Asymmetric Synthesis Flashcards
What is the definition of asymmetric synthesis?
Asymmetric synthesis is a reaction that selectively creates one configuration of one or more new stereogenic centres by the action of a chiral auxiliary or chiral catalyst on a substrate.
What is the definition of enantiomeric excess?
Enantiomeric excess (%ee) = % of major product - % of minor product
Why do we need asymmetric synthesis?
The biological effect of two enantiomers of a chiral drug or pharmaceutical can be very different in the body. This is because the receptors where they bind and act are composed of chiral proteins. One enantiomer could fit perfectly in the receptor and give a particular response. The other enantiomer will have the wrong stereochemistry and will not fit in the receptor in the same way. It may do nothing or it may give a different biological response with serious side effects.
How can we tell whether a molecule is chiral?
A molecule is chiral if it does not have a plane or centre of symmetry when drawn in any conformation.
What is the definition of a meso molecule?
A meso molecule is a molecule with more than one stereogenic centre that is overall non-chiral.
How can molecules containing sulfur or phosphorous be chiral?
A lone pair of electrons on sulfur or phosphorous can act as a substituent, which can make the molecule chiral if there is not a plane of symmetry.
Why are chiral amines very rare?
Eventhough nitrogen has a lone pair of electrons that can act as a substituent, nitrogen inversion occurs very easily so chiral amines are very rare.
Give an example of a chiral molecule with no stereogenic centres.
Allenes that do not have a plane of symmetry can exhibit axial chirality.
For example:
What are enantiomers?
Enantiomers are the two mirror image forms of a chiral molecule. They have the same properties except in the presence of other chiral molecules or in their interaction with plane polarised light.
How can you draw enantiomers?
You can draw enantiomers by drawing the compound with every stereogenic centre in the opposite configuration. To do this, keep the bonds in the plane of the paper the same (make sure the “V” still points up) and then swap over the “up” and “down” groups.
What is the difference between configuration and conformation?
Changing the configuration of a molecule means that bonds are broken. A different configuration is a different molecule. Configuration is described by (R)/(S), cis/trans or syn/anti.
Changing the conformation of a molecule means rotating about bonds, but not breaking them. Conformations of a molecule are all the same molecule.
What is a diastereoisomer?
A diastereoisomer is a stereoisomer that is not an enantiomer. Two diastereoisomers have different properties (e.g. NMR, solubility, melting point, column chromatography).
When is a racemic mixture of enantiomers formed from the reduction of a ketone?
A racemic (50:50) mixture of enantiomers is formed when the reagent is non-chiral. Attack on the top and bottom faces of the ketone is equally likely. The reaction proceeds via enantiomeric transition states which have the same activation energy.
The transition states can be made diastereoisomeric by using a chiral auxiliary or chiral catalyst.
What is the Burgi-Dunitz angle?
The trajectory of attack of a nucleophile on to a C=O group is approximately 107º and is known as the Burgi-Dunitz angle. This gives the optimal orbital overlap of the nucleophile HOMO with the C=O LUMO (i.e. π*C=O).
What are the three different ways of achieving high diastereoselectivty when a nucleophile is added to C=O?
- Cram chelation control
- Felkin-Anh model with no heteroatom or electronegative group
- Felkin-Anh model with a heteroatom or electronegative group
What controls the conformation of a chiral ketone in the Cram chelation model?
The ketone must contain a stereogenic centre α to the C=O group which has a heteroatom attached. The nucleophilc reagent must contain a good chelating metal (e.g. Mg2+, Zn2+ or Ti4+).
Chelation occurs between the metal ion and one of the oxygen lone pairs on the C=O group and one of the lone pairs of the heteroatom. This gives the conformation fix.
The C=O and heteroatom must be aligned in order to form the chelate.
What controls the direction of attack in the Cram chelation model?
It is more sterically favourable if the nucleophile attacks over the sterically small substituent at the Burgi-Dunitz angle (107º). because the activation energy for accessing the transition state will be lower. This will give the major product.
The original stereogenic centre will be unchanged.
What controls the conformation in the the Felkin-Anh model with no heteroatom or electronegative group?
The lowest energy conformation will place the largest of the three substituents at the stereogenic centre perpendicular to the C=O as this is the least sterically hindered position.
It is important to consider the steric hindrance caused by the first atom in the group, not the overall size of the group.
What controls the direction of attack in the Felkin-Anh model with no heteroatom or electronegative group?
The nucleophile will attack the face opposite the large group at the Burgi-Dunitz angle (107º). It is sterically favourable for the nucleophile to attack over the sterically small group at the Burgi-Dunitz angle because the activation energy for accessing the transition state will be lower. This will give the major product.
The original stereogenic centre is unchanged.
What controls the conformation in the Felkin-Anh model with a heteroatom or electronegative group?
The most electronegative atom is placed perpendicular to the C=O group as this gives the most reactive conformation.
What controls the direction of attack in the Felkin-Anh model with a heteroatom or electronegative group?
The nucleophile adds opposite to the electronegative group over the sterically smallest group at the Burgi-Dunitz angle (107º). The activation energy for accessing this transition state will be the lowest so it will produce the major product.
What is the definition of mol %?
1 molar equivalent of a reagent = 100 mol %
- 1 molar equivalents of a reagent = 10 mol %
- 01 molar equivalents of a reagent = 1 mol %
Ideally, we want the mol % of the catalyst to be as small as possible.
What reagents are required for the asymmetric reduction of a ketone using the CBS catalyst?
1 molar equivalent of BH3 is required because each BH3 molecule transfers just one hydride to each ketone molecule. Typically, 10 mol % of the chiral CBS catalyst is used.
Draw a curly arrow mechanism for the reduction of a ketone using the (S)-CBS catalyst.
The BH3 complexes on the bottom because the N-B bond must be cis to the C(Ph)2O group in the catalyst.
The ketone donates a lone pair of electrons to the boron of the catalyst, which brings the ketone and BH3 in close proximity.
What is the transition state model for the asymmetric reduction of a ketone using the CBS catalyst?
.The conformational fix comes from the chair conformation of the six-membered ring transition state.
Steric factors dictate that the largest ketone substituent prefers to be in an equatorial position.
The highest %ee will be obtained when there is a large difference in steric size between the two ketone substituents.
What is the CBS predictive mnemonic?
Give an RSA for the production of an alcohol from a ketone using a CBS catalyst.
Give an RSA for the production of an amine from a ketone using a CBS catalyst.
For the SN2 reaction, use an amine and a base (Cs2CO3).
Give an RSA for the production of a sulfide from a ketone using a CBS catalyst.
For the SN2 reaction use a sulfide and a base (Cs2CO3).
Draw a mechanism for the α-alkylation reaction of an amide using LDA and Et-I.
Enolate geometry is important: The formation of this enolate after α-deprotonation is the most sterically favourable.
How can an oxazolidinone chiral auxialiary be attatched to a carbonyl?
How can you synthesise an oxazolidinone chiral auxiliary?
How can you synthesise an acid chloride?
How can an oxazolidinone chiral auxiliary be removed from a carbonyl?
What is the predictive mnemonic for the asymmetric α-alkylation of enolates using oxazolidinones?
How can you protect/deprotect an alcohol group?
How can you protect/deprotect an amine?
Give an RSA for the formation of an amide from a carboxylic acid.
Draw a mechanism for the aldol reaction of an amide using LDA.
This reaction gives poor diastereoselectivity with a mixture of all four possible stereoisomeric products being formed.
As there are no external chiral catalysts of auxiliaries, a racemic mixture of syn aldol products and a racemic mixture of anti aldol products will be formed.
Draw a mechanism for the aldol reaction of an amide using a boron enolate.
How can an oxazolidinone chiral auxiliary be removed from a syn aldol product?
The hydroxyl group in the syn aldol product can cause a problem for deprotection reactions as the OH group can be deprotonated.
What is the transition state model for asymmetric syn-aldol reactions using oxazolidinones?
- Boron enolate geometry: The R group at the position α to the C=O will be cis to the OB(Bu)2 group in the boron enolate to avoid steric hindrance.
- Conformational fix: The lowest energy conformation of the boron enolate has the C-O bond of the enolate and C=O bond of the oxazolidinone opposite to each other to minimise the dipole repulsion. The aldehyde also coordinates to the boron to give a Zimmerman-Traxler transition state.
- Steric hindrance: The R group of the aldehyde will be equatorial to avoid 1,3-diaxial steric clashes.
What are the Zimmerman-Traxler transition states for each enantiomer of the oxazolidinone chiral auxiliary used for asymmetric syn-aldol reactions?
What is the predicitve mnemonic for an asymmetric syn-aldol reaction using an oxazolidinone?
Draw a curly arrow mechanism for the asymmetric anti-aldol reaction of two aldehydes using (S)-proline.
One aldehyde should be unbranched at the α position (the aldehyde that forms the enamine) and the other should be branched at the α position (the electrophile). Self-condensation reactions also work.
The reaction uses 10 mol% of proline.
What is the transition state model for an asymmetric anti-aldol reaction using proline?
- Enamine geometry: the amine and the substituent are trans to each other, which gives anti-aldol.
- Conformation fix: intramolecular hydrogen bond between COOH and amine in proline; intermolecular hydrogen bond between COOH and the oxygen of the aldehyde. In the transition state for (S)-proline, the aldehyde will be at the front.
- Steric hindrance: The bulky substituent on the aldehyde will be equatorial to give the lowest energy transition state.
What is the predictive mnemonic for an asymmetric anti-aldol reaction using proline?
Give the reactions for the catalytic asymmetric dihydroxylation of an alkene, and describe what the reactants are needed for.
(DHQ)2PHAL and (DHQD)2PHAL are diastereoisomers, but are often called “psuedo-enantiomers”.
What are the mechanistic features of the asymmetric dihydroxylation of alkenes?
What is the predictive mnemonic for the asymmetric dihydroxylation of alkenes?
How can terminal diols be converted into terminal epoxides?
The epoxide can be opened by nucleophiles regeoselectively at the least hindered position.
Give an RSA for the formation of an alkene using the Wittig reaction.
