2-trimethylsilylethyl protecting group

Stepwise alkylation of the diester 364, obtained conventionally using the Michaelis-Arbuzov reaction, leads to 365, from which the 0-(2-trimethylsilylethyl) protecting group may be removed with HF in MeCN. A Peterson reaction on the deprotected alcohol 3 (R = prenyl) results in the formation of the unsaturated phosphonic diester 367(R = prenyl) ... 

Steps a and b of this synthetic procedure were performed under standard activation and oxidation conditions. It is advantageous that in the final deprotection step c the trimethylsilylethyl group is cleaved by / -fragmentation by the action of TBAF simultaneously with tert-hutyl protective groups present in the oligopeptide chain. 

Sharpless also described the use of 2-trimethylsilylethyl carbamate 36 in the AA. This reagent leads to a product with a protective group that is easily removed by fluoride. Enantiose-lectivities in aminohydroxylation with 36 remain comparable with those obtained with benzyl carbamate 35 [78]. 

More specific anomeric protecting groups are the 2-trimethylsilylethyl (TMSE) [25] and p-methoxyphenyl glycosides [26], both introduced by glycosylation reactions on protected derivatives (Scheme 3.5). The former is cleaved by treatment with BF3-etherate conditions in which TBDMS ethers survive. p-Methoxyphenyl glycosides are cleaved by CAN-oxidation similarly to p-methoxybenzyl ethers. 

A mechanistically related and mild fragmentation is that of 2-trimethylsilylethyl esters (Tmse esters). The Tmse residue is a selectively cleavable carboxy-protecting group (see Volume 6, Chapter 3.2) Examples are known for the synthesis, via these esters, of peptides, macrolides such as curvularin and macrocyclic trichothecenes like verrucinol (Scheme 54). °... 

The total synthesis published by Schwartz and co-workers followed essentially the same approach, except they used fluoride-sensitive protective groups (such as TMSE (trimethylsilylethyl) and TEOC (trimethylsilyl-thoxycarbonyl) for pentapeptide side chains) to avoid the use of a strong base such as sodium hydroxide during the final deprotection step (22). 

Many carbamates have been used as protective groups. They are, for the most part, arranged in this chapter in order of increasing complexity of structure. The most useful compounds (not necessarily the simplest structures) are /-butyl (BOC), readily cleaved by acidic hydrolysis benzyl (Cbz or Z), cleaved by catalytic hydro-genolysis 2,4-dichlorobenzyl, stable to the acid-catalyzed hydrolysis of benzyl and /-butyl carbamates 2-(biphenylyl)isopropyl, cleaved more easily than /-butyl carbamate by dilute acetic acid 9-fluorenylmethyl, cleaved by 3-elimination with base isonicotinyl, cleaved by reduction with zinc in acetic acid 1-adamantyl, readily cleaved by trifluoroacetic acid allyl, readily cleaved by Pd-catalyzed isomerization or by nucleophilic addition to the tt-allylpalladium complex and trimethylsilylethyl, cleaved with fluoride. 

A truly orthogonal approach avoids these impediments, allowing removal without incidental loss of protection. Of the suitable candidates three carboxyl-protecting groups in particular offer a facile, generic route. Trimethylsilylethyl (OTmse) ester protection (84) has been used successfully for the synthesis of cyclic peptides on TFA-labile resin (85). Selective rapid removal is accomplished over 20 min using tetrabutylammonium fluoride (TBAF) in DMF. These favourably non-acidic conditions eliminate the... 

Phenol and Acid Protection. The synthesis of trimethylsi-lylethyl ethers and esters is readily achieved under a number of conditions. Their ease of preparation and stability under a wide variety of reaction conditions, combined with the fact that deprotection can be achieved under almost neutral conditions, have enlarged the scope of this protecting group. Protection of phenols and acids is easily achieved under Mitsunobu conditions as shown in eqs 19 and 20. Upon conpletion of the synthesis the phenol (eq 19) was deprotected using cesium fluoride in DMF at 160 °C in 89% yield. As well, en route to the synthesis of Daurichromeric acid, the trimethylsilylethyl ester (eq 20) was cleaved with TBAF in THF with a yield of 94%. 

Protection of Amines. 2-(Trimethylsilyl)ethyl chloroformate (1) is a useful reagent for the introduction of the trimethylsilylethoxycarbonyl (Teoc) protecting group for amines. " For example, p-chloroaniline reacts with (1) to form the ex-(7) pected trimethylsilylethyl carbamate (eq 1). The Teoc protecting group is stable to hydrogenation (H2, palladium on carbon) and mild acid or base. It can be removed with fluoride ion or with a strong acid (e.g. trifluoroacetic acid). It is possible to selectively cleave a t-butyldimethylsilyl... 

Recently, the 2-trimethylsilylethyl function has been prepared as a carboxyl protecting group. This may be synthesized by the reaction of the acid with 2-trimethylsilylethanol and dicyclohexylcarbodiimide (DCC, a... 

These anomeric protecting groups include the allyl, methoxyphenyl (MP), n-pentenyl, 2-trimethylsilylethyl (SE), /-butyldimethylsilyl, and t-butyldiphenylsilyl groups. Removal of this class of protecting groups releases the anomeric hydroxyl function to be converted into leaving groups [8]. 

The C.115 amino group was protected as a trimethylsilylethyl carbamate (Me3SiCH2CH20C0NHR), a group that was stable to the synthesis conditions and cleaved by the conditions used to remove the t-butyldimethylsilyl (TBS) ethers. 

These groups, along with a number of other trialkylsilylethyl derivatives, were examined for protection of phosphorothioates. Only the phenyl-substituted silyl derivative was useful, because simple trialkylsilyl derivatives were prone to acid-catalyzed thiono-thiolo rearrangement. Other trialkylsilylethyl derivatives also suffer from inherent instability upon storage,but the trimethylsilylethyl group has been used successfully in the synthesis of the very sensitive agrocin 84 and for intemucleotide phosphate protection with the phosphoramidite approach. 

Deblocking of the anomeric position, protected as the 2-trimethylsilylethyl ether, has been achieved in high yields in examples drawn from mono-, di-, and trisaccharide chemistry [112]. An example is shown in Eq. (66). In the absence of acetic anhydride, the product with a free anomeric hydroxy group is obtained. 

Protection of carboxyl groups. Trimethylsilylethyl esters, —COOCH2-CHaSiCCHala, can be prepared from N-benzyloxycarbonylamino acids and this reagent with DCC in the presence of pyridine (65 95% yield). The esters are stable under usual conditions of peptide synthesis, but are readily cleaved by fluoride ion, preferably by fetra-n-butylammonium fluoride in DMF. ... 

Another elegant reaction is the use of the 2-trimethylsilylethyl residue for protection of the carboxyl group by Sieber and colleagues in 1977 (for Ref. see e.g. in [44]). In some cases, saponification of methylesters requires alkaline conditions too strong to leave intact a sensitive peptide. Trimethylsilylethyl esters, however, in a type of jS-elimination, are decomposed at neutral pH by fluoride ions to yield trimethylfluorosilane, ethylene, and the carboxylic acid. 

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