Alcohols as silyl ethers

The protection of alcohols as silyl ethers has been reviewed62, as have the relative stabilities of the different trialkylsilyl groups63. Their stability under alcohol oxidation conditions and their oxidative deprotection have been discussed64. Methods for selective deprotection of the various silyl ethers have been the subject of an excellent review65. 

The next step gives the TBS ether 54 at this position applying standard conditions to protect primary alcohols as silyl ethers. 

Zhu and Panek s total synthesis [148] is described in Scheme 89. After conversion of aldehyde 609 to di-benzyl acetal, treatment with chiral crotylsilane 610 afforded l,2-5y -611 with high stereo- and enantioselectivity. The oxidative cleavage of the double bond and subsequent aldol reaction with silyl ketene acetal 612 provided 613, which was converted into a,P-unsaturated ester 614 via Wittig olelination. The C8 methyl group was stereoselectively introduced by treatment with dimethylcuprate in the presence of TMSCl. DIB AH treatment differentially reduced the C3 and CIO esters to alcohol and aldehyde, respectively. Protection of the alcohol as silyl ether followed by the Wittig reaction afforded 615. In a manner similar to Danishefsky s synthesis [142d], an inteimolecular Suzuki... 

Protection of alcohols as silyl ethers—added in Section 13.6... 

Silyl ethers of aliphatic alcohols are inert towards strong bases, oxidants (ozone [81], Dess-Martin periodinane [605], iodonium salts [610,611], sulfur trioxide-pyridine complex [398]), and weak acids (e.g., 1 mol/L HC02H in DCM [605]), but can be selectively cleaved by treatment with HF in pyridine or with TBAF (Table 3.32). Phenols can also be linked to insoluble supports as silyl ethers, but these are less stable than alkyl silyl ethers and can even be cleaved by treatment with acyl halides under basic reaction conditions [595], Silyl ether attachment has been successfully used for the solid-phase synthesis of oligosaccharides [600,601,612,613] and peptides [614]. 

A number of oxidants are able to selectively transform silyl ethers derived from primary alcohols into aldehydes in the presence of silyl ethers derived from secondary alcohols. This allows to perform selective oxidations, whereby persilylation of polyols is followed by the selective oxidation of primary silyl ethers, resulting in the formation of aldehydes possessing secondary alcohols protected as silyl ethers. As expected, the mild transformation of primary silyl ethers into aldehydes is only possible with silyl ethers that are not exceedingly robust, such as TMS, TES and TBS ethers. 

Chlorophenyl)glutarate monoethyl ester 87 was reduced to hydroxy acid and subsequently cyclized to afford lactone 88. This was further submitted to reduction with diisobutylaluminium hydride to provide lactol followed by Homer-Emmons reaction, which resulted in the formation of hydroxy ester product 89 in good yield. The alcohol was protected as silyl ether and the double bond in 89 was reduced with magnesium powder in methanol to provide methyl ester 90. The hydrolysis to the acid and condensation of the acid chloride with Evans s chiral auxiliary provided product 91, which was further converted to titanium enolate on reaction with TiCI. This was submitted to enolate-imine condensation in the presence of amine to afford 92. The silylation of the 92 with N, O-bis(trimethylsilyl) acetamide followed by treatment with tetrabutylammonium fluoride resulted in cyclization to form the azetidin-2-one ring and subsequently hydrolysis provided 93. This product was converted to bromide analog, which on treatment with LDA underwent intramolecular cyclization to afford the cholesterol absorption inhibitor spiro-(3-lactam (+)-SCH 54016 94. 

Even if the SMS reaction typically involves allylsilanes, carbonyls and alcohols (or silyl ethers), some transformations can be considered as belonging to the same family. For example, in 2001, Yokozawa et al. described [43] a three-component reaction between aldehydes 6, alkoxysilanes 38 and propargylsilane 88 (instead of allylsilane). Tritylperchlorate was used as the catalyst and a-allenyl ethers 89 were... 

What kinds of silylating reagent are used to protect a secondary alcohol as TDS ether ... 

Finally, alcohols can also be protected as silyl ethers. For example, the reaction of the alcohol with trimethylsilyl chloride in the presence of triethylamine (to react with the HC1 that is produced) produces the trimethylsilyl ether of the alcohol as shown in the following equation. (This reaction is a nucleophilic substitution by the oxygen on the silicon.) The silyl group can be removed in high yield by reaction with fluoride anion. 

Furthermore, Nicolaou, Kunz, and Vozny independently reported that glycosyl fluorides effectively reacted with a variety of free alcohols and silyl ethers using BF3Et20 as an activator to give the corresponding O-glycosides in good yields (O Scheme 25) [58,59,60,61]. 

Poly (vinyl alcohol) macromonomers having the hydroxyl groups protected as silyl ethers were prepared using p-formylstyrene as initiator [218] (Scheme 67). 

Protection of Alcohols as TMS Ethers. The most common method of forming a silyl ether involves the use of TMSCl and a base (eqs l-3). 9-22 Mixtures of TMSCl and Hexamethyldisi-lazane (HMDS) have also been used to form TMS ethers. Primary, secondary, and tertiary alcohols can be silylated in this manner, depending on the relative amounts of TMS and HMDS (eqs 4—6). ... 

Protection of Alcohols as TMS Ethers. Several new methods have been developed for the protection of alcohols as TMS ethers. For example, TMS silyl ethers of alcohols and phenols can be prepared efficiently by treatment of the alcohol or phenol with TMSCl and catalytic amount of imidazole or iodine under the solvent-free and microwave irradiation conditions. This transformation proved to be reversible. Under the same microwave conditions, treatment of the silyl ether in methanol and in the presence of catalytic amount of iodine releases the parent alcohol in quantitative yield. 

The reaction of 5-acetoxy-5,6,7,8-tetrahydroisoquinoline 109 with Mel followed by reduction afforded the octahydroisoquinoline 110, which upon treatment with ethyl chloroformate followed by hydrolysis gave 111. The condensation of 111 with 2-bromoisovanillin afforded 112, which was reduced to give the benzyl alcohol intermediate 113. Heck reaction of 113 led to the formation of 0-ring affording 115. The yield of the above intramolecular cyclization was increased significantly via prior protection of the alcohol in 113 as silyl ether 114. Conversion of 115 to benzyl chloride 116 was achieved via the treatment with NCS and triphenylphosphine. Further, Heck reaction of 116 afforded the tertiary amine 117 via an intramolecular A -benzylation. The amine 117 was converted into the corresponding iV-methylammonium iodide 118, which was then subjected to Stevens rearrangement with PhLi to afford ( )-desoxycodeine 119 in 83 % yield. ... 

In the synthesis of methyl-2,3-0-isopropylidene-4-0-(methoxymethyl)-6-methylene-a-D-mannopyranoside (13), the hydroxyl groups of methyl-a-o-mannopyranosides are selectively protected 6-hydroxyl group as silyl ether 2,3-hydroxyl groups as acetonides and 4-hydroxyl group as methoxymethyle-ther. The silyl group at the C-6 position is then selectively cleaved to get primary alcohol. Oxidation of the alcohol to aldehyde followed by Wittig methylenation yields the desired olefin (13, Scheme 31.13). 

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