Asymmetric Mukaiyama reaction

On the other hand, Li and Wang recently developed a highly efficient asymmetric Mukaiyama reaction by using chiral gallium catalysts with Trost s chiral semicrown ligands (Eq. 8.106).287 Such a system can achieve high enantioselectivity even in pure water. The combination... 

As above (eq 1), a major drawback of this reagent is the lack of a readily available enantiomer. There are many alternative methods for the enantioselective propionate aldol reaction. The most versatile chirally modified propionate enolates or equivalents are N-propionyl-2-oxazolidinones, a-siloxy ketones, boron enolates with chiral ligands, as well as tin enolates. Especially rewarding are new chiral Lewis acids for the asymmetric Mukaiyama reaction of 0-silyl ketene acetals. Most of these reactions afford s yw-aldols good methods for the anri-isomers have only become available recently. ... 

Recently, Wang and coworkers developed an efficient asymmetric Mukaiyama reaction using Ga(OTf)3, associated with a chiral semi-crown ligand, as the Lewis acid (Scheme 8.9). Enantioselectivities up to 87% were obtained when the reaction was performed in a mixture of water/ethanol (9 1) or even in neat water, with good chemical yields and high diastereoselectivities. 

The reaction was intensively studied for a-benzyloxyacetaldehyde 219a. When catalyzed by the PYBOX complex 217, various silyl ketene (O and S) acetals 220 give acetate aldol adducts 221 in high chemical yields and enantioselectiv-ity, as shown in Scheme 5.67. Compared with many protocols for asymmetric Mukaiyama reactions, the low catalyst loading (as little as 0.5 mol%) is remarkable. PYBOX catalysis is also an efficient tool for vinylogous Mukaiyama aldol additions, as illustrated also in Scheme 5.67 for acetoacetate-derived silicon enolate... 

As an extension of this work, these authors have applied this catalyst system to vinylogous asymmetric Mukaiyama-type aldol reactions, involving silyl vinyl ketene acetals and pyruvate esters. These reactions afforded the corresponding y,5-unsaturated a-hydroxy diesters with quaternary centres in high yields and enantioselectivities of up to 99% ee (Scheme 10.25). It was shown that the presence of CF3CH2OH as an additive facilitated the turnover of the catalyst. 

Asymmetric Mukaiyama aldol reactions have also been performed in the presence of Lewis-acid lanthanoid complexes combined with a chiral sulfonamide ligand. Similar enantioselectivities of about 40% ee were obtained for all... 

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. 

Ligands for catalytic Mukaiyama aldol addition have primarily included bidentate chelates derived from optically active diols,26 diamines,27 amino acid derivatives,28 and tartrates.29 Enantioselective reactions induced by chiral Ti(IY) complex have proved to be one of the most powerful stereoselective transformations for synthetic chemists. The catalytic asymmetric aldol reaction introduced by Mukaiyama is discussed in Section 3.4.1. 

A catalytic asymmetric amination reaction has been developed using Cu(2+) catalysts (246). The azodicarboxylate derivative 392 reacts with enolsilanes in the presence of catalyst 269c to provide the adducts in high enantioselectivity, Eq. 213. As observed in the Mukaiyama Michael reactions, alcoholic addends proved competent in increasing the rate of this reaction. Indeed, in the presence of tri-fluoroethanol as additive, the reaction time decreases from 24 to 3 h. 

Although in the recent years the stereochemical control of aldol condensations has reached a level of efficiency which allows enantioselective syntheses of very complex compounds containing many asymmetric centres, the situation is still far from what one would consider "ideal". In the first place, the requirement of a substituent at the a-position of the enolate in order to achieve good stereoselection is a limitation which, however, can be overcome by using temporary bulky groups (such as alkylthio ethers, for instance). On the other hand, the ( )-enolates, which are necessary for the preparation of 2,3-anti aldols, are not so easily prepared as the (Z)-enolates and furthermore, they do not show selectivities as good as in the case of the (Z)-enolates. Finally, although elements other than boron -such as zirconium [30] and titanium [31]- have been also used succesfully much work remains to be done in the area of catalysis. In this context, the work of Mukaiyama and Kobayashi [32a,b,c] on asymmetric aldol reactions of silyl enol ethers with aldehydes promoted by tributyltin fluoride and a chiral diamine coordinated to tin(II) triflate... 

Tor a treatise on this subject, sec Morrison Asymmetric Synthesis, 5 vols. [vol. 4 co-cditcd by Scott] Academic Press New York, 1983-1985. For books, see N6gr4di Stereoselective Synthesis VCH New York, 1986 Eliel Olsuka Asymmetric Reactions and Processes in Chemistry American Chemical Society Washington, 1982 Morrison Mosher Asymmetric Organic Reactions Prentice-Hall Englewood Cliffs, NJ, 1971, paperback reprint, American Chemical Society Washington, 1976 Izumi Tai, Ref. I. For reviews, see Ward Chem. Soc. Rev. 1990, 19, 1-19 Whitesell Chem. Rev. 1989, 89, 1581-1590 Fujita Nagao Adv. Heterocycl. Chem. 1989, 45, 1-36 Kochetkov Belikov Russ. Chem. Rev. 1987, 56, 1045-1067 Oppolzer Tetrahedron 1987, 43, 1969-2004 Seebach Imwinkelried Weber Mod. Synth. Methods 1986, 4, 125-259 ApSimon Collier Tetrahedron 1986, 42, 5157-5254 Mukaiyama Asami Top. Curr. Chem. 1985, 127, 133-167 Martens Top. Curr. Chem. 1984, 125, 165-246 Duhamel Duhamel Launay Plaqucvcnt Bull. Soc.Chim. Fr. 1984,11-421-11-430 Mosher Morrison Science 1983,221, 1013-1019 Schollkopf Top. Curr. Chem. 

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). 

It has been reported that the chiral NMR shift reagent Eu(DPPM), represented by structure 19, catalyzes the Mukaiyama-type aldol condensation of a ketene silyl acetal with enantiose-lectivity of up to 48% ee (Scheme 8B1.13) [29-32]. The chiral alkoxyaluminum complex 20 [33] and the rhodium-phosphine complex 21 [34] under hydrogen atmosphere are also used in the asymmetric aldol reaction of ketene silyl acetals (Scheme 8BI. 14), although the catalyst TON is quite low for the former complex. 

Mukaiyama s group also reported the catalytic asymmetric aldol reaction of ketene silyl acetals (28) promoted by chiral zinc complexes. These complexes are prepared in situ from... 

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... 

Asymmetric Mukaiyama aldol reactions in aqueous media [EtOH-H20 (9 1)] were reported with FeCl2 and PYBOX ligands 27a [36] and 27b [37]. The latter provides product 28 with higher yield and diastereo- and enantioselectivity (Scheme 8.9). The ee values given are for the syn-diastereoisomer. Whereas ligand 27a is a derivative ofL-serine, compound 27b has four stereogenic centers, since it was prepared from... 

Scheme 8.9 Asymmetric Mukaiyama aldol reactions with Fe(ll)-PYBOX catalysts.

Table 9.1 Asymmetric Mukaiyama-type aldol reactions of a glycine derivative catalyzed by in situ-generated chiral quaternary ammonium fluoride.

Table 9.2 Asymmetric Mukaiyama aldol reactions catalyzed by chiral quaternary ammonium fluorides4b with various methods of preparation.

The asymmetric aldol reaction is one of the most important topics in modern catalytic synthesis [54]. The products, namely />-hydroxy carbonyl compounds, have a broad range of applications and play a key role in the production of pharmaceuticals [55], Since the discovery of the catalytic asymmetric aldol reaction with enolsi-lanes by Mukaiyama et al. [56], steady improvements of the metal-catalyzed asymmetric aldol reaction have been made by many groups [57]. For this type of aldol reaction a series of chiral metal catalysts which act as Lewis acids activating the aldol acceptor have been shown to be quite efficient. It was recently shown by the Shibasaki group that the asymmetric metal-catalyzed aldol reaction can be also performed with unmodified ketones [57a], During the last few years, several new concepts have been developed which are based on use of organocatalysts [58], Enolates and unmodified ketones can be used as aldol donors. 

Asymmetric aldol reactions.4 The borane complex 3 can also serve as the Lewis acid catalyst for the aldol reaction of enol silyl ethers with aldehydes (Mukaiyama reactions).5 Asymmetric induction is modest (80-85% ee) in reactions of enol ethers of methyl ketones, but can be as high as 96% ee in reactions of enol ethers of ethyl ketones. Moreover, the reaction is syn-selective, regardless of the geometry of the enol. However, the asymmetric induction is solvent-dependent, being higher in nitroethane than in dichloromethane. 

A catalytic asymmetric vinylogous Mukaiyama reaction between silyl dienolate 896 and aliphatic ketone 897 provides the 5,6-dihydropyran-2-one 898, a key intermediate during a formal synthesis of enantiopure taurospongin A (Equation 361) <2005JA7288>. 

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. 

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

Fujiwara has reported a unique chiral lanthanoid(II) alkoxide-promoted asymmetric Mukaiyama aldol reaction.38 Stoichiometric amounts of the chiral alkoxide, however, were required for good enantioselectivity. 

Table 4.1 The chiral ammonium bifluoride 12-catalyzed asymmetric Mukaiyama-type aldol reaction of ketene silyl acetal 13 with aldehydes. (For experimental details see Chapter 14.1.5)...

Quaternary Ammonium Fluoride-Mediated Mukaiyama-Type Asymmetric Aldol Reaction [4] (p. 122)... 

CVAM catalytic asymmetric vinylogous Mukaiyama (reaction)... 

Because these asymmetric aldol reactions are ideal methods for constructing (3-hydroxy carbonyl compounds in optically active form, the development of an asymmetric aldol reaction without the use of an organostannane would be advantageous. Yamagishi and coworkers have reported the Mukaiyama aldol reaction using trimethylsilyl enol ethers in the presence of the BINAP-AgPF6 complex to afford the adducts with moderate enantioselectivities (Table 9.9).18 They have also assigned... 

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