Triisopropylsilyl TIPS Ethers

Triisopropylsilyl ethers are generally cleaved under the same conditions as those used for TBS ethers (i.e., TBAF-THF, HF-acetonitrile, or HF pyridine-THF, see above) but longer reaction times are frequently necessary consequently, TBS ethers can be removed selectively in many cases. Nevertheless, in a synthesis of Mycotrienol. a secondary TIPS ether was cleaved efficiently and rapidly with p-toluenesulfonic acid in methanol without detriment to a nearby second- 

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Magnus and coworkers have published full details55 on the direct a- or /J-azido functionalization of triisopropylsilyl (TIPS) enol ethers using an iodosylbenzene-TMS-azide combination (equation 13) the w-pathway, favoured at —78 °C, is an azide radical addition process, whereas the -pathway, favoured at —15 to — 20 °C, involves ionic dehydrogenation. Attempts to extend the /3-functionalization to other TMSX derivatives failed. 

The /J-azido triisopropylsilyl (TIPS) enol ether (96) functionalization developed by Magnus et al. from TIPS-enol ether (95) using iodosobenzene (Phl=0)-TMSN3 [70-73] provides a unique strategy for the total synthesis of an antitumor agent, (+)-pancratistatin (97) [Eq. (21)]. 

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. 

Silyl ethers, such as TMS, triethylsilyl (TES), triisopropylsilyl (TIPS), lerl-butyldi-methylsilyl (TBS), and terl-butyldiphenylsilyl (TBDPS) ethers (Scheme 2.6), are frequently used in carbohydrate chemistry due to their unique reactivity and steric effect (see Section 2.4.1) [1, 2], These groups are typically introduced onto the molecule by treatment with the corresponding silyl halide or triflate (OTf) and a base, such as Et3N, pyridine, 2,6-lutidine, or imidazole. 

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 TES group is the most labile of the common silyl protecting groups, apart from TMS, and can usually be removed in the presence of TBS, triisopropylsilyl (TIPS) and rerf-butyldiphenylsijyl (TBDPS) groups. Selective deprotection of a TES ether using aqueous trifluoroaoetic acid left two TBS ethers and two TIPS ethers intact in the Merck synthesis of the immunosuppressant FK-506 [Scheme 4.19].22 Weaker acids such as H2O-HOAC-THF (3 5 11) at room temperature,33 HF pyridine24 and pyridinium p-toluenesulfonate [Scheme 4.2Q]23 can accomplish similar transformations. 

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... 

OL-Silyl ketones,l Silyl enol ethers with sterically hindered silyl groups rearrange to a-silyl ketones in the presence of /i-BuLi (2 equiv.) and KO-f-Bu (2.5 equiv.). Tri-methylsilyl ethers do not undergo this rearrangement, but triisopropylsilyl (TIPS) and diisopropylmethylsilyl (DIMS) ethers do if they contain an allylic a-proton. The silyl group rearranges preferentially to the less hindered terminus of the intermediate allyl anion. The rearrangement is less useful with acyclic substrates because of side reactions. 

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). ... 

Sodium Azide/Ammonium Cerium(IV) Nitrate. Silyl enol ethers give a-azido ketones on treament with sodium azide and anhydrous ammonium cerium(IV) nitrate in anhydrous acetonitrile (see Eq. 97).297 325 33i With a glycal, the 2-azido-1-hydroxy nitrate derivative is formed.332 Low yields due to hydrolysis of the silyl enol ether may be improved by use of the triisopropylsilyl (TIPS) derivatives,331 although with a sterically encumbered taxane-derived enol ether the TMS derivative gives higher yields than the TIPS derivative.325 The mechanism is believed to involve addition of an azide radical to the double bond. 

In Magnus studies of jff-azidonation of triisopropylsilyl (TIPS) enol ethers, it was found that addition of TEMPO had a profound effect on the reaction pathway [82]. When TIPS protected enol ether 49 was allowed to react with PhIO and TMSN3 in the absence of TEMPO, compound 51 was obtained as the major product however, in the presence of catalytic TEMPO, compound 53 was obtained (Scheme 27). The formation of product 51 is postulated to occur via conjugate addition of azide anion to an enonium cation intermediate 50, whereas compound 53 is proposed to form via the formation of azide radical, which adds to the silyl enol ether double bond to form intermediate 52. 

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]. 

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... 

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). "... 

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