Diastereocontrol in Acyclic systems 1 Flashcards
Describe molecular orbitals for Pi-bond
- P-orbital lobes within the antibonding pi* orbital are bent outwards
- This has stereoelectronic implication for the chemistry of the C=O bond
What are the stereoelectronic implications of the molecular orbital bending
- The lowest conformation of acetaldehyde is one in which a C-H bond eclipses the C=O group as this gives the best orbital alignment for two stabilising sigmaC-H–>pi*-O interactions
- This hyperconjugative interaction is also part of the reason that ketones are less reactive than aldehydes as there are more of these interactions to stabilise the C=O group
What is the approach trajectory of nucleophiles to C=O bonds
- Burgi-Duntz angle
- 107+-2 Degrees
Why is the Burgi-Duntz angle the approach trajectory
- Maximises bonding
- Minimises antibonding
What is the conformation of an acetaldehyde undergoing nucleophilic attack
- Not the same as its ground state lowest energy conformation
- A staggered reactive conformation is adopted
- Enables a sigma* C-H–>pi*C-O LUMO-lowering interaction which makes the C=O bond a better acceptor of electron density
- Anti periplanar relationship between nuc and C-H bond lowers LUMO
What model is used to explain addition of nucleophiles to alpha-chiral aldehydes/ketones
- Felkin-Anh model
What dictates the Felkin-Anh model
- Alpha-substituents are electronically similar but differentiated by size
- TSs are reactant like (early) rather than product-like (late)
- Reaction occurs via the most reactive conformation of the carbonyl compound (sigma* orbital perpendicular to C=O bond)
What are the rules of the FA model
- The largest group is placed perpendicular to C=O to minimise steric interaction with incoming nucleophile- lowers LUMO
- Nuc approaches at 107 degrees
- Nucleophile approaches antiperiplanar to the C-L bond to give the best stereoelectronic interaction between the sigma-donor (sigmaNu-c) and sigma acceptor (sigma*C-L)
- Nuc prefers attack alongside the smaller group S than the medium group M for steric reasons
What happens when an electronegative heteroatom substituents on the alpha-stereocentre
- For aldehydes/ketones with heteroatom (x) alpha-substituents (e.g. O,N,S,Hal) the most reactive conformation is one where the C-X bond is perpendicular to the C=O group
- C-X bonds are generally better sigma-acceptors than C-H or C-C bonds (lower energy sigma*C-X orbitals) and offer greater hyperconjugative stabilisation in the transition state
What elements have the best acceptor ability of sigma bonds
- Acceptor ability of sigma bonds increases when going to the end of a period and down the group
- Enhancement of the acceptor ability of sigma bonds within periods parallels the increase in electronegativity of X
- whereas augmentation of acceptor ability in groups is opposite to the changes in electronegativity of X and is a consequence of lowering the energy of sigma*C-X orbitals
What is the Cornforth-Evans model
- Alternative to FA model based on dipole-dipole interactions
- says most reactive conformation is one in which the C=O group and polar C-X bond are opposed in order to minimise dipole-dipole repulsion
- In simple cases will lead to same prediction as polar F-A model
What is the cram chelate model
- Chelation effects can overturn the polar FA model
- Cram chelate model used when aldehydes/ketones bear an alpha-heteroatom substituent capable of chelation to a metal ion
- Predicts the opposite diastereomer to the polar F-A model
- R group is antiperiplanar to Nu
What are common alpha-heteroatom substituent groups that result in chelation
- Almost always -OR groups
- But can occur with other lewis basic moieties (OH,SR,NR2)
- OSiR3 tend to chelate very poorly or not at all
- Mg2+, Zn2+, Cu2+, Al3+, Ce3+ Ti4+ are all excellent chelators and Li+ as have high charge densities
- Na+ and K+ are poor chelators as low charge density
Are syn and anti descriptors product or mechanism dependent
- Soft descriptors
- Depend on how the chemist chooses to define the main carbon chain
- Product not mechanism dependent `
What does the partitioning between Cram chelate and polar FA pathways depend on
- dependent on the O-protecting groups
- Also dependent on the solvent and strongly Lewis basic solvents can suppress chelation by competing for the lewis acidic metal
What is examples of solvents which are strongly chelating
- THF- strongly coordinating to metals so less chelating for molecule
- Et2O is not
Describe the Frater-seebach alkylation of beta-hydroxyl carbonyl compounds
- Involves diastereoselective alkylation of chelated dianion
- steric effects override torsional effects
- Reaction occurs on the opposite face to the Me group - even though TS has small amount of twist-boat character
Describe 1,3 induction in C=O additions
- A stereogenic centre at the beta-position can also strongly influence diastereoselectivity in c=o additions
- But only when the stereocentre bears an electronegative substituent -OH or OR
- Two general models to describe diastereoselectivity, both predict same diastereomer
What are the models to describe diastereoselectivity for addition to beta position
- Chelation control - half-chair conformation, avoid twist-boat TS
- Dipole control- zig-zag conformation of the main chain, dipole minimisation - but difficult so focus on chelation control
What dictates what model applies for diastereoselectivity for addition to beta position
- Nature of lewis acid and identity of O-protecting group dictate if chelation is possible
- BF3 is monodentate and incapable of chelation - dipole model more suitable
- Steric effects only play a minor role in 1,3 induction
What product is produced when an aldehyde reacts with organometallic nucleophile and with ketone and hydride nucleophile
- 1,3-anti product
- 1,3-syn product
Describe 1,3 reduction in beta ketone- in narasaka-prasad reduction
- diastereoselective reduction of beta-hydroxy ketones to syn-1,3-diols
- Add Et2BOMe, NaBH4 to beta hydroxy ketone
- Thought to occur via a chelate formed upon exchange of the methoxy substituent on boron by the substrate alcohol
- Followed by intermolecular delivery of hydride from NaBH4
- Formation of chairlike TS
What often combines with reduction of 1,3-beta hydroxy ketones to syn-1,3-diols
- Combination with the aldol reaction
- Provide access to 1,3-diol
How can the 1,3-anti product of beta-hydroxy ketone reduction be produced
- Evans-saksena reduction
- Uses Me4N+BH(OAc)3- as the reducing agent
- Substrate directed reaction
What is another method to produce the 1,3-anti product of beta-hydroxy ketone reduction be produced
- SmI2 as a Lewis acid catalyst
- Aldehyde as reducing agent
- Can differentiate between the two resulting hydroxyl groups- one of them is selectively protected by the aldehyde in the process
