Mukaiyama aldol addition

The Mukaiyama aldol addition is an organic reaction and a type of aldol reaction between a silyl enol ether and an aldehyde catalyzed by a Lewis acid. This choice of reactants allows for a crossed aldol reaction between an aldehyde and a ketone or a different aldehyde without self-condensation of the aldehyde. For this reason the reaction is used extensively in organic synthesis. In its original scope the Lewis acid (titanium chloride) was used in stochiometric amounts but truly catalytic systems exist as well. The reaction is also optimized for asymmetric synthesis.

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The archetypical reaction published by Teruaki Mukaiyama in 1973 ^[1] is that of the silyl enol ether of cyclohexanone with benzaldehyde with one equivalent of titanium tetrachloride in dichloromethane. At room temperature it produces a diastereomeric mixture of threo (63%) and erythro (19%) β-hydroxyketone as wel as 6% of the exocyclic enone condendation product. A subsequent paper in 1974 ^[2] dealt with the reaction between isopropenyl acetate (the adduct of acetone and acetic acid) and benzaldehyde with various Lewis acids such as aluminum chloride, tin tetrachloride and boron trifluoride but many side-reaction competed with formation of the hydroxyketone. Then in another 1974 paper ^[3] returning to silyl enol ethers the reaction temperature is reduced to -78°C which results in the desired diastereoselectivity.

The trimethylsilyl group activates the enol as a nucleophile and the initial reaction product is a titanium chelate which breaks down on hydrolysis. The capture of the initial formed aldol product is a prerequisite for the success of the reaction.

A typical reaction involving two ketones is that between acetophenone as the enol and acetone:^[4]

Ketone reactions of this type require higher reaction temperatures.

For this work Mukaiyama was inspired by earlier work done by Georg Wittig in 1966 on crossed aldol reactions with lithiated imines ^{[5] [6]}. Competing work with lithium enolate aldol reactions was published also in 1973 by Herbert O. House ^[7]

Scope

Mukaiyama employed in his rendition of taxol total synthesis (1999) two aldol additions ^{[8] [9]}, one with an ketene silyl acetal and excess magnesium bromide:

and a second one with an amine chiral ligand and a triflate salt catalyst:

References