Trichlorosilyl aldolate

Enolates with Aldehydes Catalyzed by BINAP-Silver(I) Complex, J. Am Chem Soc 1997,119, 9319-9320. (d) S. E Denmark, K-T. Wong, R. A Stavenger, The Chirality of Trichlorosilyl Enolates. 2. Highly-Selective Asymmetric Aldol Additions of Ketone Enolates, J. Am Chem. Soc 1997,119,2333-2334, and references cited therein. 

Asymmetric aldol additions of trichlorosilyl enolates of cyclic ketones to aldehydes have been studied, with a particular focus on the electronic effect of the aldehyde on the selectivity achieved. ... 

Catalysed enantioselective aldol additions of latent enolate equivalents have been reviewed and electronic effects of the aldehyde component on such reactions of trichlorosilylenolates of cyclopentanone and cycloheptanone, catalysed by chiral phos-phoramides, have been interpreted in terms of initial aldehyde coordination to the trichlorosilyl enolate and aldolization via a six-membered boat-like transition state. 

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. 

Phosphoramide Catalysis. In a series of elegant studies, Denmark has described a process utilizing trichlorosilyl enolates 27 and 28 as the nucleophilic component in catalytic, enantiose-lective aldol addition reactions (Scheme 8B2.3) [151. These enoxysilanes are prepared by treatment of stannyl enolates with SiCl4. Although trichlorosilyl enolates are sufficiently reactive entities to undergo addition to aldehydes rapidly at -78°C, Denmark documented that... 

Asymmetric aldol additions of geometrically defined trichlorosilyl enolates of ketones to aliphatic and aromatic aldehydes have been carried out uncatalysed, and with a chiral phosphoramide as Lewis base promoter.54 Significant differences in rates and diastereoselectivities are interpreted in terms of the changeover from a boat-like transition state, with pentacoordinate siliconate, to a chair-like transition state with hexacoordination. 

Boron enolates bearing menthol-derived chiral ligands have been found to exhibit excellent diastereo- and enantio-control on reaction with aldehydes34 and imines.35 Highly diastereo- and enantio-selective aldol additions of geometrically defined trichlorosilyl ketone enolates (31) and (32) have been achieved by promoting the reactions with chiral Lewis bases, of which (,S., S )-(33) proved to be the most effective.36 Moderate enantiomeric excesses have been achieved by using chiral ammo alcohols as catalysts for the Baylis-Hillman condensation of aldehydes with methyl vinyl ketone the unexpected pressure effect on the reaction has been rationalized.37... 

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 mechanism A very detailed mechanistic study of this phosphoramide-catalyzed asymmetric aldol reaction was conducted by the Denmark group (see also Section 6.2.1.2) [59, 60], Mechanistically, the chiral phosphoramide base seems to coordinate temporarily with the silicon atom of the trichlorosilyl enolates, in contrast with previously used chiral Lewis acids, e.g. oxazaborolidines, which interact with the aldehyde. It has been suggested that the hexacoordinate silicate species of type I is involved in stereoselection (Scheme 6.15). Thus, this cationic, diphosphoramide silyl enolate complex reacts through a chair-like transition structure. 

Aldol reactions using phosphoramides as organocatalysts The organic base-catalyzed asymmetric intermolecular aldol reaction with ketone-derived donors can be successfully applied to the construction of aldol products with two stereogenic centers [82-86]. Trichlorosilyl enolates of type 51 have been used as nucleophiles. Such enolates are strongly activated ketone derivatives and react spontaneously with several aldehydes at —80 °C. A first important result was that in the aldol reaction of 51 catalytic amounts of HMPA led to acceleration of the rate of reaction. After screening several optically active phosphoramides as catalysts in a model reaction the aldol product anti-53 was obtained with a diastereomeric... 

The Denmark phosphoramide organocatalyst has recently been applied in the first catalytic, diastereoselective, and enantioselective crossed-aldol reaction of aldehydes [86]. It is worthy of note that such controlled stereoselective selfcondensation of aldehydes has previously found no general application, because of many side-reactions, e.g. polyaldolization, and dehydration of the products. Several previously developed solutions have limitations. In a first step the Denmark group developed a procedure for generation of stereodefined trichlorosilyl enolates of aldehydes with high geometrical purity. Use of these geometrically pure (Z) and... 

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

Scheme 7.11 Aldol addition of trichlorosilyl ketene acetals to ketones.

Ester Enolate Aldol Additions to Aldehydes. Among the first examples of aldol additions employing chiral Lewis bases as catalysts were the additions of trichlorosilyl ketene acetals to aldehydes. Silyl ketene acetal 7 could be generated by metathesis of methyl tributylstannylacetate with SiCL. Treatment of 7 with benzaldehyde and 10 mol % of a phosphoramide in CH2CI2 at —78°C afforded aldol products in good to high yields with moderate enantioselectivities for all phosphoramides employed. Reaction of 7 with pivalaldehyde provided aldol products in similar yields and with slightly improved enantioselectivities. The increase in stereoselection is presumably attributed to a less com-... 

Table 3 Aldol additions of methyl ketone trichlorosilyl enolates to benzaldehyde catalyzed by (5,5)-la...

In contrast to the -enolates derived from cyclic ketones, addition of propiophenone trichlorosilyl enolate (Z)-21 to aldehydes requires longer reaction times and higher loadings of catalyst. Although the yields of the aldol products remain high, both the diastereo- and enantioselectivities are attenuated as compared to their E counterparts (eq 9, Table 8). 

In recent years the synthetic potential and mechanistic aspects of asymmetric catalysis with chiral Lewis base have been investigated. Aldol addition reactions between trichlorosilyl enolates with aldehydes have been also intensively studied. Now, full investigations of the trichlorosilyl enolates derived from achiral and chiral methyl ketones, in both uncatalysed and catalysed reactions with chiral and achiral aldehyde acceptors have been reported. The aldol addition is dramatically accelerated by the addition of chiral phosphoramides, particularly (137) and proceed with good to high enantioselectivity with achiral enolates and aldehydes (Scheme 34). ... 

The first catalytic, diastereoselective and enantioselective cross-aldol reactions of aldehydes have also been documented. Geometrically defined trichlorosilyl enolate derivatives of aldehydes undergo diastereoselective addition to a wide range of aldehyde acceptors with good enantioselectivity. The use of chiral Lewis base (138) was critical for achieving useful enantioselectivity. ... 

Aldol reactions. Chalcones are formed by exposing aryl methyl ketones to SiCl in ethanol. With Hg(OAc)j as catalyst trimethylsilyl enol ethers are converted by SiCl to trichlorosilyl derivatives at room temperature which are useful donors in aldol reactions. 

On the basis of NLE studies coupled with kinetic analyses, Denmark has disclosed that the mechanism of the rate acceleration by chiral phosphoramides in asymmetric aldol reactions of trichlorosilyl enolates with aldehydes stemmed from the ionization of the enolate by the basic phosphoramides (Eq. (7.8)) [26]. Steri-cally demanding phosphoramides (R=Ph) exhibit a linear relationship, through binding to the enolate in a 1 1 fashion and the resulting pentacoordinated cationic siliconate. In contrast, sterically less demanding pho.sphoramides (R=Me) with (-e)-NLE can bind in a 2 1 fashion to result in the hexacoordinated cationic. siliconate. 

Lewis Basic Phosphoramides. In a series of elegant investigations, Denmark has documented an aldol process that utilizes trichlorosilyl enolates such as 101 and 105 in catalytic, enantioselective addition reactions (Eqs. (8.28) and (8.29)) [45]. These unusual enoxysilanes are prepared by treatment of the corresponding tribu-tylstannyl enolates with SiCl4. Trichlorosilyl enolates are sufficiently reactive to add to aldehydes at -78 °C, but their addition can be substantially accelerated by the addition of Lewis basic phosphoramides. The use of catalytic amounts of chiral phosphoramides leads to the formation of optically active products. Thus, treatment of the cyclohexanone or propiophenone-derived trichloroenolsilanes 101 and 105 with a variety of aldehydes afforded adducts displaying high levels of simple diastereoselectivity and up to 96% ee. On the basis of the stereochemical outcome of the reaction, Denmark has postulated that the reaction proceeds through an or-... 

This concept of Lewis base catalysis has been widely developed by Denmark and coworkers in the asymmetric aldol additions of trichlorosilyl enolates on aldehydes. These reactions were shown to be highly susceptible to acceleration by catalytic quantities of chiral phosphoramides [69-77]. In particular, a phos-phoramide derived from (S,S)-stilbenediamine was remarkably effective not only in accelerating the reaction but also in modulating the diastereoselectivity and in providing the aldol addition products in good to excellent enantioselec-tivity. For example, trichlorosilyl enolate 61 reacts with benzaldehyde in very high enantio- and diastereoselectivity with 10 mol% of phosphoramide 62 in favor of the anti diastereomer (antifsyn 60/1). The catalyzed aldol reaction depends on the bulkiness and loading of the catalyst. On the other hand, the hindered phosphoramide (S,S)-63 afforded the syn aldol product in excellent diastereoselectivity (anti syn 1/97) but with modest enantioselectivity. 

Denmark et al. have reported that trichlorosilyl enolates also undergo non-catalyzed aldol reaction with aldehydes (Scheme 10.30) [95]. The sense of diastereoselectivity depends on the geometry of the enolates - ( )-enolate 33 adds to aldehydes with high. syn selectivity, whereas low anti selectivity is observed for (Z)-enolate 35 [96], The stereochemical outcomes can be rationalized by boat-like transition structures arranged by the Lewis acidity of the silicon atom, in which the configuration around silicon is trigonal bipyramidal with aldehyde binding in the apical position. In the transition structure from 35 there are severe steric interactions caused by the enolic Z substituent, which is attributable to the low anti selectivity. 

Chiral phosphorarnides, as developed by Denmark during the late 1990s [25], are efficient catalysts for the allylation of aldehydes with allyl trichlorosilane [26a] or the aldol condensation of trichlorosilyl-enol ethers with aldehydes [26b]. However, the first example of supported chiral phosphorarnides on a polymeric matrix was reported only in 2005 [27]. 

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 a novel departure from the traditional approach to the asymmetric Mukaiyama aldol, Denmark has reported a Lewis base-catalyzed aldol addition reaction of enol trichlorosilanes and aldehydes. These unusual silyl ketene acetals are readily prepared by treatment of the tributylstannyl enolates 246 with SiC (Eq. 51). In the initial ground-breaking studies, the methyl acetate-derived trichlorosilyl ketene acetal 247 was shown to add rapidly to a broad range of aldehydes at -80 C to give adducts (89-99% yield, Eq. 52). 

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