Diastereocontrol in Acyclic systems 1

• P-orbital lobes within the antibonding pi* orbital are bent outwards • This has stereoelectronic implication for the chemistry of the C=O bond

• 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

• Burgi-Duntz angle • 107+-2 Degrees

• Maximises bonding • Minimises antibonding

• 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

• 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)

• 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

• 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

• 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

• 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

• 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

• 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

• Soft descriptors • Depend on how the chemist chooses to define the main carbon chain • Product not mechanism dependent `

• 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

• THF- strongly coordinating to metals so less chelating for molecule • Et2O is not

• 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

• 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

• 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

• 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

• 1,3-anti product • 1,3-syn product

• 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

• Combination with the aldol reaction • Provide access to 1,3-diol

• Evans-saksena reduction • Uses Me4N+BH(OAc)3- as the reducing agent • Substrate directed reaction