Methoxyethoxymethyl MEM Ethers

2-Methoxyethoxymethyi ethers were first described by Corey and co-workers. They are roughly comparable in stability to MOM and SEM ethers towards protic acids though they decompose in the presence of Lewis acids more readily than MOM ethers. MEM ethers are stable to 0.05 equivalents of anhydrous p-toluenesulfonic acid in methanol at 25 C for 3-15 h or 3 1 AcOH-water at 35 for 4 h but not to HBr in acetic acid or 2.0 M HCl.  

Benzyioxymethyl ethers are comparable in base stability to MOM, MEM, and SEM ethers. However, like benzyl ethers they can be removed by hydrogenoly-sis or Birch reduction. The advantage BOM ethers have over benzyl ethers is their easier preparation and easier removal. However, unlike benzyl ethers, they decompose in aqueous acid. The BOM group was introduced in 1975 by Stork and Isobe,- but it has not been as widely applied as MOM or MEM groups though its virtues are gaining in appreciation. 

Catalytic hydrogenolysis of BOM ethers is typically accomplished with Pd/C in ethanol, ethyl acetate or THE At the close of a synthesis of FR-900482, a phenolic benzyl ether and a benzyloxy BOM ether were hydrogenolysed without 

Hydrogenolysis of BOM ethers in the presence of alkenes is possible using Pearlman s catalyst [Pd(OH)2/C]. For example a BOM group was removed 

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An intramolecular palladium(o)-catalyzed cross-coupling of an aryl iodide with a trans vinylstannane is the penultimate maneuver in the Stille-Hegedus total synthesis of (S)-zearalenone (142) (see Scheme 38).59 In the event, exposure of compound 140 to Pd(PPh3)4 catalyst on a 20% cross-linked polystyrene support in refluxing toluene brings about the desired macrocyclization, affording the 14-membered macrolide 141 in 54% yield. Acid-induced hydrolysis of the two methoxyethoxymethyl (MEM) ethers completes the total synthesis of 142. 

The availability of oxepins that bear a side chain containing a Lewis basic oxygen atom (entry 2, Table 6.4) has further important implications in enantioselective synthesis. The derived alcohol, benzyl ether, or methoxyethoxymethyl (MEM) ethers, in which resident Lewis basic heteroatoms are less sterically hindered, readily undergo diastereoselective uncatalyzed alkylation reactions when treated with a variety of Grignard reagents [17]. The examples shown below (Scheme 6.7) demonstrate the excellent synthetic potential of these stereoselective alkylations. 

Conversion of MEM ethers to esters. 2-Methoxyethoxymethyl (MEM) ethers are converted into carboxylic esters by reaction with an anhydride in the presence of FeCl3 (0.4 equiv.) (equation I). Selective cleavage is possible in the presence of a benzyl ether but not in the presence of a f-butyl ether. Aromatic rings, if present, can undergo acylation. 

This cleavage reaction can be used to effect intramolecular homologated cyclization of hydroxy allylsilanes by conversion to the 2-methoxyethoxymethyl (MEM) ether (7, 228-229) followed by cleavage with TiCl4 to the species 6=CH2. 

Abresoline (66) was prepared recently by Quick and Ramachandra by transesterification of MB-methoxyethoxymethyl (MEM) ether of methyl ferulate with MEM derivative of quinolizidol (63a) and cleavage of protective groups with trifluoroacetic acid (103). 

The norephedrine-derived Masamune asymmetric aldol reaction was utilized in the total synthesis of (+)-testudinariol A (12), a triterpene marine natural product that possesses a highly functionalized cyclopentanol framework with four contiguous stereocenters appended to a central 3-alkylidene tetrahydropyran6 (Scheme 2.2f). The norephedrine-derived ester 13 was enolized with dicyclo-hexylboron triflate and triethylamine in dichloromethane and then treated with 3-benzyloxypropanal to afford the aldol adduct (14) as a 97 3 mixture of anti/syn diastereomers in 72% yield. Diastereoselectivity within the anti -manifold was 90 10. Protection of alcohol as the methoxyethoxymethyl (MEM) ether followed by conversion of the ester to an aldehyde by LiAlELt reduction and subsequent Swem oxidation gave the aldehyde 16 in 64% yield over three steps. 

Isopropyhhiomethyl ethers, ROCH2SCH(CHj)2. Methoxyethoxymethyl (MEM) ethers on reaction with 1 and 4-dimethylaminopyridine in CH2CI2 are converted into isopropylthiomethyl ethers. In the absence of DMAP, the MEM ether is cleaved to the free alcohol. Isopropylthiomethyl ethers can be cleaved to the alcohol under nonacidic conditions by silver nitrate and 2,6-lutidine. 

Cleavage of MEM ethers. 2-Methoxyethoxymethyl (MEM) ethers are cleaved by NaI/ClSi(CH,)3 in CHjCN at —20 or 25° in moderate to high yield, lodotrimethylsilane (commercial) is less effective. Fairly selective cleavage of MEM ethers is possible in the presence of lactones, methyl or benzyl ethers, and methyl esters. 

Cyanomethyl ethers.l Methoxyethoxymethyl (MEM) ethers are converted into cy-anomethyl ethers by reaction with excess diethylaluminum cyanide in toluene at 100° (equation I). The same reaction with methoxymethyl (MOM) ethers is considerably slower. 

Protection of tertiary alcohols,2 Methylthiomethyl (MTM) ethers have the advantage that they can be prepared from tertiary alcohols (7,135), but the disadvantage that they are prone to oxidation. They can be converted into 2-methoxyethoxymethyl (MEM) ethers, methoxy methyl (MOM) ethers, or ethoxy methyl (EOM) ethers by reaction with... 

Ajmaline (14) was chosen as a starting material because its total synthesis and absolute configuration were already established (14-16), and furthermore, the equilibrium isomer 17 from ajmaline chemically corresponds to the hypothetical intermediate 13. Ajmaline (14) was first converted into the hydrazone derivative by treatment with A,)V-dimethylhydrazine and a catalytic amount of sulfuric acid. After protection of the resulting secondary amine with methyl carbamate, the hydrazone was hydrolyzed with cop-per(II) chloride in aq. tetrahydrofuran (pH 7) to afford the aldehyde 19 in 75% yield. The hydroxy group in compound 19 was protected with the methoxyethoxymethyl (MEM) ether, and then bromine was selectively... 

Protection of hydroxy groups. Alcohols (primary, secondary, tertiary) can be protected as j3-methoxyethoxymethyl (MEM) ethers. These ethers can be prepared by reaction of (1), slight excess, with either the sodio or lithio derivative of the alcohol in THF or DME at 0° (argon). Alternatively, the ethers can be prepared by the reaction of (1) with alcohols in the presence of ethyldiisopro-pylamine. A third method for etherification is reaction of alcohols with the triethylammonium salt of (1), CH30CH2CH20CH2N (C2H5)3C1, in CH3CN at reflux. Yields by the three methods are >90%. 

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