Tetrahydropyranyl structures

Figure 2.15 Tetrahydropyranyl structures used in the investigation of the anomeric effect by X-ray crystallography.

As chemists proceeded to synthesize more complicated structures, 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-methoxytetrahydropyranyl ketaP eliminates this problem. 

The theory was tested in simple tetrahydropyranyl acetal systems, which exist in the axial conformation [92], but can be constrained to adopt the equatorial conformation [93] by building in appropriate structural features. It was found, for example, that the equatorial isomers of the oxadecalin acetals [94] are actually more reactive than the axial compounds [95], although only the latter have a lone pair on the donor ring oxygen antiperiplanar to the C-OAr bond (Kirby, 1984, 1987). This and other similar observations do not disprove the theory of stereoelectronic control because any stereoelectronic barrier can be got round if there is sufficient conformational flexibility. In other words, these are Curtin-Hammett systems, with free energy barriers between conformations much smaller than... 

An immediate interest was to compare the series of structures of axial tetrahydropyranyl acetals [96] with a corresponding series of equatorial compounds [93]. The expectation was that the absence of an antiperiplanar... 

The relationship, between magnitudes of these sensitivity parameters and the reactivity of the system concerned, was explored quantitatively for three sets of acetal structures, and a further linear relationship was found (Kirby and Jones, 1986). Figure 25 shows a plot of the sensitivity parameter against relative reactivity for series of compounds, tetrahydropyranyl-, methoxymethyl- and a-glucosyl-OX, known to react with C-OX cleavage at very different rates (relative rates of hydrolysis approximately 1, 103 5 and 106 5, respectively). The correlation is good for both the intercepts (i.e. the... 

Figure 13.4 Torsional potential energy surfaces about the two C-O bonds linking the anomeric centers of sucrose at the MM3 level (a), 2-tetrahydrofuranyl-2-tetrahydropyranyl ether at the MM3 level (b), the same ether at the HF/6-31G(d) level (c), and the sum of the difference between the last two with the first (d). Thus, the last surface may be viewed either as the effect of the sucrose hydroxyl groups on the energy surface, evaluated at the MM3 level, added to the framework surface calculated at the ab initio level, or as an MM3 surface that has been partially conected quantum mechanically. Solid triangles represent anomeric torsions in sucrose units found in various X-ray crystal structures. Note that the hybrid surface is the only one that clusters the large majority of these triangles within low-energy contours...

Scheme 2.7 Schematic chemical structures of Poly(cylohexyl methacrylate) (PCHMA), Poly(4-tetrahydropyranyl methacrylate) (P4THPMA) and poly(l,3-dioxan-5-yl-methacrylate) (PDMA). (From ref. [38])...

The structure of baloxine (236) has been confirmed by partial synthesis from vindolinine,110 which has previously been converted into 19-hydroxytabersonine (237). The tetrahydropyranyl ether (238) of the (19.S)-epimer, on hydroboration-oxidation, gave a mixture of C-14 epimeric alcohols (239) on oxidation and removal of the tetrahydropyranyl ether grouping, these gave baloxine (236) (Scheme 34). Its formulation as (19S)-hydroxy-14-oxovincadifformine is thus confirmed. 

Armengol et al. [227] used protonated Al-MCM-41 molecular sieve for alkylation of bulky aromatic compounds such as 2,4-di-rerr-butylphenol with a bulky alcohol (cinnamyl alcohol). This reaction did not occur in the presence of large pore HY zeolite indicating the importance of the mesoporous structure of the H-MCM-41 catalyst and the accessibility of active sites. Kloetstra et aL [228] obtained excellent results during the tetrahydropyranylation of alcohols and phenols over Al-MCM-41 (Scheme 3). Bulky alcohols including cholesterol, adamantan-l-ol and 2-naphthol were converted into the corresponding tetrahydropyranyl ethers in relatively short periods of time. 

Positive tone resins based on a photoacid generator and either a random copolymer of tetrahydropyranyl methacrylate and methyl methacrylate [137] or random copolymers of tetrahydropyranyl methacrylate, methyl methacrylate, and t-butyl methacrylate (180) were used for fabrication of 3D microchannel structures [264], Simple placed channels connected to cubic or prismatic trenches, which are open to the surface as well as optical grating structures, comprise a set of several parallel channels placed about 10 pm below the surface with connecting reservoirs on both ends. They were fabricated by positive TP microlithography (Fig. 3.75) [264]. 

S-Hydroxytabersonine (108), in another series of transformations, has been used in a partial synthesis of baloxine (352), an alkaloid of Melodinus balansae. Protection of the hydroxyl group in 108 as its tetrahydropyranyl ether 353, followed by regiospecific hydroboration-oxidation, gave a mixture of epimeric C-14 alcohols (354) that, on oxidation and removal of the tetrahydropyranyl group, gave baloxine (352), whose structure as 19S-hydroxy-14-oxovincadifformine is thus confirmed (241) (Scheme 17). 

The no-bond resonance model of the anomeric effect predicts that, in a series of axial aryloxytetrahydropyran derivatives, the intracyclic bond should shorten and the extracyclic bond should lengthen as the parent phenol becomes more acidic and the ion-paired canonical form any effect should be much smaller in the equatorial case. Careful X-ray crystallographic studies of a series of tetrahydropyranyl ethers (structures in Figure 2.15) indeed showed that for seven such axial compounds, with the p a of ROH spanning 8 units, the lengths (A) of the extracyclic bond (x) and the intracyclic bond n) were given by eqns (2.2) and (2.3), respectively ... 

Such a correlation is to be expected in the absence of the frontier orbital interactions of Figure 2.12, since the C-OR bond in a variety of structures lengthens with increasing acidity of ROH in a wide variety of structures, with a sensitivity comparable to that seen in the tetrahydropyranyl systems. ... 

Such exploded transition states, in which the reaction centre carries a pronounced positive charge, are the commonest type of nucleophilic displacements at acetal centres. The reactions are unambiguously bimolecular, but in quantitative measures of transition state structure they differ only slightly from those of true 5 nI reactions. Thus, the value of for the hydrolysis of aryloxytetrahydropyrans, in which the solvent-equilibrated tetrahydropyranyl cation is a true intermediate, is —1.18, modestly but significantly more negative than the value of —0.82 obtained for hydrolysis of methoxymethyl esters of the type CH30CH20C0R. ... 

Figure 15.2 Comparison between the structures of the tetrahydropyranyl ethers of 4-t-butylphenol and c s-4-methylcyclohexanol, and those of hydroxy citronellal and Lilial . The structures have been drawn with similar orientation of the polar group to better visualize similarities in size and shape of the hydrocarbon region...

F-FMISO is synthesized in one-step reaction between the protected precursor, l-(2/-nitro-l,-imidazolyl)-2-0-tetrahydropyranyl-3-0-toluenesulfonyl-propanediol (NITTP) and 18F-containing Kryptofix 2.2.2 in acetonitrile solution (Kamarainen et al, 2004). The labeled product is hydrolyzed with acid to give 18F-FMISO, which is further purified by column chromatography using a Sep-Pak cartridge. From an automated synthesis, the radiochemical yield is 34% at EOB after a synthesis time of 50 min. HPLC shows a radiochemical purity of 97%. The molecular structure of 18F-FMISO is shown in Fig. 8.2f. 

Fig. 5.18. Correlation between change in ground-state structure (q(, = (Ar Q + Ar o) ) and activation energy for spontaneous cleavage of tetrahydropyranyl acetals (dotted line). Reaction profiles for the slowest and fastest reaction are also shown...

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