Equatorial silyl enol ethers

Alkylations of enolates, enamines, and silyl enol ethers of cyclohexanone usually show substantial preference for axial attack. The enamine of 4-f-butylcyclohexanone, which has a fixed conformation because of the i-butyl group, gives 90% axial alkylation and only 10% equatorial alkylation with n-Prl. 

The ketone 88 reacts with Me3SiCl and base to give the more substituted silyl enol ether 89. This has only one chiral centre and that is at the point where the lerl-butyl group joins the ring. The silyl enol ether 89 is turned into a reactive lithium enolate by the application of MeLi. This enolate then reacts with the methyl acrylate to give 90 with the stereochemistry as shown.22 If the tertiary butyl group is in the equatorial position, which is to be expected, then the new group has been installed in an axial position 90a. It is this that needs to be explained. 

Lewis acid catalyzed aldol coupling of silyl enol ethers with substituted cyclohexanone acetals showed an excellent preference for equatorial attack (95-l(X)%). In accord with this general rule, additions of a silyl enol ether to equatorially or axially substituted chiral spiroketals derived from -menthone gave 00% equatorial attack and formation of a single one of the four possible diastereoisomers (Scheme 9) 3, 4 -pjjjg methodology, followed by protection of the hydroxy group (X = OTHP, (XIPh.i) and alkaline removal of the chiral auxiliary was used for the synthesis of several natural products. ... 

The use of the lanthanide catalyst was also investigated with sensitive highly oxygenated dienes. The cycloaddition of furfural with diene (32) occurs at room temperature using 0.5 mol % Eu(fod)3 as catalyst (Scheme 11). Treatment of the crude cycloadducts (33) with triethylamine and methanol, cleaves the silyl enol ether, while maintaining the sensitive dimethoxyketene acetal to yield compound (34a). Reduction of compound (34a) with L-selectride gives a 6 1 mixture of axial and equatorial alcohols, which... 

Scheme 7.46) [77]. The reaction was applicable to the synthesis of a-ethenyl ke- tones possessing acidic a-protons, and isomerization to the thermodynamically stable conjugated enone was not observed. Equatorial preferences were observed in the ethenylation of cyclohexanone enolates for example, the ethenylation of a silyl enol ether derived from trans-3-decalone predominantly gave an equatorial isomer (Scheme 7.47) [78]. Silyl dienolates, synthesized by the a-ethenylation of thioesters followed by silylation, were ethenylated by this method at the a-position [79]. Ethenylation also occurred with silylated 1,3-dicarbonyl compounds, and ethenylmalonate possessing an acidic a-proton was obtained (Scheme 7.48) [80]. 

Temporary tethering of radical precursors has found other applications in natural product synthesis. Crimmins and O Mahony utilized a silyl ether temporary eonnection to direct a hydro-hydroxymethylation of enol ether 139 in their synthesis of talaromycin A, 140 [54]. Since talaromycin A is susceptible to acid-catalyzed isomerization to the thermodynamically more stable talaromycin B in which the hydroxymethyl substituent is equatorial, the use of the essentially neutral conditions of a radical cyclization to install the requisite axial hydroxymethyl group would avoid any potential isomerization problems. Formation of enol ether 139 was achieved in five steps from (4R)-4-ethylvalerolac-tone 141. Exposure of 139 to Bu3SnH in benzene at reflux in the presence of AIBN as initiator effected radical cyclization with delivery of the radical to the same face to whieh the ether tether was attached. Tamao oxidation proceeded uneventfully, furnishing the desired natural product (Scheme 10-47). 

TMSLi adds to cyclohexenone in THF-HMPA to give exclusively the 1,4-addition product (eq 3). The intermediate enolate may be stereoselectively alkylated at carbon with alkyl halides, or 0-silylated with chlorotrimethylsilane to provide the enol ether. Nucleophilic 1,4-addition to cyclohexenones is quite stereoselective. Reaction of 5-methylcyclohex-2-enone with TMSLi occurs predominantly by axial attack, resulting in a 92 8 ratio of axial to equatorial products. TMSLi also undergoes diastereoselec-tive nucleophilic addition to 1-naphthyloxazolines (eq 4) however, the addition of the silyl nucleophile is not as selective as the... 

Aldol coupling of enol silyl ethers and ketals (6, 599). The reaction of the silyl ether 1 with dimethyl or dibenzyl ketals of 2-, 3-, or 4-methylcyclohexanone results in at least 92% selectivity for equatorial attack (equation I). The degree of equatorial attack... 

Partial (3, 97) or complete (98) silylation may be obtained. Hydroxyl groups at C-3, 6a, Ip, and 12 are transformed into silyl ethers when treated with hexamethyldisilazane, 0.03 ml, in dry dimethylformamide, 0.06 ml, at 50 °C for 3hr (77). Complete silylation, both of equatorial and axial hydroyxl groups, is obtained in pyridine(dry)-hexamethyldisilazane-trimethyl-chlorosilane, 10 5 2 (v/v), 15 min, room temperature (98). Prolonged reaction times may give enol silyl ethers with keto bile acids. In an analogous reaction VandenHeuvel and Brady have prepared chloromethyldimethylsilyl ethers (99). Silyl ethers are very readily hydrolyzed. 

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