Topicity, Stereoselective Synthesis and Chiral reagents Flashcards
What is needed to generate an enantiomerically pure product
- To generate an enantiomerically pure product an enantiomerically pure reagent originating from the chiral pool is needed
- Cannot be produced if all the starting materials, reagents and catalysts are either achiral or racemic
What are the 3 types of chiral reagent that could be used to generate an enantiomerically pure product
- Chiral substrate
- Chiral reagent
- Chiral catalyst
What would be formed if a Nuc was added to homotopic faces
- Homomeric (identical) products
- C2 axis in substrate
What would be formed if a Nuc was added to enantiotopic faces
- Enantiomeric products
- No C2 axis- but is a mirror plane
What would be formed if a nuc was added to diastereotopic faces
- No C2 axis or mirror plane
- Diastereomeric products formed
Does the stereogenic unit need to be adjacent to the reaction centre
- No it doesn’t need to be directly adjacent to the reaction site to generate diastereotopic faces
- But selectivity is usually highest when this is the case
- If too remote may get 50:50 mix
What is produced if a substitution reaction occurs to a carbon containing 2 homotopic groups (not involved in reaction)
- C2 axis
- Homomeric products
- No stereogenic centre
What is produced if a substitution reaction occurs to a carbon containing 2 enantiotopic groups (not involved in reaction
- No C2 axis but mirror plane
- Produces enantiomeric product
What is produced if a substitution reaction occurs to a carbon adjacent to a stereocentre
- Diastereomeric product
- 2 Stereogenic centres
What are types of enantioselective reactions
- Differentiation of enantiotopic faces with a chiral reagent
- Differentiation of enantiotopic groups using catalyst - convert one group
- Differentiation of enantiomeric molecules - only one reacts with a certain molecule
What are types of diastereoselective reactions
- Differentiation of diastereotopic faces - produces syn or anti
- Differentiation of diastereotopic groups - Intramolecular cyclisation where 2 TS are different energy so only product is formed
- Differentiation of diastereomeric molecules - One is not reactive due to orientation of groups
What happens if a racemic reagent/catalyst is added to enantiotopic faces/groups
- No ennatiocontrol- racemic product
What happens if an enantiopure reagent/catalyst is added to enantiotopic faces/groups
- Enantioenriched product
- Enantiocontrol
What happens if a racemic reagent/catalyst is added to diastereotopic faces/groups
- Induced diastereocontrol
- Enantiopure
What happens if What happens if an enantiopure reagent/catalyst is added to diastereotopic faces/groups
- Double diastereocontrol
- Want diastereotopic group + reagent and catalyst to reinforce themselves
Define substrate
- Reactant whose main structural unit is maintained throughout a reaction sequence leading to a target molecule
Define reagent
- Reactant that transfers one or more atoms/groups to or from the substrate
For the simplest case of two competing pathways how is the product ratio (P) defined
- Rate of formation of product 1 versus product 2
- P=k1/k2= exp(-DeltadeltaG(TS)/RT)
- Difference between TS Delta G / RT
What does the product ratio depend on
- Temperature
- Lower temps generally results in formation of chiral products with greater levels of stereocontrol
What temp are stereoselective reactions often carried out at
- -78 degrees
- It is easy to use an ice bath prepared from acetone and dry ice
- Maximise ee
Describe P ratio relationship to deltadeltaG(TS) and effect on what is required for high selectivity (P)
- Exponential relationship
- So energy differences DeltadeltaG(TS) required for high selectivity is surprisingly small in comparison to strength of C-C bonds
Describe allylboration of aldehydes with achiral reagent
- A racemic homoallylic alcohol is produced
- The TS are enantiomeric and equal in energy
- Si face attack on the aldehyde in one TS
- Re attacked in the other
Describe allylboration of aldehydes with a racemic reagent
- A racemic homoallylic alcohol is produced
- TS equal in energy
- S reagent gives attack on one face e.g. Re
- R reagent gives attack on opposite
Describe allylboration of aldehydes with a chiral enantiopure allylating reagent
- An enantioenriched homoallylic alcohol is produced
- Only S or R reagent present
- For one face groups are equatorial - lower TS
What are 4 different enantiopure allyl boron reagents available where the chiral modifier is on boron
- Allyl diisopino-campheylboranes (Brown)
- Tartrate-derived allylboronates (Roush)
- Corey’s reagent
- 9-BBN-derived reagents (Soderquist)
How is Browns allyl diisopinocamphenlboranes produced
- From (+)-alpha-pinene from chiral pool
- Add BH3.SMe2, then MeOH
- Then CH2CHCH2MgBr, Et2O
Describe Brown asymmetric allyl boration of an aldehyde
- Produces an enantioenriched product
- The large group of the Brown reagent creates steric hinderance with H equatorial when producing one product
- Therefore transition state where O is next to large group so no side groups coming off is prefered - less hinderance
What happens when both the substrate and reagent are chiral and enantiopure
- There are two stereocontrolling factors present that can either oppose or reinforce one another- double diastereocontrol
What are non-chelation nucleophilic additions to aldehydes bearing an alpha-stereocentre governed by
- Felkin-Anh control
If there is a mismatch in stereocontrolling factors in a Brown allylboration what factor generally overrides
- The selectivity of the Brown allylation agents typically overrides the Felkin-Anh preference of the aldehyde
What is reagent control
- Where chiral reagents can dominate the induction process
- Possible to essentially select which diastereomer you would like to make by selection of the catalyst enantiomer and regardless of any intrinsic preference of the substrate
Give an example of reagent control
- Preparation of an intermediate en route to (+)-Brasilenyne
- Using [(+)-Ipc]2Ballyl, Et2O, -78 degrees
What are some useful chiral boron reducing agents and what do they do
- Alpine-borane
- DIP-chloride
- Useful for stereoselective reduction reactions of ketones to produce synthetically useful chiral alcohols
How is Alpine-borane produced
- Enantiomer of chiral alpha-pinene + 9-BBN undergo alkene hydroboration - borane group is added opposite to bulky methyls
Describe alpine-borane reduction
- Reduces C=O to OH
- Terpene recycled
- Large group equatorial to avoid steric clash
- High ee when large difference in steric demand of R groups of ketone
- Low ee when similar steric demand- e.g. Ph and Me
Compare DIP-Chloride to alpine-borane
- More reactive, Lewis acidic version of alpine-borane due to Cl
- Generally provides higher selectivities for several ketone classes - especially aromatic ketones
Give example of where DIP-chloride is used
- In production of Azopt
What is one of the most popular chiral reducing agents
- BINAL-H
- Particularly effective in the enantioselective reduction of aromatic and unsaturated ketones
How is BINAL-H produced
- LiAlH4
- Add EtOH
- Add (s)-BINOL to produce (s)-BINAL-H
- Chiral as can’t rotate
Where is selectivity in reduction of ketones by BINAL-H thought to arise
- From a 6-membered transition state in which n-pi Repulsions between BINOLate oxygen and the substrate are minimised
- Li coordinates most basic O (OEt)
- Top biaryl moiety pointed away from OEt
- Double bond is equatorial away from Al-O regardless of size to avoid n-Pi repulsion
When are chiral pinane ligandes used
- Chiral pinane ligands on the metal atom of an enolate provides an alternative means of inducing asymmetry in aldol reactions
- Particularly useful where attachment of a chiral acyl group is not possible
What are effective chiral reagents for aldol reactions
- di(isopinocampheyl) boron enolates of ketones derived from alpha-pinene
How could you make a di(isopinocampheyl) boron enolates of a ketone
- Add [( )-ipc]2BOTf, i-Pr2NEt
- In CH2CI2, -78 degrees
- Produces chiral boron enolate
What happens if you add a boron enolate to an aldehyde
- Favoured transition state where there are least steric clashes
- Add H2O2 produce aldol product, always syn?
- 15 Degrees
What is first step of an aldol reaction
- Generate an enolate
- Take a ketone and add a base
- Can generate Z-enolate- Z is on same side as methyl group
- E-enolate- Opposite sides
What is next step of aldol reaction
- Add acid aldehyde to mix of E and Z
- Can attack either face Re or Si
- Produces Syn and Anti aldols
- 4 different products
- Racemic as no chirality in system
What are problems concerning stereocontrol with aldol reaction
- First step - 2 possible enolates
- Second step- Can attack at either face of acid aldehyde so produces 4 products
