Diastereocontrol in Cyclic systems 1

• To achieve a stereoselective reaction at the carbonyl group, the existing stereocentre would have to influence the direction of attack of the nucleophile at the C=O group • Hard as 3 bond separation and carbon chain is highly flexible- able to access many different conformations - produced racemic mixture

• Join the ends of the molecule into a ring • A cyclic molecule is much less flexible and has only one low energy conformation in a lot of cases e.g. T-bu is a conformational-biasing group as has 99% preference for equatorial

• C=O group at pointy end of chiar bisecting the angle between axial and equatorial • Flat carbon as sp2 hybridised

• Small nucleophiles = axially • Large nucleophiles = equatorially

• Large nucleophile attack suffers steric interactions with diaxial hydrogens during axial attack

• C=O bond in cyclohexanone is not exactly co-planar with the neighbouring C-H bonds- 4 degrees below • During axial attack, the onset of rehybridization form sp2 to sp3 pushes the C=O group downwards away from the neighbouring C-H • But opposite is true for equatorial attack as torsional strain increase in he TS as the molecule begins to pass through an unfavourable eclipsed conformation

• Describes reactions whose selectivity is governed by minimisation of developing torsional strain interactions in the TS

• Strain caused by the close approach of atoms or groups separated by three covalent bonds. • In the molecule W-X-Y-Z, atoms W and Z may experience torsional strain if a particular conformation (such as an eclipsed conformation) brings these atoms into close proximity.

• Li-Alkyne = Axial - v small • Me-Li = 35% axial • Phenyl-Li = 42% axial - behaves smaller than you would think as flat • Me-MgBr = 41% axial • t-Bu-MgBr = 0% axial - v large

• IRREVERSIBLE ADDITION • under kinetic control - to do with activation height of energy barrier

• reversible reaction • involving configurationally labile reactive intermediates (radicals)

• Bromine and related electrophiles add to cyclohexenes in a trans-diaxial fashion • Goes through a favoured chair-like TS - Produces diaxial chair product • Diequatorial addition goes through twist-boat-like TS, then produces diaxial twist boat - which forms diequatorial chair- equilibrium

• Both pathways are stereoelectronically-mandated to give trans-diaxial products • But through the chair-like transition state is faster as the TS is lower in energy

• For cyclohexanone-derived enolates, axial attack of electrophile is stereoelectronically required • Only way that electrophiles can interact productively with the Pi-orbital • But selectivity for alkylation of cyclohexanones is much poorer than for bromination - 55% axial favoured compared to 96%

• Poor selectivity in the enolate alkylation reflects the very early nature of the TS- Occurs much earlier on the reaction coordinate • Therefore the TS looks much more like the enolate than the products • The reaction does therefore not feel the developing strain with the twist-boat product so much • Therefore less differentiation between the competing TSs leading to lower selectivity

• Mainly because the alkylation step is so exothermic • As we regenerate a very stable C=O bond from the less strong C=C bond in the enolate ion • We make a strong C-C bond at the expense of a much weaker C-I bond • In general exothermic = earlier transition states

• Use enamines as nucleophiles • Much less reactive than lithium enolates- later TS

• Use enamines as nucleophiles • Much less reactive than lithium enolates- later TS • Produces trans isomer

• Issue with competing N-alkylation when using simple alkyl halides which lowers the yield

• Add pyrrolidine to produce an enamine • Add Alkylhalide to form iminium salt • Add H3O+ to produce the trans isomer • Then N-alkylated enamine is the major product though

• Rely on thermodynamic control via base-catalysed epimerisation • First LDA, THF then MEI • Produces not stereoselective trans isomer • Then add NaOMe, MeOH to produce cis isomer - reversible reaction

• Cyclic oxocarbenium ions • Formed in SN1 processes from cyclic acetals under acidic conditions • Attack on double bond to give a chair like TS

• Expulsion of a leaving group to give an oxocarbenium ion must also proceed from the axial isomer • Forward and reverse reactions share the same TS • Principle of microscopic reversibility

• The principle of axial attack can be extended to cyclohexenones which contain 3 contiguous sp2 centres- hence 5 co-planar ring atoms in a so-called envelope conformation