THP ether, formation

Scheme 4.20 Protonated polyvinyl pyridine — a mild solid acid for THP-ether formation.

Details of the Janda-Chen synthesis were as follows. A tetrahydropyran (THP) linker was attached to the NCPS support enabling attachment of alcohols via THP ether formation.13 The THP-NCPS resin 1 is derivatized with / -(+)-4-hydroxy-2-cyclopentanone 2, giving the THP ether-based resin 3, followed by coupling of the C13 20 fragment by enone-cuprate addition. The cuprate required was generated from the corresponding E-vinyl stannane 4. The resulting enolate was trapped as the silyl end ether... 

Procedures for THP-ether formation. Use of hydrochloric acid. Concentrated hydrochloric acid (0.3 ml) was added to a mixture of 2,3-dihydropyran (0.75 mol) and the alcohol (0.5 mol). Reaction commenced immediately on shaking and was moderated by cooling in an ice-water bath. The mixture was shaken for a further 30 minutes, allowed to stand overnight, diluted with ether (150 ml), and the solution washed twice with aqueous sodium hydrogen carbonate solution. The ethereal solution was dried and evaporated, and the residue distilled under reduced pressure. 

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. 

Ph2CHC02-2-tetrahydrofuranyl, 1% TsOH, CCI4, 20°, 30 min, 90-99% yield. The authors report that formation of the THF ether by reaction with 2-chlorotetrahydrofuran avoids a laborious proce ure that is required when dihydrofuran is used. In addition, the use of dihydrofuran to protect the 2 -OH of a nucleotide gives low yields (24-42%)." The tetrahydrofuranyl ester is reported to be a readily available, stable solid. A tetrahydrofuranyl ether can be cleaved in the presence of a THP ether. ... 

In 1975, van der Baan and Bickelhaupt reported the synthesis of imide 37 from pyridone 34 as an approach to the hetisine alkaloids, using an intramolecular alkylation as the key step (Scheme 1.3) [23]. Beginning with pyridone 34, alkylation with sodium hydride/allyl bromide followed by a thermal [3,3] Claisen rearrangement gave alkene 35. Next, formation of the bromohydrin with A -bi omosuccinimide and subsequent protection of the resulting alcohol as the tetrahydropyranyl (THP) ether produced bromide 36, which was then cyclized in an intramolecular fashion to give tricylic 37. 

The formation of unsymmetrical ethers from the reduction of aldehydes in the presence of tetrahydropyran (THP) ethers is reported (Eq. 182).340... 

Some interesting modifications with respect to the base-induced isomerization have recently been developed. For example, conversion of 4-hydroxy-l-thiophenyl-2-alkynes 299 into the corresponding 4-hydroxy-substituted thiophenylallenes 300 was achieved by treatment with potassium hexamethyldisilazide at low temperature (Scheme 8.79) [165], If the hydroxyl group is protected as the THP ether an elimination reaction occurred, resulting in the formation of an enyne instead of allene 300. 

In an alternate approach sulfuric acid adsorbed on silica (3% H2SO4 on Merck Kieselgel 60, 70-230 mesh) was employed to promote the formation of THP-ethers [108]. 

Problem 14.26 Since thp ethers are, like most ethers, stable in base, their formation can be used to protect the OH group from reacting under basic conditions. Using this fact, show how to convert HOCHjCHjCl to HOCHjCHjD via the Grignard reagent. ... 

The catalytic performance of Nafion SAC-13 in the formation of 1,1-diacetates,677 in turn, is very similar to that of HBF4-silica. In the acetalization of carbonyl compounds with ethane-1,2-diol and propane-1,3-diol, products are isolated in good to excellent yields. The formation of THP ethers of alcohols is fast and protected alcohols are isolated in high yields [Eq. (5.238)]. Nafion SAC-13 can also be used in the removal of the THP ether group677 although the transformation requires somewhat longer reaction times (30 min-6 h, 81-97% yield). Furthermore, the catalyst could be recycled in all three processes with practically no loss of activity. 

However, formation of THP ether introduces a new stereogenic centre. The introduction of the THP ether onto a chiral molecule therefore results in the formation of diastereoisomers. 

The cleavage of THP-ethers is performed under mild acidic conditions. Typically, HOAC-H2O (4 1) at 45 °C is used. If water is not suitable or the solubility of the substrate is too low, an acetal exchange process using methanol or ethanol as solvent, with catalytic amounts of acid (often p-toluenesulfonic acid, or its pyridinium salt), can be performed. For the formation of Z-13 this kind of acetal exchange process was chosen. 

Problem 3.7. Dihydropyran (DHP) reacts with alcohols under acid catalysis to give tetrahydropyranyl (THP) ethers. The alcohols can be released again by treating the THP ether with MeOH and catalytic acid. Thus, the THP group acts as a protecting group for alcohols. Draw mechanisms for the formation and cleavage of the THP ether. 

Tetrahydrofuranyl (THF) ethers are reported to be useful alternatives to tetrahydropyranyl (THP) ethers for the protection of alcohols (and thiols). THF ethers are easily formed, and are more sensitive to acidic hydrolysis than are THP ethers. We are warned that hydroboration-oxidation or peracid oxidation of simple unsaturated compounds containing a hydroxy-group protected as its THP ether has led to violent detonations. The danger comes from the ready formation of peroxides from THP ethers, and presumably also from THF ethers these peroxides, though very sensitive, are not easily removed by ordinary chemical methods. 

Construction of the acyclic segment 395 was initiated by conversion of (-)-citronellal (392) into bromo aldehyde 393. Formation of the unsaturated aldehyde via the intermediate enamine was followed by reduction to the allylic alcohol 394. Elimination of the vinyl bromide in 394 to the acetylene was followed by the addition of trimethylaluminum to give the terminal vinyl alane. The intermediate alane was then quenched with iodine to furnish the corresponding iodo-vinyl alcohol, which was protected as the THP ether to afford 395. 

THP ethers can be converted directly to an acetate or formate by reaction with ethyl acetate, acetic acid, or ethyl formate and with K5CoW 2O40-3H2O as the catalyst (20-98% yield). The transformation is most successful with primary THP ethers. ... 

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