A dioxolane can be used in this way to protect aldehydes and ketones from powerful, basic nucleophiles, and makes the first entry in the tour of important protecting groups we shall conduct you through in the next few pages.

By protecting sensitive functional groups like ketones, it becomes possible to make rea gents that would otherwise be unstable. In a synthesis of the natural product porantherine, a compound based on the structure in the margin was needed. As it’s a symmetrical second ary alcohol, a good way to make it is to add a Grignard reagent twice to ethyl formate.

But, of course, a ketone-containing Grignard is an impossibility as it would self-destruct, so an acetal-protected compound was used. Acid-catalysed hydrolysis of the two dioxolanes, coloured green, reveals the diketone.

Strongly nucleophilic reagents like Grignard reagents and organolithiums are also strong bases and may need protecting from acidic protons as well as from electrophilic carbonyl groups. Among the most troublesome are the protons of hydroxyl groups. When some American chemists wanted to make the antiviral agent Brefeldin A, they needed the simple alkynol in the margin. A synthesis could start with the same bromoketone as the one above: reduction gives an alcohol, but alkylation of an alkynyl anion with this compound is not possible because the anion will just deprotonate the hydroxyl group.

The answer is to protect the hydroxyl group with a group resistant to base, and the group chosen here was a silyl ether. Such ethers are made by reacting the alcohol with a trialkyl silyl chloride (here tert-butyldimethylsilyl chloride, or TBDMSCl) in the presence of a weak base, usually imidazole, which also acts as a nucleophilic catalyst.

Silicon has a strong affinity for electronegative elements, particularly O, F, and Cl, so tri alkylsilyl ethers are attacked by hydroxide ion, water, or fluoride ion but are more stable to carbon or nitrogen bases or nucleophiles. They are usually removed with aqueous acid or fluoride salts, particularly Bu4N+F− (tetra-n-butylammonium fluoride, known as TBAF and pronounced ‘tea-baff’), which is soluble in organic solvents. In fact, TBDMS is one member of a whole family of trialkylsilyl protecting groups and their relative stability to nucleophiles of various kinds is determined by the three alkyl groups carried by silicon. The most labile, trimethylsilyl (TMS), is removed simply on treatment with methanol, while the most stable require hydrofluoric acid.

Why can’t we just use a simple alkyl ether (methyl, say) to protect a hydroxyl group? There is no problem making the ether, and it will survive most reactions—but there is a problem getting an ether off again. This is always a consideration in protecting group chemistry— you want a group that is stable to the conditions of whatever reaction you are going to do (in these examples, strong bases and nucleophiles), but can then be removed under mild conditions that do not result in decomposition of a sensitive molecule. What we need then is an ether that has an Achilles’ heel—a feature that makes it susceptible to attack by some specifi c reagent or under specifi c conditions. One such group is the tetra hydropyranyl (THP) group. Although it is stable under basic conditions, as an ether would be, it is an acetal—the presence of the second oxygen atom is its Achilles’ heel and makes the THP protecting group susceptible to hydrolysis under acidic conditions. You could see the lone pair on the second oxygen atom as a safety catch that is released only in the presence of acid.

Making the THP acetal has to be done in an unfamiliar way because the usual ‘carbonyl plus two alcohols’ method is inappropriate (work out why!). Alcohols are protected by treating them with an enol ether, dihydropyran, under acid catalysis. Notice the oxonium just as in a normal acetal-forming reaction. In this example the THP group is at work preventing a hydroxyl group from interfering in the reduction of an ester.

The THP-protected compound above was used as an intermediate in a synthesis of the insecticide milbemycin. It needed to be converted to the alkyne in the margin—to do this the other hydroxyl group also needed protecting. This time, however, TBDMS will not do because the protecting group needs to withstand the acidic conditions needed to remove the THP protecting group! What is more, the protect ing group needs to be able to survive acid conditions in later steps of the synthesis of the insecticide. The answer is to use a third type of hydroxyl-protecting group, a benzyl ether. Benzyl (Bn) protecting groups are put on using strong base (usually sodium hydride) plus benzyl bromide, and are stable to both acid and base.

The benzyl ether’s Achilles’ heel is the aromatic ring and, after reading the fi rst half of this chapter, you should be able to suggest conditions that will take it off again: hydrogenation (hydrogenolysis) over a palladium catalyst, which cleaves benzylic C–O bonds.

Benzyl ethers can alternatively sometimes be removed by acid, if the acid has a nucleophilic conjugate base. HBr, for example, will remove a benzyl ether because Br⁻ is a good enough nucleophile to displace ROH, although only at the reactive, benzylic centre.

We said earlier that simple methyl ethers are inappropriate as protecting groups for OH because they are too hard to take off again. That is usually true, but not if the OH is phenolic— ArOH is a better leaving group than ROH, so HBr will take off methyl groups from aryl methyl ethers too.

Protecting groups may be useful, but they are also wasteful—both of time, because there are two extra steps to do (putting the group on and taking it off), and of material, because these steps may not go in 100% yield. Here’s one way to avoid using them. During the development of the anti-asthma drug salbutamol, the triol below was needed. With large quantities of salbutamol already available, it seemed most straightforward to make the triol by adding phenylmagnesium bromide to an ester available from salbutamol. Unfortunately, the ester also contains three acidic protons, making it look as though the hydroxyl and amine groups all need protecting. But, in fact, it was possible to do the reaction just by add ing a large excess of Grignard reagent: enough to remove the acidic protons and to add to the ester.

This strategy is easy to try, and, providing the Grignard reagent isn’t valuable (you can buy PhMgBr in bottles), is much more economical than putting on protecting groups and taking them off again. But it doesn’t always work—there is no way of telling whether it will until you try the reaction in the laboratory. In this closely related reaction, for example, the same chemists found that they needed to protect both the phenolic hydroxyl group (but not the other alcohol OH) as a benzyl ether and the amine NH as a benzyl amine. Both protecting groups come off in one hydrogenation step.

Benzyl groups are one way of protecting secondary amines against strong bases that might deprotonate them. But it is the nucleophilicity of amines that usually poses problems of chemoselectivity, rather than the acidity of their NH groups. The potential for pitfalls is nowhere more acute than in the synthesis of one of the most important classes of biological molecules: peptides.

مواضيع ذات صلة

The Boc protecting group—gastrin and aspartame

The Cbz protecting group—oxytocin

Peptide synthesis

How to react the less reactive group (II): protecting groups

Chemoselectivity in the reactions of dianions

How to react the less reactive group (I): react both then ‘unreact’ one

Competing reactivity: choosing which group reacts

How to oxidize primary alcohols to aldehydes

How to oxidize secondary alcohols to ketones

Birch reduction of arenes

Dissolving metal reductions

Getting rid of functional groups