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.

Additional recommended knowledge

Daily Visual Balance Check

Daily Sensitivity Test

What is the Sensitivity of my Balance?

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

^ New aldol type reaction Teruaki Mukaiyama, Koichi Narasaka and Kazuo Banno Chemistry Letters Vol.2 (1973) , No.9 pp.1011-1014 doi:10.1246/cl.1973.1011
^ REACTION OF ENOL ACETATE WITH ACETAL AND CARBONYL COMPOUND IN THE PRESENCE OF LEWIS ACID Teruaki Mukaiyama, Toshio Izawa and Kazuhiko Saigo Chemistry Letters Vol.3 (1974) , No.4 pp.323-326 doi:10.1246/cl.1974.323
^ Reactions of silyl enol ethers with carbonyl compounds activated by titanium tetrachloride Teruaki Mukaiyama, Kazuo Banno, and Koichi Narasaka J. Am. Chem. Soc.; 1974; 96(24) pp 7503–7509; doi:10.1021/ja00831a019
^ Organic Syntheses, Coll. Vol. 8, p.323 (1993); Vol. 65, p.6 (1987). http://www.orgsynth.org/orgsyn/pdfs/CV8P0323.pdf
^ Über gezielte aldokondensationen—II G. Wittig and P. Suchanek Tetrahedron Volume 22, Supplement 8, 1966, Pages 347-358 doi:10.1016/S0040-4020(01)82193-1
^ DIRECTED ALDOL CONDENSATIONS: β-PHENYLCINNAMALDEHYDE Organic Syntheses, Coll. Vol. 6, p.901 (1988); Vol. 50, p.66 (1970). G. Wittig, A. Hesse, Allan Y. Teranishi and Herbert O. House http://www.orgsynth.org/orgsyn/prep.asp?prep=cv6p0901
^ Chemistry of carbanions. XXIII. Use of metal complexes to control the aldol condensation Herbert O. House, David S. Crumrine, Allan Y. Teranishi, Hugh D. Olmstead J. Am. Chem. Soc.; 1973; 95(10); 3310-3324. doi:10.1021/ja00791a039
^ Asymmetric Total Synthesis of Taxol Teruaki Mukaiyama , Isamu Shiina, Hayato Iwadare, Masahiro Saitoh, Toshihiro Nishimura, Naoto Ohkawa, Hiroki Sakoh, Koji Nishimura, Yu-ichirou Tani, Masatoshi Hasegawa, Koji Yamada , Katsuyuki Saitoh Chem. Eur. J. 1999, 5, No. 1 doi:10.1002/(SICI)1521-3765(19990104)5:1<121::AID-CHEM121>3.0.CO;2-O
^ TBS = t-butyldimethylsilyl, Bn = benzyl, PMB = p-methoxybenzyl ether

Category: Addition reactions

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Mukaiyama_aldol_addition". A list of authors is available in Wikipedia.