Boron Ketene Acetals

More recently, several variations of the Claisen rearrangement have been reported that also possess some of the features of the Ireland variant, including the amide Claisen, S,S- and N,S-ketene acetal Claisen and the zwitterionic Qaisen rearrangements [2]. This review will focus on the Ireland variant of the Qaisen rearrangement in which a sUyl ketene acetal is an intermediate, although mention will be made of boron ketene acetals where appropriate. 

Bartlett et al. found that substantially higher diastereoselectivity was obtained in the Ireland-Claisen rearrangement of crotyl mandelate when TMSCl was omitted (Scheme 4.77) [20]. Oh et al. obtained comparable yields and stereoselectivities using boron ketene acetals (cf Scheme 4.64). 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

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. 

The reaction of O-methyl-O-tert-butyldimethylsilyl ketene acetal with N-benzyl- and A-methyl-2,3-O-Mopropylidene D-glyceraldehyde nitrones (292), in the presence of boron trifluoride etherate, affords the corresponding isoxazolidine-5-ones in high yields. These compounds were successfully applied as key intermediates in the synthesis of isoxazolidinyl nucleosides of the L-series (Scheme 2.177) (638). 

Nucleophiles other than hydride can be added to support-bound imines to yield amines. These include C,H-acidic compounds, alkynes, electron-rich heterocycles, organometallic compounds, boronic acids, and ketene acetals (Table 10.9). When basic reaction conditions are used, stoichiometric amounts of the imine must be prepared on the support (Entries 1-3, Table 10.9). Alternatively, if the carbon nucleophile is stable under acidic conditions, imines or iminium salts might be generated in situ, as, for instance, in the Mannich reaction. Few examples have been reported of Mannich reactions on insoluble supports, and most of these have been based on alkynes as C-nucleophiles. 

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>. 

In an analogous manner dimethyl ketene acetal (176) gave a polyester under the influence of boron trifluoride ... 

Three successive [2+4] cycloadditions were used in the synthesis of the pentacyclic methyl ether of G-2N by Kraus and Zhao [92] and later, by a slightly modified procedure, also of the natural product G-2N (118) [93] (Scheme 31). Thermal reaction of the cyclobutanol 112 with acrylic ester gave the dihydronaphthalene 113 which was demethylated by treatment with boron tribromide and converted into the exocyclic ketene acetal 114. This unstable diene was reacted in a second cycloaddition with 2,6-dichlorobenzoquinone (115) to afford the tetracyclic chloroquinone 116. In a last Diels-Alder reaction, ring E was anella-ted by treatment of 116 with l-methoxy-l,3-bis[(trimethylsilyl)oxy]-l,3-buta-diene (117) to yield the pentacyclic natural product G-2N (118) [93]. 

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. ... 

The use of CABs prepared from the sulfonamides of amino acids to introduce asymmetry into the Diels-Alder reaction was reported simultaneously by Takasu and Yamamoto [14] and by Helmchen and co-workers [13]. Because of the capacity of boron to complex the carbonyl moiety in this type of eatalyst, it is clear they might be effective in promoting the reaction of silyl ketene acetals with various aldehydes. 

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]. 

Silyl enol ethers and silyl ketene acetals add to aldehydes in the presence of a stoichiometric amount of a Lewis acid (generally titanium tetrachloride, boron trifluoride etherate, tin(IV) chloride) with low levels or a complete lack of simple stereoselection. The anti.syn ratios usually range from 25 75 to 80 20, depending on the particular aldehyde, Lewis acid, enol ether and on the double bond stereochem-... 

A Special feature of the boron or tin triflate mediated Claisen rearrangement of allylic glycolates or related substrates is that they avoid strongly basic conditions and thus eliminate the need to generate silyl ketene acetal intermediates in which C-silylation is a potential problem497. 

Spiroketals have been obtained by RCM of cyclic ketals 18 without loss of stereochemical integrity at the spiro linkage <04TL5505> and a stereoselective solid-phase synthesis of 6,6-spiroketals has been reported in which aldol reactions of boron enolates are the key feature <04AG(E)3195>. Spiro orthoesters are accessible from thiophenyl ketene acetals and diols (Scheme 5) <04SL2013>. 

The preparation of acetals of the unknown formylphosphonic acid was reported by treating a dialkyl hydrogenphosphonate or a dialkyl trimethylsilyl phosphite wth trialkyl orthoformate in the presence of boron trifluoride. Another method which is reported to yield acylphosphonate ketals is the addition of dialkyl hydrogenphosphonates to ketene acetals (equation 55). For dithioketals, see Section II. C. 4. b. 

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. ... 

The answer is both For the Li enolate, the usual rule makes OLI of lower priority than OMe (because Li has a smaller atomic number than C), so it s E, while the silyl enol ether (or sllyl ketene acetal ) has OSI of higher priority than OMe (Si has a larger atomic number than C), so it s Z This is merely a nomenclature problem, but It would be irritating to have to reverse all our arguments for lithium and boron enolates (as opposed to, say, tin or silicon ones). So, for the sake of consistency, it is much better to avoid the use of E and Zwith enolates and Instead use cis and trans, which then always refer to the relationship between the substituent and the anionic oxygen (bearing the metal). 

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