Catalysts for the Mukaiyama aldol reaction

Scheme 2.8. Chiral Catalysts for the Mukaiyama Aldol Reactions...

Bismuth triflate has been reported by Dubac as an efficient catalyst for the Mukaiyama aldol reaction with silyl enol ethers [27] and was recently used with a chiral ligand, as reported by Kobayashi in an elegant hydroxymethylation reaction... 

The aldol reaction constitutes one of the most fundamental bond-construction processes in organic synthesis [56]. Therefore, much attention has been focused on the development of asymmetric catalysts for the Mukaiyama aldol reaction in recent years. 

Treatment of tridentate ligand with Ti(0 Pr)4 and di-ferf-butylsalicyclic acid (163) in toluene followed by evaporation of the solvent afforded an orange complex postulated to be 165, which was shown to be an effective catalyst for the Mukaiyama aldol reaction. Under optimized conditions, the simple methyl acetate-derived enol silane 166 adds to aldehydes in the presence of as little as... 

Diphenylboronic acid (Ph2BOH), which is soluble in water, is an effective catalyst for the Mukaiyama aldol reaction in the presence of dodecyl sulfate (SDS) as surfactant. Yields of 93% with syn/anti ratios of 94 6 have been reached according to Eq. (3). The proposed mechanism of this reaction is shown in Scheme 1 [10b]. 

Figure 5.6. Chiral catalysts for the Mukaiyama aldol reaction (a) Kiyooka catalyst [112,113] (b) Masamune catalyst [114] (c) Corey catalyst [115] (d) Yamamoto catalyst [116,117] (e-f) Kobayashi-Mukaiyama catalysts [118-120].

Kobayashi et al. have reported that Ph2BOH is also an effective catalyst for the Mukaiyama aldol reaction in the presence of benzoic acid as a cosodium dodecyl sulfate as a sur ctant (Equation 3) [3]. The use of water as a solvent is essential in this reaction. The reaction proceeds sluggishly in organic solvents such as didiloromethane and dietiiyl ether. Compared to water, much lower yields are obtained under neat conditions. High syn selectivity is observed when Z-enolates are used, while relatively low anti selectivity is observed with -enolates. 

Polymer encapsulated and supported scandium trillate Lewis acid catalysts were used as heterogeneous Lewis acid catalysts for the Mukaiyama aldol reaction (Equation (8.61)) [118,126]. 

Scheme 7.53 Chiral disulfonimide as catalyst for the Mukaiyama aldol reaction.

Oxamborolidenes. There are noteworthy advances in the design, synthesis, and study of amino acid-derived oxazaborolidene complexes as catalysts for the Mukaiyama aldol addition. Corey has documented the use of complex 1 prepared from A-tosyl (S)-tryptophan in enantioselective Mukaiyama aldol addition reactions [5]. The addition of aryl or alkyl methyl ketones 2a-b proceeded with aromatic as well as aliphatic aldehydes, giving adducts in 56-100% yields and up to 93% ee (Scheme 8B2.1, Table 8B2.1). The use of 1-trimethylsilyloxycyclopentene 3 as well as dienolsilane 4 has been examined. Thus, for example, the cyclopentanone adduct with benzaldehyde 5 (R = Ph) was isolated as a 94 6 mixture of diastereomers favoring the syn diastereomer, which was formed with 92% ee, Dienolate adducts 6 were isolated with up to 82% ee it is important that these were shown to afford the corresponding dihydropyrones upon treatment with trifuoroacetic acid. Thus this process not only allows access to aldol addition adducts, but also the products of hetero Diels-Alder cycloaddition reactions. 

Keck also investigated asymmetric catalysis with a BINOL-derived titanium complex [102,103] for the Mukaiyama aldol reaction. The reaction of a-benzyloxyalde-hyde with Danishefsky s dienes as functionalized silyl enol ethers gave aldol products instead of hetero Diels-Alder cycloadducts (Sch. 40) [103], The aldol product can be transformed into hetero Diels-Alder type adducts by acid-catalyzed cyclization. The catalyst was prepared from BINOL and Ti(OPr )4, in 1 1 or 2 1 stoichiometry, and oven-dried MS 4A, in ether under reflux. They reported the catalyst to be of BINOL-Ti(OPr% structure. 

One of the most powerful catalysts of the Mukaiyama aldol reaction is a chiral Ti(IV)-Schiff base complex 91 prepared from Ti(0 Pr)4 and enantiomerically pure salicylaldimine reported by Carreira [103-105]. This catalyst furnished aldol adducts in good yields and with excellent enantioselectivity. The Ti(IV)-Schiff base catalyst system is unique among the aldol catalysts yet reported in terms of operational simplicity, catalyst efficiency, chirality transfer, and substrate generality. Because the Ti(IV)-Schiff base complexes are remarkably efficient catalysts for the addition of ketene acetals to a wide variety of aldehydes, the polymeric version of catalyst 92 was prepared [106]. The activity and enantioselectivity of the polymer-supported chiral Ti(IV)-Schiff base complex were, however, much lower than were obtained from the low-molecular-weight catalyst (Eq. 28). 

The Eu-catalyst Eu(dppm)3 provides a remarkable level of chemoselectivity but is only effective for the Mukaiyama-aldol reaction of aldehydes with several ketene silyl acetals (KSA) (Table 2-3) [55]. When ketones and aldehydes are treated, respectively, with KSA and ketone-derived silyl enol ethers, no reaction results. The rate enhancement by chelation control (entry 4, Table 2-3) is intriguing. This is a feature common to other Lewis acids such as TiC [56] or LiC104 [57],... 

Sc(() l f) ( is an effective catalyst of the Mukaiyama aldol reaction in both aqueous and non-aqueous media (vide supra). Kobayashi et al. have reported that aqueous aldehydes as well as conventional aliphatic and aromatic aldehydes are directly and efficiently converted into aldols by the scandium catalyst [69]. In the presence of a surfactant, for example sodium dodecylsulfate (SDS) or Triton X-100, the Sc(OTf)3-catalyzed aldol reactions of SEE, KSA, and ketene silyl thioacetals can be performed successfully in water wifhout using any organic solvent (Sclieme 10.23) [72]. They also designed and prepared a new type of Lewis acid catalyst, scandium trisdodecylsulfate (STDS), for use instead of bofh Sc(OTf) and SDS [73]. The Lewis acid-surfactant combined catalyst (LASC) forms stable dispersion systems wifh organic substrates in water and accelerates fhe aldol reactions much more effectively in water fhan in organic solvents. Addition of a Bronsted acid such as HCl to fhe STDS-catalyzed system dramatically increases the reaction rate [74]. 

In recent years, catalytic asymmetric Mukaiyama aldol reactions have emerged as one of the most important C—C bond-forming reactions [35]. Among the various types of chiral Lewis acid catalysts used for the Mukaiyama aldol reactions, chirally modified boron derived from N-sulfonyl-fS)-tryptophan was effective for the reaction between aldehyde and silyl enol ether [36, 37]. By using polymer-supported N-sulfonyl-fS)-tryptophan synthesized by polymerization of the chiral monomer, the polymeric version of Yamamoto s oxazaborohdinone catalyst was prepared by treatment with 3,5-bis(trifluoromethyl)phenyl boron dichloride ]38]. The polymeric chiral Lewis acid catalyst 55 worked well in the asymmetric aldol reaction of benzaldehyde with silyl enol ether derived from acetophenone to give [i-hydroxyketone with up to 95% ee, as shown in Scheme 3.16. In addition to the Mukaiyama aldol reaction, a Mannich-type reaction and an allylation reaction of imine 58 were also asymmetrically catalyzed by the same polymeric catalyst ]38]. 

The use of Cu(II) complexes as Lewis acid catalysts for the Mukaiyama aldol addition reaction has been documented and studied by Evans [120a, 120b, 121a,... 

Polymeric BINOL aluminum chloride. Prepared by Ni(0)-catalyzed cross- coupling of chiral 6,6 -dibromo-BINOL diacetate, hydrolysis, and treatment with EtjAlCl, the chiral catalyst is effective for the Mukaiyama aldol reaction. 

Fluorous solid catalyst 8 is highly effective for the Mukaiyama aldol reaction [Eq. (9)] and Sakurai-Hosomi allylation reaction [Eq. (lO)j. These reactions have been performed at -78 °C and room temperature, respectively, under heterogeneous conditions. Post-reaction, 8 has been recovered in high yield by decanting the liquids at room temperature. 

Other chiral zinc based Lewis acid, such as zinc(II) complex with pybox, showed good stability in aqueous media and gave syn-adducts in moderate to excellent catalytic activity and enantioselectivity for asymmetric Mukaiyama aldol reactions (113,114). A simple combination of Lewis acidic zinc salt (Zn(OTf)2) and organocatalyst is also shown to be effective catalysts for the direct aldol reaction of acetone and aldehydes in the presence of water (115). 

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). 

Bismuth tris-trifluoromethanesulfonate has been found to be an efficient catalyst for the Mukaiyama aldol-type reactions (Equation (8.14)). The catalytic activity of this catalyst is higher than the one reported for the rare earth triflates M(OTf)3 (M = Sc, Ln). In its presence the mechanism involves a transmetallation step [33]. The catalyst s water stability allows the recovery and recycling. 

Masamune examined the use of Ca-alkylated a-amino acids for the generation of optically active oxazaborolidines 249 which were used as Lewis acid catalysts (Scheme 4.30) [125, 126]. The expectation in these studies was that the additional rigidity proffered by the unnatural amino acid scaffold would lead to improved selectivities. Several excellent catalysts for asymmetric Mukaiyama aldol reactions with a broad range of aldehydes were identified, both for acetate aldol reactions [125] and for the addition of isobutyrate-derived silyl enol ethers [126], as shown for the case of catalyst 249. 

During the past decades, the scope of Lewis acid catalysts was expanded with several organic salts. The adjustment of optimal counter anion is of significant importance, while it predetermines the nature and intensity of catalytic Lewis acid activation of the reactive species. Discovered over 100 years ago and diversely spectroscopically and computationally investigated [131-133], carbocations stiU remain seldom represented in organocatalysis, contrary to analogous of silyl salts for example. The first reported application of a carbenium salt introduced the trityl perchlorate 51 (Scheme 49) as a catalyst in the Mukaiyama aldol-type reactions and Michael transformations (Scheme 50) [134-142]. 

In the Mukaiyama aldol additions of trimethyl-(l-phenyl-propenyloxy)-silane to give benzaldehyde and cinnamaldehyde catalyzed by 7 mol% supported scandium catalyst, a 1 1 mixture of diastereomers was obtained. Again, the dendritic catalyst could be recycled easily without any loss in performance. The scandium cross-linked dendritic material appeared to be an efficient catalyst for the Diels-Alder reaction between methyl vinyl ketone and cyclopentadiene. The Diels-Alder adduct was formed in dichloromethane at 0°C in 79% yield with an endo/exo ratio of 85 15. The material was also used as a Friedel-Crafts acylation catalyst (contain-ing7mol% scandium) for the formation of / -methoxyacetophenone (in a 73% yield) from anisole, acetic acid anhydride, and lithium perchlorate at 50°C in nitromethane. 

Lewis acids are quite often used as catalysts in organic synthesis. Although most Lewis acids decompose in water, it was found that rare earth triflates such as Sc(OTf)3, Yb(OTf)3, etc. can be used as Lewis acid catalysts in water or water-containing solvents (water-compatible Lewis acids) [6-9]. For example, the Mukaiyama aldol reactions of aldehydes with silyl enol ethers were catalyzed by Yb(OTf)3 in water-THF (1 4) to give the corresponding aldol adducts in high yields [10, 11]. Interestingly, when the reactions were carried out in dry THF (without water), the yield of the aldol adducts was very low (ca. 10%). Thus, this catalyst is not only compatible with water but also is activated by water, probably due to dissociation of the counteranions from the Lewis acidic metal. Furthermore, the catalyst can be easily recovered and reused. 

BINOL-derived titanium complex was found to serve as an efficient catalyst for the Mukaiyama-type aldol reaction of ketone silyl enol ethers with good control of both absolute and relative stereochemistry (Scheme 8C.24) [57]. It is surprising, however, that the aldol products were obtained in the silyl enol ether (ene product) form, with high syn-diastereoselec-tivity from either geometrical isomer of the starting silyl enol ethers. 

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