Chiral Boron Ketene Acetals

Hepatite Virus NS3/4A having the pyrrolidine-5,5-trans-lactam skeleton [83], starting from (R)- and (S)-methionine, respectively. The key step is the addition of the proper silyl ketene acetal to an iminium ion, e.g., that generated by treatment of the intermediate 177 with boron trifluoride, which provided the adduct 178 with better diastereoselectivity than other Lewis acids. Inhibitors of hepatitis C virus NS3/4A were efficiently prepared by a similar route from (S)-methionine [83]. The addition of indole to a chiral (z-amino iminium ion was a completely diastereoselective step in a reported synthesis of tilivalline, a natural molecule which displays strong cytotoxicity towards mouse leukemia L 1210 [84]. 

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

Included in this class of olefins is ( )-stilbene (entry 20), which throughout studies of AD has usually been the olefin dihydroxylated with the highest degree of enantioselectivity. Availability of (R,R) or (.5,5)-1,2-diphenyl-1,2-ethanediol (also referred to as stilbenediol or dihydrobenzoin) with high enantiomeric purities has led to reports of a number of applications, including incorporation into chiral dioxaphospholanes [50], chiral boronates [51], chiral ketene acetals [52], chiral crown ethers [53], and conversion into 1,2-diphenylethane-1,2-diamines [54]. Dihydroxylation of the substituted rran.r-stilbene 46 with Os04/NMO and DHQD-CLB gives the i ,/ -diol 47 with 82% ee in 88% yield [55]. 

The /3-aminoester 385, synthesized by coupling of a chiral imine with a ketene acetal, cyclized toward cis-3-hydroxy-4-phenylazetidin-2-one 386 in the presence of boron tribromide (Scheme 57) <1998BML1619>. 

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. ... 

Although the asymmetric aldol reaction of benzaldehyde and di ketene has been reported with a catalyst generated from di-iso-propyl tartrate and iso-propanol, low induction and low yields were observed for the d-hydroxyl-y5-keto ester 27 [8], Low induction was also observed for aldol reactions mediated by chiral aluminum catalysts generated from a-amino acids [9]. These types of catalyst have been very successful when employing boron as the Lewis acid, as illustrated in the aldol reaction of ketene acetal 10 with the boron catalyst 31 derived from (5)-valine (Sch. 4) [9,10]. Catalysts derived from A-tosyl-(5 )-valine and Et2AlCl and i-BuyAl were relatively ineffective (< 15 % ee) [9]. 

Chiral boronales are generated m situ by reaction of binaphthols 3.7 (R = H, Ph) [231] with BH3 in the presence of acetic acid [778], with H BBr [781] or with B(OPh)3 [782, 783], Chiral borates are formed by reactions of substituted (S)-prolinol derivative 2.13 (R =- CPl OH) and BBr3 [784], These boronates and borates are valuable catalysts in asymmetric Diels-Alder reactions [73, 231, 601, 780], Tartaric acid derivatives, such as borate 3.8 and acyloxyboranes 3.9 recommended by Yamamoto and coworkers [73,601,778,780,785-791], are very efficient catalysts in asymmetric Diels-Alder reactions and in condensations of aldehydes with allylsilanes, enoxysilanes or ketene acetals. These catalysts are generated in situ from substituted monobenzoates of (RJl)- or (S -tartaric acid and BH3 (R = H) or an arylboric acid (R = Ar). The best asymmetric inductions are observed with catalysts 3.9, R = /-Pr. 1,3,2-OxazaboroMnes 3.10, prepared from a-aminoacids [44, 601, 780, 792, 793], are efficient catalysts in asymmetric Diels-Alder reactions. The catalyst generated from A -tosyltrytophan 3.11 is more efficient than borolidines 3.10 (R = Et, /-Pr). The catalysts 3.10 prepared from 3.11, 3.12 and 3.13 are also useful in asymmetric condensations of aldehydes with ketene acetals [794-797]. 

The addition of silyl ketene acetals to chiral aldonitrones requires the use of Lewis acids as activating reagents. Whereas activation with TMSOTf followed by a treatment with hydrofluoric acid-pyridine leads to the syw-adducts of isoxazolidin-5-ones (eq 91), the use of diethylaluminium chloride or boron trifluoride etherate leads to awft -compounds. ... 

Other reports deal with a pyrrolidine-catalysed homo-aldol condensation of aliphatic aldehydes (further accelerated by benzoic acid), a diastereoselective aldol-type addition of chiral boron azaenolates to ketones,the use of TMS chloride as a catalyst for TiCU-mediated aldol and Claisen condensations, a boron-mediated double aldol reaction of carboxylic esters, gas-phase condensation of acetone and formaldehyde to give methyl vinyl ketone, and ab initio calculations on the borane-catalysed reaction between formaldehyde and silyl ketene acetal [H2C=C(OH)OSiH3]. ... 

A chiral boron reagent, derived from equimolar amounts of (R)-or (5)-binaphthol and triphenyl borate, promotes the condensation of chiral imines with t-butyl acetate silyl ketene acetal in high diastereomeric excess (eq 12). ... 

A large variety of propionic acid esters and higher homologs having a chiral alcohol moiety have been used in additions to aldehydes [56, 57]. It turned out, however, that the lithium enolates result in only moderate simple diastereoselectivity and induced stereoselectivity, in contrast with the corresponding boron, titanium, tin, or zirconium enolates and silyl ketene acetals, with which stereoselectivity is excellent. The same feature has been observed in enolates derived from chiral amides and oxazolidinones, as... 

Many attempts have been made to add chiral acetates to aldehydes or prochiral ketones, to obtain non-racemic y -hydroxycarboxylic esters. Here again, several variants based on boron and titanium enolates and on Mu-kaiyama aldol additions of silyl ketene acetals have been developed, and will be described in Chapter 2 (titanium enolates). Chapter 3 (boron enolates) and in Part II (Mukaiyama reaction), for enolates of group 1 and 2 elements the following fruitful approaches were elaborated. 

P-Amino esters. By means of double stereodifferentiation using chiral imines and a chiral BINOL-boronate catalyst, the condensation with ketene silyl acetals is a simple method for the synthesis of /3-amino esters in optically active forms, a-Hydroxy-/3-amino esters are similarly accessible. ... 

Asymmetric Aldol Reaction of Difluoroketene Silyl Acetal 1 Catalyzed by Chiral Lewis Acids. We turned our attention to evaluating several chiral Lewis acid catalysts, which are known to be capable of serving as asymmetric catalysts in the aldol reaction of nonfluorinated ketene silyl acetals, for Ifaeir usefulness in the reaction of the difluoroketene acetal 1 with aldehydes. A couple of boron complexes, Masamune s catalyst 6 (55,56) and Kiyooka s catalyst 7 (57, 58), were found to be effective for our study. For Masamune s catalyst 6, the reaction was carried out by adding an aldehyde in nitroethane to a solution of the acetal 1 and the catalyst 6 in the same solvent over 3 h at -78 C with stining at fliat temperature for an additional hour prior to quenching. With Kiyooka s catalyst 7, an aldehyde in nitroethane was added to a solution of the acetal 1 and the catalyst 7 in nitroethane at -45 C for 5 min, followed by stirring at -45 C for 2 h (28,29), Nitroethane is the best medium for the enantioselectivity. 

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