T-butyldimethylsilyl enolate

Very few pericyclic reactions of carbene complexes have been studied that are not in the cycloaddition class. The two examples that are known involve ene reactions and Claisen rearrangements. Both of these reactions have been recently studied and thus future developments in this area are anticipated. Ene reactions have been observed in the the reactions of alkynyl carbene complexes and enol ethers, where a competition can exist with [2 + 2] cycloadditions. Ene products are the major components firom the reaction of silyl enol ethers and [2 + 2] cycloadducts are normally the exclusive products with alkyl enol ethers (Section 9.2.2.1). As indicated in equation (7), methyl cyclohexenyl ether gives the [2 -t- 2] adduct (84a) as the major product along with a minor amount of the ene product (83a). The t-butyldimethylsilyl enol ether of cyclohexanone gives the ene product 9 1 over the [2 + 2] cycloadduct. The reason for this effect of silicon is not known at this time but if the reaction is stepwise, this result is one that would be expected on the basis of the silicon-stabilizing effect on the P-oxonium ion. 

In combination wifh t-butyldimethylsilyl chloride, InClj catalyzes the aldol reaction between aldehydes and t-butyldimethylsilyl enol ethers in anhydrous organic solvents [140]. It has recently been found that the InCh-catalyzed Mukaiyama aldol reaction proceeds in water (Tab. 8.26) [141]. The reaction proceeds cleanly under almost neutral conditions to give /1-hydroxy ketones. The aqueous phase with IriClj can be reused. Water-soluble aldehydes such as glyoxylic acid and a commercial formaldehyde solution can be used directly for these reactions. 

Recently Mukaiyama and coworkers introduced the use of trityl salts as efficient catalysts for the aldol reaction. Using a catalytic amount of trityl perchlorate (5 mol %) and t-butyldimethylsilyl enol ethers, the anti aldols were preferentially obtained (anti 73-84%) regardless of the double bond geometry. With trityl triflate (5 mol %) and dimethylphenylsilyl enol ethers, the syn isomers are produced predominantly (syn 63-79% Scheme 1). Several variations of the catalyst system have been developed. Trityl... 

Ireland s group has described in detaiF an elegant use of a [3,3] sigmatropic rearrangement in a synthesis of unsaturated acids from allyl esters via the corresponding enolates (Scheme 3). t-Butyldimethylsilyl enolates were found to be most useful, the low temperature transformation normally giving rise to the E-isomer, with yields in the range of 66—88%. 

Scheme 12.3. Synthesis of prostaglandin Et using a three-component conjugate addition/enolate trapping on cyclopentenones, by Noyori and co-workers [10], TBS = t-butyldimethylsilyl, THF = tetrahydrofuran,...

Scheme 12.4. Multiple metal variant of the conjugate addition/ enolate trapping 3CR on cyclopentenones, by Lipshutz and Wood [13]. THF = tetrahydrofuran, TBS = t-butyldimethylsilyl.

The structure and chiral properties of the enolate intermediate were then investigated. Treatment of 40 with KHMDS (1.1 equiv) in toluene-THF (4 1) at —78°C for 30 minutes followed by t-butyldimethylsilyl (TBS) triflate gave Z-enol silyl ether 54 and its -isomer 55 in respective isolated yields of 57% and 27%.30 In the lH NMR spectra of both 54 and 55, methylene protons of the MOM groups appeared as AB quartets, which indicates restricted rotation of the C(l)-N bonds. The rotational barrier of the C(l)-N bond of the major Z-isomer 54 was determined to be 16.8 kcal/mol at 92°C by variable-temperature NMR measurements in toluene- (400 MHz 1 H... 

UButylmethoxyphenylsilyl ethers (r-BMPSi ethers). In DMF in the presence of NfCjHj), this bromosilane reacts with primary, secondary, and tertiary alcohols to form silyl ethers in good yield, and also with some enolizable ketones to form enol silyl acetals. Selective silylation of primary alcohols is possible by use of CHjClj as solvent. The hydrolytic stability of these ethers is intermediate between that of t-butyldimethylsilyl ethers and that of t-butyidiphenylsilyl ethers. The most useful feature of this new protecting group is the selective cleavage by fluoride ion in the presence of other silyl ethers. 

Transsilylation. Several reagents have been recommended for preparation of t-butyldimethylsilyl ethers by transsilylation. These include allyl-r-butyldimethyl-silane and r-butyldimethylsilyl enol ethers of pentane-2,4-dione and methyl aceto-acetate,2 both prepared with r-butyldimethylchlorosilane and imidazole. Unlike the reaction of f-butyldimethylchlorosilane with alcohols, which requires a base catalyst, these new reagents convert alcohols to silyl ethers under slightly acidic conditions (TsOH) in good yield. The trimethylsilyl ethers of pentane-2,4-dione and methyl acetoacetate convert alcohols to trimethylsilyl ethers at room temperature even with no catalyst. The former reagent is also useful for silylation of nucleotides.3... 

IT., cn. leOH t-butyldimethylsilyl T.. 3.1 ethers are not affected, ir.- nat are adducts of silyl enol iF M- SiOTf. Thus, hydrodesilyloxy-... 

Silylation at nitrogen with t-butyldimethylsilyl triflate, generates pyridinium salts which, because of the size of the A -substitutent, react with Grignard reagents exclusively at C-4 montmorillonite-catalysed addition of silyl enol ethers to pyridines has a comparable effect in producing l-trimethylsilyl-l,4-dihydropyridines carrying an acylalkyl substituent at C-4. ... 

The use of the more sterically hindered silyl chloride, t-butyldimethylsilyl-chloride, leads to silylation of pristinamycin 11 at the 37-ketone function as the enol-ether (see Sect. 5.4.2). 

Reaction of pristinamycin 11 with 1.2 equivalents of t-butyldimethylsilyl chloride in the presence of ethyldiisopropylamine afforded the enol-silylether (71) together with a small amount of the disilyl ether (72) (Scheme 16). With 2.4 equivalents of t-butyldimethylsilyl chloride the sole product was the disilyl ether. 

The stereoselectivity of the room-temperature Claisen rearrangement of the secondary enynol enolacetate (99) is enhanced to 98% to produce the E-enyne (100) when the enol is protected with the bulky t-butyldimethylsilyl group. The enyne (100), so derived in 30% yield, has been used in a novel route to the E,Z-d ne bombykol (101) (Scheme 18). ... 

Hudrlik and Kulkarni have shown that a-t-butyldimethylsilyl aldehydes serve as vinyl cation equivalents for the synthesis of /3,y-unsaturated ketones (and esters). Addition of lithium enolates to the a-silyl aldehydes is highly erythro-selective, enabling products of either E- or Z-geometry to be obtained (Scheme 58). In a related process, phenylselenoacetaldehyde has been used to transform ketones into the corresponding a-vinylketones (Scheme 59) phenyl-selenoacetone enables a- isopropenylation of ketones in an analogous fashion. ... 

Three approaches to the problem of preparing t-butyldimethylsilyl derivatives have appeared this year, two of which make use of silyl enol ether derivatives. Both (135) and (136, R = CH3, OCHa) " give silylated products under mild... 

Modified Amine Base. The regioselectivity of ketone deprotonation was improved by the use of lithium t-butyldimethylsilyl-amide as base. The base was prepared by deprotonation of isopropylamine with n-BuLi in THF (eq 22). The resulting anion was quenched with TBDMSCl to give the amine in 70% yield after distillation. Deprotonation of various ketones using this amide base was found to be equally or more selective than LDA. For example, the TBDMS-modified base gave a 62 38 ratio of kinetic to thermodynamic enolate, whereas LDA gave a 34 66 ratio with phenyl acetone. 

Depending on the experimental conditions, reaction of (1) with f-butyldimethylsilyl trifluoromethanesulfonate leads either to the expected /3-trimethysilyl enol ether (11), or to its isomer (12) formed by a 1,3-migration of the trimethylsilyl group from the oxygen atom to the carbon atom (1 13). Reaction with f-butyldimethylchlorosilane always gives (12). Trimethylsilyl enol ether (11) is easily hydrolyzed to 2-(t-butyldimethylsilyl)-acetaldehyde (14) (eq 7). ... 

Scheme 14.22 Catalytic generation and reactions of NHC-enolates from ketenes (HMDS = hexamethyldisilazide TBDMS = t-butyldimethylsilyl).

Trimethylsilyl enol ethers can be prepared directly from ketones. One procedure involves reaction with trimethylsilyl chloride and a tertiary amine. This procedure gives the regioisomers in a ratio favoring the thermodynamically stable enol ether. Use of t-butyldimethylsilyl chloride with potassium hydride as the base also seems to favor the thermodynamic product.Trimethylsilyl trifluoromethanesulfonate (TMS triflate), which is more reactive, gives primarily the less substituted trimethylsilyl enol ether (entry 5, Scheme 1.3). The best ratio of less substituted to more substituted enol ether is obtained by treating a mixture of ketone and trimethylsilyl chloride with LDA at Under these conditions, the kinetically preferred... 

The completion of the synthesis requires some functionalization and a change in stereochemistry at C-5. The C-16—C-17 hydroxylation is accomplished in step L and is stereoselective as the result of a steric effect by the large t-butyldimethylsilyl protective group. Step M accomplishes reductive removal of the extraneous hydroxyl group at C-11. Inversion at C-5 is accomplished by an oxidation to an enone, followed by lithium metal reduction. The stereochemistry is governed by the protonation of the enolate intermediate (as discussed in Section 5.5.1). The final functionalization at C-3 and C-4 is similar to the early steps in Schemes 13.33 and 13.34. 

Although alkylatirai of -hydroxy ester dianions occurs with high diastereofacial selectivity, the aldol reaction of the dianion obtained from methyl 3-hydroxybutanoate with benzaldehyde gives all four dia-stereomeric aldols in a ratio of 43 34 14 9 (equation 117). On the other hand, dianions of 5-hydroxy esters show rather good diastereofacial preferences under the proper conditions. Deprotonation of t-butyl-5-hydroxyhexanoate with lithium diethylamide in the presence of lithium triflate gives an enolate that reacts with benzaldehyde to give aldols (196) and (197) in a ratio of 91 9 (equation 118). Use of the t-butyldimethylsilyl ether instead of the alcohol resulted in no facial preference. 

Yamamoto and coworkers have found that the (Ib)-promoted aldol reaction of t-butyldimethylsilyl (TBS) enolate (63) provides only the corresponding TBS aldolate (64a) (Scheme 9.37), and that a competitive reaction of two silyl enolates bearing different silyl and enoxy groups forms crossover products [101], These results are indicative of path C for the (Ib)-promoted reaction. In contrast, the (la)-promoted aldol reaction of (63) forms the corresponding TMS aldolate (64b) predominantly. Thus, it is probable that the (la)-promoted reaction proceeds by path A. 

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