An introduction to diastereoselective aldol reactions using soft enolisation techniques to selectively synthesise one enolate geometry and a Zimmerman-Traxler transition state model to form the new C-C bond and two new stereogenic centres (stereocentres) at the same time.
Cyclohexylboron chloride (Cy2BCl) is used as a Lewis acid to promote the soft enolisation of a ketone. Pre-coordination of the Lewis acid makes the alpha protons much more acidic, such that they can be deprotonated by even a weak base like triethylamine (TEA, Et3N). In this enolisation there is a requirement that the molecular orbitals (MOs) that are involved in the mechanism are properly overlapped and able to interact. This means that the reactive conformation for forming the boron enolate is one where the C-H bond is perpendicular to the carbonyl bond; in this way it can overlap with the C-O pi star antibonding orbital. There are two reactive conformers, but one is more populated than the other as there is less steric clash with the big Lewis acid. Hence enolisation proceeds diastereoselectively to the E-enolate (trans enolate).
The boron enolate is both itself a Lewis acid and a nucleophile. Indeed, when it coordinates and activates an aldehyde electrophile, it becomes a better nucleophile itself. As the enolate can pre-coordinate to the electrophile, an aldol reaction is now favourable that is intramolucular. This intramolecular aldol reaction proceeds through a 6-membered ring transition state. This transition state can be modelled using the Zimmerman-Traxler model.
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