Enolsilanes

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). 

In the titanium tetrachloride-promoted aldol condensations of stereochemically defined enolsilanes (eq. [58]) variable levels of aldol diastereoselection have been noted (Table 26) (73). A detailed analysis of this reaction in terms of probable intermediates and transition state awaits further studies however, some experimental observations suggest that titanium enolates may not be involved (73b). 

Related reactions, catalyzed by tetra-n-butylammonium fluoride (TBAF), have been reported (74). Under the influence of 5 to 10 mol % of TBAF (THF, -78°C), enolsilane 75 afforded the erythro and threo adducts 76E and 76T whose ratios were time dependent (5 min, E T =1 2 10.5 hr, E T =1 3) (74). The reaction of enolsilane 77 at various temperatures has also been reported (2). At -78 C (1 hr) complete kinetic erythro diastereoselection was observed under the conditions reported by Noyori (74), but at higher temperatures product equilibration was noted (2). It is significant that the kinetic aldol condensation of this tetraalkylammonium enolate exhibits complete erythro selection as noted for the analogous lithium derivative. 

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

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

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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. 

Highly stereoselective formation of. syn-adducts (syn/anti. >95 < 5) results from the titanium(IV) chloride induced addition ofa-unsubsliluled enolsilanes, as well as of the a-dimethyl silylketene acetal, to 2-benzyloxypropanal3. 

Both complete simple diastereosclcctivity and high induced stereoselectivity result from the titanium(IV) chloride mediated reaction of 2-benzyloxypropanal with (Z)-enolsilane as below. Thus, the formation of the two 2,3-a t/-diastcrcomers can be avoided completely, and the predominance of chelation control over nonchelation control leads to the almost exclusive generation of one of the. yvw-ketones7. 

Complete chelation control but lower simple diaslereoselectivity is observed when the corresponding ( ,)-enolsilane reacts with (S)-2-benzyloxypropanal the ratio of diastereomers [(2S,3.S,45)/(2/ .3.S,4S)] is 85 153. 

Incomplete simple diastereoselectivity. combined in at least some cases with lower induced stereoselectivity, is also found in the addition of silylketene acetals 1-alkoxy-l-trirnethylsilyloxy-l-propene to 2-benzyloxypropanal3. On the other hand, a single diastereomeric adduct results from the tin(IV) chloride mediated addition of the following enolsilane to (S )-2-benzyloxypropanal12. 

The Mukaiyama variation of the aldol reaction also allows 1,3-induced chelation control. Thus, the reaction of the enolsilane or silylketene acetal with (5 )-3-benzyloxybutanal results in both cases in the predominant formation of the cwt/ -adduct (92 8 and 90 10), respectively14. 

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. 

Q Chiral racemic y-alkyl-substituted enones the titanium(IV) chloride mediated addition of enol silanes and silylketene acetals to 7 shows high induced diastereoselection (diastereomeric ratios from 89 11 to more than 97 3) and the major isomer 8 results from addition of the enolsilane with ul topicity288. Re face attack on the S enantiomer of 7.)... 

Asymmetric conjugate addition of dialkyl or diaryl zincs for the formation of all carbon quaternary chiral centres was demonstrated by the combination of the chiral 123 and Cu(OTf)2-C H (2.5 mol% each component). Yields of 94-98% and ee of up to 93% were observed in some cases. Interestingly, the reactions with dialkyl zincs proceed in the opposite enantioselective sense to the ones with diaryl zincs, which has been rationalised by coordination of the opposite enantiofaces of the prochiral enone in the alkyl- and aryl-cuprate intermediates, which precedes the C-C bond formation, and determines the configuration of the product. The copper enolate intermediates can also be trapped by TMS triflate or triflic anhydride giving directly the versatile chiral enolsilanes or enoltriflates that can be used in further transformations (Scheme 2.30) [110],... 

It is well known that acrylates undergo transition metal catalyzed reductive aldol reaction, the silanes R3SiH first reacting in a 1,4 manner and the enolsilanes then participating in the actual aldol addition.57,58 A catalytic diastereoselective version was discovered by arrayed catalyst evaluation in which 192 independent catalytic systems were screened on 96-well microtiter plates.59 Conventional GC was used as the assay. A Rh-DuPhos catalyst turned out to be highly diastereoselective, but enantioselectivity was poor.59... 

Similarly, enolsilanes 44 and 45 are afforded when silyl-protected alcohols and alkynes are reacted with ruthenium catalyst 41 (Equation (27)).40 The linear to branched ratio typically ranged from 2-4 1, except when the alkyne terminus was substituted with a TMS group. These internal alkynes afforded only the branched products. 

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... 

Catalyst 86a also catalyzed the enantioselective aldol reaction between a-keto esters and silylketene acetals or enolsilanes with high ee (ranging from 93% to 99%).58... 

Silylketene acetals and enolsilanes can also undergo conjugate addition to a,/ -unsaturated carbonyl derivatives. This reaction is referred to as the Mukaiyama-Michael addition and can also be used as a mild and versatile method for C-C bond formation. As shown in Scheme 8-34, in the presence of C2-symmetric Cu(II) Lewis acid 94, asymmetric conjugate addition proceeds readily, giving product with high yield and enantioselectivity.75... 

Reipig (39,40), Pfaltz (41), and Andersson and their co-workers (42) independently showed that these catalysts are capable of effecting the selective cyclopropanation of enol ethers and enolsilanes. Methyl vinyl ketone and acetophenone enolsilanes provide high selectivities in the cyclopropane products, but both isomers are formed equally. The trisubstituted dihydropyran 65 leads to cyclopropane adducts in high diastereoselectivities and enantioselectivities using 55c CuOTf as catalyst. 

Shibasaki and co-workers (47) modified bis(oxazoline) (55c) by slightly increasing the steric demand and found that the resulting ligand-copper complex exhibited good facial selectivity in the intramolecular cyclopropanation of enolsilanes. Enantioselectivity was improved from 78% for 55c to 92% for 55e. The product cyclopropane (73) is a component of the phorbol skeleton. 

From a practical standpoint, this reaction is subject to many of the same limitations as cyclopropanation. Decomposition of the iodinane to toluenesulfonamide is competitive necessitating a high relative concentration of alkene. The use of a large excess of alkene is unnecessary if the concentration of the medium is kept relatively high (1 M in alkene). The exception to this statement is the use of more nucleophilic alkenes such as enolsilanes. Aziridination of acetophenone enolsilane proceeds in high yield at -20°C using only 1.5 equiv of alkene. It is significant to note that the products of these reactions are a-amino ketones (74). 

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. 

Scheme 24. Proposed mechanism for the bis(oxazoline)-Cu(II) catalyzed aldol reaction between pyruvate esters and enolsilanes. [Adapted from (235).]...

J0rgensen and co-workers (230) reported the aldol reaction between enolsilanes and ketomalonate esters. Catalyst 269c proved to be nearly nonselective in these reactions. Optimal conditions involve the use of < /-269d in Et20 at -78°C. The reactions are quite sluggish under these conditions. Benzosubarone-derived enol-silane affords the aldol adduct in 93% ee, Eq. 200, while propiophenone enolsilane provides the aldol product in 90% ee under identical conditions, Eq. 201. Other nucleophiles are less selective. No model was advanced to account for the observed enantioselectivities. 

The success of bis(oxazoline)-copper(II) catalyzed Diels-Alder reactions involving acryloylimides as dienophiles has been extended to the Michael reaction, Eqs. 204 and 205. The observed enantiofacial discrimination in the Diels-Alder reactions was expected to translate well to Michael reactions involving enolsilanes as nucleophiles. Indeed, fumarate-derived imides afford Michael adducts of enolsilanes in high enantioselectivity (240). Diastereoselectivity in these reactions may be regulated by judicious choice of thioester and enolsilane geometry to provide either diastereomer in high selectivity (>99 1 syn or 95 5 anti). 

In an attempt to further elucidate the mechanism of this process, these workers monitored the reaction between propiophenone enolsilane and fumaroylimide by in situ infrared (IR) spectroscopy, Scheme 25 (240). In the absence of alcoholic additives, the accumulation of an intermediate is observed prior to appearance of product. When i-PrOH is introduced, immediate decomposition of the intermediate occurs with concomitant formation of product. Evans suggests that the intermediate observed in this reaction is dihydropyran (374). Indeed, this reaction may be viewed as a hetero-Diels-Alder cycloaddition followed by alcohol induced decomposition to the desired Michael adduct. That 374 may be acting as a competent inhibitor was suggested by an observed rate reduction when this reaction was conducted in the presence of IV-methyloxazolidinone. 

Scheme 25. In situ IR spectroscopy of the Michael addition of enolsilane to fumaroylimide catalyzed by 271c observation of an intermediate and effect of alcohol on the reaction. [Adapted from (240).]...

Mukaiyama Michael reactions of alkylidene malonates and enolsilanes have also been examined (244). The stoichiometric reaction between enolsilane (342a) and alkylidene malonate (383) proceeds in high selectivity however, catalyst turnover is not observed under these conditions. The addition of HFIP effectively promotes catalyst turnover, presumably by protonation and silyl transfer from the putative copper malonyl enolate generated in this reaction. The reaction proved general for bulky P-substituents (aryl, branched alkyl), Eq. 209. 

A catalytic asymmetric amination reaction has been developed using Cu(2+) catalysts (246). The azodicarboxylate derivative 392 reacts with enolsilanes in the presence of catalyst 269c to provide the adducts in high enantioselectivity, Eq. 213. As observed in the Mukaiyama Michael reactions, alcoholic addends proved competent in increasing the rate of this reaction. Indeed, in the presence of tri-fluoroethanol as additive, the reaction time decreases from 24 to 3 h. 

A corollary to the above argument is that enantioselectivities depend on alkene geometry. Indeed, isomeric enolsilanes provide enantiomeric products. Because obtaining enolsilanes such as 344 in high isomeric purity is difficult, enantioselectivities with these nucleophiles are reflective, Eqs. 214 and 215. Pyrrole-derived enolsilanes are accessible in very high isomeric purity (>99 1) thus providing a convenient solution to this problem. Their use in the catalytic amination reaction provides access to a-hydrazino acid derivatives in high enantioselectivity. 

The diastereoselective addition to imines proceeds well with aromatic enolsi-lanes (249). Propiophenone- and tetralone-derived enolsilanes provide good levels of diastereoselectivity (>95 5) and excellent enantioselectivity (>98% ee) with selective formation of the anti diastereomer. Nonaromatic enolsilanes are somewhat less selective although cyclohexanone enolsilane still provides useful levels of diastereoselectivity and enantioselectivity (92 8 anti/syn and 88% ee at -78°C). A one-pot procedure using glyoxylate, sulfonamide, and enolsilane as coupling partners was developed subsequently, leading to the product in comparable yields and selectivities (250, 251). 

NMR study, 42 162 oxidation of, 25 327, 328 reaction with ethylene oxide, 35 295-297 Acetals, aldol condensation of enolsilanes, 38 265-273 Acetic acid... 

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... 

In large measure, the problem associated with the execution of a stereoselective aldol condensation has been reduced to the generation of a specific enolate geometry. The recent results of Kuwajima (66a), which demonstrate that enolsilanes may be transformed into boryl enolates without apparent loss of stereochemistry (eq. [53]), should enhance the utility of vinyloxyboranes in stereoselective synthesis. The only current drawback to this procedure is associated with the presence of trimethylsilyl triflate (69), which must be removed from the reaction medium before the aldol condensation. It has recently been established that 69 is an effective catalyst for the aldol process (4). 

Noyori (4) has recently disclosed the mechanistically intriguing condensation of enolsilanes and acetals, which is catalyzed by tri-methylsilyl triflate (69) (eq. [61]). The results of a set of representative condensations between stereochemically defined enolates and... 

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