Lewis silyl ketene acetals

Lewis acid promoted condensation of silyl ketene acetals (ester enolate equiv.) with aldehydes proceeds via "open" transition state to give anti aldols starting from either E- or Z- enolates. 

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 Mukaiyama aldol reaction refers to Lewis acid-catalyzed aldol addition reactions of silyl enol ethers, silyl ketene acetals, and similar enolate equivalents,48 Silyl enol ethers are not sufficiently nucleophilic to react directly with aldehydes or ketones. However, Lewis acids cause reaction to occur by coordination at the carbonyl oxygen, activating the carbonyl group to nucleophilic attack. 

Entries 4 and 9 are closely related structures that illustrate the ability to control stereochemistry by choice of the Lewis acid. In Entry 4, the Lewis acid is BF3 and the (3-oxygen is protected as a f-butyldiphenylsilyl derivative. This leads to reaction through an open TS, and the reaction is under steric control, resulting in the 3,4-syn product. In Entry 9, the enolate is formed using di-n-butylboron triflate (1.2 equiv.), which permits the aldehyde to form a chelate. The chelated aldehyde then reacts via an open TS with respect to the silyl ketene acetal, and the 3,4-anti isomer dominates by more than 20 1. 

The scope of the conjugate addition reaction can be further expanded by use of Lewis acids in conjunction with enolate equivalents, especially silyl enol ethers and silyl ketene acetals. The adduct is stabilized by a new bond to the Lewis acid and products are formed from the adduct. 

Silyl enol ethers and silyl ketene acetals also offer both enhanced reactivity and a favorable termination step. Electrophilic attack is followed by desilylation to give an a-substituted carbonyl compound. The carbocations can be generated from tertiary chlorides and a Lewis acid, such as TiCl4. This reaction provides a method for introducing tertiary alkyl groups a to a carbonyl, a transformation that cannot be achieved by base-catalyzed alkylation because of the strong tendency for tertiary halides to undergo elimination. 

The controlled polymerization of (meth)acrylates was achieved by anionic polymerization. However, special bulky initiators and very low temperatures (- 78 °C) must be employed in order to avoid side reactions. An alternative procedure for achieving the same results by conducting the polymerization at room temperature was proposed by Webster and Sogah [84], The technique, called group transfer polymerization, involves a catalyzed silicon-mediated sequential Michael addition of a, /f-unsaluralcd esters using silyl ketene acetals as initiators. Nucleophilic (anionic) or Lewis acid catalysts are necessary for the polymerization. Nucleophilic catalysts activate the initiator and are usually employed for the polymerization of methacrylates, whereas Lewis acids activate the monomer and are more suitable for the polymerization of acrylates [85,86]. 

Silyl ketene acetal addition to nitrone (292) is likely to generate four diastere-omers. Depending on the employed Lewis acid, either O-silylhydroxylamines or free hydroxylamines (Scheme 2.175) are obtained (635). 

Silyloxy)alkenes were first reported by Mukaiyama as the requisite latent enolate equivalent to react with aldehydes in the presence of Lewis acid activators. This process is now referred to as the Mukaiyama aldol reaction (Scheme 3-12). In the presence of Lewis acid, anti-aldol condensation products can be obtained in most cases via the reaction of aldehydes and silyl ketene acetals generated from propionates under kinetic control. 

Preparation of (R)-(+)-3-hydroxy-4-methylpentanoic acid has been reported previously by the submitters.5 Alternative syntheses of (R)-(+)- or (S)-(-)-3-hydroxy-4-methylpentanoic acid rely on aidoi reactions of chiral ketone, ester, or amide enolates,2 8 10 and Lewis-acid mediated additions of chiral silyl ketene acetals to Isobutyraldehyde.3 11 Since both enantiomers of HYTRA are readily available this method enables one to prepare (S)-3-hydroxy-4-methylpentanoic acid as well. 

Carreira et al. used their experience in the addition of simple silyl ketene acetals to aldehydes under Lewis acid catalysis [15]. In these experiments their 2-amino-2 -hydroxy-l,rbinaphthyl-derived catalyst (19) was used to provide aldol products with very high enantioselectivity (Scheme 8, Table 7). 

Denmark utilized chiral base promoted hypervalent silicon Lewis acids for several highly enantioselective carbon-carbon bond forming reactions [92-98]. In these reactions, a stoichiometric quantity of silicon tetrachloride as achiral weak Lewis acid component and only catalytic amount of chiral Lewis base were used. The chiral Lewis acid species desired for the transformations was generated in situ. The phosphoramide 35 catalyzed the cross aldolization of aromatic aldehydes as well as aliphatic aldehydes with a silyl ketene acetal (Scheme 26) [93] with good yield and high enantioselectivity and diastereoselectivity. 

For the anionic polymerization of methacrylonitrile (MAN), many initiators have been developed, which include alkali-metal alkyls such as butyllithium [42], triphenylmethylsodium [43], phenylisopropylpotassium [43], the disodium salt of living a-methylstyrene tetramer [44], alkali-metal amides [45], alkoxides [46], and hydroxide [47], alkali metal in liquid NH3 [48], quaternary ammonium hydroxide [49], and a silyl ketene acetal coupled with nucleophilic or Lewis acidic catalysts [50]. However, only a single example of the synthesis of PMAN with narrow molecular-weight distribution can be cited, and the reported number-average molecular weights were much higher than those calculated from the stoichiometry of the butyllithium initiator [42]. 

The addition of acetate-derived, achiral lithium enolates to monoprotected a-amino aldehydes is controlled by chelation, and leads to a modest stereochemical preference in favor of the 3,4-syn configuration (Table 1, entry a). 18 The formation of the 3, A-syn-product is enhanced by the use of acetate-derived silyl ketene acetals and the addition of titanium(IV) chloride or tin(IV) chloride to the reaction mixture (Table 1, entries b and c). 22-23 The same enolates add stereoselectively to A2 A-dibenzyl a-amino aldehydes but with diastereomeric ratios in favor of the Felkin-Ahn 3,4-anti-product (Table 1, compare entries a and d, and b and f). 22-24 Reverse stereocontrol is observed in the presence of a Lewis acid such as tita-nium(IV) chloride, but the yield is low (Table 1, entry e). 24 ... 

Alcohols can also be prepared from support-bound carbon nucleophiles and carbonyl compounds (Table 7.4). Few examples have been reported of the a-alkylation of resin-bound esters with aldehydes or ketones. This reaction is complicated by the thermal instability of some ester enolates, which can undergo elimination of alkoxide to yield ketenes. Traces of water or alcohols can, furthermore, lead to saponification or transesterification and release of the substrate into solution. Less prone to base-induced cleavage are support-bound imides (Entry 2, Table 7.4 see also Entry 3, Table 13.8 [42]). Alternatively, support-bound thiol esters can be converted into stable silyl ketene acetals, which react with aldehydes under Lewis-acid catalysis (Entries 3 and 4, Table 7.4). 

The Lewis acid-catalyzed addition of silyl ketene acetals occurred in high yield, and when the ketene acetal bore a substituent, the reactions occurred with modest diastereofacial selectivity [6] (equation 7) (Table 3)... 

Remarkable solvent effects have been reported for select silyl ketene acetal-enone additions for example, acetonitrile suffices to promote additions in the absence of a Lewis acid.86 Alternatively, addi-... 

Except for the well-documented conjugate additions of diethylaluminum cyanide,92 triethylaluminum-hydrogen cyanide and Lewis acid-tertiary alkyl isonitriles,93 examples of Lewis acid catalyzed conjugate additions of acyl anion equivalents are scant Notable examples are additions of copper aldimines (233),94, 94b prepared from (232), and silyl ketene acetals (234)940 to a,(3-enones which afford 1,4-ketoal-dehydes (235) and 2,5-diketo esters (236), respectively (Scheme 37). The acetal (234) is considered a glyoxylate ester anion equivalent. 

Further versatility of this approach has been realized with contrasting Lewis acid promoted additions of silyl ketene acetals, (191) to (194), to ethyl propynoate (Scheme 42). In fact, the tandem 1,4-conjugate addition-electrophile trapping protocol is feasible when titanium(IV) tetrachloride is employed. In situ functionalization of the intermediate titanate enoate (259), with select electrophiles, affords a-substituted enoates (260) to (262). On the other hand, the zinc iodide and zirconium(IV) tetrachloride protocols afford directly -y-alkoxycarbonyl-a-trimethylsilylenoates (263) and [2 + 2] adducts (264), respectively.100... 

Aldol reactions of aldehydes with cycloakanones were performed in ionic liquids and catalyzed by FeCl3-6H20 [32]. Mukaiyama aldol reactions of silylenol ethers with aldehydes can be carried out in aqueous media however, among several Lewis acidic catalysts investigated, iron compounds were not the optimal ones [33], If silyl ketene acetals are applied as carbon nucleophiles in Mukaiyama aldol reactions, cationic Fe(II) complexes give good results. As catalysts, CpFe(CO)2Cl [34] and [CpFe(dppe) (acetone)] BF4 [35] [dppe = l,2-bis(diphenylphosphano)ethane] were applied (Scheme 8.8). No diastereomeric ratio was reported for product 26a. 

The molecular mechanisms for the nucleophilic addition of lithium enolates and silyl ketene acetals to nitrones in the absence and in the presence of a Lewis acid catalyst to give isoxazolidin-5-ones or hydroxylamines have been investigated by DFT methods at the B3LYP/6-31G level.13 An analysis of the global electrophilicity of the reagents accounts for the strong electrophile activation of the Lewis acid-coordinated nitrone, (g) and the analysis of the local indices leads to an explanation for the experimentally observed regioselectivity. 

Catalytic, enantioselective addition of silyl ketene acetals to aldehydes has been carried out using a variant of bifunctional catalysis Lewis base activation of Lewis acids.145 The weakly acidic SiCU has been activated with a strongly basic phor-phoramide (the latter chiral), to form a chiral Lewis acid in situ. It has also been extended to vinylogous aldol reactions of silyl dienol ethers derived from esters. 

The observed rc-face differentiation of the electrophilic animation process was rationalized by the authors [14b]. NMR Nuclear Overhauser experiments agree with the ( -configuration of the O-silyl ketene acetals 35 and with a j-yn-periplanar disposition of the C -OSi and C2-Ha bonds. Electrophiles E+ , such as Lewis acids-co-ordinated DTBAD, attack 35 preferentially from the less hindered C(a)-Si (back) face (Scheme 17). 

Michael addition to a., -enoates- Aluminum ion-exchanged montmorillonite (Al-Mont1) is a very effective catalyst for Michael addition of silyl ketene acetals or silyl enol ethers to a,(3-enoates. In fact this heterogeneous catalyst is more effective than Lewis acids, which are generally required in a stoichiometric amount. It also facilitates Michael addition to a,p-enones.2 Examples ... 

It is even possible to use a silyl enol ether to create a new C-C bond that joins two new quaternary centres. In this example the silyl ketene acetal does conjugate addition on an unsaturated ketone catalysed by the usual Lewis acid (TiCl4) for such reactions. 

The Lewis acid catalyzed additions of silyl ketene acetals to (5)-8 occur in high yield to give products 9 and, when the ketene acetal bears a substituent, the reactions occur with modest diastereofacial selectivity (Table 1). ... 

Monomer addition, which is catalyzed by anions like HF , F , CN or selected Lewis acids, proceeds by Michael addition in which the silyl group is transferred to the new monomer unit to renew the terminal silyl ketene acetal. (A Michael reaction, in general, is the addition of an enolate to an a,/9-unsaturated carbonyl compound.)... 

Both silyl enolates and allylsilanes are excellent nucleophiles for alkylation by other stabilized carbocations such as the tertiary alkyl cations 111 or 112 (Scheme 2.42). Similarly, Michael-like additions, for example, the coupling of 113 with silyl ketene acetal 114, can be also achieved.Owing to the high electrophilicty of the enone system, this reaction proceeds smoothly in polar solvents, even in the absence of Lewis acids. 

Coupling with Silyl Enol Ethers and Silyl Ketene Acetals. Silyl enol ethers can couple to the bromooxazinone to give both the syn and anti diastereomers. - The reaction can proceed via the Sn 1 mechanism discussed above or by a Lewis acid assisted Sn2 displacement of the bromide. The reaction conditions can be manipulated to favor the SnI (stronger Lewis acids, more polar solvents) or Sn2 path (weaker Lewis acids, less polar solvents) (eq 12 and eq 13). ... 

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. ... 

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