THP Protecting Group (Tetrahydropyranyl Ether)

What is the THP Protecting Group?

Tetrahydropyranyl ethers were one of the first protecting groups for alcohols. Nowadays, they are seen less commonly, though still used. The THP group is easily removed under acidic conditions (mechanism below) and stable to organometallic nucleophiles, electrophiles (as the protected oxygen is less nucleophilic), reduction or base. The protected THP ethers are actually a type of acetal (‘double-ether’).

THP Protection Mechanism

THP protection uses acid catalysis and 3,4-dihydro-2H-pyran. The mechanism proceeds by THP pre-activation with acid, leading to a stabilized cation. Here, the oxonium is drawn but you can imagine the other resonance form with the positive charge on the carbon which is ultimately where the ion is most electrophilic.
Our free hydroxyl group then attacks the carbon in a nucleophilic addition, and loses a proton to give the protected THP ether. The last step regenerates our acid catalyst.

The most common protection conditions are catalytic TsOH or pyridinium p-toluenesulfonate (PPTS, a form of TsOH with lower acidity) together with 3,4-dihydro-2H-pyran in dichloromethane.

THP Deprotection Mechanism

THP deprotection proceeds really similarly to THP protection – acid catalysis activates the acetal system towards dissociation of our initially protonated alcohol. Again, it’s the same stabilized cation intermediate but based on the choice of solvent used, we have different potential byproducts. The solvent is obviously present in large excess, so it will preferentially attack the carbocation instead of our just liberated hydroxyl group. For example, methanol gives the methyl-substituted THP ether while use of water would give the free hydroxyl group (this can open to the linear aldehyde).

The most common deprotection conditions are AcOH:THF:H₂O or PPTS in EtOH.

THP PRotecting grouP Diastereomers

One of the drawbacks of the THP protecting group versus the TBS protecting group, beyond its lower stability, is that it introduces a second chiral center.
If our starting material has already at least one chiral carbon, we form diastereomers. This can complicate the separation and identification (e.g., NMR) of products – because as you know, diastereomers have different physicochemical properties.

Interestingly, some older research [1] tried to make use of this ‘drawback’. In this work, the chemists used a THP-derivative as a chiral auxiliary for nucleophilic additions to an aldehyde in the molecule.

In these derivatives, one side of the aldehyde is shielded from nucleophilic attack while the other is exposed. This leads to very high diastereoselectivity at the newly formed carbon (a tertiary alcohol). It’s not terrible useful but interesting that a protecting group can be used to exert diastereoselectivity. You could imagine this potentially being useful in some complicated total syntheses.

Thanks for reading, and check out the other protecting group articles!

THP Protecting Group References

• P. G. M. Wuts, T. W. Greene: Greene’s Protective in Organic Synthesis (Wiley)
• [1] The tetrahydropyranyl group as a chiral auxiliary for the nucleophilic addition to α-alkoxy ketones | André B. Charette , Abdel F. Benslimane , Christophe Mellon | Tetrahedron Letters 1995, 36, 8557