THP removal

Scheme 4.307],528 If water is an objectionable component or low solubility a problem, THP removal can be accomplished by an acetal exchange process using methanol or ethanol as solvent Scheme 4.308 illustrates the deprotection of an acid-sensitive allylic alcohol using camphor sulfonic add in methanol.448 Pyridi-nium p-toluenesulfonate in methanol or ethanol (pH 3.0) can also be used, but higher temperatures (45-55 C) are required [Scheme 4.309].558 559 Ion exchange resins in methanol cleave THP ethers at room temperature.5601561 Other THP deprotection conditions to beware or exploit are CAN in the presence of pH 8 buffer,562 DDQ in aqueous acetonitrile,563 and Montmorilonite clay in methanol.564... 

TsOH, MeOH, 25°C, 1 h, 94% yield. The use of 2-propanol as solvent was found to enhance the selectivity for THP removal in the presence of a 1,3-TBDPS group. TBDPS ethers are not affected by these conditions. ... 

Benzyl, allyl, methyl, THP, TBDMS, and TBDPS ethers are all stable to these conditions. A primary MEM group could be selectively removed in the presence of a hindered secondary MEM group. 

The introduction of a THP ether onto a chiral molecule results in the formation of diastereomers because of the additional stereogenic center present in the tetrahy-dropyran ring (which can make the interpretation of NMR spectra somewhat troublesome at times). Even so, this is one of the most widely used protective groups employed in chemical synthesis because of its low cost, the ease of its installation, its general stability to most nonacidic reagents, and the ease with which it can be removed. 

The pixyl ether is prepared from the xanthenyl chloride in 68-87% yield. This group has been used extensively in the protection of the 5 -OH of nucleosides it is readily cleaved by acidic hydrolysis (80% AcOH, 20°, 8-15 min, 100% yield, or 3% trichloroacetic acid). It can be cleaved under neutral conditions with ZnBrj, thus reducing the extent of the often troublesome depurination of A -6-benzyloxy-adenine residues during deprotection. Conditions which remove the pixyl group also partially cleave the THP group (t,/2 for THP at 2 -OH of ribonucleoside = 560 s in 3% Cl2CHC02H/CH2Cl2). ... 

The tetrahydropyranyl ether, prepared from a phenol and dihydropyran (HCl/EtOAc, 25°, 24 h) is cleaved by aqueous oxalic acid (MeOH, 50-90°, 1-2 h). Tonsil, Mexican Bentonite earth, HSZ Zeolite, and H3[PW,204o] have also been used for the tetrahydropyranylation of phenols. The use of [Ru(ACN)3(triphos)](OTf)2 in acetone selectively removes the THP group from a phenol in the presence of an alkyl THP group. Ketals of acetophenones are also cleaved. ... 

The chemoselectivity of converting one OH in (16) into a leaving group will be easier if the other OH Is protected, so it is best to Introduce protection at the start. The easily removed THP group is ideal (Table T 9,1 ). The required Grlgnard reagent is from available halide (17) (p T 1). 

The THP group can be removed by dilute aqueous acid. The chemistry involved in both the introduction and deprotection stages is the reversible acid-catalyzed formation and hydrolysis of an acetal (see Part A, Section 7.1). 

The MTM group is selectively removed under nonacidic conditions in aqueous solutions containing Ag+ or Hg2+ salts. The THP and MOM groups are stable under these conditions.161 The MTM group can also be removed by reaction with methyl iodide, followed by hydrolysis of the resulting sulfonium salt in moist acetone.162... 

Merrifield resin (1 % crosslinked) was employed as the solid support. The problem of oligomerization was prevented by protection of the hydroxyl of 38 as a THP ether by treatment with 3,4-dihydro-2H-pyran (DHP) in the presence of pyridinium /7-toluenesulfonate (PPTS) to give 46. Immobilized 46 was successfully coupled with 24 to give disaccharide 47. The THP group of 47 was easily removed by treatment with acetic acid/water to yield 45. 

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