Ketene silyl thioacetals

Scheme 2.2 illustrates several examples of the Mukaiyama aldol reaction. Entries 1 to 3 are cases of addition reactions with silyl enol ethers as the nucleophile and TiCl4 as the Lewis acid. Entry 2 demonstrates steric approach control with respect to the silyl enol ether, but in this case the relative configuration of the hydroxyl group was not assigned. Entry 4 shows a fully substituted silyl enol ether. The favored product places the larger C(2) substituent syn to the hydroxy group. Entry 5 uses a silyl ketene thioacetal. This reaction proceeds through an open TS and favors the anti product. 

A Mukaiyama-type aldol reaction of silyl ketene thioacetal (48) with an aldehyde with large and small a-substituents (e.g. Ph and Me), catalysed by boron trifluoride etherate, gives mainly the iyn-isomer (49), i.e. Cram selectivity. For the example given, changing R from SiBu Me2 to Si(Pr )3 raises the syn preference considerably, which the authors refer to as the triisopropylsilyl effect. Even when the and R groups are as similar as ethyl and methyl, a syn. anti ratio of 5.4 was achieved using the triisopropylsilyl ketene thioacetal. 

The reaction of Cjq with silylated nucleophiles [47] requires compounds such as silyl ketene acetals, silylketene thioacetals or silyl enol ethers. It proceeds smoothly and in good yields in the presence of fluoride ions (KF/18-crown-6) (Scheme 3.10). The advantage of the latter synthesis is the realization of the cyclopropanation under nearly neutral conditions, which complements the basic conditions that are mandatory for Bingel reactions. Reaction with similar silyl ketene acetals under photochemical conditions and without the use of F does not lead to methanofullerenes but to dihydrofullerene acetate [48]. 

Evans et al. recently reported the use of structurally well-defined Sn(II) Lewis acids for the enantioselective aldol addition reactions of a-heterosubstituted substrates [47]. These complexes are readily assembled from Sn(OTf)2 and C2-symmetric bis(oxazoline) ligands. The facile synthesis of these ligands commences with optically active 1,2-diamino alcohols, which are themselves readily available from the corresponding a-amino acids. The Sn(II)-bis(oxazoline) complexes were shown to function optimally as catalysts for enantioselective aldol addition reactions with aldehydes and ketone substrates that are suited to putatively chelate the Lewis acid. For example, use of 10 mol % Sn(II) catalyst, thioacetate, and thiopropionate derived silyl ketene acetals added at -78 °C in dichloromethane to glyoxaldehyde to give hydroxy diesters in superb yields, enantioselectivity, and diastereoselectivity (Eq. 27). The process represents an unusual example wherein 2,3-ant/-aldol adducts are obtained stereoselec-tively. 

Aldol additions to methyl pyruvate by silyl ketene thioacetals have been shown to proceed in high yield and with excellent asymmetric induction (Eq. 28). This process is an uncommon example of catalytic, asymmetric aldol additions to ketones, providing access to synthetically useful compounds. The remarkable ability of the catalyst to differentiate between subtle steric differences of substituents flanking a 1,2-diketone has been elegantly demonstrated in highly enantioselective additions to 2,3-pentane-dione (Eq. 29). Tlie aldol adduct of 5-ferr-butyl thiopropionate derived silyl ketene acetal afforded 2,3-anh-aldol adduct (>99 1 antilsyn) in 98 % ee and 97 3 chemoselec-tivity for the methyl ketone. 

Aldol reactions. The enantioselectivity in condensations involving silyl enol ethers and silyl ketene acetals (also thioacetals) has been actively pursued. Valuable catalysts include 102, 103. Subsequent to the development of Cj-symmetric... 

As part of a series of studies on the use of BINOL-Ti(IV) complex 53 as a catalyst in a number of C-C bond-forming reactions, Mikami has reported the aldol addition reactions of thioacetate-derived silyl ketene acetals 55, 56 to a collection of highly functionalized aldehydes (Eq. (8.13)) [28]. As little as 5 mol% of the catalyst mediates the addition reaction and furnishes adducts 57 in excellent yields and up to 96% ee. One of the noteworthy features of the Mikami process is the fact that aldehyde substrates containing polar substituents can be successfully employed, a feature exhibited by few other Lewis-acid-catalyzed aldehyde addition reactions. 

Keywords / -lactam, silyl ketene thioacetal, imine, scandium triflate... 

Sc(OTf)3 (0.015 g, 0.03 mmol), imine 2 (0.062 g, 0.3 mmol), and silyl ketene thioacetal 1 (0.169 g, 0.6 mmol) were added in this order to a 2-mL glass vial and the resulting dark mixture was stirred for 20 h at room temperature. Di-chloromethane (0.25 mL) was then added and the resulting suspension was purified by flash chromatography with a 10 90 AcOEl/hexane mixture as eluent. The trans-product 3t (0.028 g, 35.5% yield) was eluted first as a thick pale yellow oil followed by the cis-product 3c (0.028 g, 35.5% yield) which was also a thick pale yellow oil. 

The addition reaction of fert-butyl thioacetate-derived silyl ketene acetal produces the corresponding aldol adducts in 84% yield and up to 96% enantiomeric excess (Eq. 16). The enantioselectivity of the products was observed to be optimal with toluene as solvent the use of the more polar dichloromethane consistently produced adducts with 10-15% lower enantiomeric excess. The bulkier ferf-butylthioacetate-derived enol silane was found to lead to uniformly higher levels of enantioselectivity than the smaller S-ethyl thioketene acetal. This process is impressive in that it tolerates a wide range of aldehyde substrates for instance, the aldol addition reaction has been successfully conducted with aldehydes substituted with polar functionaUty such as N-Boc amides, chlorides, esters, and 0-benzyl ethers. A key feature of this system when compared to previously reported processes was the abiUty to achieve high levels of stereoselectivity at 0 °C, in contrast to other processes that commonly prescribe operating temperatures of -78 °C. 

The addition of thioacetate-derived silyl ketene acetals to trifluoroacetal-dehyde affords adduct in 96% ee (Eq. 18). The corresponding aldol addition of substituted enolates produces a mixture of syn/anti adducts 55%-89% enantiomeric excess (Eq. 19). 

Thiol esters can be converted to the corresponding 0-silyl ketene thioacetals. The thiol ester (56), under different silylating conditions, can be converted stereoselectively into either the ( )- or the (Z)-isomers of (57). ... 

These and similar catalysts are effective with silyl ketene acetals and silyl ketene thioacetals. ... 

The silyl ketene acetal derived from t-butyl thioacetate is much more selective than that derived from t-butyl acetate which gives a low ratio (< 2 1). With stereogenic enolsilanes usually two of the four possible diastereoisomers were obtained using stannic chloride or... 

Additions of non-stereogenic enolsilanes to a-methyl-3-alkoxy aldehyde 8 were reported to proceed with high selectivity. Chelation control was obtained with TiCl4 due to the formation of the 1 1 complex 9 which was shown to be quite rigid and essentially conformationally locked. Similarly to other cases discussed above the acetate derived silyl ketene acetal was found much less selective than the thioacetate. ... 

Aldol Reactions. The title reagent and its various congeners continue to find application in Mukaiyama-t3fpe aldol reactions as versatile nucleophilic propionate synthons with predictable behavior.For example, the ( )-isomer of the reagent produced the expected major isomer in a boron trifiuoride etherate mediated addition to a complex aldehyde en route to a C19-C35 subunit of swinholide A (eq 14). Remote stereoinduction in Mukaiyama aldol reactions of the reagent with (2-sulfinylphenyl)acetaldehydes was recently observed anti aldol adducts were obtained preferentially regardless of the geometry of the silyl ketene thioacetal employed. ... 

Less traditional Lewis acid catalysts have also been employed to mediate additions of silyl ketene thioacetals to imines and hy-drazones, including scandium(III) triflate and bismuth(III) triflate. In a significant recent advance, Mukaiyama and coworkers reported Lewis base catalyzed additions of the trimethylsilyl congener of the title reagent to iV-sulfonyl aldimines (eq 18). The reaction is tolerant of water and competent Lewis base activators include readily obtained salts such as lithium acetate and lithium benzamide. 

The reactions proceeded efficiently under mild conditions in short time. The silyl enol ethers reacted with the activated acetals or aldehydes at -78 °C to give predominant erythro- or threo-products [136, 137] respectively. In the same manner, the aldol reaction of thioacetals, catalyzed by an equimolar amount of catalyst, resulted in <-ketosulfides [139] with high diastereoselectivity. In the course of this investigation, the interaction of silyl enol ethers with a,]3-unsaturated ketones, promoted by the trityl perchlorate, was shown to proceed regioselec-tively through 1,2- [141] or 1,4-addition [138]. The application of the trityl salt as a Lewis acid catalyst was spread to the synthesis of ]3-aminoesters [142] from the ketene silyl acetals and imines resulting in high stereoselective outcome. 

Sc(() l f) ( is an effective catalyst of the Mukaiyama aldol reaction in both aqueous and non-aqueous media (vide supra). Kobayashi et al. have reported that aqueous aldehydes as well as conventional aliphatic and aromatic aldehydes are directly and efficiently converted into aldols by the scandium catalyst [69]. In the presence of a surfactant, for example sodium dodecylsulfate (SDS) or Triton X-100, the Sc(OTf)3-catalyzed aldol reactions of SEE, KSA, and ketene silyl thioacetals can be performed successfully in water wifhout using any organic solvent (Sclieme 10.23) [72]. They also designed and prepared a new type of Lewis acid catalyst, scandium trisdodecylsulfate (STDS), for use instead of bofh Sc(OTf) and SDS [73]. The Lewis acid-surfactant combined catalyst (LASC) forms stable dispersion systems wifh organic substrates in water and accelerates fhe aldol reactions much more effectively in water fhan in organic solvents. Addition of a Bronsted acid such as HCl to fhe STDS-catalyzed system dramatically increases the reaction rate [74]. 

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