Lewis Base Catalysis of the Mukaiyama Directed Aldol Reaction: 40 Years of Inspiration and Advances

Abstract

Since the landmark publications of the first directed aldol addition reaction in 1973, the site, diastereo-, and enantioselective aldol reaction has been elevated to the rarefied status of being both a named and a strategy-level reaction (the Mukaiyama directed aldol reaction). The importance of this reaction in the stereoselective synthesis of untold numbers of organic compounds, both natural and unnatural, cannot be overstated. However, its impact on the field extends beyond the impressive applications in synthesis. The directed aldol reaction has served as a fertile proving ground for new concepts and new methods for stereocontrol and catalysis. This Minireview provides a case history of how the challenges of merging site selectivity, diastereoselectivity, enantioselectivity, and catalysis into a unified reaction manifold stimulated the development of Lewis base catalyzed aldol addition reactions. The evolution of this process is chronicled from the authors' laboratories as well as in those of Professor Teruaki Mukaiyama.

The Chelation-controlled Mukaiyama Aldol Reaction of Chiral α- and β-Alkoxy Aldehydes

“…1 This seminal paper sparked extensive methodology development in the area of crossed aldol reactions, which are CC bondforming processes of fundamental importance in synthetic organic chemistry. 2 Several overviews by the inventor, Teruaki Mukaiyama, 3 and by other authors 2,4 have appeared which cover this particular version of the aldol reaction, including the recent reviews by Murakami, 5 Denmark, 6 and Paterson. 7 Control of stereoselectivity is a crucial issue.…”

Synthesis of Structurally Complex Silicon Frameworks through the First Sila‐Aldol Reaction

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Herein, we report on the first sila-aldol reaction, which emphasizes the tight connection between silicon and carbon chemistry.T his novel synthetic method provides straightforwarda ccess to 2-oxahexasilabicyclo[3.2.1]octan-8ide,astructurally complex silicon framework, in quantitative yield. [9] Forsilicon-based compounds,however, such siliconcarbon bond-forming reactions have not been reported, although they must be considered as ap owerful alternative to standard coupling techniques,s uch as the Wurtz reaction and related methods, [10] hydrosilylation, [11] as well as transition-metal-catalyzed silicon-carbon coupling reactions. The complete mechanism of this highly selective rearrangement cascade is outlined and supported by density functional theory (DFT) calculations,w hich highlight the thermodynamic driving force and the low activation barriers of this powerful silicon-carbon bond-forming strategy.

The classical aldol reaction, and in particular its power in the reversible formation and cleavage of carbon-carbon bonds,is one of the most important biosynthetic tools for the evolution of life on earth.

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“…[1] On the basis of this general strategy,namely the merging of two carbonyl compounds,s ynthetic chemists have put al ot of emphasis on stereoselective aldol reactions over the last couple of centuries to accomplish results comparable to those achieved by organisms and enzymes in nature. [9] Forsilicon-based compounds,however, such siliconcarbon bond-forming reactions have not been reported, although they must be considered as ap owerful alternative to standard coupling techniques,s uch as the Wurtz reaction and related methods, [10] hydrosilylation, [11] as well as transition-metal-catalyzed silicon-carbon coupling reactions. [9] Forsilicon-based compounds,however, such siliconcarbon bond-forming reactions have not been reported, although they must be considered as ap owerful alternative to standard coupling techniques,s uch as the Wurtz reaction and related methods, [10] hydrosilylation, [11] as well as transition-metal-catalyzed silicon-carbon coupling reactions.…”

American Chemical Society 2014 National Award Winners

“…He has recently published a Minireview in Angewandte Chemie on Lewis base catalysis. [8] Robert G. [9] Stephen J. Lippard (MIT) is the recipient of the Priestley Medal, which is the highest honor of the ACS. Lippard studied at Haverford College, and completed his PhD (supervised by F. Albert Cotton) at MIT in 1965.…”