Aldol reactions of silyl ketene acetals

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

Al ion-exchanged montmorillonite efficiently catalyzes the aldol reactions of silyl ketene acetals with carbonyl compounds and acetals. ... 

Acid type catalysts catalyze cross aldol reaction of silyl ketene acetals with carbonyl compounds and acetals. Aluminum cation and proton exchange montmorillonites are effective catalysts. Although the detailed reaction mechanism is not clear, Bronsted acid sites are considered to be the catalytic sites. 

Scheme 7.S Aldol reaction of silyl ketene acetal.

In 2009, List introduced a binaphthyl-derived, chiral disuUbnimide (28) as a new structural motif of a powerful chiral Bronsted add that could activate simple aldehydes [80, 81]. Evaluation of the catalytic activity and stereocontrolling ability of 28 in the Mukaiyama aldol reaction of silyl ketene acetal with naphthaldehyde revealed that 28 was not only far more reactive than phosphoric acid 29 and phos-phoramide 30 but also capable of affording the aldol product with high enantiose-lectivity (Scheme 7.53). 

AldolCondensations. Cation-exchanged montmorillonites accelerate the aldol condensation of silyl enol ethers with acetals and aldehydes. Similarly, the aldol reaction of silyl ketene acetals with electrophiles is catalyzed by solid-acid catalysts. Neither report discussed the use of iron montmorillonite for these reactions however, some reactivity is anticipated. 

This reaction of silyl ketene acetals with aldehydes, using 29 as a stoichiometric chiral reagent (Eq. 46), was reported by Reetz et al. [42]. The aldol addition of l-(trimethyl-siloxy)-l-methoxy-2-methyl-l-propene and 3-methylbutanal provides the aldol in only 57 % yield, but with 90 % ee. 

The use of CAB as a chiral reagent seems to be more effective for this reaction, which proceeds faster and with higher yields and enantiomeric excess. Kiyooka et al. first described the use of various chiral oxaborolidines, derived from sulfonamides of a-amino acids and borane, in the course of the selective aldol reaction between silyl ketene acetals and aldehydes (Eq. 47) [43a]. Stereoselectivity and yields were relatively high. 

Asymmetric Mukaiyama aldol reactions and reactions of silyl ketene acetals have been reported, " usually using chiral additives" although chiral auxiliaries... 

Conjugate additions. Cyclopentaneacetic esters are readily prepared by cyclization of -iodo-a,P-unsaturated esters. The Michael reaction of silyl ketene acetals with enones (and Mukaiyama aldol reaction) can be promoted by Sml,. " However, thermodynamic enolsilylation of carbonyl compounds under similar conditions is noted. 

The use of chiral Lewis acids for enantioselective Diels-Alder and hetero Diels-Alder reactions and for other processes of C—C bond formation has recently received great attention. Reetz and coworkers reported that a stoichiometric amount of the chiral Lewis acid (137) effectively promotes the reaction of silyl ketene acetal (98) to give the aldol product in 57% yield and 90% ee (equation 48, R = Me2CHCH2—). When a catalytic amount (5 mol %) of the chiral rhodium perchlorate (138) is used, the aldol product is obtained in >75% yield and 12% ee (equation 48 R = Ph). ° Both reactions probably proceed through the corresponding metal enolates. - The development of new efficient chiral catalysts for the Mukaiyama reaction is certainly one of the challenges of the 1990s. 

Zhu and Panek s total synthesis [148] is described in Scheme 89. After conversion of aldehyde 609 to di-benzyl acetal, treatment with chiral crotylsilane 610 afforded l,2-5y -611 with high stereo- and enantioselectivity. The oxidative cleavage of the double bond and subsequent aldol reaction with silyl ketene acetal 612 provided 613, which was converted into a,P-unsaturated ester 614 via Wittig olelination. The C8 methyl group was stereoselectively introduced by treatment with dimethylcuprate in the presence of TMSCl. DIB AH treatment differentially reduced the C3 and CIO esters to alcohol and aldehyde, respectively. Protection of the alcohol as silyl ether followed by the Wittig reaction afforded 615. In a manner similar to Danishefsky s synthesis [142d], an inteimolecular Suzuki... 

A catalytic enantioselective aldol-type reaction of ketene silyl acetals with achiral aldehydes also proceeds smoothly with 3a, which can furnish erythro p-hydroxy esters with high optical purities (Equation 42) [42b, c]. A remarkable finding is the sensitivity of this reaction to the substituents of the starting silyl ketene acetals. The reactions of silyl ketene acetals derived from more common ethyl esters are totally stereorandom, and give a mixture of syn and anti isomers in even ratios with improved chemical yields. In sharp contrast, the use of silyl ketene acetals generated from phenyl esters leads to good diastereo- and enantioselectivities with excellent... 

In the Mukaiyama addition of the aldol reaction [16], silyl ketene acetals or silyl enol ethers are added to aldehydes in a reaction mediated by Lewis acids or fluoride. Here again the Z-syn correlation is sometimes not observed [69, 70]. Thus, the Z-syn, E-anti correlation seems to be a rule with several exceptions [71]. 

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. 

Paterson et al. [98] in their attempt used a similar disconnection for rhizopodin as described by Menche (fragments 144 and 149) (Scheme 2.151). However, unlike, Menche, they used silyl ketene acetal 16 in an asynunetric VMAR for the addition to ( )-iodoacrolein (142) to obtain dioxinone 143 in 94% ee. Methanolysis removed the aceto-nide, and the subsequent Narasaka reduction [99] provided the syn-diol 144 in 80% yield and a 10 1 selectivity for the desired isomer. The synthesis of segment 149 started with aldehyde 145, which was ultimately derived from Roche ester. Carbon chain extension was achieved through a chelation-controlled Mukaiyama aldol reaction with silyl ketene acetal 146, which installed the new chiral center with excellent stereocontrol (20 1 dr). For the installation of the third secondary alcohol, six-membered lactone 148 was obtained by treatment with K COj in methanol. Subsequent borane reduction provided stereospecifically the desired alcohol, which was then further transformed to the desired acid (149). 

This concept has been further applied to the development of various stereoselective bond-forming reactions using chiral bis-phosphoramides as catalysts. The most well-explored system is the aldol addition of silyl ketene acetals to aldehydes [6). In general, combination of a catalytic amount of 2 and a stoichiometric quantity of SiCl, was very effective for the reactions of methyl acetate-derived silyl ketene acetal with various aldehydes (Scheme 7.5). 

Cu(II) and Sn(II) Bisoxazolinc Complexes. Evans has prepared and studied a family of Cu(II) complexes prepared from bisoxazoline ligands [8]. Utilizing these complexes a number of different addition reactions can be successfully conducted on pyruvate, benzyloxyacetalde-hyde, and glyoxylates. Whereas the focus of the work in the context of aldol addition reactions has been on the use of silyl ketene acetals (vide infra), the addition of ketone-derived enoxy silanes 8a-b with methyl pyruvate has been examined (Eq. 8B2.1). The additions of 8a-b proceed in the presence of 10 mol % Cu(II) catalyst at -78°C in CH2Cl2, affording adducts of acetophenone 9a and acetone 9b with 99% and 93% ee, respectively. 

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 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). ... 

In Kiyooka s approach to acetate aldols by use of a stoichiometric amount of 3f, the enantiomeric excess obtained in the reaction with silyl ketene acetals derived from a-unsubstituted acetates was much lower (ca 10-20 %) than that obtained in the reaction with l-ethoxy-2-methyl-l-(trimethylsiloxy)-l-propene (> 98 % ee). Introduction of an removable substituent, e.g., a methylthio or bromo substituent, after aldol reaction at the a-position of chiral esters, resolved this problem [43e], Asymmetric synthesis of dithiolane aldols was achieved in good yield by using the silyl ketene acetal derived from l,3-dithiolane-2-carboxylate in the 3f-promoted aldol reaction, and desulfurization of the dithiolane aldols resulted in production of the acetate aldols in high enantiomeric purity (Eq. 56). 

Several examples of Sc(OTf)3-catalyzed aldol reactions of silyl enolates with aldehydes were been examined. Silyl enolates derived from ketones, thioesters, and esters reacted smoothly with different types of aldehyde in the presence of 5 mol % Sc(OTf)3 to afford the aldol adducts in high yields. Sc(OTf)3 was also found to be an effective catalyst in aldol-type reactions of silyl enolates with acetals. The reactions proceeded smoothly at -78 °C or room temperature to give the corresponding aldol-typc adducts in high )delds without side-reaction products. It should be noted that aldehydes were more reactive than acetals. For example, while 3-phenylpropionalde-hyde reacted with the ketene silyl acetal of methyl isobutyrate at -78 °C to give the aldol adduct in 80 % yield, no aldol-type adduct was obtained at -78 °C in the reaction of the same ketene silyl acetal with 3-phenylpropionaldehyde dimethyl acetal. The acetal reacted with the ketene silyl acetal at 0 °C to room temperature to give the... 

Akiyama, Y, Ishikawa, K, OzaM, S, Asymmetric synthesis of functionalized tertiary alcohols by diastereoselective aldol reaction of silyl enol ether and ketene silyl acetals with a-keto esters bearing an optically active cyclitol as a chiral auxihary, Synlett, 275-276, 1994. 

Mikami K, Matsukawa S, Kayaki Y, Ikariya T. Asymmetric Mukaiyama aldol reaction of a ketene silyl acetal of thioester catalyzed by a binaphthol-titanium complex in supercritical fluoroform. Tetrahedron Lett 2000 41 1931-1934. 

In a landmark study of Mukaiyama aldol addition reactions, Heathcock proposed that the observed stereochemical outcome of the products in the Lewis acid-mediated addition of silyl ketene acetals to aldehydes was consistent with extended, open transition-state structures [38a, 38b]. This analysis has gained wide acceptance as a consequence of its predictive power. Alternative models involving cyclic, closed structures have also been postulated, in particular, the latter have been invoked with increasing regularity in the analyses of catalytic, enantioselective aldol addition reactions [7,30b,39a,39b. ... 

---