Dihydropyran, protecting alcohols with

Treatment of the monochloro diethylene glycol 9 with dihydropyran yields the protected alcohol 10. Reaction of 2,2, 2"-triaminotriethylamine (tren) 11 with toluenesulfonyl chloride gives the tritoluenesulfonyl derivative 12. The pyranyl ether 10 may be condensed with the tris(sodium) salt of 12 leading to 13. Removal of the tetrahydropyranyl group is achieved in high yield under... 

Treatment of an alcohol with dihydropyran yields an acetal called a tetrahyd pyranyl ether, a reaction that can be used as a method of protecting alcohols S tion 17.9). Show the mechanism of the reaction. 

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. 

We protect one hydroxyl terminus of the commercially available 1,8-octane diol 1 by reaction with dihydropyran to give the monoalcohol, 8-tetrahydropyranyloxyoctanol 2. The protected alcohol 2 is oxidized to the aldehyde with pyridinium chlorochromate to give 8-tetrahydropyranyl-oxyoctanal 3. 1-Heptyne 4 is coupled with propargyl bromide 5 in a copper catalyzed reaction to produce the diacetylenic 1,4-decadiyne 6. 

We just saw in Section 16.7C that an aldehyde or a ketone can be protected by conversion to an acetal. A similar strategy can be used to protect a primary or secondary alcohol. Treatment of the alcohol with dihydropyran in the presence of an acid catalyst, commonly anhydrous HCl or a sulfonic acid, RSO3H, converts the alcohol into a tetrahydropyranyl (THP) ether. 

Torii S, Inokuchi T, Kondo K, Ito H (1985) Electrogenerated acid as an efficient catalyst for the protection and deprotection of alcohols with dihydropyran and transesterification of glyceride. Bull Chem Soc Jpn 58 1347-1348. doi 10.1246/ bcsj.58.1347... 

Aldehyde 123 was then reacted in a stereoselective Homer-Wadsworth-Emmons reaction with the sodium salt of phosphonate 124 to produce enone 125 (Scheme 3.31). Chemo- and stereoselective rednction of enone 125 with zinc borohydride provided secondary alcohol 126 as a 1 1 mixture of C-15 epimers, which could be separated by chromatography. Next, solvolysis of the acetate in 126 with basic methanol was followed by protection of the two alcohols with dihydropyran in the presence of a catalytic amount of para-toluenesulfonic acid. Reduction with DIBAL-H then provided lactol 127. Wittig reaction of 127 with the nonsta-bilized ylide 128 and snbsequent deprotection produced ( )-prostaglandin F (113). 

Tetrahydropyranylation of Alcohols. Protection of alcohol functionality as the THP ether is an often-utilized tool in organic synthesis. It must be noted that the reaction of a chiral alcohol with dihydropyran introduces an additional asymmetric center and hence a diastereomeric mixture is obtained (eq 1). This can lead to difficulties with purification, assignment of spectral features, etc., but does not prevent successful implementation. ... 

Protocols have been developed which utilize an insoluble solid catalyst in combination with dihydropyran to effect the protection of alcohols as their corresponding THP ethers. These procedures are advantageous in that the catalyst may be recovered by simple filtration and the products isolated by evaporation of volatiles. In many cases the catalyst can be reused without regeneration. Reaction of alcohols with dihydropyran in the presence of Amberlyst H-15 (25 °C, 1 h, 90-98%) yields THP derivatives. Alternatively, a solution of dihydropyran and the alcohol may be passed slowly through a column of silica overlaid with Amberlyst H-15 to yield the THP ethers directly (73-97%). The acidic clay Montmorillonite KIO (25 °C, 15-30 min, 63-95%) is similarly applicable, Reillex 425 resin (86 °C, 1,5 h, 84-98%) is applicable with the advantage that it does not promote the sometimes troublesome polymerization of dihydropyran. Polymeric derivatives of pyridinium p-toluenesulfonate are also effective. Poly(4-vinylpyridinium p-toluenesulfonate) and poly(2-vinylpyridinium p-toluenesulfonate) catalysts yield tetrahydropyranyl derivatives of primary, secondary, and tertiary alcohols (24 °C, 3-8 h, 72-95%). ... 

More recently, the synthesis of a novel dihydropyran with a UV-handle has also been reported as a protecting group for supported alcohols [155]. 

Acetalation with Enol Ethers Under Kinetically Controlled Conditions. The first mention of the use of an enol ether to protect the hydroxyl group of an alcohol was developed by Paul [46], who introduced the reaction with dihydropyran to give tetrahydro-pyranyl ethers, which is still used 60 years later. In spite of some noticeable developments, such as the preparation of 2 3 -0-aIkylidene derivatives of nucleosides [33] the synthesis of 4,6-O-ethylidene-a-D-glucopyranoside with use of methylvinylether [47] the intra-... 

The alkenic bond in dihydrothiopyrans in one case is a thioenol system in the other it is effectively an isolated double bond. The thioenol readily adds alcohols or thiols (c/. dihydropyran) it has been suggested as a protecting group for alcohols, and is readily removable with Ag+ under neutral conditions (66JOC2333). If conjugated with a carbonyl function, thiols will add under basic conditions (equation 34) (81JA4597). 

Under acidic conditions, dihydropyran will undergo additions with alcohols at room temperature to form 2-tetrahydropyranyl ethers (equation 247).398 This reaction constitutes an important method for the protection of primary and secondary alcohols.400... 

An intramolecular Heck-carbonylation/cyclization of the vinyl iodide 881 provides the 5,6-dihydropyran-2-one 882 during a total synthesis of manoalide (Equation 354) <1997CC1139>. The reaction of but-3-yn-l-ol with diaryl sulfides and carbon monoxide in the presence of a palladium(O) catalyst leads to a novel thiolactonization and hence arylthiosubstituted 5,6-dihydropyran-2-one 883 (Equation 355). Similar results are obtained with diaryl diselenides (Equation 355) <1997JOC8361>. Hydrozirconation of O-protected homopropargylic alcohols followed by carbonyla-tion and quenching with iodine provides a simple route to 5,6-dihydropyran-2-ones <1998TA949>. 

One method that has found widespread use for the protection of an alcohol is reaction with dihydropyran to form a tetrahydropyranyl ether. Once the desired reaction has been accomplished, the protecting group can be removed by treatment with aqueous acid or acid and ethanol. The formation of a tetrahydropyranyl ether and its cleavage are illustrated in the following equation ... 

The mechanism of the formation of the tetrahydropyranyl ether (see Figure 23.1) is an acid-catalyzed addition of the alcohol to the double bond of the dihydropyran and is quite similar to the acid-catalyzed hydration of an alkene described in Section 11.3. Dihydropyran is especially reactive toward such an addition because the oxygen helps stabilize the carbocation that is initially produced in the reaction. The tetrahydropyranyl ether is inert toward bases and nucleophiles and serves to protect the alcohol from reagents with these properties. Although normal ethers are difficult to cleave, a tetrahydropyranyl ether is actually an acetal, and as such, it is readily cleaved under acidic conditions. (The mechanism for this cleavage is the reverse of that for acetal formation, shown in Figure 18.5 on page 776.)... 

A similar reaction occurs when enol ethers react with alcohols in acid solution and in the absence of water, but now we are starting in the middle of the acetal hydrolysis mechanism and going the other way, in the direction of the acetal A useful example is the formation of THP (= TetraHydroPyranyl) derivatives of alcohols from the enol ether dihydropyran. You will see THP derivatives of alcohols being used as protecting groups in Chapter 24. 

Acid Catalyst. Camphorsulfonic acid (CS A) has been used extensively in synthetic organic chemistry as an acid catalyst. It has particularly been used in protecting group chemistry. For example, hydroxyl groups can be protected as tetrahydropyranyl (THP) ethers using dihydropyran and a catalytic amount of CSA (eq 1). Both 1,2- and 1,3-diols can be selectively protected by reaction with orthoesters in the presence of camphorsulfonic acid to form the corresponding cyclic orthoester (eq 2) This method of protection is particularly useful in that reduction of the orthoester with Diisobutylaluminum Hydride forms the monoacetal, which allows for preferential protection of a secondary alcohol in the presence of a primary alcohol. Ketones have also been protected using catalytic CSA (eq 3). ... 

The THP group is a widely used protecting group it is readily introduced by reaction of the enol ether dihydropyran with an alcohol in the presence of an acid catalyst, such as TsOH, BF3 OEt2, or POCI3. For sensitive alcohols such as allylic alcohols, PPTS (pyridinium p-toluenesulfonate) is used as a catalyst for tetrahydropy-ranylation. As an acetal, the THP group is readily hydrolyzed under aqueous acidic conditions with AcOH-THF, TsOH, PPTS-EtOH, or Dowex-H (cation exchange resin). 

Ethyl 5-oxohexanoate (51) was reduced with NaBH4 and the resulting alcohol protected with dihydropyran to give 52. Reduction of the ester moiety to a primary alcohol followed by conversion to the bromide 53 was achieved by conventional means. Alkylation of the dianion of ethyl acetoacetate with 53 afforded a 78% yield the p-keto ester 54, which possesses all the carbons required for the construction of the diplodialides. Protection of the ketone as the dithiane... 

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