TIPS group ethers

PdO, cyclohexene, methanol, 30 min for a primary ROH, 90-95% yield. Secondary alcohols require longer times. The primary TBDPS and TIPS groups are cleaved much more slowly (18-21 h). Benzylic TBDMS ethers are cleaved without hydrogenolysis. ... 

Next the generated secondary alcohol is protected as triisopropylsilylether using TIPSOTf. The greater bulk of the TIPS group makes it more stable than the TBS group towards acidic hydrolysis therefore reaction with 5 % H2SO4 cleaves the TBS ether selectively to yield 11. 

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. 

An intermediate in the synthesis of laulimalide by Davidson8 illustrates the differential protection of alcohols. The starting materials 56 and 57 already have an alcohol protected as a TBDMS silyl ether and a diol protected as an acetal. The alcohol in 58 is protected as a p-methoxybenzyl ether and the acetal hydrolysed by acetal exchange to give the free diol 60. Selective protection of the primary alcohol by a bulky acyl group (pivaloyl, i-BuCO ) 61 allows silylation of the secondary alcohol with a TIPS group 62. Finally the pivaloyl group is selectively removed by DIBAL reduction to release just one free alcohol 63. 

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. 

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). ... 

Ceric ammonium nitrate, MeOH, 0 C, 15 min, 82-95% yield. Dioxolanes and some THP ethers are not affected, but in general, with extended reaction times, THP ethers are cleaved. Silica gel-supported CAN was found to be advantageous for the deprotection of nucleosides and nucleotides with primary TBS groups cleaved in preference to secondary derivatives. The TIPS group can also be cleaved by this method. This method was found effective where more traditional methods failed. ... 

Methyl-a-D-galactopyranoside (13) was used for the synthesis of suitable intermediates for the synthesis of (+)-pancratistatin (3) and (+)-narciclasine (9) (Scheme 1). Protection of the primary hydroxyl group in 13 as the TIPS ether followed by per-benzylation afforded 14, and then removal of the TIPS group followed by Swern oxidation afforded 15. Reaction of 15 with 16 gave a mixture of diastereomers 17, which underwent bromination with Ph3PBr2 to produce 18. Heating of 18 in dry pyridine afforded 19 as an and Z mixture in 75%... 

The (3-azidation reaction of triisopropylsilyl enol ethers (Schemes 3.186 and 3.187) has been effectively utilized in organic synthesis [563-565]. Magnus and coworkers have developed a mechanistically different enone synthesis that involves treatment of (3-azido TIPS enol ethers 469 and 471 with fluoride anion to effect desilylation and concomitant (3-elimination to give an a,(3-enone [563]. Alternatively, the (3-azido group in 469 or 471 can be ionized with MesAl or Me2AlCl and the intermediate enonium ion trapped by various nucleophiles, such as an allylstannane, electron-rich aromatics and trimethylsilyl enol ethers, to give various (3-substituted TIPS enol ethers. Reduction of the (3-azido TIPS enol ether provides access to the synthetically useful p-amino TIPS enol ethers [563]. 

With this key union effected, only a few operations separated 48 from the substrate needed to test enyne metathesis (i.e. 12, Scheme 9). First, the controlled exposure of this compound (48) to 2 equivalents of TBAF in THF at 0°C effected the lysis of both the phenolic silyl ether and the TMS group append onto the terminal position of the alkyne, but, importantly, not the TIPS group on the other acetylene group. As such, in the next operation partial reduction with Lindlar s catalyst (Pd on BaS04 poisoned with quinoline) was accomplished selectively on only one alkyne to provide the needed terminal olefin. Finally, cleavage of the alky-nyl TIPS moiety under more forcing conditions (TBAF, THF, 25 °C), followed by silylation of both the allylic hydroxy and the phenolic groups (TBSCl, imid, DMF), then completed the assembly of enyne metathesis precursor 12 in 62% overall yield from 48. 

Taking the steric effect to its next extreme, the triisopropylsilyl (TIPS) group has seen some very interesting applications. Yamamoto has shown that TIPS silyl ether 77 is at least 100 times more reactive than the corresponding TMS and 11 times more reactive than the TBS silyl ethers in the enantiospecific copper-catalyzed hetero-Diels-Alder reaction of heteroaryl nitroso compound 78. The argument is made that the steric demands of the OTIPS group provide a higher concentration of the requisite s-cis conformation of 77 (eq lO). "... 

Two new procedures have appeared for the regeneration of alcohols from their TBDMS ethers, using either NBS in aqueous DMSO (a cheap and easy alternative) or a tetrafluoroborate salt (lithium or trityl). The tri-isopropylsilyl (TIPS) group has been examined as a protecting function for hydroxy-groups. TIPS ethers are found to be intermediate in stability towards acid hydrolysis between TBDMS ethers and the more resistant t-butyldiphenylsilyl (TBDPS) ethers. Base hydrolysis is slower than in acid, and TBDPS ethers now react more rapidly than TIPS ethers. Not surprisingly the TIPS group may be removed by fluoride ion. 

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