Aldol reaction enantioselective variants

This chapter will begin with a discussion of the role of chiral copper(I) and (II) complexes in group-transfer processes with an emphasis on alkene cyclo-propanation and aziridination. This discussion will be followed by a survey of enantioselective variants of the Kharasch-Sosnovsky reaction, an allylic oxidation process. Section II will review the extensive efforts that have been directed toward the development of enantioselective, Cu(I) catalyzed conjugate addition reactions and related processes. The discussion will finish with a survey of the recent advances that have been achieved by the use of cationic, chiral Cu(II) complexes as chiral Lewis acids for the catalysis of cycloaddition, aldol, Michael, and ene reactions. 

Ketone donors bearing a-heteroatoms are particularly useful donors for the enamine-catalyzed aldol reactions (Scheme 18). Both anti and syn aldol products can be accessed in remarkably high enantioselectivities using either proline or proline-derived amide, sulfonamide, or peptide catalysts. The syn selective variant of this reaction was discovered by Barbas [179]. Very recently, Luo and Cheng have also described a syn selective variant with dihydroxyacetone donors [201], and the Barbas group has developed improved threonine-derived catalysts 71 (Scheme 18) for syn selective reactions with both protected and unprotected dihydroxyacetone [202]. 

Catalytic, enantioselective addition of silyl ketene acetals to aldehydes has been carried out using a variant of bifunctional catalysis Lewis base activation of Lewis acids.145 The weakly acidic SiCU has been activated with a strongly basic phor-phoramide (the latter chiral), to form a chiral Lewis acid in situ. It has also been extended to vinylogous aldol reactions of silyl dienol ethers derived from esters. 

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 most intensely studied aldol addition mechanisms are those beUeved to proceed through closed transition structures, which are best understood within the Zimmerman-Traxler paradigm (Fig. 5) [Id]. Superposition of this construct on the Felkin-Ahn model for carbonyl addition reactions allows for the construction of transition-state models impressive in their abiUty to account for many of the stereochemical features of aldol additions [50a, 50b, 50c, 51]. Moreover, consideration of dipole effects along with remote non-bonding interactions in the transition-state have imparted additional sophistication to the analysis of this reaction and provide a bedrock of information that may be integrated into the further development and refinement of the corresponding catalytic processes [52a, 52b]. One of the most powerful features of the Zimmerman-Traxler model in its application to diastereoselective additions of chiral enolates to aldehydes is the correlation of enolate geometry (Z- versus E-) with simple di-astereoselectivity in the products syn versus anti). Consequently, the analyses of catalytic, enantioselective variants that display such stereospecificity often invoke closed, cyclic structures. Further studies of these systems are warranted, since it is not clear to what extent such models, which have evolved in the context of diastereoselective aldol additions via chiral auxiliary control, are applicable in the Lewis acid-catalyzed addition of enol silanes and aldehydes. 

Enantioselective additions of lithium enolates to aldehydes forming aldols ( 3-hydroxyaldehydes) are synthetically well established and have been reviewed elsewhere [20]. A catalytic variant, the Mukaiyma aldol reaction, i.e., the addition of silyl enol ethers to aldehydes, is usually mediated by chiral Lewis acids [21,22]. 

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). 

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. 

The first amine-catalyzed, asymmetric intermolecular aldol reactions were developed by List et al. in 2000 [29-33]. Initially it was found that excess acetone in DMSO containing sub-stoichiometric amounts of (S)-proline reacted with some aromatic aldehydes and isobutyraldehyde to give the corresponding acetone aldols (134) with good yields and enantioselectivity (Scheme 4.25). Particularly high ee were achieved with a-branched aldehydes. Similarly to the intramolecular enolendo variant, the only side-product in proline-catalyzed intermolecular aldol reactions are the condensation products (Scheme 4.25). 

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). 

At the time the chemistry of main group enolates flourished already for a while, that of late transition metals had a shadowy existence in synthetic organic chemistry. Their stoichiometric preparation and the sluggish reactivity - tungsten enolates, for example, required irradiation to undergo an aldol addition [24a] - did not seem to predestine them to become versatile tools in asymmetric syntheses [27]. The breakthrough however came when palladium and rhodium enolates were discovered as key intermediates in enantioselective catalyses. After aldol reactions of silyl enol ethers or silyl ketene acetals under rhodium catalysis were shown to occur via enolates of the transition metal [8] and after the first steps toward enantioselective variants were attempted [28], palladium catalysis enabled indeed aldol additions with substantial enantioselectivity... 

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. 

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