Aldehydes, enolsilanes

A stereoconvergent reaction without any correlation between the geometry of the enolate and simple diastereoselectivity occurs when fluoride ions are used to induce an aldol addition of enolsilanes to aldehydes. For example, both a 99 1 and a 9 91 mixture of the following (Z)/( )-enolsilane lead predominantly to the formation of the. un-adduct in a highly selective manner, when the addition is mediated by tris(diethylamino)sulfonium difluorotrimethylsili-conate27,28. 

High simple, as well as induced, stereoselectivity emerge in the addition of the (Z)-enolsilane to the same aldehyde, resulting in mainly one diastcrcomer the diastereomeric ratio is 92 8 (major isomer/sum of all other diastereomers)14. 

The aldol reaction between enolsilanes and aldehydes mediated by chiral Lewis acids may be considered the most notable achievement in the area of asymmetric aldol reactions. However, the design of new catalyst systems to tolerate... 

The addition of an enolsilane to an aldehyde, commonly referred to as the Mukaiyama aldol reaction, is readily promoted by Lewis acids and has been the subject of intense interest in the field of chiral Lewis acid catalysis. Copper-based Lewis acids have been applied to this process in an attempt to generate polyacetate and polypropionate synthons for natural product synthesis. Although the considerable Lewis acidity of many of these complexes is more than sufficient to activate a broad range of aldehydes, high selectivities have been observed predominantly with substrates capable of two-point coordination to the metal. Of these, benzy-loxyacetaldehyde and pyruvate esters have been most successful. 

Circulation flow system, measurement of reaction rate, 28 175-178 Clausius-Clapeyron equation, 38 171 Clay see also specific types color tests, 27 101 compensation behavior, 26 304-307 minerals, ship-in-bottle synthesis, metal clusters, 38 368-379 organic syntheses on, 38 264-279 active sites on montmorillonite for aldol reaction, 38 268-269 aldol condensation of enolsilanes with aldehydes and acetals, 38 265-273 Al-Mont acid strength, 38 270-271, 273 comparison of catalysis between Al-Mont and trifluorometfaanesulfonic acid, 38 269-270... 

A number of methods that utilize enolsilanes directly in the aldol process with either aldehydes or acetals have been developed recently. These reactions may be catalyzed with either Lewis acids such as titanium tetrachloride (73) or with fluoride ion (74). 

Condensations of Enolsilanes and Aldehydes Promoted by Titanium Tetrachloride (73)... 

Enolsilane Aldehyde [at r (°C)] Erythro-Threo Ratio Yield (%)... 

Mikami has also reported a related ene-like process involving glyoxylates and ketone-derived enolsilanes 42 (Eq. 8B2.11) [17]. The enol ether adducts 43 yield the corresponding P-hydroxy ketone upon treatment with mild acid. On the basis of an analysis of the stereo- and regiochemical outcome of the addition reaction Mikami has invoked a monodentate complex between aldehyde and metal, in contrast to the typical transition-state structures involving glyoxylates that are suggested to involve metal/aldehyde chelates. 

Asymmetric induction in the aldol reaction of enolsilane and metal enolate nucleophiles with yS-substituted aldehydes gives rise to both excellent yields and good diastereoselectivities (equation 128)507. The best diastereoselectivity was obtained using a trimethylsilyl enolate in the presence of boron trifluoride-etherate (92 8 anti. syn). The key step in the synthesis of the N-terminal amino acid analogue of nikkomycin B and Bx (nucleoside peptide antibiotics) has been performed using this type of methodology508. 

A. Aldol Condensation of Enolsilanes with Aldehydes and Acetals... 

In recent organic synthesis, stereoselective aldol condensations has been performed under two different conditions. Under the influence of acid, stabilized enol derivatives, enolsilanes (M = SiMe3), can condense with aldehydes or acetals in a stereoselective fashion [Eq. (12)]. In this reaction the role of the acid is to activate aldehydes or acetals. Alternatively, under basic conditions, the same process can be carried out directly with aldehydes and reactive, preformed metal enolates (M = Li, MgL, ZnL, AIL2, BL2, etc.) of defined geometry. 

Table XVII shows the maximum acid strength of Al-Mont catalyst in various organic solvents. In CHjClj or PhCHj, strongly acidic sites (//q < —8.2) were detected on Al-Mont. On the other hand, the acid strength of Al-Mont was weakened to -5.6 < Hq < -3.0 in DME. 1,2-Dimethoxyethane is a relatively basic molecule and thus interacts with the acid sites on montmoril-lonite to reduce their acid strength. The diastereoselectivity of the aldol reaction catalyzed by Al-Mont probably relates to the acid strength of Al-Mont because the degree of interaction between aldehydes (acetals) and acid sites on Al-Mont is affected by the acid strength of acid sites and influences the stabilities of the transition states which involve both enolsilane and aldehyde.

In the Held of chiral electrophiles, diastereoselective additions of enolsilanes to chiral a-fluoro-a-methyl-P-alkoxy aldehydes, a-methyl aldehydes, a-alkoxy aldehydes, a,p-dialkoxy aldehydes and a-methyl-P-alkoxy aldehydes were reported to proceed with good stereocontrol following Felkin-Anh or chelation models (c/. Section 2.4.4.1). Very good selectivities were reported in the addition of enolsilanes to chiral imines, particularly those derived from carbohydrates (Scheme 17 and 18).i. 6... 

The Rubottom oxidation1 is the peracid-mediated oxidation of trimethylsilyl enol ethers to afford a-silyloxy- or a-hydroxy aldehydes or ketones.2,3 Use of an aqueous workup generally affords the hydroxy compounds, whereas nonaqueous workups provide the silyloxy derivatives. For example, the enolsilane 1 derived from cycloheptanone was converted to 2 in 77% yield by treatment with /w-CPBA followed by workup with 10% aqueous sodium hydroxide. Omission of the aqueous workup afforded 3 in 85% isolated yield,1 ... 

The first examples of enolsilane oxidations were described independently by Brook,lb Hassner,lc and Rubottom in late 1974-early 1975. Brook reported that oxidation of enolsilanes derived from cyclic and acyclic ketones with w-CPBA affords a-silyloxy ketones in good yields subsequent hydrolysis of these products provided the corresponding alcohols. Rubottom noted that either a-silyloxy ketones or a-hydroxy ketones could be obtained depending on the nature of the workup (nonaqueous vs. aqueous). Hassner observed that enolsilanes derived from both aldehydes and ketones are suitable substrates for these transformations. Subsequent studies by Rubottom and others led to significant expansions of this methodology along with a more complete understanding of the mechanism of these reactions.2,3... 

Rubottom oxidation reactions have been conducted on enolsilanes derived from a number of different carbonyl derivatives including carboxylic acids and esters.15 For example, the Rubottom oxidation of bis(trimethylsilyl)ketene acetal 30 provided a-hydroxy carboxylic acid 31 in 81% yield. Use of alkyl trimethylsilyl ketene acetal substrates generates a-hydroxy esters, as seen in the conversion of 32 to 33.16 The synthesis of 3-hydroxy-a-ketoesters (e.g., 36) has been accomplished via Rubottom oxidation of enolsilanes such as 35 that are prepared via Homer-Wadsworth-Emmons reactions of aldehydes and ketones with 2-silyloxy phosphonoacetate reagent 34.17 The a-hydroxylation of enolsilanes derived from P-dicarbonyl compounds has also been described, although in some cases direct oxidation of the P-dicarbonyl compound is feasible without enolsilane formation.18... 

The same authors [97] reported a stereoselective synthesis of 1-P-meth-ylthienamycin precursor 245 from a chelation controlled aldol addition of the enolsilane 240, derived from t rt-butyl thioacetate, to the chiral aldehyde 227. The aldol adduct 241 was produced in 80% yield and in high degree of diastereoselectivity (>97%). Transformation of 241 to the p-lactam 242 was accomplished in the usual manner and this was transformed into the acetonide 245 by established procedures. 

Table I. Ratio of Diastereoisomers in the Lewis Acid Mediated Reaction of Enolsilanes with Aldehydes. ...

When the electrophile is chiral, besides simple stereoselection, a second type of diastereoselectivity termed "distereofacial selectivity" is possible. This sort of diastereofacial preference, qualitatively predictable by Cram s rule for asymmetric induction or one of its modem descendants, is typical of additions to chiral aldehydes. Chiral a-methyl aldehydes show exceptional diastereofacial preferences in their I wis acid mediated reactions with enolsilanes. The reason for this selectivity may be due to an approach trajectory of the nucleophile closer to the chiral center when the carbonyl is bound to the Lewis acid. ... 

Additions to chiral a-alkoxy aldehydes were studied with both non-stereogenic and steieogenic enolsilanes. With non-stereogenic enolsilanes usually a single isomer was obtained using stannic chloride or titanium chloride as promoter. " This high facial selectivity is due to the formation of a chelated complex between the aldehyde and the Lewis acid and addition of the nucleophile to the less encumbered face of the complex. 

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. ... 

Additions of stereogenic enolsilanes to aldehyde 8 are reported in Table III. Excellent ratios were obtained with thiolester silyl ketene acetals and TiCl4 as a result of chelation control (C-3,C-4 anti) and syn simple stereoselection (C-2.C-3 syn). 

Table III. Ratio of Diasteieoisomers in the Reaction of Stereogenic Enolsilanes with Aldehyde 8.

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