Protection as silyl ethers

Since a-branched aldehydes gave rather higher asymmetric induction (Scheme 6.166), Nagasawa et al. extended the biphasic strategy to the diastereoselective Henry reaction of nitromethane with enantiomerically pure (S)-configured N,N -dibenzyl protected a-amino aldehydes and a-hydroxy aldehydes protected as silyl ethers. The screening reaction (Scheme 6.169) demonstrated a match/mismatch... 

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. 

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. 

The intramolecular 1,4-conjugate addition can be accomplished starting from a hydroxy group protected as silyl ether. The cyclization of the enone 13, however, performed by treatment with tetrabutylammonium fluoride in refluxing tetrahydrofuran, gives the 2,6-fra/t.s-tetrahydropy-ran 14 in only 11 % yield160. 

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

Stereoselective aldol reactions of a-methyl aldehydesThe lithium enolatc of this ethyl ketone (1) reacts with various a-methyl aldehydes to form aldols, which after protection as silyl ethers and thermolysis (500 ) were isolated as the a, / -unsaturated ketones 2 and 3. The diastcrcoselectivity is highly dependent on the R group. Thus... 

The hydrosilylation of aldehydes and ketones is of interest since it provides the corresponding alcohols protected as silyl ethers and the hydroxy function can subsequently be regenerated under mild conditions. Although the mechanism of carbonyl hydrosilylation is not as well-established as for olefin hydrosilylation, a few variations have been discussed by Ojima, Zhang and Chan and, more recently, Gade. ... 

In 2005 Jorgensen [12] and Hayashi [13] developed almost at the same time diarylproHnol derivahves protected as silyl ethers (Figure 33.4) as a suitable catalysts for inline and enamine achvation. 

In some cases hydrogen donating functions can be protected hydroxyethyl methacrylate and glyceryl methacrylate 16,17) can undergo anionic polymerization as silyl-ether or-acetal, respectively. After polymerization the OH functions are recovered by mild acid hydrolysis. Similarly, p-hydroxyethylstyrene can be polymerized an-... 

In the first step the cyclic acetal is subjected to acid cleavage, after which all the free alcohol functions are protected as TBS ethers with the aid of the very reactive silylation reagent I BS triflate. The primary alcohol is then deprotected under mild conditions and oxi-di/ed with FDC to a carboxylic acid. 

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. 

The resulting propargylic alcohol is protected as TIPS ether by a standard procedure using the corresponding silyl chloride and imidazole in DMF. Optionally the more reactive silyl triflate and 2,6-lutidine may be employed in order to shorten the reaction time. Under acidic conditions TIPS and TPS are nearly stable protecting groups. Therefore the TBS ether is selectively cleaved with acetic acid even in presence of the acetal moiety.13 Subsequent reaction with iodine and triphenylphosphine, known as the Appel reaction14, provides the desired iodide 4. 

Si2.3 Examples of protection of hydroxy groups as silyl ethers... 

Before the TPS ether is cleaved with TBAF, secondary alcohol 7 has to be protected as methyl ether. TBAF is a reagent to cleave every silyl ether. Most other functional groups are not affected (see Chapter 2). In the next two steps the conversion of alcohol 33 into mesylate 34, which is a good leaving group, and then into iodide 35 in a Finkelstein type reaction occurs. Acetone is the solvent of choice, because Nal is better soluble in it than NaOMs and consequently reaction equilibrium is forced to the product side. Direct transformation from an alcohol to an iodide is possible with PPha and I2 in an Appel-like reaction, but in some cases this reaction fails. Final procedure is the generation of phosphonium salt 8. 

This strategy was followed in the example shown in Scheme 5.5, Scheme 5.6 and Scheme 5.7 using the tert-butyldimethylsilyl ether as the temporary protecting group. Silyl ethers, allyl, p-methoxyphenyl and 2-(trimethylsilyl)ethyl groups are all commonly used for temporary protection of the anomeric position. 

---