Ethers, 2-methoxyethoxymethyl alcohol protection

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. 

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... 

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%. 

The methoxymethyl (MOM) and jS-methoxyethoxymethyl (MEM) groups are used for protecting alcohols and phenols as formaldehyde acetals. These groups are introduced by reaction of an alkali metal salt of the alcohol with methoxymethyl chloride (chloromethyl methyl ether) or -methoxyethoxymethyl chloride. An... 

Protection of Phenols. Methoxyethoxymethyl chloride can also be used to protect phenols. The conditions for its introduction are similar to those used for alcohols (NaH, THE, 0°C MeOCH2CH20CH2Cl, 0°C 25°C, 2 h, 75% yield). In contrast to the alcohol derivatives, phenolic MEM ethers can be cleaved with Trifluoroacetic Acid (CH2CI2, 23 °C, 1 h, 74% yield). 1 M HCl (THE, 5 h, 60 °C) and HBr/EtOH will also effect cleavage. In general, the cleavage conditions used for alcohols are also effective with the phenolic derivatives. During an examination of the asymmetric reduction of an acetophenone derivative with (+)-B-Chlorodiisopinocampheylborane, it was found that a phenolic MEM ether was slowly cleaved (eq 4). ... 

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