Aldol reactions of trichlorosilyl enol ethers

In the following a few examples of the asymmetric aldol reaction are given. Silyl enol ethers (0-Si) resemble very much allylsilanes (C-Si) in terms of structure and mode of action. That is why Lewis base catalyzed aldol reactions of silyl enol ethers have been extensively studied. The first example of Lewis base catalyzed asymmetric aldol reaction of trichlorosilyl enol ether with chiral phosphoramide [80-91] was reported by Denmark et al. (Scheme 24). 

Next to phosphoramides, Denmark reported an axially chiral A -oxide to catalyze the asymmetric aldol reaction of trichlorosilyl enol ethers with ketones [99]. Hashimoto reported an aldol reaction with 3 mol% of another axially chiral A -oxide [100] which gave good yields and enantioselectivities. 

A similar pattern is observed in the reactions of silyl enol ethers derived from aldehydes. Aldehyde-aldehyde aldol reactions had already been reduced to practice in the context of the Lewis base-catalyzed aldol reaction of trichlorosilyl enol ethers, thanks to the stabilizing effect of the trichlorosilyl chlorohydrin (Scheme 9) [25-27]. Because the product of the aldehyde-aldehyde aldol reaction is an aliphatic aldehyde, it can be quickly transformed into an umeactive chlorohydrin such... 

Nakajima M, Yokota T, Saito M, Hashimoto S (2004) Enantioselective aldol reactions of trichlorosilyl enol ethers catalyzed by chiral iVA/-dioxides and monodentate V-oxides. Tetrahedron Lett 45 61-64... 

After the first reports of the above-mentioned highly eflident catalytic enantioselective aldol reaction, some groups independently reported catalytic symmetric aldol reactions of silicon enolates vith aldehydes using chiral boron [72], titanium [73], zirconium [74], and copper Le vis acids [75], or by transmetalation to chiral Pd(II) enolates [44]. Chiral phosphoramide-promoted aldol reactions of trichlorosilyl enol ethers have been reported as Le vis base-catalyzed asymmetric aldol reactions [76]. 

This class of chiral Lewis base catalysts was also applicable to the enantioselective aldol reactions of trichlorosilyl enol ethers (Scheme 7.14) [24, 25). As included in Scheme 7.14, Denmark devised chiral bipyridine N.N -dioxide 8 and demonstrated that it smoothly catalyzed the aldol addition of methyl acetate-derived trichlorosilyl ketene acetal to a series of ketones with good to high enantioselectivi-ties [25],... 

The potential of 9 as a chiral Lewis base catalyst was further demonstrated by application to the aldol reaction of trichlorosilyl enol ethers of ketones with aldehydes, which proceeded with high diastereo- and enantioselectivity [32], The observed stereospecificity suggested the intervention of a six-membered cyclic transition state (Scheme 7.17). Notably, enoHzation of cyclohexanone derivatives and aliphatic aldehydes appeared feasible by SiCLt with the assistance of amine base and 9, leading to the estabhshment of a new protocol for direct aldol-type reactions between ketones and aldehydes or two aldehydes (Scheme 7.18) [33]. 

Scheme 7.17 Aldol reactions of trichlorosilyl enol ethers.

Trichlorosilyl enol ethers. The reaction of tributylstannyl enol ethers with SiCl results in trichlorosilyl analogs that are highly reactive as donors in aldol reactions without catalysts. Asymmetric synthesis in the presence of chiral phosphoramides is realized. 

According to Mayr s nucleophilicity scale (N), silyl enol ethers derived from aldehydes (N > 3.5) and ketones (N > 5) and, in particular, silyl ketene acetals (N > 8) [70] represent powerful nucleophihc reagents. Indeed, the aldol-type addition of trichlorosilyl enol ethers 76a-d to aldehydes 1 proceeds readily at room temperature without a catalyst (Scheme 15.14), which is in contrast with the lack of reactivity of allyl silanes in the absence of a catalyst. As a result, the reaction exhibits simple first-order kinetics in each component [71, 72]. Nevertheless, the reaction is substantially accelerated by Lewis bases, which provides a sohd ground for the development of an asymmetric variant The required trichlorosilyl enol ethers 76 can be generated in various ways, for example (i) from the corresponding trimethylsilyl enol ethers on reaction with SiCLt, catalyzed by (AcO)2Hg,... 

This supported triamide was utilized in the model reaction between the trichlorosilyl enol ether of cyclohexanone and benzaldehyde (Scheme 3.2), carried out at — 78 °C after 3 h the aldol product was obtained in 80% yield and 1 1 synjanti diastereoselectivity when the temperature was increased to — 23 °C,... 

In the aldol addition of chiral trichlorosilyl enol ethers 21.97 containing a remote stereogenic centre the latter has been found to exercise only a weak to modest influence on the stereochemical course of this reaction. In most cases, diastereoselectivity was controlled mainly by the chiral catalyst [e.g., 21.102). ... 

Nakajima has further shown that enantio- and diastereoselective aldol reactions can be effectively catalysed by BINAPO (21.14) in dichloromethane at —78 °C (Scheme 21.13). Thus, at 10 mol% catalyst loading and in the presence of z-PrNEta (1.2 equivalents), the reaction of the cyclohexanone-derived trichlorosilyl enol ether (21.97e) with various aromatic, a,p-unsaturated, and aliphatic aldehydes 21.4 can reach up to 48 1 diastereomeric ratio in favour of the antz-21.100 with up to 96% enantiomeric excess. ... 

In 1996, Denmark introduced chiral phosphoramide 1, which could be readily synthesized from the parent commercially available (R)-2,2 -diamino-l,l-binaphthalene, as an effective catalyst for the aldol reaction of the preformed trichlorosilyl enol ether of methyl acetate with aldehydes under mild conditions (Scheme 7.1) (2). 

This system could be successfully extended to the catalytic enantioselective crossed-aldol reaction of aldehydes [3], The geometrically defined ( )- and (Z)-trichlorosilyl enol ethers of aldehydes underwent efficient, highly diastereoselec-tive addition to different aldehydes under the influence of chiral bis-phosphoramide 2, which possess a tether of five methylene units, to give the corresponding anti-and syn-P-hydroxy aldehydes as a form of dimethyl acetal, respectively, with good yet variable enantioselectivity (Scheme 7.2). 

Furthermore, the combined use of a catalytic amount of 9 with SiCU allowed for the broadly useful, stereoselective double aldol reaction of ketones with aldehydes as depicted in Scheme 7.21 [36]. This asymmetric transformation involved the initial cross aldol reaction between ketone and aldehyde controlled by 9 and subsequent enolization of the resulting trichlorosilyl ether activated by 9 to generate the chiral cyclic enol ether that, in turn, underwent a second aldol process with another aldehyde in a diastereoselective fashion. 

One practical limitation is the availability, storage, and handling of reactive tri-chlorosilyl enolates. Addressing this issue, Denmark et al. developed an interesting, more practical procedure entailing in situ preparation of those reactive species. Starting from a TMS enol ether 29, in situ preparation of the trichlorosilyl enolate with tetrachlorosilane and mercury acetate, followed by subsequent asymmetric al-dol reaction, gave the aldol product (S)-25 in 89% yield and with 92% ee (Scheme 6.14). 

The concept of Lewis base activation of Lewis acids was developed by Denmark, and it takes advantage of the fact that the Lewis acidity of silicon is increased when the coordination sphere is enlarged. If chiral Lewis bases are provided, here chiral phosphoramides and bisphosphoramide, SiCl can be efficiently employed in asymmetric Mukaiyama aldol reactions. The Lewis base activation can be performed on trichlorosilyl enolates (24), which can be generated in situ by mercury-mediated trans-silylalion of a TMS silyl enol ether (18) in the presence of SiCl. Generation of the hypervalent silicon species produces a more Lewis acidic silicon moiety, which acts to coordinate and activate the aldehyde that has to be brought to reaction (Scheme 2.128) [48]. 

---