Meerwein–Ponndorf–Verley Reduction - Stereoselectivity

Stereoselectivity

The aluminium based Meerwein-Ponndorf-Verley reduction can be performed on prochiral ketones leading to chiral alcohols. The three main ways to achieve the asymmetric reduction is by use of a chiral alcohol hydride source, use of an intramolecular MPV reduction, or use of a chiral ligand on the aluminium alkoxide.

One method of achieving the asymmetric MPV reduction is with the use of chiral hydride donating alcohols. The use of chiral alcohol (R)-(+)-sec-o-bromophen-ethyl alcohol gave 82%ee (percent enantiomeric excess) in the reduction of 2-chloroacetophenone. This enantioselection is due to the sterics of the two phenol groups in the six membered transition state as shown in Figure 3. In Figure 3, 1 is favored over 2 due to the large steric effect in 2 from the two phenyl groups.

The use of an intramolecular MPV reduction can give good enantiopurity. By tethering the ketone to the hydride source only one transition state is possible (Figure 4) leading to the asymmetric reduction. This method, however, has the ability to undergo the reverse Oppenauer Oxidation due to the proximity of the two reagents. Thus the reaction runs under thermodynamic equilibrium with the ratio of the products related to their relative stabilities. After the reaction is run the hydride-source portion of the molecule can be removed.

Chiral ligands on the aluminium alkoxide can effect the stereochemical outcome of the MPV reduction. This method lead to the reduction of substituted acetophenones in up to 83%ee (Figure 5). The appeal of this method is that it uses a chiral ligand as opposed to a stoiciometric source of chirality. It has been recently shown that the low selectivity of this method is due to the shape of the transition state. It has been shown that the transition state is a planar six member transition state. This is different than the believed Zimmerman-Traxler model like transition state.