2-Alkoxytetrahydropyran

Fig. 29 Comparison of the structure-reactivity correlation of the data from Fig. 27, with reaction profiles calculated for a parent 2-alkoxytetrahydropyran and an aryloxy derivative [96]. ( ) Experimental points. Reprinted with permission from Biirgi and Dubler-Steudler (1988b). Copyright 1988b American Chemical Society.

When reacted with an alcohol in the presence of a catalytic amount of a strong acid, 3,4-dihydro-2/f-pyran yields a base-stable 2-alkoxytetrahydropyran (a cyclic acetal) (Scheme 4.13). The reaction is reversed if the acetal is treated with aqueous acid (see Section 3.3.4, page 54), so that this provides a simple way of protecting alcohols in syntheses where a strong base might otherwise deprotonate them. The conformational preferences of 2-alkoxytetrahydopyrans, mediated by the anomeric effect, were commented upon earlier (Section 1.5.3). 

Oxidation of 167 with peroxy acids in the presence of alcohols led71 to trfm.s-2-alkoxytetrahydropyran-.3-ol (173) in 65-80% yield. 

The chemical shifts of a range of cis and trans isomeric pairs of 2-alkoxytetrahydropyrans (73) and (74) show a consistent upheld shift of the three carbon atoms attached to oxygen in the axial isomers. The effect is greatest at C-6 and smallest at the alkoxy carbon atom (81JOC4948). 

The greater stability of the axial conformer of 2-alkoxytetrahydropyrans, ascribed to the anomeric effect, has been confirmed by a combined NMR and dipole moment investigation (69T3365). Additionally, out of the six conformers which in principle can arise from rotational isomerism about the exocyclic C—OR bond, two were shown to predominate in the equilibrium mixture. 

The very marked anomeric effect shown by 2-alkoxytetrahydropyran-3-ones (199) has been interpreted in terms of stabilizing orbital interactions (77NJC79). The influence of the heteroatom and the carbonyl group on the stabilization of the conformer in which the alkoxy group is axial is apparent. 

Irradiation of 2-alkoxytetrahydropyrans (553) in non-aqueous solvents converts them into the lactone (554), the yields being higher when propargyl or allyl groups are present. A 6-methoxy substituent alters the course of the photolysis to give an open chain ester (552) (77BSF101). 

Other oxygen-containing systems that have been studied include 2,2,6,6-tetramethyltetrahydropyran-3-one,225 2-alkoxytetrahydropyran-3-ones,226 2-acyl-2,3-dihydro-4W-pyrans,227 cyclic acetals,228 and a wide variety of carbonyl-containing pyranoside derivatives.229... 

On the basis of the above results and discussion, the glycosides can now be considered. Efforts have been made previously to evaluate the magnitude of the anomeric effect by undertaking equilibration studies between equatorial and axial isomers at the anomeric center in carbohydrates (48), in monosubstituted 2-alkoxytetrahydropyrans (49, 50) and in more rigid systems (51). The anomeric effect has been evaluated to be of the order of 1.2 to 1.8 kcal/mol from these studies. In these evaluations, the conformation of the OR group in the axial and in the equatorial isomer was not considered the influence of the exo-anomeric effect was therefore neglected (3). Nevertheless, these studies demonstrated the importance of the anomeric effect. 

N-Acetyl-L-phenylalanylsarcosine amide, 348 O-Acetylserine, 148 N-0 Acyl migrations, 157 Acyl-enzyme, 342-350 Z-0-Acylisoamide, 295 1,4-Addition, 221-242 1,6-Addition, 231 L-Ala-L-Ala-pNA,350 f-Ala-T-Pro-pNA, 350 AicohoT dehydrogenase, 340-341 Aldehydes, 209-211 Aldol condensation, 304-306 2-Alkoxytetrahydrofuran, 86 2-Alkoxytetrahydropyran, 18, 85-90 Alkylation of enamine, 282 Alkylation of enolate, 280 C and 0-Alkylation, 240 O-Alkylbenzohydroximoyl chloride, 155... 

This rationalization indicates that internal delivery of a hydride is not a requisite for the observed stereospecificity. Reduction of the oxonium ion with an external hydride reagent should also give equatorially oriented bicyclic ether only. Accordingly (112), reduction of tricyclic spiroketal 145 with sodium cyanoborohydride at pH =3-4 yields only the equatorial bicyclic ether alcohol (J47, CHO=CH2OH). Eliel and co-workers (113) have previously suggested that the orientation of the electron pairs of oxygen atoms influence the course of the reduction of 2-alkoxytetrahydropyran with lithium aluminium hydride-aluminium trichloride. 

Some 2-alkoxytetrahydropyrans show a reactivity toward oxidants which parallels the reactivity of polycyclic amines discussed above, and which is in line with the hypothesis that weakening of C-H bonds by hyperconjugation should also increase the rate of C-H bond cleavage. For instance, of the two epimeric pyrans sketched in Scheme 2.15 only that with an axial 2-H is oxidized by ozone [51]. The same selectivity has been observed in the oxidation of methyl a- and /3-glucopyranoside with ozone [52], and in homolytic C-H bond cleavage in cyclic ethers [53],... 

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