Mukaiyama aldol reaction enantioselective variants

The use of chiral copper Lewis acids in enantioselective aldol processes has seen rapid development over the past 10 years. In particular, copper-catalyzed variants of the Mukaiyama aldol reaction received considerable attention in the years leading up to the new millennium. Evans and coworkers first demonstrated Cu(II)/pybox complex (59) as an efficient catalyst for highly enantioselective addition of a variety of silylketene acetals to aldehydes capable ofbidentate coordination (Scheme 17.12) [17]. In reactions utilizing silylketene acetals (61) and (63) with an additional stereoelement, diastereoselectivities and enantioselectivities were also high. A square pyramidal model (65), which has been further supported by a crystal structure of the complex, with the a-alkoxy aldehyde bound in a bidentate fashion accounts for the observed selectivity. 

While the order of silyl transfer or cleavage is inconsequential to bond formation, it is one of the more important and hotly debated aspects of the mechanism owing to its importance in the development of catalytic enantioselective variants of the Mukaiyama aldol reaction. Intramolecular silyl transfer, as shown in the formation of 10, would regenerate the chiral,... 

While substantial utility has been demonstrated for the Mukaiyama aldol reaction in diastereoselective natural product syntheses, more recent research efforts have been focused on the development of catalytic enantioselective variants of the reaction. These enantioselective variants of the reaction have provided creative solutions to problems associated with stereocontrolled syntheses of molecules of polyacetate origin. A wide range of chiral Lewis acid and Lewis base catalysts have been developed that exhibit high levels of enantioselectivity in the Mukaiyama aldol reaction. While the list is certainly not exhaustive, some such catalysts are shown below (65-72). 

Carbonyl groups are also activated by Lewis acids to participate in various condensation reactions. One of the most important of these is the Mukaiyama aldol reaction. The first version of this in the 1970s (Figure 23.9) was not catalytic, but catalytic versions and enantioselective variants were quickly developed. The advantage of the process is that a crossed-aldol reaction is achieved without any risk of self-condensation of either component, and reaction conditions are exceptionally mild. However, the starting silyl enol ether does need to be prepared. Some examples are shown in Figure 23.10. The first reaction is one on which many common catalysts... 

Modem variants of the Mukaiyama aldol addition start from silyl enol ethers, not from enol ethers, and use an aldehyde instead of the acetal as the electrophile. Mukaiyama aldol additions of this kind have been included in the C,C coupling reactions that build the basic repertoire of modem synthetic chemistry and can even be performed in a catalytic enantioselective fashion. 

The structural variant 7 of Corey s bifluoride catalyst 4 was prepared later by Andrus and coworkers and applied as a catalyst (20mol%) to the asymmetric Mukaiyama-type aldol reaction of aldehydes with the enol silylether 8 [6]. Excellent diastereoselectivity (up to >99/1) for the syn-aldol product 9 was achieved, especially with aromatic aldehydes. However, only moderate to good enantioselectivity (44—83% ee) was obtained (Scheme 8.3). 

The aldol reaction and related processes have been of considerable importance in organic synthesis. The control of syn/anti diastereoselectivity, enantioselectivity and chemoselectivity has now reached impressive levels. The use of catalysts is a relatively recent addition to the story of the aldol reaction. One of the most common approaches to the development of a catalytic asymmetric aldol reaction is based on the use of enantiomerically pure Lewis acids in the reaction of silyl enol ethers with aldehydes and ketones (the Mukaiyama reaction) and variants of this process have been developed for the synthesis of both syn and anti aldol adducts. A typical catalytic cycle is represented in Figure 7.1, where aldehyde (7.01) coordinates to the catalytic Lewis acid, which encourages addition of the silyl enol ether (7.02). Release of the Lewis acid affords the aldol product, often as the silyl ether (7.03). 

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