause serious side effects.

Question 4

What is the best way to tell if a molecule is chiral or not?

Answer 4

A chiral molecule does not have a plane or centre of symmetry in its structure when drawn in any conformation.

Question 5

What is a meso molecule?

Answer 5

A molecule with more than one stereogenic centre that is overall non-chiral.

Question 6

Name two other types of chiral molecules (other than with a carbon centre) and explain how they can be chiral

Answer 6

Sulfoxides and phosphines; the lone pair on sulfur/phosphorus can also be a substituent.

Question 7

Why are chiral amines so rare?

Answer 7

Because nitrogen inversion occurs too easily ie they very rarely have a fixed conformation.

Question 8

What are enantiomers?

Answer 8

The two mirror image forms of a chiral molecule; every stereocentre has the opposite configuration (as long as backbone has the ‘Vs’ the same way up).

Question 9

Explain the difference between configuration and conformation

Answer 9

A different conformation is a different molecule (eg R/S, cis/trans, syn/anti) whereas conformations of a molecule are readily interconvertible and are all the same molecule. Changing conformation= breaking bonds, changing conformation= rotating bonds.

Question 10

What is a diastereoisomer?

Answer 10

A stereoisomer (different stereocentre) that is not an enantiomer; ie not all of the stereogenic centres are the exact opposite.

Question 11

What is a racemic mixture?

Answer 11

A 50:50 ratio of the enantiomers.

Question 12

Why can a 50:50 (racemic) mixture of enantiomers be formed?

Answer 12

Reagent is non-chiral, attack on top and bottom faces is equally likely. The reaction proceeds via enantiomeric transition states; these have mirror images and so have the same activation energy.

Question 13

How does a chiral auxillary/chiral catalyst give preferential formation of one entnatiomer?

Answer 13

By using a chiral auxillary/catalyst, the transition states of the reaction are made diastereomeric, and sice diastereoisomers are different, the activation energy to access each diastereomeric transition state will be different. This means we have preferential of one (S or R) enantiomer over the other.

Question 14

What is a common method in synthesis for forming new stereogenic centres from aldehydes/ketones? Name some typical reagents

Answer 14

Nucleophillic addition to the C=O group. Typical nucleophiles include: reducing agents= source of H- (NaBH4 LiAlH4 BH4 AlH4), grignard and organolithium reagents= source of R- (R-MgX R-Li), enolates.

Question 15

What is the Burgi-Dunitz angle?

Answer 15

Approx 107 degrees- the trajectory attack of a nucleophile onto a C=O group. At 107 degrees, there is the best orbital overlap of the nucleophile HOMO with the C=O LUMO.

Question 16

Name the 3 ways of achieving high diastereoselectivity of nucleophillic addition to carbonyls

Answer 16

Cram chelation control, Felkin-Anh model, use of a CBS catalyst (ketones).

Question 17

What are the two things which kead to high diastereoselectivity in cram chelation control?

Answer 17

Conformation fix- the starting material hasa conformational preference.
Steric hindrance- once the conformation of the ketone is fixed then steric factors control which face of the C=O is preferentially attacked.

Question 18

How can you control the conformation in Cram chelation control?

Answer 18

The ketone structure: stereogenic centre alpha to the C=O group which has a heteroatom attached. The nucleophillic reagent: eg the Grignard reagent contains a Mg2+ ion. These can lead to a chelation effect to fix the conformation of the starting ketone; chelation occurs between Mg2+ (Grignard) and one of the O LPs of the C=O group and the heteroatom.

Question 19

How can you control the direction of attack of the nucleophile in Cram chelation control?

Answer 19

Once the conformation is fixed, in this case by chelation, then we can consider the steric hindrance involved on attacking each face of the C=O group on the Burgi-Dunitz trajectory. High steric hindrance= high energy transition state so minor product, vice versa for major product.

Question 20

What are the 2 requirements for Cram chelation control to occur?

Answer 20

1. Need a heteroatom at the carbon alpha to the C=O group which can donate a LP- oxygen and sulfur atoms with alkyl groups are the best (exception is OTBDMS as too sterically bulky to do chelation).
2. Need a metal cation that is a good chelating metal.

Question 21

What are the most common chelating metals?

Answer 21

Mg2+ Zn2+ (also Ti4+)

Question 22

When is the Felkin-Anh model used in asymmetric synthesis?

Answer 22

If there are no heteroatom/electronegative groups ie no chelating groups (so no Cram chelation control).

Question 23

What is the conformational fix in the Felkin-Anh model?

Answer 23

The lowest energy conformations will place the largest of the 3 substituents (on the alpha stereogenic centre) perpendicular to the C=O as this is the least sterically hindered position.

Question 24

How can the direction of attack be controlled in the Felkin-Anh model?

Answer 24

Once the conformation is fixed (largest group perpendicular to the C=O), then can consider the steric hindrance involved on attacking the C=O group on the Burgi-Dunitz trajectory from the face opposite to the large group.

Question 25

If there is a heteroatom at the alpha stereogenic centre, when can the Felkin-Anh model be used and what provides the conformational fix?

Answer 25

If the reagent does not have a chelating model (eg Na+or Li+) then a modified Felkin-Anh model can be used. The conformation fix is provided by placing ht emost electronegative atom (eg Cl) perpendicular to the C=O group.

Question 26

What is the difference between NaBH4 (ie BH4-) and BH3 and how does BH3 work together with the CBS catalyst?

Answer 26

BH4- (nucleophile) is negatively charged and can deliver a hydride to a C=O group quickly. BH3 is neutral (Lewis acid) and needs to complex to a lone pair on a heteroatom to give a Lewis acid-Lewis base complex before it will deliver a hydride to a C=O. Therefore, BH3 will only reduce the ketone very slowly.
The amine of the CBS catalyst will donate its lone pair to the BH3 and gives a very reactive borohydride-like species that will carry out the reduction.

Question 27

If there are 6 atoms in a cyclic structure in a transition state, what conformation are they likely to be in?

Answer 27

A chair conformation.

Question 28

If you have a Me and a Ph group in a chair conformation group, which will go axial and which will go equatorial?

Answer 28

Ph>Me so Ph will occupy the equatorial position; the least sterically hindered group goes axial.

Question 29

What 2 things are required in order to obtain high %ee in the transition state?

Answer 29

Conformational fix (chair conformation of the 6-membered transition state) and steric factors (largest substituent goes equatorial). Since the TS relies on a difference between the 2 groups on the ketone, the highest %ee will be obtained for examples with the largest difference in steric size between the groups.

Question 30

What substitution proceeds with inversion of stereochemistry?

Answer 30

SN2

Question 31

What is a chiral auxillary?

Answer 31

A chiral control element that is temporarily introduced into a substrate to direct the configuration of a new stereogenic centre in a reaction. The chiral auxillary should be easy to introduce and remove. `

Question 32

What are oxazolidinones used for?

Answer 32

Chiral auxillary in the asymmetric alpha-alkylation of enolates.

Question 33

How does the oxazolidinone provide a conformational fix?

Answer 33

Chelation of the Lithium enolate to C=O of the oxazolidinone and the steric hindrance of the iPr group on the bottom face.

Question 34

What can be used to remove the oxazolidinone chiral auxillary?

Answer 34

LiOH or 2Equivalents of LIAlH4 then H+

Question 35

Name 2 ways of purifiying an organic product

Answer 35

Column chromatography and recrystallisation (if solid).

Question 36

Name the 3 steps in the asymmetric alpha-alkylation using a chiral auxillary.

Answer 36

1. Synthesis of the chiral auxillary
2. Synthesis of the acid chlorides
3. Diastereomeric products and ‘purification’

Question 37

Describe the advantages and disadvantages of using a chiral auxillary

Answer 37

Advantages: Diastereomers can be purified to improve %ee of product, chiral auxillary can be removed and recovered.
Disadvantages: Extra steps in the synthesis to put on/take off the chiral auxillary, a soichiometric amount of the chirality is needed (more than in asymmetric catalysis where low mol% of chiral ligand/catalyst is typically used).

Question 38

What is an Aldol reaction?

Answer 38

Alpha-deprotonation of an amide using a strong base such as LDA, followed by reaction with an aldehyde as the electrophile. It forms a bond between the C2-C3 carbons in the product which is known as a 1,3-hydroxyamide.

Question 39

What do the terms syn-/anti- refer to in Aldol reactions?

Answer 39

Describe the relative stereochemistry of the group at the alpha-position to the C=O in the starting material and the OH from the aldehyde.

Question 40

How can an asymmetric version of the syn-Aldol reaction be designed?

Answer 40

Use an oxazolidinone as a chiral auxillary.

Question 41

What is used to remove a TBDMS group?

Answer 41

TBAF

Question 42

How does the conformational fix differ in the asymmetric syn-Aldol reaction using oxazolidinones compared to enolate alpha-alkylation?

Answer 42

In the asymmtric syn-Aldol reaction, the conformational fix comes from dipoles pointing in opposite directions.

Question 43

How can an asymmetric version of the anti-Aldol reaction be designed?

Answer 43

Use (S)-proline as a catalyst (10mol%) in DMF solvent at 4 degrees C.

Question 44

Where does the conformational fix come from in the anti-Aldol reaction?

Answer 44

2 hydrogen bonds to the carboxylic acid proton on the (S)-proline catalyst: intramolecular H-bond to the amine, intermolecular H-bond to the O of the aldehyde.

Question 45

For assigning R/S stereochemistry, which configuration is CW and which is ACW?

Answer 45

CW= R, ACW= S.

Question 46

What is the difference between stereospecific and stereoselective reactions?

Answer 46

Stereospecific reactions lead to the production of a single isomer (enantiomer or diastereomer) as a direct result of the mechanism of the reaction and the stereochemistry of the starting material. There is no choice; the reaction gives a different stereoisomer of the product from each stereoisomer of the starting material.
Stereoselective reactions give one predominant product (enantiomer or diastereomer) because the reaction pathway has a choice. Either the pathway of lower Ea is preferred (kinetic control) or the more stable product is preferred (thermodynamic control).