Catalytic Asymmetric Mukaiyama-Aldol Reactions

Pro-chiral pyridine A-oxides have also been used as substrates in asymmetric processes. Jprgensen and co-workers explored the catalytic asymmetric Mukaiyama aldol reaction between ketene silyl acetals 61 and pyridine A-oxide carboxaldehydes 62 <06CEJ3472>. The process is catalyzed by a copper(II)-bis(oxazoline) complex 63 which gave good yields and diastereoselectivities with up to 99% enantiomeric excess. 

Studies of catalytic asymmetric Mukaiyama aldol reactions were initiated in the early 1990s. Until recently, however, there have been few reports of direct catalytic asymmetric aldol reactions [1]. Several groups have reported metallic and non-metallic catalysts for direct aldol reactions. In general, a metallic catalysis involves a synergistic function of the Bronsted basic and the Lewis acidic moieties in the catalyst (Scheme 2). The Bronsted basic moiety abstracts an a-pro-ton of the ketone to generate an enolate (6), and the Lewis acidic moiety activates the aldehyde (3). 

Keck [63] and Carreira [64] have independently reported catalytic asymmetric Mukaiyama aldol reactions. Keck et al. also reported the aldol reaction of an a-benzyloxy aldehyde with a Danishefsky s diene. The aldol product was transformed to the corresponding HDA-type product through acid-catalyzed cyclization. In these reactions, the catalyst that is claimed to... 

Figure 45. Catalytic, asymmetric Mukaiyama aldol reaction promoted by die chiral Yb complex.

Mukaiyama aldol reactions are useful means of constructing complex molecules for the total synthesis of natural products. Although catalytic asymmetric Mukaiyama aldol reactions have been achieved by use of a variety of chiral Lewis acids [42], no report of the use of chiral lanthanide catalysts was available until recently, despite the potency of these catalysts. Shibasaki and co-workers reported the first examples of chiral induction with chiral lanthanide complexes (Sch. 7) [43]. Catalysts prepared from lanthanide triflates and a chiral sulfonamide ligand afforded the corresponding aldol products in moderate enantiomeric excess (up to 49% ee). 

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]. 

Kobayashi, S., Nagayama, S. and Busujima T, Catalytic asymmetric Mukaiyama aldol reactions in aqueous media, Tetrahedron, 1999, 55, 8739-8746. 

Mukaiyama aldol reactions, whereby trimethylsilyl enol ethers react with aldehydes in aqueous solution to form -ketoalcohols, have been promoted by new chiral lanthanide-containing complexes and a chiral Fe(II)-bipyridine complex with 0 outstanding diastereo- and enantio-selectivities. Factors controlling the diastereoselec-tivity of Lewis-acid-catalysed Mukaiyama reactions have been studied using DFT to reveal the transition-state influences of substituents on the enol carbon, the a-carbon of the silyl ether, and the aldehyde. The relative steric effects of the Lewis acid and 0 trimethyl silyl groups and the influence of E/Z isomerism on the aldol transition state were explored. Catalytic asymmetric Mukaiyama aldol reaction of difluoroenoxysilanes with /-unsaturated a-ketoesters has been reported for the first time and studied extensively. ... 

This review describes the first catalytic asymmetric Mukaiyama-aldol reaction of fluorine-substituted ketene silyl acetals with aldehydes and the catalytic asymmetric He (nitroaldol) reaction of 2,2-difluoroaldehydes with nitromethane to provide the optically active aldols and nitroaldols, respectively, which must be versatile synthetic intermediates for the fluorinated protease inhibitors. 

Corey examined and documented another class of amino-acid-derived N-sulfonamide oxazaborolidines, characterized by their convenient synthesis, for the catalytic asymmetric Mukaiyama aldol reaction. Oxazaborolidine 256, for example, can be assembled from the condensation of L-N-tosyl-tryp-tophan and n-butylboronic acid. It was shown to be an effective catalyst for the Mukaiyama addition of enoxysilanes with a variety of aldehydes (Equation 25) [127]. 

As discussed in Section III J, in general, catalytic asymmetric aldol reactions have been studied using enol silyl ethers, enol methyl ethers, or ketene silyl acetals as a starting material. So far several types of chiral catalysis have been reported.75-85 The chiral lanthanoid complex prepared from Ln(OTf)3 and a chiral sulfonamide ligand was effective in promoting an asymmetric Mukaiyama aldol reaction with a ketene silyl acetal.86 The preparation of the catalyst and a representative reaction are shown in Figure 45. 

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). 

A chiral lanthanide complex catalyzes asymmetric Mukaiyama aldol reactions in aqueous media (Scheme 24). The changes in the water-coordination number is key to the mechanism of die catalytic reaction. The precatalysts yielded -hydroxy carbonyl compounds from aliphatic and aryl substrates widi high diastereomeric ratios and enantiomeric excesses of up to 49 1 and 97%, respectively. 

For example in the so-called Mukaiyama aldol reaction of an aldehyde R -CHO and a trimethylsilyl enol ether 8, which is catalyzed by Lewis acids, the required asymmetric environment in the carbon-carbon bond forming step can be created by employing an asymmetric Lewis acid L in catalytic amounts. 

The third part of this chapter reviews previously described catalytic asymmetric reactions that can be promoted by chiral lanthanoid complexes. Transformations such as Diels-Alder reactions, Mukaiyama aldol reactions, several types of reductions, Michael addition reactions, hydrosilylations, and hydroaminations proceed under asymmetric catalysis in the presence of chiral lanthanoid complexes. 

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 %. 

Miscellaneous. There are several other reports on the application of this ligand to catalytic asymmetric reactions, although enantioselectivities are modest. Those reports include the Mukaiyama-Michael reaction, allylation of aldehydes, asymmetric Diels-Alder reaction, Mukaiyama-Aldol reaction of ketomalonate, aziridination reaction of a-imino esters, and asymmetric hetero-Diels-Alder reaction. ... 

The BINAP silver(I) complex can be further applied as a chiral catalyst in the asymmetric aldol reaction. Although numerous successful methods have been developed for catalytic asymmetric aldol reaction, most are the chiral Lewis acid-catalyzed Mukaiyama aldol reactions using silyl enol ethers or ketene silyl acetals [32] and there has been no report which includes enol stannanes. Yanagisawa, Yamamoto, and their colleagues found the first example of catalytic enantioselective aldol addition of tributyltin enolates 74 to aldehydes employing BINAP silver(I) complex as a catalyst (Sch. 19) [33]. 

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. 

A convergent total synthesis of polyene macrolide roflamycoin was achieved by S.D. Rychnovsky and co-workers." " In their approach, they introduced the C25 stereocenter via an asymmetric catalytic Mukaiyama aldol reaction utilizing Carreira s chiral titanium catalyst." ... 

The activation of the carbonyl group by Lewis acids was another leap made in the 1960s as typified by Mukaiyama-aldol reaction. In sharp contrast to the conventional carbonyl addition reactions that had been run under basic conditions, this new method allowed the addition of various nucleophiles under acidic conditions with high chemo- and stereocontrol and, consequently, the scope of the carbonyl addition reaction was extensively expanded. The Lewis acid-promoted ally-lation with allylmetals and ene reaction also received as much attention as the aldol-type reaction. It should be further pointed out that the catalytic versions of asymmetric reactions, which represent one of the most exciting topics in recent synthetic chemistry, owe their development strongly to the Lewis acid activation protocol. The design of a variety of chiral ligands for metals has produced luxuriant fruits in this field. 

In all of the examples considered so far, the chiral element has been employed in stoichiometric quantities. Ultimately, it would be desirable to require only a small investment from the chirality pool. This is only possible if the chiral species responsible for enantioselectivity is catalytic. It is worth stating explicitly that, in order to achieve asymmetric induction with a chiral catalyst, the catalyzed reaction must proceed faster than the uncatalyzed reaction. One example of an asymmetric aldol addition that has been studied is variations of the Mukaiyama aldol reaction [110] whereby silyl enol ethers react with aldehydes with the aid of a chiral Lewis acid. These reactions proceed via open transition structures such as those shown in Figure... 

Mechanistically related to the Mukaiyama aldol reaction, the carbonyl ene reaction is the reaction between an alkene bearing an allylic hydrogen and a carbonyl compound, to afford homoallylic alcohols. This reaction is potentially 100% atom efficient, and should be a valuable alternative to the addition of organometallic species to carbonyl substrates. However, the carbonyl ene reaction is of limited substrate scope and works generally well in an intermolecular manner only with activated substrates, typically 1,1-disubstituted alkenes and electron-deficient aldehydes (glyoxylate esters, fluoral, a,p-unsaturated aldehydes, etc.), in the presence of Lewis acids. The first use of chiral catalyst for asymmetric carbonyl ene was presented by Mikami et al. in 1989. ° By using a catalytic amount of titanium complexes prepared in situ from a 1 1 ratio of (rPrO)2titaniumX2 (X = Cl or Br) and optically pure BINOL, the homoallylic alcohols 70a,b were obtained in... 

Chiral Catalysts Containing Group 11 Metals (Cu, Ag, and Au). The most recent publications on the chiral copper catalysts are mainly dealing with those containing bis(oxazoline)-type ligands (Fig. 22). Cationic [Cu( Bu-BOX)] + complexes with OTf , [SbFe] , counterions catalyze Michael reactions, and various types of cycloadditions (292). Copper(II)-PYBOX complexes have been shown to catalyze enantioselective Mukaiyama aldol reactions (293). Similarly, bisoxa-zoline derivatives serve as ligands in the catalytic system prepared in situ from Cud) salts and are used for asymmetric peroxidation and enantioselective Meer-wein arylation of activated olefins (294). The copper-BOX-triflate complexes have found wide applications in cyclopropanation of alkenes (60), furans (295), and aziridination of alkenes (296). 

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