Tetrahydropyranylations

X = Cl, 0-tetrahydropyranyl, 0-CH(CH3)OCjH5 The starting compounds can be easily synthesized by standard procedures in acetylene chemistry. 

Six protective groups for alcohols, which may be removed successively and selectively, have been listed by E.J. Corey (1972B). A hypothetical hexahydroxy compound with hydroxy groups 1 to 6 protected as (1) acetate, (2) 2,2,2-trichloroethyl carbonate, (3) benzyl ether, (4) dimethyl-t-butylsilyl ether, (5) 2-tetrahydropyranyl ether, and (6) methyl ether may be unmasked in that order by the reagents (1) KjCO, or NH, in CHjOH, (2) Zn in CHjOH or AcOH, (3) over Pd, (4) F", (5) wet acetic acid, and (6) BBrj. The groups may also be exposed to the same reagents in the order A 5, 2, 1, 3, 6. The (4-methoxyphenyl)methyl group (=MPM = p-methoxybenzyl, PMB) can be oxidized to a benzaldehyde derivative and thereby be removed at room temperature under neutral conditions (Y- Oikawa, 1982 R. Johansson, 1984 T. Fukuyama, 1985). 

The polymerization of A/-(2-tetrahydropyranyl)aziridine with subsequent hydrolysis of the resulting polymers has been described as an alternative route for the synthesis of linear polyethyleneimine (359). Linear polyethyleneimine, in contrast to branched polyethyleneimines, is only sparingly soluble in water at room temperature. 

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. 

SEM ethers are stable to the acidic conditions (AcOH, H2O, THE, 45°, 7 h) that are used to cleave tetrahydropyranyl and t-butyldimethylsilyl ethers. 

The cleavage proceeds by initial reduction of the nitro groups followed by acid-catalyzed cleavage. The DNB group can be cleaved in the presence of allyl, benzyl, tetrahydropyranyl, methoxy ethoxy methyl, methoxymethyl, silyl, trityl, and ketal protective groups. 

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). ... 

The cyclohexylidene ketal, prepared from a catechol and cyclohexanone (AI2O3/ TsOH, CH2CI2, reflux, 36 h), is stable to metalation conditions (RX/BuLi) that cleave aiyl methyl ethers. The ketal is cleaved by acidic hydrolysis (coned. HCl/ EtOH, reflux, 1.5 h, 20°, 12 h) it is stable to milder acidic hydrolysis that cleaves tetrahydropyranyl ethers (1 AHCl/EtOH, reflux, 5 h, 91% yield). ... 

The tetrahydropyranyl cyanohydrin was prepared from a steroid cyanohydrin (di-hydropyran, TsOH, reflux, 1.5 h) and cleaved by hydrolysis (cat, coned. HCl, acetone, reflux, 15 min, followed by aq. pyridine, reflux, 1 h)."... 

The /-propyldimethylsilyl ester is prepared from a carboxylic acid and the silyl chloride (Et3N, 0°). It is cleaved at pH 4.5 by conditions that do not cleave a tetrahydropyranyl ether (HOAc-NaOAc, acetone-H20, 0°, 45 min - 25°, 30 min, 91% yield). ... 

An S-2-tetrahydropyranyl monothioacetal is oxidized to a disulfide by iodine or thiocyanogen, (SCN)2- ... 

In the latter case, one end of the glycol is protected as its tetrahydropyranyl ether. Upon hydrolysis, a two-armed crown is revealed which may then be treated with the bis-crown precursor identified above. The result will be a tris-crown system and the approach is illustrated below in Eq. (3.35). 

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