Ethers, triisopropylsilyl alcohol protection

Silyl-derived protective groups are also used to mask the thiol function. A complete compilation is not given here, since silyl derivatives are described in the section on alcohol protection. The formation and cleavage of silyl thioethers proceed analogously to those of simple alcohols. The Si-S bond is weaker than the Si-O bond, and therefore, sulfur derivatives are more susceptible to hydrolysis. For the most part, silyl ethers are rarely used to protect the thiol function, because of their instability. Silyl ethers have been used for in situ protection of the-SH group during amide formation. The use of the sterically demanding and thus more stable triisopropylsilyl thioether may prove worthwhile. ... 

We can also easily convert hydroxyl groups to silyl ethers. Section 14-10B covered the use of the triisopropylsilyl (TIPS) protecting group for alcohols. Similarly, sugars can be converted to their silyl ethers by treatment with a silyl chloride, such as chlorotrimethylsilane (TMSC1), and a tertiary amine, such as triethylamine. 

The triisopropylsilyl (TIPS) group is introduced under the same conditions as TBS groups.5 Instead of imidazole DMAP can be used, too. Under these conditions only the primary alcohol functionality is selectively protected as TIPS ether. 

Triisopropylsilyl ethers are formed under essentially the same conditions as TBS ethers — i.e. primary or unhindered secondary alcohols are treated with triisopropylsilyl chloride (bp 198 °C/98.5 kPa) in dichloromethane or DMF in the presence of imidazole or DMAP [Scheme 4.85J.138 The TIPS group is too bulky to react with a tertiary alcohol and protection of hindered secondary alcohols can be very slow in which case triisopropylsilyl triflate in the presence of 2,6-lutidine is used.100 However, even with the triflate as the silylating reagent, the reaction can be slow as illustrated by the reaction in Scheme 4.86.61 Triisopropylsilyl triflate is commercially available and it can be easily prepared on a large scale from triisopropylsilane and triflic acid in 97% yield. 

During a monumental synthesis of Strychnine, the Overman group encountered difficulties with the simple selective protection of the primary alcohol function in diol 87,1 as its TIPS ether [Scheme 4.89].143 The best method involved treatment of diol 87.1 with 2 equivalents of triisopropylsilyl chloride and 2.2 equivalents of 1,1,3,3-tetramethylguanidine at 0 °C in N-methylpyrrolidinone until the diol could no longer be detected by thin layer chromatography. This treatment... 

First conversion of primary alcohol 3 to the ferf-butyldiphenylsilyl ether 15 occurs. In the field of silyl ethers the TPS group as well as the triisopropylsilyl (TIPS) group are the most stable protecting groups against a large variety of reaction conditions - consequently they are frequently used in organic synthesis (see Chapter 2). ... 

Protection of Hydroxyl Groups. Triisopropylsilyl chloride (TIPSCl) continues to be widely used as the means of introducing the TIPS protecting groups onto alcohols. The steric bulk of the three isopropyl groups on the silicon atom provides considerable stability under acidic and basic conditions and allows selective removal of smaller, more labile silyl groups in the presence of TIPS ethers.i2.i3... 

Finally, the desired lactam III-53 was synthesized following the sequence shown in Scheme 4.28. Thus, triisopropylsilyl ether-protection (TIPS) of alcohol III-50 [134], oxidative of pyrrolidine III-51, using the Sharpless and KatsuM conditions [135], afforded 2-pyrrolidone III-52 [140], which was subsequently deprotected to give the lactam III-53 [141]. 

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