Silicon-based protecting groups

The synthetic potential of silyl ethers as protecting groups for hydroxyls is based on the fact that they can be easily introduced and cleaved under mild conditions and their relative stability can be tuned by varying the substituents on silicon. In carbohydrate chemistry, the tert-butyl-dimethylsilyl (TBDMS), terl-butyldiphenylsilyl (TBDPS) and triethyl-silyl (TES) ethers are the most often applied silicon-based protecting groups (Scheme 2.9).23... 

Silicon-based protecting groups for alcohols are the best because they are the most versatile. They are removed by nucleophilic displacement with fluoride or oxygen nucleophiles and the rate of removal depends mostly on the steric bulk of the silyl group. The simplest is trimethylsilyl (Mt Si or often just TMS) which is also the most easily removed as it is the least hindered. Tn fact, it is removed so easily by water with a trace of base or acid that special handling is required to keep this labile group in place. 

Tris(dimethylainino)sulfur trimethylsilyidifluoride (TAS-F). 13,336 15, 355 18,393 Desilylation. Silicon-based protecting groups such as A(-[2-(trimethylsilyl) ethoxycarbonyl] are readily removed by TAS-F in DMPU at room temperature (8 examples, 68-98%). 

Figure 6.25 Silicon-based protecting groups and their introduction and consequences.

These PG s must stay on until the very end, thus a robust long-term PG is needed, It would simplify things If they were orthogonal to silicon based protecting groups, which will be the work-horses of the sequence. 

The reagent (188) aminates 0-(trimethylsilyl)aldehyde cyanhydrin anions, to give iV,iV-dimethylamides after hydrolysis, and a multitude of derivatives of (189) have been prepared by various routes, all of which involve the use of MeaSiCN at some stage. The first of two new silicon-based protecting groups reported this year is (190), which protects 1,2-, 1,3-, and 1,4-diols under mild... 

Recently silicon-based protection has matured into a new Ix oad area of protecting group chemistry (see Section 3.1.3.2) and amines can also be conveniently blocked with appropriate silicon reagents. In organometallic syntheses, e.g. in the alkylation of amino acid enolates, the so-called stabase adducts (30) serve to temporarily protect the a-amino group (Scheme 21). In the absence of hard nucleophiles, in particular of 0-nucleophiles, the Si—N bonds are stable, but deprotection is readily effected in the presence of water and acids. 

Silicon finds a plethora of applications in organic chemistry, as silyl-based protecting groups and as other types of reagents. The great majority of these applications hinge around silicon s oxophilicity. 

Silyl ethers are ethers with a substituted silicon atom replacing one of the alkyl groups of an ether. Silyl ethers share some of the properties of ethers (resistant to some acids, bases, and oxidizing agents), but they are more easily formed and more easily hydrolyzed. These properties make them useful as protecting groups, and silyl ethers are frequently used to protect alcohols. 

An ether protecting group can be difficult to remove (deprotect). It often requires strong acid, which can react with the free hydroxyl group or other parts of the molecule. Ethers based on silicon (silyl ethers) are much easier to remove than carbon-based ethers. In aqueous or organic solvents, fluoride ion removes silyl ethers under gentle conditions because the silicon-fluorine bond is exceptionally strong. 

The simultaneous protection of the 3 and S hydroxy groups of nucleosides and the 4,6- or 3,4-hydroxyls of hexopyranoses is a common problem in organic synthesis. In the case of hexopyranoses, we have already seen that benzylidene acetals and, in certain circumstances, isopropyiidene acetals can be used to good effect. An alternative silicon-based group would offer a wider repertoire of conditions for mild deprotection and such a group was devised by Markiewicz the 1,1,3,3-tetraisopropyldisiloxanylidene group (abbreviated TIPDS),22 229 TIPDS groups are stable to water, 0.3 M p-toluenesulfonic acid in dioxane, 10% tri-fluo mace tic acid in chloroform, 5 M ammonium hydroxide in dioxane-H20 (4 1), and tertiary amines in pyridine,... 

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