Asymmetric Synthesis Flashcards
Definition of asymmetric synthesis
a reaction that selectively creates one configuration of one or more new stereogenic centres by action of a chiral auxiliary or chiral catalyst on a substrate.
What is enantiomeric excess (% ee)
% of major enantiomer - % of minor enantiomer
To protect/deprotect alcohol
TBDMS-Cl + imidazole
TBAF
To protect/deprotect alcohol
NaH then Bn-Br
H2, Pd/C
To protect/deprotect amines
Boc2O
TFA
What makes a molecule chiral?
Chiral molecule does not have a plane or a centre of symmetry in its structure when drawn in any confirmation
Can sulfoxides and phosphines be chiral?
Lone pair on S or P can be treated as a substituent so both can be chiral
Can amines be chiral?
Nitrogen (umbrella) inversion occurs too easily so chiral amines are rare as the stereogenic centre usually not fixed due to inversion
What are enantiomers
2 mirror images of a chiral molecule
All stereogenic centres are opposite configuration
How do the properties of 2 enantiomers differ?
2 enantiomers have the same properties ( e.g. mp, NMR, solubility, density) except in interaction of plane polarised light or presence of other chiral molecules
What are diastereoisomers
2 diastereoisomers are 2 completely different compounds.
A stereoisomer that is not an enantiomer (e.g molecule with 2 stereogenic centres and same molecule with only 1 stereogenic centre opposite)
How do the properties of 2 diastereoisomers differ
As they are completely different compounds they have different properties (13C NMR, 1H NMR, solubility, density, mp, potentially different RF values so can be separated by column chromatography
How do chiral auxiliaries work?
The transition state of the reaction of a chiral molecule is made diastereoisomeric and since diastereoisomers are completely different compounds the Ea to get to the T.S are different
Lower energy T.S = major product
Burgi Dunitz angle
The trajectory of attack of the nucleophile to C=O group is close to 109 bond angle that is found in product - it is approx 107.
This gives the best orbital overlap of Nu HOMO with C=O LUMO (𝜋* C=O)
Cram- Chelation control
Conformational Fix and steric hindrance
- Conformational fix - chelating metal (Mg2+, Zn2+, Ti4+) holds C=O and heteroatom (S or O) attached to stereogenic centre 𝛼 to C=O in 5 membered ring
- Steric Hindrance - Nu attack of 107 to C=O over least bulky substituent gives major product
Felkin Ahn Model (No heteroatom/ electroneg groups)
Conformational Fix and steric hindrance
- Conformational Fix - Lowest energy conformations will place the largest of the 3 substituents at the 𝛼 stereogenic centre perpendicular to C=O
- Steric hindrance - Nu attack of 107 to C=O over least bulky substituent gives major product
Felkin Ahn Model (with heteroatom/ electroneg groups)
Conformational Fix and steric hindrance
- Conformational Fix - Lowest energy conformations will place the most electroneg of the 3 substituents at the 𝛼 stereogenic centre perpendicular to C=O
Non-chelating metal present eg. Na+ or Li+ - Steric hindrance - Nu attack of 107 to C=O over least bulky substituent gives major product
Asymmetric reduction of ketones using CBS catalyst conditions
BH3
10 mol % (R) or (S) CBS catalyst
Predictive mnemonic for asymmetric reduction of ketones using CBS catalyst
Place largest group on the ketone on the left hand side
(S) - CBS catalyst adds hydride to the front
(R) - CBS catalyst adds hydride to the back
Why do we use BH3 in asymmetric reduction of ketones using CBS catalyst
BH3 is neutral and needs to complex to a lone pair on a lewis base (e.g. the N lone pair in the CBS catalyst) to give an LA-LB adduct before it can deliver a hydride C=O. This gives a chiral species that will carry out reduction
Key points of transition state of asymmetric reduction of ketones using CBS catalyst
Conformational Fix and steric hindrance
- Conformational fix - comes from the chair conformation of 6 membered ring
- Steric hindrance - largest ketone substituent will be in equatorial position on chair
Conditions for Asymmetric 𝛼 alkylation of enolate using oxazolidinones
BuLi to attach acid chloride to oxazolidinone (chiral auxiliary)
Then add LDA to form enolate (Cis enolate) and add electrophile
How to remove chiral auxiliary in asymmetric 𝛼 alkylation of enolate using oxazolidinones
LiOH = carboxylic acid product
2 eq. LiAlH4 = primary alcohol product
2 eq. LiAlH4 then PCC = aldehyde product
3 important aspects of transition state model for asymmetric 𝛼 alkylation of enolate using oxazolidinones
- Enolate has cis geometry of R group and O
- conformational fix by chelation of Li to enolate O and oxazolidinone carbonyl makes 5 membered transition state
- Steric hindrance from bulky isopropyl group on chiral auxiliary means enolate attacks electrophile on opposite face to iPr group
