In the Mukaiyama aldol reaction

The salt 18 was explored in the Mukaiyama aldol reaction with acetophenone, and a yield of 96% was obtained after 1 h at -78 °C (Scheme 11). When MejSiOTf was used as a catalyst, a yield of 0% was observed. Me3SiNTf3 and Et3SiNTf3 resulted in 12% and 8% yield, respectively. 

It appears likely that the reaction proceeds through the ene reaction pathway, although such an ene reaction pathway has not been previously recognized as a possible mechanism in the Mukaiyama aldol reaction. In general, an acyclic antiperiplanar transition-state model has been used to explain the formation of the syn-diastereomer from either ( )- or (Z)-silyl enol ethers [58]. However, the cyclic ene mechanism now provides another rationale for the. vyra-diastereose-lection regardless of the enol silyl ether geometiy (Figure 8C.7). 

In the Mukaiyama aldol reaction an aldehyde (1) reacts with a silyl enol ether (3) under Lewis-acid catalysis to yield the aldol adduct (4). The use of a chiral Lewis acid (L offers the opportunity to perform the reaction in an a.sym-metric manner (Scheme 1) [5]. 

In 1995 Carreira et al. [19] reported a catalytic variant of the asymmetric carbonyl-ene reaction (Scheme Ha). By treatment of the aldehyde 60 with 2 mol % of titanium catalyst 35, already used in the Mukaiyama aldol reaction, the / -hy-droxyketone 61 is formed in quantitative yield and with an excellent ee value. Here, the ene-compound, 2-methoxypropene, is used simultaneously as solvent in a large excess. The high en-antioselectivity is still limited to aldehydes similar to 60 benzaldehyde for instance is converted with an ee of only 66 %. 

In the Mukaiyama aldol reaction, Zr cationic catalysts can be used. They act very quickly and require only low catalyst loadings (0.5% [Cp2Zr(OTf)2 thf ). But, the reactions show only modest diastereoselectivity. ... 

Optically active l,l -binaphthols are among the most important chiral ligands of a variety of metal species. Binaphthol-aluminum complexes have been used as chiral Lewis acid catalysts. The l,T-binaphthyl-based chiral ligands owe their success in a variety of asymmetric reactions to the chiral cavity they create around the metal center [107,108]. In contrast with the wide use of these binaphthyls, the polymer-supported variety has been less popular. The optically active and sterically regular poly(l,l -bi-naphthyls) 96 have been prepared by nickel-catalyzed dehalogenating polycondensation of dibromide monomer 95 (Sch. 7) [109] and used to prepare the polybinaphthyl aluminum(III) catalyst 97 this had much greater catalytic activity than the corresponding monomeric catalyst when used in the Mukaiyama aldol reaction (Eq. 29). Unfortunately no enantioselectivity was observed in the aldol reaction. 

Activation of the (f )-binolato-Ti(OiPr)2 (2) by highly acidic and sterically demanding alcohols as achiral rather than chiral activators is also effective to provide higher levels of enantioselectivity than those attained by the parent enantio-pure binolato-Ti(OiPr) catalyst (2) in the Mukaiyama aldol reaction of silyl enol ethers (Eq. (7.22)) [55]. 

Trost and coworkers developed a chiral zinc phenoxide for the asymmetric aldol reaction of acetophenone or hydroxyacetophenone with aldehydes (equations 62 and 63) . This method does not involve the prior activation of the carbonyls to silyl enol ethers as in the Mukaiyama aldol reactions. Shibasaki and coworkers employed titanium phenoxide derived from a phenoxy sugar for the asymmetric cyanosilylation of ketones (equation 64). 2-Hydroxy-2 -amino-l,l -binaphthyl was employed in the asymmetric carbonyl addition of diethylzinc , and a 2 -mercapto derivative in the asymmetric reduction of ketones and carbonyl allylation using allyltin ° . ... 

A similar aluminum cation was also available in the Mukaiyama-aldol reaction. It is worth noting that the t-butyldimethylsilyloxy (TBSO) group, which otherwise is unable to make chelation complex with neutral bidentate Lewis acids, is under chelation control with excess Me2AlCl or MeAlfJh. [12]. Aldehyde and ketone carbonyls are capable of participating in the chelation-controlled aldol reaction to give anti-6 with high diastereoselectivity (Scheme 6.4). 

The utility of BF3-OEt2, a monodentate Lewis acid, for acyclic stereocontrol in the Mukaiyama aldol reaction has been demonstrated by Evans et al. (Scheme 10.3) [27, 28]. The BF3-OEt2-mediated reaction of silyl enol ethers (SEE, ketone silyl enolates) with a-unsubstituted, /falkoxy aldehydes affords good 1,3-anti induction in the absence of internal aldehyde chelation. The 1,3-asymmetric induction can be reasonably explained by consideration of energetically favorable conformation 5 minimizing internal electrostatic and steric repulsion between the aldehyde carbonyl moiety and the /i-substituents. In the reaction with anti-substituted a-methyl-/ -alkoxy aldehydes, the additional stereocontrol (Felkin control) imparted by the a-substituent achieves uniformly high levels of 1,3-anti-diastereofacial selectivity. 

Copper(II) complexes of two imino nitrogen atoms belonging to chiral oxazoline and sulfoximine moieties (70) are able to elicit asymmetric consequences in the Mukaiyama-aldol reaction of enol silyl ethers and a-keto esters/ ... 

The Lewis acidic nature of these catalysts has permitted their extended use in the Mukaiyama aldol reaction. In this application of CBS reagents, one such example involved the condensation of ketene acetals 72 with aldehydes 73 to produce adducts 74.20... 

The reaction can be applied to silyl enol esters as well. Good asymmetric induction can be achieved in the Mukaiyama aldol reaction. The reaction of silyl enol thioether 246 and nonanal, for example, gave 247 in 60% yield and in 93% ee when the (/ )-BINOL-titanium catalyst shown was used. In this work, the reaction was also done in supercritical fluoroform and in supercritical carbon dioxide. A similar reaction was reported using catalysts closely related to 244 and dichloromethane as the solvent.Chiral oxazaborolidine catalysts have also been shown to be effective for enantioselective Mukaiyama aldol reactions. 

Bidentate Lewis acid. This useful catalyst (1) with a high propensity for double coordination of the carbonyl group is prepared from the corresponding phenol and two equivalents of McjAI in CH Clj at room temperature. It catalyzes the reduction of 5-nonanone by BujSnH at -78° in 86% yield, whereas a reaction in the presence of the monodentate 0-dimethylaluminum 2,6-xylenoxide affords 5-nonanol in only 6%.. Accordingly, different catalytic efficiencies are also found in the Mukaiyama aldol reaction (e.g., 87% vs. 0% in the reaction between 1-trimethylsiloxy-l-cyclohexene and benzaldehyde) and the Claisen rearrangement of (fil-cinnamyl vinyl ether (96% vs. 0%). The contrasting ( >Zi-selectivity of the Michael adducts also reflects the different coordination states. 

Aldol and imino-aldol reactions. A Yb complex prepared from YbfOTflj and a C -symmetric a,a -bistriflamidobibenzyl has been used in the Mukaiyama aldol reaction," resulting in moderate asymmetric induction. Imines are activated toward enol derivatives, such as ketene silyl ethers. iV-(a-aminoalkyl)benzotriazoles are suitable surrogates of imines. One-pot syntheses of p-amino esters and ketones can also be achieved. 

Kobayashi and coworkers further developed a new immobilizing technique for metal catalysts, a PI method [58-61]. They originally used the technique for palladium catalysts, and then applied it to Lewis acids. The PI method was successfully used for the preparation of immobilized Sc(OTf)3. When copolymer (122) was used for the microencapsulation of Sc(OTf)3, remarkable solvent effects were observed. Random aggregation of copolymer (122)-Sc(OTf)3 was obtained in toluene, which was named as polymer incarcerated (PI) Sc(OTf)3. On the other hand, spherical micelles were formed in THF-cyclohexane, which was named polymer-micelle incarcerated (PMI) Sc(OTf)3.. PMI Sc(OTf)3 worked well in the Mukaiyama-aldol reaction of benzaldehyde with (123) and showed higher catalytic activity compared to that of PI Sc(OTf)3 mainly due to its larger surface area of PMI Sc(OTf)3. This catalyst was also used in other reactions such as Mannich-type (123) and (125) and Michael (127) and (128) reactions. For Michael reactions, inorganic support such as montmorilonite-enwrapped Scandium is also an efficient catalyst [62]. 

M. Woyciechowska, G. Forcher, S. Buda, J. Mlynarski, General switch in regioselectivity in the Mukaiyama aldol reaction of silyloxyfuran with aldehydes in aqueous solvents, Chem. Commun. 48 (2012) 11029-11031. 

Alternatively, a Friedel-Crafts mechanism has been proposed to account for bond formation via the Mukaiyama aldol reaction. As stated, attack of the enol silane 11 on the activated aldehyde 12 provides carbocation 13. Prior to silyl group transfer or outright silyl cleavage seen in the mechanism above, removal of the a-hydrogen regenerates the enol silane 14. While highly dependent on specific reaction conditions, the isolation of 15 leads to the suggestion of 14 as a potential intermediate in the Mukaiyama aldol reaction. 

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). 

Guindon and coworkers have presented a very nice example of stereochemical control in the Mukaiyama-aldol reaction by making use of either the monodentate BF3 OEt2 or the chelating Bu2BOTf (after the loss of a triflate group) to access the 3,4-syn product (89) or the diastereomeric 3,4-anti product (90) (Equation 55) [55]. 

In 2009, List introduced a binaphthyl-derived, chiral disulfonimide (28) as a new structural motif of a powerful chiral Brensted acid that could activate simple aldehydes [80, 81]. Evaluation of the catalytic activity and stereocontrolling abihty of 28 in the Mukaiyama aldol reaction of sUyl ketene acetal with naphthaldehyde revealed that 28 was not only far more reactive than phosphoric acid 29 and phos-phoramide 30 but also capable of affording the aldol product with high enantiose-lectivity (Scheme 7.53). 

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