Acetate enolates enantioselective aldol reaction

Covalently bonded chiral auxiliaries readily induce high stereoselectivity for propionate enolates, while the case of acetate enolates has proved to be difficult. Alkylation of carbonyl compound with a novel cyclopentadienyl titanium carbohydrate complex has been found to give high stereoselectivity,44 and a variety of ft-hydroxyl carboxylic acids are accessible with 90-95% optical yields. This compound was also tested in enantioselective aldol reactions. Transmetalation of the relatively stable lithium enolate of t-butyl acetate with chloro(cyclopentadienyl)-bis(l,2 5,6-di-<9-isopropylidene-a-D-glucofuranose-3-0-yl)titanate provided the titanium enolate 66. Reaction of 66 with aldehydes gave -hydroxy esters in high ee (Scheme 3-23). 

Enantioselective aldol reaction -hydroxy esters.2 The lithium enolate 4 of t-butyl acetate reacts with an aldehyde in the presence of 2 to form P-hydroxy esters 6 in 90-96% ee. 

The asymmetric aldol reaction of enol silyl ethers of thioesters with aldehydes is performed in high enantiomeric excess by employing a chiral promoter, tin(II) trifluoromethanesulfonate coordinated with chiral diamine 1 and tri-n-butyltin fluoride (eqs 20 and 21). Highly enantioselective aldol reactions of achiral ketene silyl acetals with achiral aldehydes are carried out by means of the same chiral promoter (eq 22). ... 

The original methods for directed aldol and aldol-type reactions of aldehydes and acetals with silyl enolates required a stoichiometric amount of a Lewis acid such as TiCh, Bl i-OI y, or SnCl.j [18]. Later studies have introduced many Lewis acids which accelerate these processes with a catalytic quantity (vide infra). In addition, it has been found that fluoride ion sources also work as effective catalysts of the aldol reaction [19]. In the last decade, much attention has been paid for the development of diastereo- and enantioselective aldol reactions [20, 21], aqueous aldol reactions using water-stable Lewis acids [22], and novel types of silyl enolate with unique reactivity. 

Kiyooka et al. have reported that stoichiometric use of chiral oxazaborolidines (e.g. (S)-47), derived from sulfonamides of a-amino acids and borane, is highly effective in enantioselective aldol reactions of ketene TMS acetals such as 48 and 49 (Scheme 10.39) [117]. The use of TMS enolate 49 achieves highly enantioselective synthesis of dithiolane aldols, which can be readily converted into acetate aldols without epimerization. The chiral borane 47-promoted aldol reaction proceeds with high levels of reagent-control (Scheme 10.40) [118] - the absolute configuration of a newly formed stereogenic center depends on that of the promoter used and not that of the substrate. 

Masamune et al. examined the catalytic activity of several boron Lewis acids derived from BH3 THF and the p-toluenesulfonamides of simple a-amino acids towards the aldol reaction of benzaldehyde with TMS enolate 48 [121]. As a result, the borane catalysts derived from a,a-disubstituted glycine p-tolueriesulforiarriides were found to have high activity. The disubstitution would accelerate the second step (Step II) of the catalytic cycle (Scheme 10.43). On the basis of this observation, they developed chiral borane catalysts 47 c and 47 d, which enable highly enantioselective aldol reactions of KSA and thioketene silyl acetals (84—99% ee with 48). 

An important development is the use of D-glucose-derived alkoxy ligands on titanium in cyciopentadi-enyldi(alkoxy)titanium enolates, which undergo efficient enantioselective aldol reactions with aldehydes. The chiral titanium reagent (30), prepared from reaction of cyclopentadienyltitanium trichloride with two equivalents of (l,2 5,6)-di-0-isopropylidene-a-D-glucofuranose, can be used to transmetal late the lithium enolate of t-butyl acetate in ether solution (equation 10). The titanium enolate generated is then... 

Table 4 Enantioselective Aldol Reactions of the Chiral Titanium Enolate of t-Butyl Acetate...

The aldol reaction is one of the most useful carbon-carbon bond forming reactions in which one or two stereogenic centers are constructed simultaneously. Diastereo-and enantioselective aldol reactions have been performed with excellent chemical yield and stereoselectivity using chiral catalysts [142]. Most cases, however, required the preconversion of donor substrates into more reactive species, such as enol silyl ethers or ketene silyl acetals (Scheme 13.45, Mukaiyama-type aldol addition reaction), using no less than stoichiometric amounts of silicon atoms and bases (Scheme 13.45a). From an atom-economic point of view [143], such stoichiometric amounts of reagents, which afford wastes such as salts, should be excluded from the process. Thus, direct catalytic asymmetric aldol reaction is desirable, which utilizes unmodified ketone or ester as a nucleophile (Scheme 13.45b). Many researchers have directed considerable attention to this field, which is reflected in the increasing... 

This class of chiral Lewis base catalysts was also applicable to the enantioselective aldol reactions of trichlorosilyl enol ethers (Scheme 7.14) [24, 25). As included in Scheme 7.14, Denmark devised chiral bipyridine N.N -dioxide 8 and demonstrated that it smoothly catalyzed the aldol addition of methyl acetate-derived trichlorosilyl ketene acetal to a series of ketones with good to high enantioselectivi-ties [25],... 

Perlmutter used an oxymercuration/demercuration of a y-hydroxy alkene as the key transformation in an enantioselective synthesis of the C(8 ) epimeric smaller fragment of lb (and many more pamamycin homologs cf. Fig. 1) [36]. Preparation of substrate 164 for the crucial cyclization event commenced with silylation and reduction of hydroxy ester 158 (85-89% ee) [37] to give aldehyde 159, which was converted to alkenal 162 by (Z)-selective olefination with ylide 160 (dr=89 l 1) and another diisobutylaluminum hydride reduction (Scheme 22). An Oppolzer aldol reaction with boron enolate 163 then provided 164 as the major product. Upon successive treatment of 164 with mercury(II) acetate and sodium chloride, organomercurial compound 165 and a second minor diastereomer (dr=6 l) were formed, which could be easily separated. Reductive demercuration, hydrolytic cleavage of the chiral auxiliary, methyl ester formation, and desilylation eventually led to 166, the C(8 ) epimer of the... 

The cationic iridium complex [Ir(cod)(PPh3)2]OTf, when activated by H2, catalyzes the aldol reaction of aldehydes 141 or acetal with silyl enol ethers 142 to afford 143 (Equation 10.37) [63]. The same Ir complex catalyzes the coupling of a, 5-enones with silyl enol ethers to give 1,5-dicarbonyl compounds [64]. Furthermore, the alkylation of propargylic esters 144 with silyl enol ethers 145 catalyzed by [Ir(cod)[P(OPh)3]2]OTf gives alkylated products 146 in high yields (Equation 10.38) [65]. An iridium-catalyzed enantioselective reductive aldol reaction has also been reported [66]. 

The aldol reaction is well established in organic chemistry as a remarkably useful synthetic tool, providing access to p-hydroxycarbonyl compounds and related building blocks. Intensive efforts have raised this classic process to a highly enantioselective transformation employing only catalytic amounts of chiral promoters, as reviewed in the previous section (Chap. 29.1). While some effective applications have been reported, most of the methodologies necessarily involve the preformation of latent enolates 2, such as ketene silyl acetals, using... 

Some of the most impressive advances in the area of catalytic, enantioselective aldol addition reactions have taken place in the development of catalytic methods for enantioselective acetate aldol additions, a reaction type that has long been recalcitrant. Thus, although prior to 1992 a number of chiral-auxiliary based and catalytic methods were available for diastereo- and enantiocontrol in propionate aldol addition reactions, there was a paucity of analogous methods for effective stereocontrol in the addition of the simpler acetate-derived enol silanes. However, recent developments in this area have led to the availability of several useful catalytic processes. Thus, in contrast to the state of the art in 1992, it is possible to prepare acetate-derived aldol fragments utilizing asymmetric catalysis with a variety of transition-metal based complexes of Ti(IV), Cu(II), Sn(II), and Ag(I). 

Aldol Addition. A catalyst generated upon treatment of Cu(OTf)2 with the (5,5)-r-Bu-box ligand has been shown to be an effective Lewis acid for the enantioselective Mukaiyama aldol reaction. The addition of substituted and unsubstituted enolsilanes at -78 °C in the presence of 5 mol % catalyst was reported to be very general for various nucleophiles, including silyl dienolates and enol silanes prepared from butyrolactone as well as acetate and propionate esters. 

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. ... 

Analogous with the previous results of enol silyl ethers of ketones, nonsubstituted ketene silyl acetals are found to exhibit lower levels of stereoregulation, while the propionate-derived ketene silyl acetals display a high level of asymmetric induction. The reactions with aliphatic aldehydes, however, resulted in a slight reduction in optical and chemical yields. With phenyl ester-derived ketene silyl acetals, syn adducts predominate, but the selectivities are moderate in most cases in comparison with the reactions of ketone-derived silyl enol ethers. Exceptions are a,p-unsaturated aldehydes, which revealed excellent diastereo- and enantioselectivities. The observed syn selectivity and re-face attack of nucleophiles on the carbonyl carbon of aldehydes are consistent with the aforementioned aldol reactions of ketone-derived enol silyl ethers. 

The Mukaiyama aldol reaction of carbonyl substrates with silyl enol ethers is the most widely accepted of Lewis acid-promoted reactions. Many Lewis acids for the reaction have been developed and used enantioselectively and diastereoselectively. In 1980, catalytic amounts of la were found by Noyori et al. to effect aldol-type condensation between acetals and a variety of silyl enol ethers with high stereoselectivity [2c,20]. Unfortunately, la has poor Lewis acidity for activation of aldehydes in Mukaiyama s original aldol reaction [21]. Hanaoka et al. showed the scope and limitation of 11-cat-alyzed Mukaiyama aldol reaction, by varying the alkyl groups on the silicon atom of silyl enol ethers [22]. Several efforts have been since been made to increase the reactivity and/or the Lewis acidity of silicon. One way to enhance the catalyst activity is to use an additional Lewis acid. 

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]. 

The tributyltin enolates 74 are readily prepared from the corresponding enol acetates and tributyltin methoxide in the absence of solvent [34]. The tin enolates thus obtained occur in the 0-Sn form and/or the C-Sn form, and both species can be used for the aldol reaction of this system. Although the tin enolates themselves have adequate reactivity toward aldehydes [34c], in the presence of the BINAP silver(I) catalyst the reaction proceeds much faster even at -20 °C. Optimum conditions entail the use of THF as solvent and the results employing these conditions in the catalytic enan-tioselective aldol reaction of a variety of tributyltin enolates with typical aromatic, a,/3-unsaturated, and aliphatic aldehydes are summarized in Table 2. TTie characteristic features are (i) All reactions proceed to furnish the corresponding aldol adducts 75 in moderate to high yield in the presence of 10 mol % (i )-BINAP AgOTf complex at -20 °C for 8 h, and no dehydrated aldol adduct is observed (ii) with an a,j3-unsaturated aldehyde, the 1,2-addition reaction takes place exclusively (entry 3) (iii) a bulky alkyl substituent of tin enolate increases the enantioselectivity of the aldol reaction. For instance, the highest ee (95 % ee) is obtained when the tin enolate prepared from pinacolone 77 or rert-butyl ethyl ketone 79 is added to aldehydes (entries 2, 7, and 8) (iv) addition of the cyclohexanone-derived enol tributylstannane 78 (( )-... 

Aldol reactions. The enantioselectivity in condensations involving silyl enol ethers and silyl ketene acetals (also thioacetals) has been actively pursued. Valuable catalysts include 102, 103. Subsequent to the development of Cj-symmetric... 

The pioneering discovery by Mukaiyama in 1974 of the Lewis acid mediated aldol addition reaction of enol silanes and aldehydes paved the way for subsequent explosive development of this innovative method for C-C bond formation. One of the central features of the Mukaiyama aldol process is that the typical enol silane is un-reactive at ambient temperatures with typical aldehydes. This reactivity profile allows exquisite control of the reaction stereoselectivity by various Lewis acids additionally, it has led to the advances in catalytic, enantioselective aldol methodology. Recent observations involving novel enol silanes, such as enoxy silacyclobutanes and O-si-lyl M(9-ketene acetals have expanded the scope of this process and provided additional insight into the mechanistic manifolds available to this versatile reaction. 

Chiral auxiliary-bound substrates have also been used for the asymmetric process. The aldol reaction of chiral pyruvates such as 46 is a reliable method for highly enantioselective synthesis of functionalized tertiary alcohols (Scheme 10.38) [112]. The Lewis acid-catalyzed aldol-type reactions of chiral acetals with silyl enolates are valuable for the asymmetric synthesis of -alkoxy carbonyl compounds ]113, 114]. 

The catalytic system using 62 is applicable to highly enantioselective preparation of acetoacetate aldol adducts (Scheme 10.55) [152]. The use of 1-3 mol% 62 and 0.4 equiv. 2,6-lutidine promotes the aldol reaction of a variety of aldehydes with silyl dienolate 64 in good to high optical yields. The dienolate addition provides a convergent and enantioselective route to 1,3-polyols by appending a protected acetoacetate in a single step. The 62-catalyzed aldol reactions of methyl acetate TMS enolate and dienolate 64 have been used in the total syntheses of Rofla-mycoin [153] and Macrolactin A [154], respectively. In the latter both enantiomers... 

The catalytic process has found successful application in several natural product total syntheses. In 1996, Simon reported a synthesis of the antitumor dep-sipeptide FR-9001,228 in which the aldol addition reaction of 168 and the ethyl acetate-derived enol silane furnished a key synthetic intermediate (Eq. 23). The enantioselective aldol addition reaction of 168 was conducted with 165 and its enantiomer ent-165 to separately provide both enantiomers of the aldol adducts 169 and 170 (Scheme 14). These were then utilized in the preparation of diastereomeric seco acids 171 and 172 [101]. Macrocyhzation of 172 through a Mitsonobu reaction yielded the desired natural product 173. 

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