Acetals Mukaiyama aldol reaction

Mukaiyama aldol reactions have been reported, usually using chiral additives although chiral auxiliaries have also been used. This reaction can also be run with the aldehyde or ketone in the form of its acetal R R C(OR )2> in which case the product is the ether R COCHR2CR R OR instead of 27. Enol acetates and enol ethers also give this product when treated with acetals and TiCLi or a similar catalyst. When the catalyst is dibutyltin bis(triflate), Bu2Sn(OTf)2, aldehydes react, but not their acetals, while acetals of ketones react, but not the ketones themselves. 

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. 

In addition to aldehydes, acetals can serve as electrophiles in Mukaiyama aldol reactions.64 Effective catalysts include TiCl4,65 SnCl4,66 (CH3)3Si03SCF3,67 and... 

The Mukaiyama aldol reaction can provide access to a variety of (3-hydroxy carbonyl compounds and use of acetals as reactants can provide (3-alkoxy derivatives. The issues of stereoselectivity are the same as those in the aldol addition reaction, but the tendency toward acyclic rather than cyclic TSs reduces the influence of the E- or Z-configuration of the enolate equivalent on the stereoselectivity. 

Several catalysts based on Ti(IV) and BINOL have shown excellent enantiose-lectivity in Mukaiyama aldol reactions.156 A catalyst prepared from a 1 1 mixture of BINOL and Ti(0-i-Pr)4 gives good results with silyl thioketene acetals in ether, but is very solvent sensitive.157... 

In aldol reactions, especially Mukaiyama aldol reactions, TiIV compounds are widely employed as efficient promoters. The reactions of aldehydes or ketones with reactive enolates, such as silyl enol ethers derived from ketones, proceed smoothly to afford /3-hydroxycarbonyl compounds in the presence of a stoichiometric amount of TiCl4 (Scheme 17).6, 66 Many examples have been reported in addition to silyl enol ethers derived from ketones, ketene silyl acetals derived from ester derivatives and vinyl ethers can also serve as enolate components.67-69... 

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. 

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. 

Another chiral auxiliary for controlling the absolute stereochemistry in Mukaiyama aldol reactions of chiral silyl ketene acetals has been derived from TV-methyl ephedrine.18 This has been successfully applied to the enantioselec-tive synthesis of various natural products19 such as a-methyl-/ -hydroxy esters (ee 91-94%),18,20 a-methyl-/Miydroxy aldehydes (91% ee),21 a-hydrazino and a-amino acids (78-91% ee),22 a-methyl-d-oxoesters (72-75% ee),20b cis- and trans-l1-lactams (70-96% ee),23 and carbapenem antibiotics.24... 

The isomerization of an O-silyl ketene acetal to a C-silyl ester is catalyzed by a cationic zirconocene—alkoxide complex [92], This catalysis was observed as a side reaction in the zirconocene-catalyzed Mukaiyama aldol reactions and has not yet found synthetic use. The solvent-free bis(triflate) [Cp2Zr(OTf)2] also catalyzes the reaction in nitromethane (no reaction in dichloromethane), but in this case there may be competitive catalysis by TMSOTf (cf. the above discussion of the catalysis of the Mukaiyama aldol reaction) [91] (Scheme 8.51). 

Scheme 25 Vinylogous Mukaiyama aldol reaction of aldehyde 53 and ketene acetal 54 catalyzed by different Lewis acids...

Scheme 26 Vinylogous Mukaiyama aldol reaction using y-substituted ketene acetals...

The 9-catalyzed Mukaiyama-aldol reaction [74] of benzaldehyde and 1,2-dimethoxy benzaldehyde with a ketene silyl acetal in the presence of 10mol% thiourea 9 furnished the target product in low yield (36%), while the same reaction... 

Scheme 6.4 Mukaiyama-aldol reaction of benzaldehydes with a ketene silyl acetal catalyzed by thiourea 9.

One of the early syntheses of orlistat (1) by Hoffmann-La Roche utilized the Mukaiyama aldol reaction as the key convergent step. Therefore, in the presence of TiCU, aldehyde 7 was condensed with ketene silyl acetal 8 containing a chiral auxiliary to assemble ester 9 as the major diastereomer in a 3 1 ratio. After removal of the amino alcohol chiral auxiliary via hydrolysis, the a-hydroxyl acid 10 was converted to P-lactone 11 through the intermediacy of the mixed anhydride. The benzyl ether on 11 was unmasked via hydrogenation and the (5)-7V-formylleucine side-chain was installed using the Mitsunobu conditions to fashion orlistat (1). 

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. 

Scheme 8.8 Mukaiyama aldol reactions of silyl ketene acetals with aldehydes.

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. 

Table 6.45 Taddol-catalyzed Mukaiyama aldol reactions of N,Q-acetals.

Bis(pentafluorophenyl) tin dibromide effects the Mukaiyama aldol reaction of ketene silyl acetal with ketones, but promotes no reaction with acetals under the same conditions. On the other hand, reaction of silyl enol ether derived from acetophenone leads to the opposite outcome, giving acetal aldolate exclusively. This protocol can be applied to a bifunctional substrate (Equation (105)). Keto acetal is exposed to a mixture of different types of enol silyl ethers, in which each nucleophile reacts chemoselectively to give a sole product.271... 

The Mukaiyama aldol reaction could be catalyzed by chiral bis(oxazoline) copper(II) complexes resulting in excellent enantioselectivities (Fig. 7) [23]. A wide range of silylketene acetals 46 and 49 were added to (benzyloxy[acetaldehyde 45 and pyruvate ester 48 in a highly stereoselective manner. The authors were also able to propose a model to predict the stereochemical outcome of these reactions. 

The authors used (5)-carvotanacetone (dihydrocarvone) as starting material (Scheme 34). To prepare the linearly conjugated sUylenol ether, they used the Kharash protocol and attained y-alkylation by Mukaiyama aldol reaction with trimethylorthoformate (195). The ketoacetal 295 was a-hydroxylated according to Rubottom by silylenol ether formation followed by epoxidation and silyl migration. Acid treatment transformed 296 to the epimeric cyclic acetals 297 and 298. endo-Aceta 297 was equilibrated thereby increasing the amount of exo-acetal 298. The necessary unsaturated side chain for the prospected radical cyclization was introduced by 1,4-addition of a (trimethylsilyl)butynylcopper compound. 

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. 

Mukaiyama aldol reactions of silylketene acetal and pyruvate ester (eq 14) in the presence of 10 mol % Cu[(5,5)-/-Bu-box] (OTf)2 catalyst furnish the corresponding aldol product in excellent enantiomeric excess (98%). Furthermore, the addition reactions of ketene acetals derived from /-butyl thioacetate and ben-zyloxyacetaldehyde with only 5 mol % catalyst afford the aldol product in 91% ee (eq 15). It is also noteworthy that the addition of both propionate-derived (Z)- and ( )-silylketene acetals stereoselectively forms the jyn-adduct in 97% and 85% ee, respectively. 

The aldol reaction of ketene silyl acetals with several aldehydes (Mukaiyama aldol reaction) assisted by Li has been described briefly by Reetz et al. Wirth 5.0 m LPDE a clean reaction began within 1 h with the sole formation of the silylated aldol 112, whereas the use of a catalytic amount (3 mol %) of LiC104 in Et20 (3 mol % LPDE) required a reaction time of 5 days for 86 % conversion. As observed in the hetero-Diels-Alder reaction of a-alkoxyaldehyde, the higher rate of reaction of 79 compared with that of benzaldehyde can be attributable to chelation. Indeed, the use of 3 mol % LPDE required only 20 h at room temperature for complete uptake of 79 with a diastereoselectivity (syn-113lanti-113) of >96 % (Sch. 55). 

Mukaiyama aldol reactions of various silyl enol ethers or ketene silyl acetals with aldehydes or other electrophiles proceed smoothly in the presence of 2 mol % B(CgF5)3 [151a,c]. The following characteristic features should be noted (i) the products can be isolated as j8-trimethylsilyloxy ketones when crude adducts are worked-up without exposure to acid (ii) this reaction can be conducted in aqueous media, so that the reaction of the silyl enol ether derived from propiophenone with a commercial aqueous solution of formaldehyde does not present any problems (iii) the rate of an aldol reaction is markedly increased by use of an anhydrous solution of B(C6Fs)3 in toluene under an argon atmosphere and (iv) silyl enol ethers can be reacted with chloromethyl methyl ether or trimethylorthoformate hydroxymethyl, methoxy-methyl, or dimethoxymethyl Cl groups can be introduced at the position a to the carbonyl group. These aldol-type reactions do not proceed when triphenylborane is used (Eq. 92). 

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. 

Aldol-type condensation of silyl enol ethers with acetals under the influence of la is rather familiar. Unlike the Mukaiyama aldol reaction, 1-5 mol % loading of la is enough to complete the coupling reaction under mild conditions [20]. This transformation is applicable to the synthesis of a wide variety of / -alkoxy carbonyl substrates and has three characteristic features ... 

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]. 

---