Aldol Addition of Trichlorosilyl Enol Ethers

Despite this background reaction, the reaction rate is substantially accelerated by Lewis bases, which provides an opportunity for developing an asymmetric variant. The required enoxytrichlorosilanes 21.97 can be generated in various ways, e.g., from the corresponding trimethylsilyl enol ethers on reaction with silicon tetrachloride, catalysed by mercury(ii) acetate from carbonyl compounds or trimethylsilyl enol ethers on treatment with trichlorosilyl triflate from cx-chloroketones on reaction with trichlorosilane and triethylamine or from the corresponding tributyl-stannyl enol ethers, etc.  

Along this manifold, enol ether 21.97e with fixed ( )-configuration of the double bond gave rise to the corresponding q ra-21.100.  

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).  

Chiral AT-oxides have also been employed as catalysts to promote aldol reactions but their true potential remains to be realised. Catalysis by N-oxides follows the same general trends that were established for the phosphoramide activators, though with reduced enantioselectivity. Thus, Nakajima has demonstrated that the reaction of aldehydes 21.4 with silyl enol ethers 21.97, catalysed by bidentate bis-iV-oxides 21.17 and 21.105 [3 mol% of the catalyst, 1 equivalent of (z-Pr2)NEt, dichloromethane, -78 °C], proceeds via a chair-like transition state 21.98, resulting in high diastereoselectivity and moderate-to-good enantioselectivity ( 82% ee). On the other hand, aldol reaction of cyclic silyl enol ethers of type 21.97e with aromatic aldehydes, catalysed by bulky mono-oxides 21.27 and 21.106, displayed syn-selectivity, consistent with participation of the boat-like transition state 21.101. The enantioselectivity remained rather modest in the latter case (up to 72% enantiomeric excess).  

As a further reflection of their high nucleophilicity, silyl ketene acetals, such as 21.109, proved to be reactive not only toward aromatic, heteroaromatic, and cinnamyl aldehydes but, veiy importantly, even to aliphatic aldehydes. Furthermore, the catalyst loading can be reduced to 1 mol% without erosion of enantioselectivity.  

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Scheme 7.10 Asymmetric aldol addition of trichlorosilyl enol ethers to aldehydes.

Scheme 7.14 Aldol additions of trichlorosilyl enol ethers.

Following from the examples of allyltrichlorosilanes 21.5, Denmark introduced the related eno)g4 richlorosilanes 21.97 (Scheme 21.13) to cany out Mukaiyama-lype nucleophilic additions to carbonyl compounds. " According to Mayr s nucleophilicity scale, silyl enol ethers derived from aldehydes and ketones and, in particular, silyl ketene acetals are even more powerful nucleophilic reagents than the respective allyl silanes. Indeed, the aldol-type addition of trichlorosilyl enol ethers 21.97a-d to aldehydes 21.4 proceeds readily at room temperature without a catalyst exhibiting simple first-order kinetics in each component (Scheme 21.13), which contrasts with the lack of reactivity of allyl silanes in the absence of a catalyst. 

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],... 

Michael additions [202]. Phosporamide 66 was prepared as an insoluble equivalent for HMPA and was studied for the aldol condensation between trichlorosilyl enol ethers and aldehydes to give keto alcohols 70 (Scheme 10.13). Moderate to good yields and selectivities were obtained. In the presence of 10% of the catalyst at -23 °C the rate was significantly accelerated, albeit the syn/anti stereoselectivity was decreased by a factor of 5 [203]. 

Demnark SE, Fujimori S, Pham SM (2005) Base catalyzed aldol additions of chiral trichlorosilyl enolates and silyl enol ethers. J Org Chem 70 10823—10840... 

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). 

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