Dihydropyran, acid catalyzed

As chemists proceeded to synthesize more complicated stmctures, they developed more satisfactory protective groups and more effective methods for the formation and cleavage of protected compounds. At first a tetrahydropyranyl acetal was prepared, by an acid-catalyzed reaction with dihydropyran, to protect a hydroxyl group. The acetal is readily cleaved by mild acid hydrolysis, but formation of this acetal introduces a new stereogenic center. Formation of the 4-methoxytetrahy-dropyranyl ketal eliminates this problem. 

The first total synthesis of the marine dolabellane diterpene (+)-4,5-deoxy-neodolabelline (70) was accomplished by D. R. Williams et al. [58]. The trans-disubstituted dihydropyran moiety in key intermediate 69 was efficiently prepared from mixed acetal 66 by RCM with second-generation catalyst C and subsequent Lewis acid-catalyzed allylation of ethyl glycosides 67 with allylsi-lane 68 (Scheme 12) [59]. 

Lewis-acid catalyzed inverse electron-demand Diels-Alder reactions between conjugated carbonyl compounds and simple alkenes and enolethers also allow dihydropyranes to be prepared. SnCU-Catalyzed cycloaddition of... 

An additional example of an oxonium ion generated via the acid catalyzed rearrangement has been used to prepare a dihydropyran <06TL6149>. The oxonium ion 54 generated by the reaction of an epoxide with ZrCl4 can be trapped by a nucleophile such as butynol to prepare dihydropyran 55. A variety of mono- and disubstituted epoxides have been used in this reaction. 

A number of efforts have been devoted to the simplified, acid catalyzed reaction between dihydropyran and alcohols to form THP-ethers. Thus, employing the hydrochloride salt of Reillex 425 (34) [a cross-linked macroreticular poly(4-vinylpyri-dine) resin] the tetrahydropyranylation even of hindered alcohols proceeds under mild conditions in high yields without side-reactions (Scheme 4.20) [107]. 

This protective group is introduced by an acid-catalyzed addition of the alcohol to the vinyl ether moiety in dihydropyran. />-Toluenesulfonic acid or its pyridinium salt is used most frequently as the catalyst,3 although other catalysts are advantageous in special cases. 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 8.1). 

The acid-catalyzed cyclization of the diol (209), available from penta-1,3-diene and bromomesityl oxide via the hydroxyketone, gives a mixture of the fused dihydropyrans (210) and (211), edulan I and II, respectively (Scheme 40) <75JCS(P1)1736). The former compound predominates when an ion exchange resin is used as the catalyst, but the latter... 

The dianion derived from but-2-ynoic acid reacts with aldehydes to give 5-hydroxyalk-2-ynoates (539). Partial reduction over a Lindlar catalyst and acid-catalyzed cyclization of the resulting enoate gives the dihydropyran-2-one (78LA337). The route is exemplified by the synthesis of the naturally occurring massoia lactone (Scheme 200). In previous work (46JCS954) the hydroxyalkynoic acids themselves, obtained from epoxides and acetylene, were used. 

Usually, 3- and 4-substituted thianes are prepared from the 3- and 4-oxothians by the common techniques applicable to alicyclic chemistry. Reduction affords alcohols which may be etherified or halogenated, while oximation and reduction produces the amino derivatives, which are also accessible via the halo compounds. 2-Alkoxy and 2-alkylthio compounds are made by acid catalyzed addition of alcohols and thiols to 3,4-dihydro-2H-thiopyran (75MI22502) in a reaction analogous to the use of dihydropyran for protection of alcohols as THP ethers. 

Some heterocycles can be linked to supports as tetrahydropyranyl derivatives. Attachment of indoles, purines, or tetrazoles (Table 3.29) has been achieved by treatment of a support-bound dihydropyran with the heterocycle in the presence of catalytic amounts of pyridinium tosylate [487], camphorsulfonic acid [539], or TFA [540] in DCE at 60-80 °C for 16-24 h. Indole-derived orthoesters, such as that in Entry 7 (Table 3.29), can be prepared by heating the indole with triethyl orthoformate (160 °C, 24 h) followed by acid-catalyzed reaction of the resulting orthoester with a resin-bound diol [541,542], As illustrated by Entry 8 (Table 3.29), indoles can also be linked to the Wang resin or related supports as carbamates. Cleavage by TFA is, how-... 

Treatment of cycloprop [c]pyrans 520 with acid leads to chromans 521 with a 5,8-substitution pattern, which is difficult to obtain by other synthetic methods (Scheme 114). This novel reaction is believed to proceed via a retro-hDA opening of the dihydropyran ring to afford 522 followed by an acid-catalyzed aldol-type cyclization and dehydration (Scheme 114) <20040L3191>. 

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.)... 

Saccharin 1 adds on to activated double bonds. In a base-catalyzed reaction with methyl vinyl ketone, N-(3-ketobutyl)saccharin150 is formed. Acid catalyzed addition of 1 to 2,3-dihydropyran occurs as expected, again at the nitrogen,151,152... 

The formation of cyclic acetals by the acid-catalyzed addition of hydroxy compounds (both aromatic and aliphatic) to dihydropyran takes place in excellent yields. The simple procedure consists in allowing the two compounds to stand in the presence of a trace of concentrated hydrochloric acid for several hours, followed by neutralization and distillation. The method is valuable for protecting the hydroxyl group in reactions that are conducted in basic media. ... 

In a clever piece of work, Snider et al. have used a quasi intramolecular carbonyl Diels-Alder cycloaddition to produce a key intermediate for syntheses of pseudomonic acid A (175) (Scheme 20). Thus a Lewis acid catalyzed ene reaction of alkene (170) and formaldehyde afforded (171), which com-plexed with additional formaldehyde to give (172). Intramolecular [4 + 2] cycloaddition of (172) gave adduct (173) which produced dihydropyran (174) upon hydrolysis. 

Before all these acetal-based protecting groups were introduced, the tetrahydropyranyl (THP) ether had found extensive use in organic synthesis. It can easily be synthesized from a variety of hydroxy-containing compounds like carbohydrates, amino acids, steroids and nucleotides by the acid-catalyzed reaction with dihydropyran. It is stable to bases, but the protection is removed through acidic hydrolysis with hydrochloric acid, toluenesulfonic acid or acidic ion-exchange resin (Scheme 27). In the case of acid sensitive substrates, e.g. containing an epoxide or a further acetal, pyridinium p-toluenesulfonate should be applied for particularly mild deprotection conditions. ... 

A variant of the THP linker, in which the TH P unit is attached via an ester function to fhe sohd support, has been applied to the synfhesis of biphenyl tetrazole derivatives 47, as outlined in Scheme 23 [51]. Bromophenyl tetrazole was attached to polymer-bound dihydropyran to yield 46. This step was followed by Suzuki coupling and acid-catalyzed release from the support to yield fhe desired compounds 47. 

In contrast to dihydropyran rearrangements, the rearrangement of 1,4-dioxins is believed to proceed via a chairlike transition state with the substituents in axial positions. Dihydro-1,4-dioxins 10 and 11, obtained by acid-catalyzed double-bond isomerization of 9. on heating in a sealed tube, undergo a sigmatropic shift to give dihydropyrans 12 and 13322 323. 

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